Clinical trial NCT03627494
Conditions: Muscular Dystrophies
Keywords: Dose proportionality Food effect Pharmacokinetics FTIH Pharmacodynamics Dose Escalation
Sponsor: GlaxoSmithKline
Start date: 2018-08-30; Completion date: 2019-08-26
Enrollment: 66 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The FTIH study with GSK3439171A will evaluate the safety of GSK3439171A in healthy subjects in order to avoid confounding factors due to the disease or concomitant drugs in patients. The study design is based on pre-clinical findings for GSK3439171A, contributing to the frequency, type and duration of safety assessment and monitoring during treatment periods in each cohort. The single dose assessments in Part A will be conducted to determine safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of the study intervention in individuals before progressing to doses explored further in other parts of the study and will allow for any adjustments needed based on emerging safety, tolerability, and PK information. Part A will also serve to identify a dose for use in examining the effect of food on GSK3439171A exposure in Part C. In Part B, a single dose safety, tolerability and PK will be collected followed by progression of these subjects to the repeat dose portion of the study. The up to 14-day dosing was chosen as it is thought to provide sufficient safety and tolerability data to bridge to longer duration studies. The dosing period can be adjusted depending on PK and PD data collected in Part A of the study. Part B will involve more detailed PK/PD/metabolite assessments to better understand the impact of GSK3439171A on target engagement and metabolism in humans. Approximately 150 subjects will be screened to achieve 75 randomly assigned to study intervention. Duration for Part A, B and C will be approximately 10 weeks, 9 weeks and 8 weeks respectively.

Detailed description:

Arms: arm 1: Subjects will administer oral solution with doses 0.5 milligram (mg) up to 4.5 mg and capsule for doses 5 mg and upwards of GSK3439171A and placebo as per randomized sequence placebo (PBO) followed by Dose 2 of GSK3439171A followed by Dose 3 of GSK3439171A in period 1 (P1). There will be a washout period of 7 days or 5 half-lives, whichever is longer in between the doses. arm 2: Subjects will administer oral solution with doses 0.5 mg up to 4.5 mg and capsule for doses 5 mg and upwards of GSK3439171A and PBO as per randomized sequence: Dose 1 of GSK3439171A followed by PBO followed by Dose 3 of GSK3439171A in P1. There will be a washout period of 7 days or 5 half-lives, whichever is longer in between the doses. arm 3: Subjects will administer oral solution with doses 0.5 mg up to 4.5 mg and capsule for doses 5 mg and upwards of GSK3439171A and placebo as per randomized sequence: Dose 1 of GSK3439171A followed by Dose 2 of GSK3439171A followed by PBO in P1. There will be a washout period of 7 days or 5 half-lives, whichever is longer in between the doses. arm 4: Subjects will administer oral solution with doses 0.5 mg up to 4.5 mg and capsule for doses 5 mg and upwards of GSK3439171A and placebo as per randomized sequence: PBO followed by Dose 5 of GSK3439171A followed by Dose 6 of GSK3439171A in period 2 (P2). There will be a washout period of 7 days or 5 half-lives, whichever is longer in between the doses. arm 5: Subjects will administer oral solution with doses 0.5 mg up to 4.5 mg and capsule for doses 5 mg and upwards of GSK3439171A and placebo as per randomized sequence: Dose 4 of GSK3439171A followed by PBO followed by Dose 6 of GSK3439171A in P2. There will be a washout period of 7 days or 5 half-lives, whichever is longer in between the doses. arm 6: Subjects will administer oral solution with doses 0.5 mg up to 4.5 mg and capsule for doses 5 mg and upwards of GSK3439171A and placebo as per randomized sequence: Dose 4 of GSK3439171A followed by Dose 5 of GSK3439171A followed by PBO in P2. There will be a washout period of 7 days or 5 half-lives, whichever is longer in between the doses. arm 7: Subjects will administer oral solution with doses 0.5 mg up to 4.5 mg and capsule for doses 5 mg and upwards of GSK3439171A and placebo as per randomized sequence: PBO followed by Dose 8 of GSK3439171A followed by Dose 9 of GSK3439171A in Period 3 (P3). There will be a washout period of 7 days or 5 half-lives, whichever is longer in between the doses. arm 8: Subjects will administer oral solution with doses 0.5 mg up to 4.5 mg and capsule for doses 5 mg and upwards of GSK3439171A and placebo as per randomized sequence: Dose 7 of GSK3439171A followed by PBO followed by Dose 9 of GSK3439171A in P3. There will be a washout period of 7 days or 5 half-lives, whichever is longer in between the doses. arm 9: Subjects will administer oral solution with doses 0.5 mg up to 4.5 mg and capsule for doses 5 mg and upwards of GSK3439171A and placebo as per randomized sequence: Dose 7 of GSK3439171A followed by Dose 8 of GSK3439171A followed by PBO in P3. There will be a washout period of 7 days or 5 half-lives, whichever is longer in between the doses. arm 10: Subjects will administer oral solution with doses 0.5 mg up to 4.5 mg and capsule for doses 5 mg and upwards of GSK3439171A in part B arm 11: Subjects will administer oral solution with doses 0.5 mg up to 4.5 mg and capsule for doses 5 mg and upwards of Placebo in part B arm 12: Subjects will administer GSK3439171A in Fed condition in Part C P1 followed by GSK3439171A in fasted condition in Part C P2. There will be a washout period of 7 days or 5 half-lives, whichever is longer in between the doses. arm 13: Subjects will administer GSK3439171A in fasted condition in Part C P1 followed by GSK3439171A in fed condition in Part C P2. There will be a washout period of 7 days or 5 half-lives, whichever is longer in between the doses.
Interventions: intervention 1: GSK3439171A intervention 2: Placebo
Intervention descriptions: intervention 1: Oral solution with doses 0.5 mg up to 4.5 mg and capsule for doses 5 mg and upwards intervention 2: Placebo oral solution to match with doses 0.5 mg up to 4.5 mg and capsule for doses 5 mg and upwards

Protocol documents:
Prot_000.pdf: 
2018N361438_05
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GlaxoSmithKline group of companies
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TITLE PAGE
Protocol Title: A Three-Part FTIH Study to Evaluate Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of Single and Repeat Oral Doses of 
GSK3439171A, in a Randomized, Double-Blind (sponsor unblinded), Placebo-
Controlled, Dose Escalation study and to Evaluate the Effect of Food on a Single Oral 
Dose of GSK3439171A in Healthy Adult Participants
Protocol Number: 209275/ Amendment 03
Compound Number:
GSK3439171
Study Phase: Phase 1
Short Title: FTIH Study to evaluate the safety, pharmacokinetics, and 
pharmacodynamics of single and repeat doses of GSK3439171A in healthy participants; 
food effect
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): 
IND: 139312
Approval Date: 09-MAY-2019
Copyright 2019 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


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SPONSOR SIGNATORY: 
 
 
 
 
 
 
 
 
 
 
 
05/09/2019

David Neil, MD MFPM  
  
 
 
 
Date 
Clinical Director, MM-DPU, FPD 













  
2 
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 3
09-MAY-2019
2018N361438_05
Amendment 2
13-MAR-2019
2018N361438_04
Republishing - Amendment 1
31-AUG-2018
2018N361438_03
Republished - Amendment 1
29-AUG-2018
2018N361438_02
Amendment 1
27-AUG-2018
2018N361438_01
Original Protocol
3-JUL-2018
2018N361438_00
Amendment 3: 09-MAY-2019
Overall Rationale for the Amendment: Part B has been updated with an additional 
subpart to examine repeat doses of GSK3439171 for a shorter duration at higher 
exposures. This will help characterize the PK and safety at higher exposures 
corresponding to the predicted therapeutic dose. The IC50 of GSK3439171 has also been 
updated to correct the minute typographic error in the ng/mL value as per the human 
HPGDS enzyme assay. Minor editorial changes have also been made in the protocol.
Section # and Name
Description of Change
Brief Rationale
1.1 Synopsis- Rationale
Addition of 7 day dosing 
cohort in Part B
7 Day repeat dosing will be 
performed in Part B to characterize 
PK and safety of GSK3439171 at 
higher exposures for a shorter 
duration
1.3 Schedule of Activities
Addition of SoA for 7 day 
repeat dosing period
7 Day repeat dosing will be 
performed in Part B to characterize 
PK and safety of GSK3439171 at 
higher exposures for a shorter 
duration
2.3.1 Risk Assessment
Updated to reflect changes in 
exposure limits
7 Day repeat dosing will be 
performed in Part B to characterize 
PK and safety of GSK3439171 at 
higher exposures for a shorter 
duration
3 Objectives and 
Endpoints
Addition of Ctrough samples 
during 7 day dosing period
7 Day repeat dosing will be 
performed in Part B to characterize 
PK and safety of GSK3439171 at 
higher exposures for a shorter 
duration


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Section # and Name
Description of Change
Brief Rationale
4.1 Overall Design
Clarification of discharge 
days due to 7 Day repeat 
dosing.
7 Day repeat dosing will be 
performed in Part B to characterize 
PK and safety of GSK3439171 at 
higher exposures for a shorter 
duration
4.3 Justification of Dose
Updated to reflect changes in 
increased exposure limits
7 Day repeat dosing will be 
performed in Part B to characterize 
PK and safety of GSK3439171 at 
higher exposures for a shorter 
duration
4.3 Dose Justification
Update for consistency of 
units (ng/mL) based on the 
human HPGDS enzyme 
assay
GSK3439171 concentrations will be 
reported in units (ng/mL) and based 
on the corrected human HPGDS 
enzyme assay, IC50 is 7.77 ng/mL 
which was previously written in a 
minor error.
6.6 Dose Modification
Updated language to reflect 
increased exposure limits for 
7 day dosing
7 Day repeat dosing will be 
performed in Part B to characterize 
PK and safety of GSK3439171 at 
higher exposures for a shorter 
duration.
7.1 Dose Discontinuation 
Updated language to reflect 
increased exposure limits for 
7 day dosing
7 Day repeat dosing will be 
performed in Part B to characterize 
PK and safety of GSK3439171 at 
higher exposures for a shorter 
duration.
9.4 Statistical Analysis
Addition of days due to 7 day 
dosing cohort in Part B
7 Day repeat dosing will be 
performed in Part B to characterize 
PK and safety of GSK3439171 at 
higher exposures for a shorter 
duration.
Throughout
Updated language to align to 
addition of 7 day dosing in 
Part B
7 Day repeat dosing will be 
performed in Part B to characterize 
PK and safety of GSK3439171 at 
higher exposures for a shorter 
duration.


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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
PROTOCOL SUMMARY..........................................................................................8
1.1.
Synopsis.......................................................................................................8
1.2.
Schema ......................................................................................................12
1.3.
Schedule of Activities (SoA)........................................................................14
2.
INTRODUCTION....................................................................................................48
2.1.
Study Rationale ..........................................................................................48
2.2.
Background ................................................................................................48
2.2.1.
Hematopoietic prostaglandin D2 synthase (H-PGDS)..................48
2.2.2.
GSK3439171A.............................................................................49
2.3.
Benefit/Risk Assessment ............................................................................49
2.3.1.
Risk Assessment: ........................................................................51
2.3.2.
Benefit Assessment.....................................................................55
2.3.3.
Overall Benefit: Risk Conclusion..................................................55
3.
OBJECTIVES AND ENDPOINTS...........................................................................55
4.
STUDY DESIGN ....................................................................................................57
4.1.
Overall Design ............................................................................................57
4.2.
Scientific Rationale for Study Design ..........................................................59
4.3.
Justification for Dose ..................................................................................60
4.3.1.
Maximum Recommended Starting Dose (MRSD)........................62
4.3.2.
Dose Predicted to Achieve the Therapeutic Exposure 
Target..........................................................................................62
4.3.3.
Minimum Anticipated Biological Effect Level (MABEL) 
Dose............................................................................................63
4.3.4.
Dose Predicted to Achieve Exposure at the NOAEL Dose 
Level and Single Dose Stopping Limit..........................................63
4.3.5.
Summary .....................................................................................63
4.4.
End of Study Definition ...............................................................................63
5.
STUDY POPULATION...........................................................................................64
5.1.
Inclusion Criteria.........................................................................................64
5.2.
Exclusion Criteria........................................................................................65
5.3.
Lifestyle Considerations..............................................................................67
5.3.1.
Meals and Dietary Restrictions ....................................................67
5.3.2.
Caffeine, Alcohol, and Tobacco ...................................................68
5.3.3.
Activity .........................................................................................68
5.4.
Screen Failures...........................................................................................68
6.
STUDY INTERVENTION........................................................................................69
6.1.
Study Intervention(s) Administered .............................................................69
6.2.
Preparation/Handling/Storage/Accountability..............................................70
6.3.
Measures to Minimize Bias: Randomization and Blinding ...........................71
6.3.1.
Randomization.............................................................................71
6.3.2.
Blinding........................................................................................72
6.4.
Study Intervention Compliance ...................................................................73


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6.5.
Concomitant Therapy..................................................................................74
6.6.
Dose Modification .......................................................................................74
6.6.1.
Dose Escalation in Part A ............................................................75
6.6.2.
Dose escalation in Part B.............................................................76
6.7.
Intervention after the End of the Study........................................................77
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.....................................................................77
7.1.
Discontinuation of Study Intervention..........................................................77
7.1.1.
Liver Chemistry Stopping Criteria ................................................77
7.1.1.1.
Study Intervention Restart or Rechallenge after 
liver stopping criteria met............................................78
7.1.2.
QTc Stopping Criteria ..................................................................78
7.1.3.
Individual Stopping Criteria ..........................................................79
7.1.4.
Dose Adjustment/Discontinuation Pharmacokinetic Criteria.........79
7.1.5.
Temporary Discontinuation ..........................................................79
7.1.6.
Study Stopping Criteria................................................................79
7.1.6.1.
Safety Study Stopping Criteria....................................79
7.1.6.2.
PK Study Stopping Criteria.........................................80
7.2.
Participant Discontinuation/Withdrawal from the Study ...............................80
7.3.
Lost to Follow Up........................................................................................80
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................81
8.1.
Efficacy Assessments.................................................................................81
8.2.
Safety Assessments ...................................................................................82
8.2.1.
Physical Examinations.................................................................82
8.2.2.
Vital Signs....................................................................................82
8.2.3.
Electrocardiograms......................................................................82
8.2.4.
Telemetry.....................................................................................83
8.2.5.
Holter Monitoring .........................................................................83
8.2.6.
Clinical Safety Laboratory Assessments ......................................84
8.2.7.
Hormone Monitoring ....................................................................84
8.2.8.
Suicidal Ideation and Behaviour Risk Monitoring .........................85
8.3.
Adverse Events and Serious Adverse Events.............................................85
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................85
8.3.2.
Method of Detecting AEs and SAEs.............................................85
8.3.3.
Follow-up of AEs and SAEs.........................................................86
8.3.4.
Regulatory Reporting Requirements for SAEs .............................86
8.3.5.
Pregnancy ...................................................................................86
8.4.
Treatment of Overdose...............................................................................86
8.5.
Pharmacokinetics .......................................................................................87
8.5.1.
Blood Sample Collection..............................................................87
8.5.2.
Urine Sample Collection ..............................................................87
8.5.3.
Bile Sample Collection.................................................................88
8.5.4.
Sample Analysis ..........................................................................88
8.6.
Pharmacodynamics ....................................................................................88
8.6.1.
Urine Pharmacodynamics Assessment........................................89
8.6.2.
Muscle Biopsy .............................................................................89
8.7.
Genetics .....................................................................................................89
8.8.
Biomarkers .................................................................................................89


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8.9.
Health Economics or Medical Resource Utilization and Health 
Economics..................................................................................................89
9.
STATISTICAL CONSIDERATIONS........................................................................90
9.1.
Statistical Hypotheses.................................................................................90
9.2.
Sample Size Determination ........................................................................90
9.3.
Populations for Analyses ............................................................................90
9.4.
Statistical Analyses.....................................................................................91
9.4.1.
Safety Analyses...........................................................................94
9.4.2.
Other Analyses ............................................................................94
9.5.
Interim Analyses .........................................................................................94
9.5.1.
Data Monitoring Committee (DMC)..............................................94
10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...............................................................................................95
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................95
10.1.1.
Regulatory and Ethical Considerations ........................................95
10.1.2.
Financial Disclosure.....................................................................95
10.1.3.
Informed Consent Process ..........................................................96
10.1.4.
Data Protection............................................................................96
10.1.5.
Dissemination of Clinical Study Data ...........................................97
10.1.6.
Data Quality Assurance ...............................................................97
10.1.7.
Source Documents ......................................................................98
10.1.8.
Study and Site Closure ................................................................99
10.1.9.
Publication Policy.........................................................................99
10.2.
Appendix 2: Clinical Laboratory Tests.......................................................100
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................102
10.3.1.
Definition of AE..........................................................................102
10.3.2.
Definition of SAE........................................................................103
10.3.3.
Recording and Follow-Up of AE and SAE..................................104
10.3.4.
Reporting of SAE to GSK...........................................................106
10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................107
10.4.1.
Contraception Guidance: ...........................................................107
10.4.2.
Collection of Pregnancy Information: .........................................108
10.5.
Appendix 5: Genetics................................................................................109
10.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ............................................................................................110
10.7.
Appendix 7: Abbreviations and Trademarks..............................................112
10.8.
Appendix 8: Protocol Amendment History.................................................116
11. REFERENCES.....................................................................................................119


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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: A Three-Part FTIH Study to Evaluate Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of Single and Repeat Oral Doses of 
GSK3439171A, in a Randomized, Double-Blind (sponsor unblinded), Placebo-
Controlled, Dose Escalation study and to Evaluate the Effect of Food on a Single Oral 
Dose of GSK3439171A in Healthy Adult Participants
Short Title: FTIH Study to evaluate the safety, pharmacokinetics, and 
pharmacodynamics of single and repeat doses of GSK3439171A in healthy participants; 
food effect
Rationale: The FTIH study with GSK3439171A will evaluate the safety of 
GSK3439171A in healthy participants in order to avoid confounding factors due to the 
disease or concomitant drugs in patients. The study design is based on pre-clinical 
findings for GSK3439171A, contributing to the frequency, type and duration of safety 
assessment and monitoring during treatment periods in each cohort.
The single dose assessments in Part A will be conducted to determine safety, tolerability, 
pharmacokinetics (PK), and pharmacodynamics (PD) of the study intervention in 
individuals before progressing to doses explored further in other parts of the study and 
will allow for any adjustments needed based on emerging safety, tolerability, and PK 
information. Part A will also serve to identify a dose for use in examining the effect of 
food on GSK3439171A exposure in Part C.
In Part B, a single dose safety, tolerability and PK will be collected followed by
progression of these participants to the repeat dose portion of the study. The up to 14-day 
dosing was chosen as it is thought to provide sufficient safety and tolerability data to 
bridge to longer duration studies. The dosing period can be adjusted depending on PK 
and PD data collected in Part A of the study. Part B will involve more detailed 
PK/PD/metabolite assessments to better understand the impact of GSK3439171A on 
target engagement and metabolism in humans. In addition, based on the PK obtained in 
Part A, an additional cohort will be enrolled to study higher exposures of GSK3439171A 
for a shorter duration of time.


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Objectives and Endpoints:
Objective
Endpoint
Primary

To assess the safety and 
tolerability of GSK3439171A 
following single and repeat doses 
in healthy participants

To characterize the PK of 
GSK3439171A, following single 
and repeat doses in healthy 
participants

Adverse events (AE), clinical 
laboratory values, vital signs, 
and electrocardiograms (ECG)

Derived PK parameters for 
GSK3439171A including area 
under the plasma drug 
concentration versus time curve 
(AUC(0-t), AUC(0-inf), 
maximum observed plasma drug 
concentration (Cmax), time to 
maximum observed plasma drug 
concentration (tmax), and 
apparent terminal half-life (t1/2) 
as appropriate
Secondary

To assess the effect of food on the 
PK of GSK3439171A following an 
oral dose in healthy participants 

To assess preliminary dose 
proportionality of GSK3439171A 
following single and repeat oral 
doses, as data permit

Derived PK parameters for 
GSK3439171A including area under 
the plasma drug concentration versus 
time curve (AUC(0-t), AUC(0-inf), 
maximum observed plasma drug 
concentration (Cmax), time to 
maximum observed plasma drug 
concentration (tmax), and apparent 
terminal half-life (t1/2) as appropriate

AUC(0-t), AUC(0-inf), and Cmax 
following single dose and AUC(0-τ) 
and Cmax following repeat dose for 
the assessment of dose 
proportionality


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Objective
Endpoint

To examine the extent of 
accumulation and achievement of 
steady-state following repeat oral 
doses of GSK3439171A, as data 
permits

Determine observed accumulation 
based on AUC(Ro) and Cmax
(RCmax) and determine the steady-
state ratio (Rss) 

Trough plasma concentrations at the 
end of the dosing interval (Cτ) 
collected pre-dose for repeat doses 3, 
4, 12, 13, and 14 (or repeat doses 
3,4, 6, and 7 during 7 day repeat 
dosing period) to assess the 
achievement of steady-state of 
GSK3439171A.
Exploratory

To evaluate the PD properties of 
GSK3439171A

To assess the effect of 
GSK3439171A on QTc in healthy 
adult volunteers

To evaluate additional 
biomarkers of GSK3439171A 
target engagement after single 
and repeat doses.

To investigate the plasma, 
urinary and biliary (Part B) 
metabolic pathways of 
GSK3439171A in healthy 
subjects.

Levels of mediators on 
prostaglandin and/or 
inflammatory metabolic pathways 
such as, but not limited to, PGD2, 
and PGE2. 

Holter monitor data collection 
and storage for evaluation of the 
correlation between plasma levels 
of GSK3439171A and changes in 
the QTc interval in the future, if 
appropriate

Levels of change in novel 
biomarkers in blood, muscle, or 
urine, such as, but not limited to, 
urine tetranor PGDM and PGEM 
(tPGDM, tPGEM), PGD2, and 
PGE2

GSK3439171A-related material 
in plasma, urine and bile


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Overall Design:
Part A is a randomized, double blind (sponsor unblinded), placebo-controlled, crossover, 
single dose escalation study in healthy participants. Participants will be randomized to 
placebo or active study intervention groups after screening.
Part B is a randomized, double blind (sponsor unblinded), placebo-controlled, parallel 
group, repeat dose escalation study in healthy participants. Participants will be 
randomized to placebo or active study intervention groups after screening.
Part C is a randomized, open label, crossover, food effect study in healthy participants. 
Participants will be randomized to fed or fasted groups after screening.
Disclosure Statement: 
Part A is a Crossover group single ascending dose study with 2 arms per cohort that is 
participant and investigator blinded.
Part B is a Parallel group repeat dose study with 2 arms per cohort that is participant and 
investigator blinded.
Part C is a Crossover group food effect study with 2 arms per cohort that is not-masked.
Number of Participants:
Approximately 150 participants will be screened to achieve 75 randomly assigned to 
study intervention and 75 evaluable participants for an estimated total of 27 evaluable 
participants in Part A, 36 evaluable participants in Part B, and 12 evaluable participants 
in Part C. Additional participants/cohorts may be enrolled to allow for evaluation of 
additional dose levels.
Intervention Groups and Duration:
Part A will be a double-blind (sponsor unblinded), single oral dose, dose-rising, placebo-
controlled, randomized (with respect to placebo allocation), 3 period crossover study in 
approximately 3 cohorts of participants.  Participants will be enrolled in the study for 
approximately 10 weeks (approximately 30 days screening, 3 in-house dose assessment 
periods of approximately 6 days, 3 wash out periods between each dose of approximately 
7 days and an approximately 14 day follow-up period).
Part B will be double-blind (sponsor unblinded), up to 14 day repeat oral dosing, placebo-
controlled, randomized (with respect to placebo allocation), dose escalation study with at 
least three (single or twice-daily) repeat dose levels in 3 separate cohorts of participants 
who were not enrolled into Parts A or C of this study. Participants will be enrolled in the 
study for approximately 9 weeks (approximately 30 days screening, approximately 15-22
day in-house dose assessment period, and an approximately 14 day follow-up period. 
Part C will be an unblinded, randomized, crossover study where a single dose will be 
administered fasted or fed conducted in a separate cohort of participants than those who 


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were enrolled in Parts A or B. Participants recruited into Part C will spend approximately 
8 weeks enrolled in the study (approximately 30 days screening, approximately 5 day in-
house assessment period, and an approximately 14 day follow-up period.
Data Monitoring Committee: Dose Escalation Committee
1.2.
Schema
Part A: Single Ascending Dose 
Figure 1
Single Ascending Dose Schematic

Within a cohort, participants will be randomized to one of 3 treatment sequences such 
that each participant receives 2 active doses and 1 placebo dose resulting in each active 
dose being administered to 6 participants and placebo to 3 participants

Starting dose (Dose 1) = 5 mg

Subsequent dose escalations will be determined based on safety and PK data

Maximum predicted dose = 500 mg (Genotoxic Risk Assessment Limit= 3000mg)

Washout= 7 days or 5 half-lives, whichever is longer
    = Dose escalation meeting
      PBO= Placebo
       *Note: dosing strategy is for illustrative purposes and does not represent the randomization 
strategy   
Part B: Single and Repeat Dose 7 or 14-day dose-rising
Figure 2
Repeat Dose Schematic (Part B)
Screening 
(~30 days pre-
first dose)
Follow-up 
(~14 days 
post-
final dose per 
cohort)
Treatment Period
Cohort B1, n=12 (9A:3P)
Cohort B2 n=12 (9A:3P)
Cohort B3, n=12 (9A:3P)
Dose 1
Dose 2
Dose 3
SD
RD
                  Doses will be selected based on safety, tolerability and PK data from Part A
           = Dose escalation meeting


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Part C: Food Effect
Figure 3
Food Effect Schematic (Part C)
- 7-day or 5 half-lives (whichever is longer) washout period/ participant crossover to 
fasted/fed arm


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1.3.
Schedule of Activities (SoA)
Part A- Single Dose 
Procedure
Screening 
(up to 30
days 
before Day 
1)
Treatment Period [Days] (for each dosing period)
Follow-
up
(~14±1
days 
post last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
-1
1
2
3
4
E.D.
Informed consent
X
Inclusion and 
exclusion criteria 
(including drug 
screens)
X
X
Recheck clinical status before 
randomization and/or 1st dose of 
study medication.
Demography
X
Physical examination 
including height and 
weight
F
B
B
(B)
F
F: Full exam; B: Brief Exam; height 
is only taken once at screening
Medical history 
(includes substance 
usage and family 
history of premature 
cardiovascular (CV) 
disease and any 
changes in health 
status occurring 
between screening 
and admission to the 
unit)
X
X
Substances: Drugs, Alcohol, 
tobacco, and caffeine
Past and current 
medical conditions  
X
X


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Part A- Single Dose 
Procedure
Screening 
(up to 30
days 
before Day 
1)
Treatment Period [Days] (for each dosing period)
Follow-
up
(~14±1
days 
post last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
-1
1
2
3
4
E.D.
Human 
Immunodeficiency 
Virus (HIV), Hepatitis 
B and C screening
X
If test otherwise performed within 3 
months prior to first dose of study 
intervention, testing at screening is 
not required
Admission to Clinical 
Unit
X
Safety Laboratory 
assessments 
(include liver 
chemistries)
X
X
X
X
X
X
(X)
X
Predose; 8 hr, 24 hr, and, 48 hr, and 
72 hr post-dose and at follow-up visit
Routine Urinalysis
X
X
X
X
X
(X)
X
Predose; 8 hr, 24 hr, 48 hr, and 72 
hr post-dose and at follow-up visit 
12-lead 
Electrocardiogram 
(ECG)
X
X
======================X=====================
(X)
X
ECGs assessed at screening 
(triplicate) and admission (single).  
During treatment period ECGs 
assessed predose (triplicate at least 
5 minutes (min) intervals) and 
single measurements postdose 
every 30 min for 1 hr, hourly up to 6 
hr, and at 12 hr, 24 hr, 36 hr and 48 
hr and 72 hr post-dose 


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Part A- Single Dose 
Procedure
Screening 
(up to 30
days 
before Day 
1)
Treatment Period [Days] (for each dosing period)
Follow-
up
(~14±1
days 
post last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
-1
1
2
3
4
E.D.
Vital signs (pulse 
rate, blood pressure 
(bp), respiratory rate, 
and oral 
temperature)
X
X
======================X======================
(X)
X
Vitals assessed at screening 
(triplicate measurements for pulse 
and (bp)) (and admission (single 
measurements).  During treatment 
period vitals assessed predose 
(triplicate measurements for pulse 
and bp) and postdose (single 
measurements) every 15 min for 1 
hr, hourly up to 6 hr, then at 12 hr, 
24 hr, 36 hr, 48 hr, and 72 hr post-
dose.
See Section 8.2.2 for further 
information
Randomization
X
Randomization will occur before 
first dose in period 1.
Genetic sample
X
Any time predose on Day 1. 
This research may be described in 
a separate Informed Consent Form 
(ICF) or as part of a combined ICF.  
A separate signature is required 
where participant participation is 
optional
Study intervention
X


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Part A- Single Dose 
Procedure
Screening 
(up to 30
days 
before Day 
1)
Treatment Period [Days] (for each dosing period)
Follow-
up
(~14±1
days 
post last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
-1
1
2
3
4
E.D.
Telemetry
X
Telemetry performed starting 30 
min (10 min) pre-dose to 12 hr 
(20 min) post-dose
Adverse Event (AE) 
review
=======================X====================
(X)
X
Serious Adverse 
Event (SAE) review
X
===========================X=============================
(X)
X
Concomitant 
medication review
X
======================X=====================
(X)
X
24hr urine sampling 
for 
Pharmacodynamics 
(PD)
X1
X2
X3
X3
(X)
1combined void for windows of 24-
22 hr, 22-20 hr, 20-18 hr, 18-16 hr, 
16-12 hr, and 12-0 hr predose.
2 combined void for windows of 0-2 
hr, 2-4 hr, 4-6 hr, 6-8 hr 8-12 hr, 
and 12-24 hr post-dose 
3combined void for 24 hr


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Part A- Single Dose 
Procedure
Screening 
(up to 30
days 
before Day 
1)
Treatment Period [Days] (for each dosing period)
Follow-
up
(~14±1
days 
post last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
-1
1
2
3
4
E.D.
Blood sampling for 
Pharmacokinetics 
(PK)
======================X=====================
(X)
Predose, 5min, 30min, 1 hr, 1.5 hr, 
2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 10 hr, 12 
hr, 18 hr, 24 hr, 36 hr, and 48 hr, 60 
hr, and 72 hr post-dose
24 hr Holter 
Monitoring
X
Predose through 24 hr post-dose
Discharge from 
Clinical Unit
X
(X)

The timing and number of planned study assessments, including safety, PK, PD/biomarker 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 as the result of emerging 
pharmacokinetic/pharmacodynamic data from this study must be documented and approved by the relevant study team member and then 
archived in the sponsor and site study files, but will not constitute a protocol amendment. The Competent Authority (CA) and ethics 
committee (EC) will be informed of any safety issues that constitute a substantial amendment and require alteration of the safety 
monitoring scheme or amendment of the ICF. The changes will be approved by the CA and the EC before implementation. 


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Part B – Repeat Dose 
Procedure
Screeni
ng 
(up to 
30 days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow
-up
(~14±
1 days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5-7
8
9-11
12
13-14
15
16
17
18
19
20
Informed consent
X
Inclusion and 
exclusion criteria 
(including drug 
screens)
X
X
Recheck clinical status 
before randomization and 
prior to muscle biopsy/or 
1st dose of study 
medication.
Demography
X
Full physical 
examination including 
height and weight
F
B
B
(B)
F
F: Full exam; B: Brief exam; 
height is only taken once at 
screening
Medical history 
(includes substance 
usage and family 
history of premature 
CV disease and any 
changes in health 
status occurring 
between screening 
and admission to the 
unit)
X
X
Substances: Drugs, 
Alcohol, tobacco, and 
caffeine
Past and current 
medical conditions  
X
X


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Part B – Repeat Dose 
Procedure
Screeni
ng 
(up to 
30 days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow
-up
(~14±
1 days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5-7
8
9-11
12
13-14
15
16
17
18
19
20
HIV, Hepatitis B and 
C screening
X
If test otherwise performed 
within 3 months prior to first 
dose of study intervention, 
testing at screening is not 
required
Admission to Clinical 
Unit
X
Safety Laboratory 
assessments (include 
liver chemistries)
X
X
X
X1
X1
X1
X
(X)
X1
Pre-randomization 
assessments for eligibility 
must be performed PRIOR 
to predose muscle biopsy
Predose, 24 hr, and 48, 
and 72 hr post-Day 1 dose; 
additional timepoints may 
be added based on findings 
in Part A
1Days 7, 11, 17, 20, and 
follow-up
Routine urinalysis
X
X
X
X2
X2
X2
X2
(X)
X2
Predose, 24 hr, 48 hr, and 
72 hr post-Day 1 dose; 
additional timepoints may 
be added based on findings 
in Part A
2Days 7, 11,17, 20, and 
follow-up


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Part B – Repeat Dose 
Procedure
Screeni
ng 
(up to 
30 days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow
-up
(~14±
1 days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5-7
8
9-11
12
13-14
15
16
17
18
19
20
Hormone monitoring 
X
X
(X)
Samples to be taken at 
midnight and 9am (10 min) 
on Days -1 and 17 
Samples taken at midnight 
will be analysed for 
adrenocorticotropic hormone 
(ACTH) and cortisol
Samples taken at 9am will 
be analysed for ACTH, 
cortisol, luteinizing hormone 
(LH), follicle stimulating 
hormone (FSH), thyroid 
stimulating hormone (TSH), 
total testosterone, 
dihydrotestosterone (DHT), 
triiodothyronine (T3), and 
free thyroxine (free T4) 
See Section 8.2.7 for 
information regarding 
monitoring of abnormal 
hormone results


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Part B – Repeat Dose 
Procedure
Screeni
ng 
(up to 
30 days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow
-up
(~14±
1 days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5-7
8
9-11
12
13-14
15
16
17
18
19
20
12-lead ECG
X
X
=====X5=====
X5
X5
X5
X5
X5
(X)
X
ECGs assessed at 
screening (triplicate 
measure) and admission 
(single measure).  During 
treatment period ECGs 
assessed predose 
(triplicate measure at at 
least 5 min intervals) and 
post-dose (single measure) 
every 30 min for 1 hr, 
hourly up to 6 hr, at 12 hr 
post-dose then at 24 hr, 36 
hr, 48 hr, and 72 hr post-
dose 
5 Days 7,11, 15, and 17, 
and 20 Post-dose at Cmax 
based on observed Cmax 
in Part A (currently 
estimated to occur at ~2 hr 
post dose), except for Day 
20. Day 20 ECG to occur 
any time before Discharge


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Part B – Repeat Dose 
Procedure
Screeni
ng 
(up to 
30 days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow
-up
(~14±
1 days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5-7
8
9-11
12
13-14
15
16
17
18
19
20
Vital signs (pulse 
rate, bp, respiratory 
rate, and oral 
temperature)
X
X
X6
X7
X6
(X)
X
6Vitals assessed at 
screening (triplicate 
measurements for pulse 
and bp) and admission 
(single measurements).  
During treatment period 
vitals assessed predose 
(triplicate measurements 
for pulse and bp) and 
postdose (single 
measurements) every 15 
min for 1 hr, hourly up to 6 
hr, and at 12 hr, 24 hr, 36 
hr, 48 hr, and 72 hr post-
dose
7Vitals assessed once 
every 24 hr
See Section 8.2.2 for 
further information
Randomization
X


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Part B – Repeat Dose 
Procedure
Screeni
ng 
(up to 
30 days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow
-up
(~14±
1 days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5-7
8
9-11
12
13-14
15
16
17
18
19
20
Genetic sample
X
Any time predose on Day 1
This research may be 
described in a separate ICF 
or as part of a combined 
ICF.  A separate signature 
is required where 
participant participation is 
optional
Study intervention
X
====================X======================
Telemetry
X
Telemetry performed 
starting 30 (10 min) pre-
dose to 12 hr (20 min) 
post-dose
AE review
=============================X==============================
SAE review
=========================================X========================================
Concomitant 
medication review
=========================================X========================================


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Part B – Repeat Dose 
Procedure
Screeni
ng 
(up to 
30 days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow
-up
(~14±
1 days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5-7
8
9-11
12
13-14
15
16
17
18
19
20
Urine sampling PD
X8
X9
X9
X9, 10
X9
(X)
8combined void for 
windows of 24-22 hr, 22-20 
hr, 20-18 hr, 18-16 hr, 16-
12 hr, and 12-0 hr predose. 
9combined void for 
windows of 0-2 hr, 2-4 hr, 
4-6 hr, 6-8 hr, 8-12 hr, and 
12-24 hr post-dose 
10 Day 10 only
Aliquots will be removed 
prior to pooling for urine 
PK. Total urine volume will 
be recorded before aliquots 
for PD are removed.


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Part B – Repeat Dose 
Procedure
Screeni
ng 
(up to 
30 days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow
-up
(~14±
1 days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5-7
8
9-11
12
13-14
15
16
17
18
19
20
24h urine sampling 
for PK and metabolite 
profiling
X
X
X
X
(X)
Voids from urine 
pharmacodynamic (PD) 
sampling windows will be 
combined into 0-24 hr pools 
on Day -1,1, and 17 after 
aliquoting for PD. 
These voids will be 
combined for PK/metabolite 
analysis only after aliquots 
for urine PD are removed
See study reference 
manual (SRM) for details 
on samples and processing


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Part B – Repeat Dose 
Procedure
Screeni
ng 
(up to 
30 days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow
-up
(~14±
1 days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5-7
8
9-11
12
13-14
15
16
17
18
19
20
Blood sampling for 
PK
X11
X12
X12
X12
X11
(X)
11Day 1 and Day 17: 
Predose, 5 min, 30 min, 1 
hr, 1. 5hr, 2 hr, 3 hr, 4 hr, 6 
hr, 8 hr, 10 hr, 12 hr, 18 hr, 
24 hr, 36 hr, 48 hr, 60 hr, 
and 72 hr post-dose
12pre-dose samples 
collected on days 6,7, 9-11 
and 15-16
Blood sampling for 
metabolite profiling
X
X
Day 1 and Day 17: 
Predose, 5 min, 30 min, 1 
hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 
hr, 8 hr, 10 hr, 12 hr, 18 hr, 
24 hr, 36 hr, 48 hr, 60 hr, 
and 72 hr post-dose
Blood sampling for 
Pharmacodynamics 
and biomarkers
X13
X13
X14
X14
(X)
13Predose and 24 hr post-
dose on Day 1  
14Predose Days 10 and 17


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Part B – Repeat Dose 
Procedure
Screeni
ng 
(up to 
30 days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow
-up
(~14±
1 days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5-7
8
9-11
12
13-14
15
16
17
18
19
20
Muscle Biopsy
X15
X16
(X)
Muscle biopsies must be 
performed AFTER clinical 
safety assessments on the 
corresponding days
15Day -1 muscle biopsy to 
occur 1-6 hr after estimated 
timing of initial dose on Day 
1. Time of sample 
collection to be recorded
16 Day 17 muscle biopsy to 
occur within 1-6 hr after last 
dose administered
Time of sample collection 
to be recorded. Muscle 
biopsy can be performed at 
any time during pre-dose 
period.


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Part B – Repeat Dose 
Procedure
Screeni
ng 
(up to 
30 days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow
-up
(~14±
1 days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5-7
8
9-11
12
13-14
15
16
17
18
19
20
Enterotest (bile 
sample collection)
X
For second or third dose-
level only (depending on 
PK results in Part A)
Enterotest capsule to be 
swallowed ~2 hr after 
dosing and removed ~7 hr 
after dosing (~1 hr after 
food cue)
Enterotest food cue
X
For second or third dose-
level only (depending on 
PK results in Part A)
Food cue will be given 6 hr 
post-dose
Discharge from 
Clinical Unit
X
(X)

The time to start the second dose in Part B can be modified based on the estimates of half-life from Part A.

Duration of dosing in Part B can be modified based on the estimates of half-life from Part A.


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
The timing and number of planned study assessments, including safety, PK, PD/biomarker 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 as the result of emerging 
pharmacokinetic/pharmacodynamic data from this study must be documented and approved by the relevant study team member 
and then archived in the sponsor and site study files, but will not constitute a protocol amendment. The CA and EC will be 
informed of any safety issues that constitute a substantial amendment and require alteration of the safety monitoring scheme or 
amendment of the ICF. The changes will be approved by the CA and the EC before implementation.


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Part B .2– 7 Day Repeat Dose 
Procedure
Screeni
ng 
(up to 
30 days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5
6
7
8
9
10
11
12
13
Informed consent
X
Inclusion and 
exclusion criteria 
(including drug 
screens)
X
X
Recheck clinical status before 
randomization and prior to muscle 
biopsy/or 1st dose of study 
medication.
Demography
X
Full physical 
examination including 
height and weight
F
B
B
(B)
F
F: Full exam; B: Brief exam; height 
is only taken once at screening
Medical history 
(includes substance 
usage and family 
history of premature 
CV disease and any 
changes in health 
status occurring 
between screening 
and admission to the 
unit)
X
X
Substances: Drugs, Alcohol, 
tobacco, and caffeine
Past and current 
medical conditions  
X
X


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Part B .2– 7 Day Repeat Dose 
Procedure
Screeni
ng 
(up to 
30 days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5
6
7
8
9
10
11
12
13
HIV, Hepatitis B and 
C screening
X
If test otherwise performed within 3 
months prior to first dose of study 
intervention, testing at screening is 
not required
Admission to Clinical 
Unit
X
Safety Laboratory 
assessments (include 
liver chemistries)
X
X
X
X1
X1
X1
(X)
X1
Pre-randomization assessments 
for eligibility must be performed 
PRIOR to predose muscle biopsy
Predose, 24 hr, and 48, and 72 hr 
post-Day 1 dose; additional 
timepoints may be added based on 
findings in Part A
1Days 7, 10, 13, and follow-up
Routine urinalysis
X
X
X
X2
X2
X2
(X)
X2
Predose, 24 hr, 48 hr, and 72 hr 
post-Day 1 dose; additional 
timepoints may be added based on 
findings in Part A
2Days 7, 10, 13, and follow-up


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Part B .2– 7 Day Repeat Dose 
Procedure
Screeni
ng 
(up to 
30 days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5
6
7
8
9
10
11
12
13
Hormone monitoring 
X
X
Samples to be taken at midnight 
and 9am (10 min) on Days -1 and 
10
Samples taken at midnight will be 
analysed for adrenocorticotropic 
hormone (ACTH) and cortisol
Samples taken at 9am will be 
analysed for ACTH, cortisol, 
luteinizing hormone (LH), follicle 
stimulating hormone (FSH), thyroid 
stimulating hormone (TSH), total 
testosterone, dihydrotestosterone 
(DHT), triiodothyronine (T3), and 
free thyroxine (free T4) 
See Section 8.2.7 for information 
regarding monitoring of abnormal 
hormone results


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Part B .2– 7 Day Repeat Dose 
Procedure
Screeni
ng 
(up to 
30 days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5
6
7
8
9
10
11
12
13
12-lead ECG
X
X
=====X=====
X5
X5
X5
(X)
X5
ECGs assessed at screening 
(triplicate measure) and admission 
(single measure).  During 
treatment period ECGs assessed 
predose (triplicate measure at at 
least 5 min intervals) and post-
dose (single measure) every 30 
min for 1 hr, hourly up to 6 hr, at 12 
hr post-dose then at 24 hr, 36 hr, 
48 hr, and 72 hr post-dose 
5 Days 7,10, 13, and Follow-up
Post-dose at Cmax based on 
observed Cmax in Part A (currently 
estimated to occur at ~2 hr post 
dose), except for Day 13 . Day 13 
ECG to occur any time before 
Discharge


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Part B .2– 7 Day Repeat Dose 
Procedure
Screeni
ng 
(up to 
30 days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5
6
7
8
9
10
11
12
13
Vital signs (pulse 
rate, bp, respiratory 
rate, and oral 
temperature)
X
X
X6
X7
X6
(X)
X
6Vitals assessed at screening 
(triplicate measurements for pulse 
and bp) and admission (single 
measurements).  During treatment 
period vitals assessed predose 
(triplicate measurements for pulse 
and bp) and postdose (single 
measurements) every 15 min for 1 
hr, hourly up to 6 hr, and at 12 hr, 
24 hr, 36 hr, 48 hr, and 72 hr post-
dose
7Vitals assessed once every 24 hr
See Section 8.2.2 for further 
information
Randomization
X
Genetic sample
X
Any time predose on Day 1
This research may be described in 
a separate ICF or as part of a 
combined ICF.  A separate 
signature is required where 
participant participation is optional


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Part B .2– 7 Day Repeat Dose 
Procedure
Screeni
ng 
(up to 
30 days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5
6
7
8
9
10
11
12
13
Study intervention
X
==================X===================
Telemetry
X
Telemetry performed starting 30 
(10 min) pre-dose to 12 hr (20 
min) post-dose
AE review
=========================================X==========================================
SAE review
====================================================X========================================================
Concomitant 
medication review
========================================================X================================================


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Part B .2– 7 Day Repeat Dose 
Procedure
Screeni
ng 
(up to 
30 days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5
6
7
8
9
10
11
12
13
Urine sampling PD
X8
X9
X9
X9
(X)
8combined void for windows of 24-
22 hr, 22-20 hr, 20-18 hr, 18-16 hr, 
16-12 hr, and 12-0 hr predose. 
9combined void for windows of 0-2 
hr, 2-4 hr, 4-6 hr, 6-8 hr, 8-12 hr, 
and 12-24 hr post-dose 
Aliquots will be removed prior to 
pooling for urine PK. Total urine 
volume will be recorded before 
aliquots for PD are removed.


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Part B .2– 7 Day Repeat Dose 
Procedure
Screeni
ng 
(up to 
30 days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5
6
7
8
9
10
11
12
13
24h urine sampling 
for PK and metabolite 
profiling
X
X
X
(X)
Voids from urine 
pharmacodynamic (PD) sampling 
windows will be combined into 0-24 
hr pools on Day -1,1, and 10 after 
aliquoting for PD. 
These voids will be combined for 
PK/metabolite analysis only after 
aliquots for urine PD are removed
See study reference manual (SRM) 
for details on samples and 
processing
Blood sampling for 
PK
X10
X11
X11
X11
X10
(X)
10Day 1 and Day 10: Predose, 5 
min, 30 min, 1 hr, 1. 5hr, 2 hr, 3 hr, 
4 hr, 6 hr, 8 hr, 10 hr, 12 hr, 18 hr, 
24 hr, 36 hr, 48 hr, 60 hr, and 72 hr 
post-dose
11pre-dose samples collected on 
days 6, 7, and 9


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Part B .2– 7 Day Repeat Dose 
Procedure
Screeni
ng 
(up to 
30 days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5
6
7
8
9
10
11
12
13
Blood sampling for 
metabolite profiling
X
X
Day 1 and Day 10 Predose, 5 min, 
30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 
6 hr, 8 hr, 10 hr, 12 hr, 18 hr, 24 hr, 
36 hr, 48 hr, 60 hr, and 72 hr post-
dose
Blood sampling for 
Pharmacodynamics 
and biomarkers
X12
X12
X13
X13
(X)
12Predose and 24 hr post-dose on 
Day 1  
13Predose Days 7 and 10


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Part B .2– 7 Day Repeat Dose 
Procedure
Screeni
ng 
(up to 
30 days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5
6
7
8
9
10
11
12
13
Muscle Biopsy
X14
X15
(X)
Muscle biopsies must be 
performed AFTER clinical safety 
assessments on the corresponding 
days
14Day -1 muscle biopsy to occur 1-
6 hr after estimated timing of initial 
dose on Day 1. Time of sample 
collection to be recorded
15Day 10 muscle biopsy to occur 
within 1-6 hr after last dose 
administered
Time of sample collection to be 
recorded. Muscle biopsy can be 
performed at any time during pre-
dose period.
Discharge from 
Clinical Unit
X
(X)


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
The time to start the second dose in Part B can be modified based on the estimates of half-life from Part A.

Duration of dosing in Part B can be modified based on the estimates of half-life from Part A.

The timing and number of planned study assessments, including safety, PK, PD/biomarker 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 as the result of emerging 
pharmacokinetic/pharmacodynamic data from this study must be documented and approved by the relevant study team member 
and then archived in the sponsor and site study files, but will not constitute a protocol amendment. The CA and EC will be 
informed of any safety issues that constitute a substantial amendment and require alteration of the safety monitoring scheme or 
amendment of the ICF. The changes will be approved by the CA and the EC before implementation.


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Part C- Food Effect 
Screening 
(up to 30
days 
before Day 
1)
Treatment Period [Days] (with or without food)
Follow-
up
(~14±1
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–1
1
2
3
4
E.D.
Informed 
consent
X
Inclusion and 
exclusion criteria 
(including drug 
screens)
X
X
Recheck clinical status 
before randomization and/or 
1st dose of study medication.
Demography
X
Physical 
examination 
including height 
and weight
F
B
B
(B)
F
F: Full exam; B: Brief Exam; 
height is only taken once at 
screening


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Part C- Food Effect 
Screening 
(up to 30
days 
before Day 
1)
Treatment Period [Days] (with or without food)
Follow-
up
(~14±1
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–1
1
2
3
4
E.D.
Medical history 
(includes 
substance 
usage and 
family history of 
premature CV 
disease and any 
changes in 
health status 
occurring 
between 
screening and 
admission to the 
unit)
X
X
Substances: Drugs, Alcohol, 
tobacco, and caffeine
Past and current 
medical 
conditions  
X
X
HIV, Hepatitis B 
and C screening
X
If test otherwise performed 
within 3 months prior to first 
dose of study intervention, 
testing at screening is not 
required
Admission to 
Clinical Unit
X


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Part C- Food Effect 
Screening 
(up to 30
days 
before Day 
1)
Treatment Period [Days] (with or without food)
Follow-
up
(~14±1
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–1
1
2
3
4
E.D.
Safety 
Laboratory 
assessments 
(including liver 
chemistries)
X
X
X
X
X
X
(X)
X
Predose; 8 hr, 24 hr, 48 hr, 
and 72 hr post-dose and at 
follow-up visit
Routine 
Urinalysis
X
X
X
X
X
(X)
X
Predose; 8 hr, 24 hr, 48 hr, 
and 72hr post-dose and at 
follow-up visit
12-lead ECG
X
X
===========================X===============================
(X)
X
ECGs assessed at screening 
(triplicate) and admission 
(single).  During treatment 
period ECGs assessed 
predose (triplicate at least 5 
min intervals) and single 
measurements postdose 
every 30 min for 1 hr, hourly 
up to 6 hr, and at 12 hr, 24 
hr, 36 hr, 48 hr, and 72 hr 
post-dose 


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Part C- Food Effect 
Screening 
(up to 30
days 
before Day 
1)
Treatment Period [Days] (with or without food)
Follow-
up
(~14±1
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–1
1
2
3
4
E.D.
Vital signs (pulse 
rate, bp, 
respiratory rate, 
and oral 
temperature)
X
X
=======================X=======================
(X)
X
Vitals assessed at screening 
(triplicate measurements for 
pulse and bp) and admission 
(single measurements).  
During treatment period vitals 
assessed predose (triplicate 
measurements for pulse and 
bp) and postdose (single 
measurements) every 15 min 
for 1 hr, hourly up to 6 hr, and 
at 12 hr, 24 hr, 36 hr, 48 hr, 
and 72 hr post-dose
See Section 8.2.2 for further 
information
Randomization
X
Genetic sample
X
Sample can be obtained at 
any point during dosing. This 
research may be described in 
a separate ICF or as part of a 
combined ICF.  A separate 
signature is required where 
participant participation is 
optional


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Part C- Food Effect 
Screening 
(up to 30
days 
before Day 
1)
Treatment Period [Days] (with or without food)
Follow-
up
(~14±1
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–1
1
2
3
4
E.D.
Test Meal
X
Fed Arm only. See Section 
5.3.1 for timings regarding 
meals, fasting, and treatment 
administration
Study 
intervention
X
Telemetry
X
Telemetry performed starting 
30 min (10 min) pre-dose to 
12hrs (20 min) post-dose
AE review
===================X===================
(X)
X
SAE review
X
             ================================X==============================
(X)
Concomitant 
medication 
review
X
================================X==============================
(X)
X
Blood sampling 
for PK
======================X=====================
(X)
Predose, 5 min, 30 min, 1 hr, 
1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 
hr, 10 hr, 12 hr, 18 hr, 24 hr, 
36 hr, and 48 hr, 60 hr, and 
72 hr post-dose


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Part C- Food Effect 
Screening 
(up to 30
days 
before Day 
1)
Treatment Period [Days] (with or without food)
Follow-
up
(~14±1
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–1
1
2
3
4
E.D.
Discharge from 
Clinical Unit
X
(X)

Duration of dosing in Part C can be modified based on the estimates of half-life from Part A.

The timing and number of planned study assessments, including safety, PK, PD/biomarker 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 as the result of emerging 
pharmacokinetic/pharmacodynamic data from this study must be documented and approved by the relevant study team member and then 
archived in the sponsor and site study files, but will not constitute a protocol amendment. The CA and EC will be informed of any safety 
issues that constitute a substantial amendment and require alteration of the safety monitoring scheme or amendment of the ICF. The 
changes will be approved by the CA and the EC before implementation.


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2.
INTRODUCTION
2.1.
Study Rationale
This study is the first time into human study (FTIH) for GSK3439171A. The study will 
evaluate the safety, tolerability and pharmacokinetics (PK) of single ascending and repeat 
oral doses of GSK3439171A in healthy adult participants. A food effect assessment will 
be undertaken using a crossover design to investigate the influence of food on the PK of 
GSK3439171A. Pharmacodynamic (PD) and biomarker effects of GSK3439171A in 
healthy adult volunteers will also be explored. The results of this study are intended to be 
used to identify appropriate and well tolerated oral doses to be used in further studies 
investigating GSK3439171A in diseases in which prostaglandin-mediated pathways are 
involved.
2.2.
Background
2.2.1.
Hematopoietic prostaglandin D2 synthase (H-PGDS)
Figure 4
Prostanoid Synthesis
Prostaglandin D2 (PGD2) is a downstream product of the arachidonic acid cascade 
(Figure 4) and is synthesized by mast cells in response to stimulation via multiple 
injurious mechanisms and cellular activation pathways [Lewis, 1982].  Other cells such 
as dendritic cells, T helper 2 (Th2) cells, and epithelial cells also produce PGD2, but at 
lower levels than mast cells.  PGD2 mediates its effects via activation of the specific G-
protein coupled receptors DP1 [Boie, 1995] and DP2 (CRTH2) [Abe, 1999] and also acts 
via the receptor for thromboxane A2 (TXA2), the TP receptor, on target cells [Hirata, 
2011].


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The cyclo-oxygenase (COX) enzymes convert arachidonic acid in a two-step process, 
first to PGG2 and then to the unstable endoperoxide, PGH2.  The PGD synthase (PGDS) 
enzyme is subsequently responsible for the catalytic isomerization of PGH2 to PGD2
[Smith, 2011].  PGD2 is generated by the action of either H-PGDS (hematopoietic-type or 
H-type) or L-PGDS (lipocalin-type or L-type) enzymes [Urade, 2000]).  PGDS is the key 
regulator of PGD2 synthesis by mast cells and antigen-presenting cells of the immune 
system, and orchestrates mechanisms of inflammation in muscle disorders (acute injury 
and chronic degenerative diseases), allergy and asthma.  Strong biological evidence 
demonstrates H-PGDS-mediated PGD2 production impairs skeletal muscle repair [Mohri, 
2009], and blockade of this signal via gene manipulation, using knock-out (KO) mice, 
and small molecule inhibition of either H-PGDS or the PGD2 receptors DP1 and DP2 
accelerates the kinetics of muscle remodeling and functional recovery.  Additionally, 
tissue levels of H-PGDS and PGD2 are elevated in acutely injured tissue and chronically 
inflamed tissue.  Notably, H-PGDS inhibitors increase markers of myogenesis (MyoD 
and myogenin) following muscle injury in animals.  Taken together, selective inhibition 
of H-PGDS offers potential to improve muscle adaptation, aiding recovery from injury, 
for example during rehabilitation.
Importantly, other products of arachidonic acid metabolism such as PGE2 and PGF2α 
produce beneficial signaling in muscle [Korotkova, 2014] and therefore approaches that 
decrease global inflammatory signaling (e.g. nonsteroidal anti-inflammatory drugs, 
NSAIDs) are not efficacious.  This may be especially pertinent to populations recovering 
from surgical interventions involving tendons and associated structures, where NSAIDs 
can block tendon healing [Cohen, 2006; Connizzo, 2014].
2.2.2.
GSK3439171A
GSK3439171A is a potent, reversible, and highly selective azetidine urea inhibitor of 
H-PGDS – the major enzyme responsible for the production of PGD2 in mast cells. All 
information regarding non-clinical safety and pharmacology is available in the 
Investigator’s Brochure (IB) [GlaxoSmithKline Document Number 2018N359817_00]. 
GSK3439171A has not been previously administered to human participants; therefore, 
there are no clinical data available.
This first clinical study, which will constitute the initial administration to humans, will be 
conducted in healthy human participants.
2.3.
Benefit/Risk Assessment
Consistent with GlaxoSmithKline (GSK) guidance for early phase studies, 
GSK3439171A will be administered in an in-patient setting (with sufficient overnight 
facilities) in the United States with appropriate monitoring.
In order to minimise the risk of the initial human administration of GSK3439171A, a 
sentinel dosing strategy will be utilized in each of the cohorts in Part A: 1 participant will 
receive GSK3439171A and 1 participant will receive placebo. After the GSK medical 
monitor and investigator have reviewed the safety data through 48 hrs post-dose, (or 5 
half-lives, whichever is longer) the remaining participants from that cohort will be dosed. 


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Once all assessments through 48 hours post-dose (or 5 half-lives, whichever is longer)
have been completed for a minimum of 4 participants on active treatment at each dose 
level, the GSK team and the investigator will review all of the available safety and PK 
data from all participants before proceeding to the next dose level. 
Summaries of findings from non-clinical studies conducted with GSK3439171A can be 
found in the Investigator’s Brochure. The following section outlines the risk assessment 
and mitigation strategy for this protocol:


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2.3.1.
Risk Assessment:
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [e.g., GSK3439171A]
Potential effect on liver
In adult dogs at oral doses levels up to 600 mg/kg/day for 
6 weeks, GSK3439171 was associated with minimal to 
slight changes in the liver (mixed periportal 
inflammatory cell infiltrates at ≥100 mg/kg/day) that 
generally correlated with increases in serum ALT, 
glutamate dehydrogenase (GLDH) and/or alkaline 
phosphatase (ALKP).  Mean serum levels were increased 
for ALT: 2.4 to 4.7 times, for GLDH: 2.6 to 4 times, and 
for ALKP: 1.1 to 2.2 times Baseline values.  Findings 
were dose and exposure-responsive with respect to 
magnitude, severity and incidence. The dog liver finding 
is considered monitorable in clinical setting and not dose 
limiting. The high dose of 600 mg/kg/day was associated 
with systemic exposure AUC (0-t) of 57.8 µg.h/mL in 
male dogs.
The stopping exposure limits for the single 
dose phase were set by the dog liver toxicity 
and the following liver chemistry criteria are 
in place:
Elevation of alanine aminotransferase 
(ALT) and other liver tests (aspartate 
aminotransferase [AST], bilirubin [total and 
direct])
Potential effect on endocrine 
system (adrenal gland)
In juvenile rats, recoverable, dose responsive findings 
were noted in the adrenal gland (cortical hypertrophy of 
the zona fasciculata) with associated increased adrenal 
weights, pale discoloration and/or enlargement in males 
given ≥100 mg/kg/day and females given ≥10 
mg/kg/day.  As the findings may be considered 
potentially adverse for repeat clinical dosing, the no 
adverse effect level (NOEL) for adrenal gland histologic 
The AUC stopping exposure limit of 
11 µg.hr/mL for the repeat dose phase is 
below (0.24 times) the lowest effect 
exposure for rat adrenal toxicity and 
participants will be monitored at times 
indicated in the SoA for changes in the 
following levels:


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
effects was 10 mg/kg/day in male and female rats, with 
associated AUC (0-t) of 3.94 µg.h/mL. The lowest 
individual AUC at lowest effected dose level (LOEL) of 
100 mg/kg/day for male juvenile rat adrenal effects is
46 µg.h/mL.  
adrenocorticotropic hormone (ACTH), 
cortisol
luteinizing hormone (LH), 
follicle stimulating hormone (FSH), 
thyroid stimulating hormone (TSH)
total testosterone
dihydrotestosterone (DHT)
thyroxine (T4) 
triiodothyronine (T3) 
Potential effect on female 
reproductive tissues
In female juvenile rats, recoverable, dose responsive 
microscopic findings were also noted in the ovary 
(vacuolation of interstitial cells) and mammary gland 
(lobuloalveolar hypertrophy/hyperplasia) at ≥100 
mg/kg/day; and pituitary (increased mitoses of cells in 
the pars distalis) at 600 mg/kg/day.  
All women will be excluded from this study.
The nonclinical toxicology and 
efficacy studies were 
conducted using 
non-micronized material, while 
The rat and dog toxicity studies with non-micronized 
material attained AUC and Cmax exposures substantially 
over the NOAEL to effectively characterize the 
nonclinical safety of GSK3439171.  Additionally, the 
Conservative assumptions were used for the 
minimum anticipated biological effect level 
(MABEL) simulations and the predictions 
for the first dose are expected to be well 


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
this clinical study will use 
micronized, thus there is a risk 
that the clinical PK will be 
different than predicted
impurity profile of the micronized material was 
consistent with that of the non-micronized material.  
Thus, the nonclinical safety data is considered supportive 
of clinical use of micronized compound.
below the dog NOAEL exposure margins, 
110- and 270-fold lower for AUC(0-inf) and 
Cmax, respectively. 
The suspension used for non-clinical studies 
was homogenised and the particle size thus 
reduced smaller than non-micronised.  
Solubility does not change on micronisation 
but in-vitro bio-relevant dissolution data 
shows a proportional response in rate of 
dissolution for non-micronised, ground and 
micronized. 
Study Procedures
Entero-Test
Streaks of blood on the string 
due to local irritation have 
been infrequently noted. 
Rarely, a patient will be unable 
to swallow the capsule because 
of gagging or will vomit after 
doing so. Gagging upon 
retrieval of the string can 
occur. On a few occasions, an 
entire string has been 
swallowed without ill effects 
The use of Entero-Test has been approved 
by the FDA (510(k), Summary of safety and 
effectiveness). The string will be securely 
taped in place during the collection time to 
minimize risk of swallowing the entire 
string. Any subject incapable of swallowing 
the capsule will be allowed to participate in 
the study without duodenal bile collection.


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
and passes from the body in the 
feces. Consider risks associated 
with comparators, challenge 
agents, imaging agents, 
medical devices, etc
Muscle Biopsy
Localized pain from muscle 
biopsy procedure can occur
Low risk of bleeding or 
infection could occur as result 
of the procedure. There is a 
very low risk of nerve damage 
as a result of the procedure
Local anesthetic will be employed during 
muscle biopsy procedures.
Acetaminophen or another medication 
selected by the investigator and the medical 
monitor can be administered to participants 
to control post-procedural pain.
Biopsy procedure will be performed by staff 
experienced in the technique. Participants 
will be followed up for any adverse events 
resulting from the biopsy and managed 
appropriately, if needed.


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2.3.2.
Benefit Assessment
There will be no benefit to the participant taking part in this study. However, participants 
will be contributing to the process of developing new therapies by taking part in the 
study.
2.3.3.
Overall Benefit: Risk Conclusion
The measures taken to minimize the potential risks identified in association with 
GSK3439171A are considered sufficient to justify participation by healthy participants.
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To assess the safety and 
tolerability of GSK3439171A 
following single and repeat doses in 
healthy participants

To characterize the PK of 
GSK3439171A, following single 
and repeat doses in healthy 
participants

Adverse events (AE), clinical 
laboratory values, vital signs, and 
electrocardiograms (ECG)
Derived PK parameters for 
GSK3439171A including area 
under the plasma drug concentration 
versus time curve (AUC(0-t), 
AUC(0-inf), maximum observed 
plasma drug concentration (Cmax), 
time to maximum observed plasma 
drug concentration (tmax), and 
apparent terminal half-life (t1/2) as 
appropriate
Secondary

To assess the effect of food on the PK 
of GSK3439171A following an oral 
dose in healthy participants 

To assess preliminary dose 
proportionality of GSK3439171A 

Derived PK parameters for 
GSK3439171A including area under 
the plasma drug concentration versus 
time curve (AUC(0-t), AUC(0-inf), 
maximum observed plasma drug 
concentration (Cmax), time to 
maximum observed plasma drug 
concentration (tmax), and apparent 
terminal half-life (t1/2) as appropriate

AUC(0-t), AUC(0-inf), and Cmax 
following single dose and AUC(0-τ) 


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Objectives
Endpoints
following single and repeat oral doses, 
as data permit

To examine the extent of accumulation 
and achievement of steady-state 
following repeat oral doses of 
GSK3439171A, as data permits
and Cmax following repeat dose for 
the assessment of dose proportionality

Determine observed accumulation 
based on AUC(Ro) and Cmax 
(RCmax) and determine the steady-
state ratio (Rss) 

Trough plasma concentrations at the
end of the dosing interval (Cτ) 
collected pre-dose for repeat doses 3, 
4, 12, 13 and 14 (repeat doses 3,4,6, 
and 7 for 7 day dosing) to assess the 
achievement of steady-state of 
GSK3439171A 
Exploratory

To evaluate the PD properties of 
GSK3439171A

To assess the effect of 
GSK3439171A on QTc in healthy 
adult volunteers

To evaluate additional biomarkers 
of GSK3439171A target 
engagement after single and repeat 
doses.

To investigate the plasma, urinary 
and biliary (Part B) metabolic 
pathways of GSK3439171A in 
healthy subjects

Levels of mediators on 
prostaglandin and/or inflammatory
metabolic pathways such as, but not 
limited to, PGD2, and PGE2.

Holter monitor data collection and 
storage for evaluation of the 
correlation between plasma levels 
of GSK3439171A and changes in 
the QTc interval in the future, if 
appropriate

Levels of change in novel 
biomarkers in blood, muscle, or 
urine, such as, but not limited to, 
urine tetranor PGDM and PGEM 
(tPGDM, tPGEM), PGD2, and 
PGE2

GSK3439171A-related material in 
plasma, urine and bile.


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4.
STUDY DESIGN
4.1.
Overall Design
This is a three-part study (Parts A, B and C).  Part A will be a double-blind (sponsor 
unblinded), single oral dose, dose-rising, placebo-controlled, randomized (with respect to 
placebo allocation), 3 period crossover study in approximately 3 cohorts of participants.  
Part B will be double-blind (sponsor unblinded), up to 14 day repeat oral dosing, placebo-
controlled, randomized (with respect to placebo allocation), dose escalation study with at 
least three dose levels in 3 separate cohorts of participants who were not enrolled into 
Parts A or C of this study.  Part C will be an unblinded, randomized, crossover study 
where a single dose will be administered fasted or fed conducted in a separate cohort of 
participants than those who were enrolled in Parts A or B. 
The starting dose for Part A will be 5 mg (see Section 4.3.3). 
Part A: Single Ascending Dose 
Each participant will participate in 3 dosing periods and will receive 2 doses of 
GSK3439171A and 1 dose of placebo in a randomized fashion.  There will be an 
approximately 7 day (or 5 half-lives, whichever is longer) washout period between 
dosing in each session.
Approximately 9 participants will be enrolled in each cohort. Participants will be 
admitted to the clinical unit on Day -2 and will remain in the unit until completion of 
assessments on Day 4 as outlined in the SoA. Participants will be discharged from 
clinical unit for the washout period between dosing sessions and will return 
approximately 14 days after dosing in their last dosing session for a follow-up visit. 
Participants will be randomized to treatment sequences such that in each period up to 6 
participants will receive active dose and up to 3 participants will receive placebo. A 
minimum of three cohorts is anticipated.  If a participant is withdrawn from the study, the 
participant may be replaced as necessary with another participant assigned to the same 
treatment sequence with respect to active and placebo doses to ensure that at least 4 
participants receive each active dose and 1 participant receives a placebo, and that these 
participants complete safety and PK assessments through at least 72hr post-dose (or 5 
half-lives, whichever is longer).  Additional participants may be dosed at a given level if 
additional data are necessary to establish safety, tolerability or PK parameters prior to 
dose escalation.
Each active dose level will be administered initially to a smaller group of participants (1 
on active and 1 on placebo) to evaluate safety at each dose level. These sentinel 
participants will be followed clinically for 48 hr (or 5 half-lives, whichever is longer) to 
allow for adequate observation of safety (given a predicted half-life of 6.1 hr for
GSK3439171A) after dose administration to monitor for emergence of adverse events.  If 
no acute safety issues are observed in this smaller group of sentinel participants 
(including review of 48 hr safety laboratory results), then the remaining participants 
(approximately 5 participants on active and 2 participants on placebo) will receive this 


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same dose prior to dose escalation. See Section 6.6 for information on the decision to 
proceed to the next dose level.
Part B: Single and Repeat Dose up to 14-day dose-rising
In each cohort of Part B of the study, approximately twelve participants will be 
randomized to either one dose level of GSK3439171A or placebo according to a 
randomization schedule prepared prior to the start of the study.  The study will be 
conducted sequentially starting with Dose 1 Cohort B1. Participants will receive repeat 
daily or twice daily (BID) doses of the study intervention or placebo based on ongoing 
PK data obtained in Parts A and B.
Participants will report to the Clinical Research Unit on Day -2 and will remain in the 
unit for the duration of Part B. Participants will randomly be assigned to receive a single 
dose (or a BID dose depending on data obtained in Part A) of GSK3439171A or placebo 
(approximately 9 study intervention: 3 placebo).  Plasma and urine PK, PD, and 
biomarker samples (including a pre-dose muscle biopsy) will be collected for up to 72 hr 
after initial dosing. After completion of assessments at 72 hr (Day 4), participants will 
begin a repeat dosing regimen consisting of one dose (or a BID dose depending on data 
obtained in Part A) per day for up to 14 days. This time period is based on a predicted 
half-life of GSK3439171A of 6.1 hours (with a range of 4-22 hours) calculated from 
preclinical data and is designed to allow GSK3439171A to reach steady state during the 
dosing period. The actual repeat dose duration can be altered based on PK data in Part A 
of the study.  For example, if the predicted half-life is confirmed from Part A of the study 
then the duration of dosing in Part B will be much shorter to achieve steady-state than 
planned currently. Dosing duration in Part B and follow-up will be shortened 
appropriately based on emerging PK data from Part A. Participants will be discharged on 
the morning of Day 13 (3 days post last dose during the 7 day repeat dose period) or Day 
20 (3 days post-last dose during the 14 day repeat dose period) following completion of 
study assessments, including a post-dose muscle biopsy.  Safety, tolerability and PK data 
review for a minimum of 6 participants receiving active treatment will be carried out 
upon completion of assessments on Day 13 or 20 (72 hours post-last dose) before 
initiation of dosing in the next cohort.  The dose of GSK3439171A may be adjusted 
(lower or higher) based on data from Part A and for cohorts going forward based upon 
the safety, tolerability, PK, and preliminary PD data from the previous cohort. 
All participants will return to the clinical unit for a follow-up visit approximately 14 days 
following the administration of the last dose of study medication.  
Part C: Food Effect
In this crossover design, approximately 12 participants will take part in two
approximately 4-day study sessions with dosing in each session separated by 
approximately 7 days (or 5 half-lives of the study intervention, whichever is longer).  In 
each study session, participants will be admitted to the clinical unit and receive a single 
dose of GSK3439171A either in the fasted state or after a high fat meal. Participants will 
be randomly assigned to one of two treatment sequences in a two-period crossover design 
(fed/fasted or fasted/fed). The timing of assessments in Part C can be altered based upon 
data obtained in Parts A and B.


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The dose of GSK3439171A to be administered will be determined from Parts A and B to 
ensure an adequate safety margin assuming an arbitrary 2-fold increase in exposure to 
GSK3439171A when administered with food. Participants will remain in the unit for 
completion of safety and PK assessments before being discharged on Day 4. Participants 
will return for a follow-up visit approximately 14 days following the administration of 
the last dose of study medication.
The total duration of the study for each participant recruited into Part A will be 
approximately 10 weeks. For participants recruited into Part B, the total study duration 
will be up to approximately 9 weeks.  For participants recruited into Part C, the total 
study duration will be up to approximately 8 weeks.  
4.2.
Scientific Rationale for Study Design
The FTIH study with GSK3439171A will evaluate the safety of GSK3439171A in 
healthy participants in order to avoid confounding factors due to the disease or 
concomitant drugs in patients. The study design is based on pre-clinical findings for 
GSK3439171A, contributing to the frequency, type and duration of safety assessment and 
monitoring during treatment periods in each cohort.
The single dose assessments in Part A will be conducted to determine safety, tolerability, 
PK, and PD of the study intervention in individuals before progressing to doses explored 
further in other parts of the study. The sequential design of the single dose components 
will allow for dose escalation to occur approximately every two weeks with a 7-day 
period of washout.  This approach allows for any adjustments needed based on emerging 
safety, tolerability, and PK information. The crossover design within each cohort in Part 
A is preferred as it allows for each participant to serve as their own control for the 
assessment of safety and provides PK assessment in the same individual at two different 
dose levels, reducing the influence of inter-individual variability.
In Part B, a single dose safety, tolerability and PK will be collected followed by 
progression of these participants to the repeat dose portion of the study. The 7 or 14-day 
dosing was chosen as it is thought to provide sufficient safety and tolerability data to 
bridge to longer duration studies. The dosing period can be adjusted depending on PK 
and PD data collected in Part A of the study.
Prostaglandin species, particularly prostaglandin D2, are virtually undetectable in the 
blood or plasma of unchallenged and/or otherwise healthy human subjects. However, 
skeletal muscle contains high levels of prostanoids in the basal state, and our preclinical 
data reveal significant dose-dependent reductions in prostaglandin D2 levels in skeletal 
muscle following administration of H-PGDS inhibitors [GSK3439171A Investigator’s 
Brochure]. Therefore, muscle biopsies will be performed both pre- and post-study 
intervention in Part B to assess the effect of GSK3439171A on prostanoid levels in situ in 
a tissue of potential clinical interest.
During preclinical pharmacokinetic assessments, GSK3439171A was found to be highly
bioavailable (generally >40%); however, recovery of GSK3439171A in urine was low 
(<2% of the administered dose) [GSK3439171A Investigator’s Brochure]. In order to 
characterize potential biliary elimination pathways, this study will also employ the 


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Entero-Test for sampling of bile to conduct qualitative assessment of drug metabolites in 
this matrix. The Entero-Test is an easy-to-use and minimally-invasive method for 
sampling bile from the duodenum.
Entero-Test is a FDA approved device for human non-invasive sampling of upper gastro-
intestinal 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.  As sufficient data from the Entero-Test string is expected following one dose of 
the study drug, this assessment will be restricted to only one cohort in Part B (anticipated 
to be the second or third dose level depending on PK results in Part A) at participants’ 
last dose.  In addition, urine will be collected and used to investigate the urinary 
elimination of parent drug and any metabolites alongside bile analysis as well as analysis 
of PK samples for drug and metabolites (under a separate protocol).
Additionally, Holter monitor data will be collected and stored for a future evaluation of 
the correlation between plasma levels of GSK3439171A and changes in the QTc interval, 
if appropriate.
The crossover design for assessing the effect of food on GSK3439171A in Part C allows   
each participant to serve as their own control, reducing the influence of potential inter-
individual variability in this part of the study.
The 7-day (or 5 half-lives, whichever is longer) washout utilized in Parts A and C of the 
study is believed to provide sufficient washout based on preclinical data and simulations 
but can be modified based on emerging data in Part A.
4.3.
Justification for Dose
Dose selection of GSK3439171A for this FTIH study was based on NOAEL data in the 
most sensitive species, predicted PK of humans using the PK data from preclinical 
species, and a target therapeutic exposure based on the in-vitro H-PGDS recombinant 
enzyme assay, and in-vivo dose-response evaluation of GSK3439171A in wild-type 
(WT) eccentric damage and dystrophin deficient (mdx) mouse models. 
The human PK parameters were calculated from preclinical mouse, rat, dog and monkey 
data. A range of human clearance and volume of distribution values were estimated by a 
variety of liver blood flow (LBF), allometric scaling, and Physiologically Based PK 
(PBPK) methods using GlaxoSmithKline software package PK Predictor Pro version 
2.0.2.8, Excel and GastroPlus 9.0, respectively. Human bioavailability was estimated by 
averaging the oral bioavailability of mice, rat, dogs, and monkeys and estimated from 
LBF and single species scaling. Based on allometry and LBF, the predicted median 
human clearance was 10.8 mL/min/kg. The predicted median (range) human volume of 
distribution was 4.6 L/kg (3.2-6.0) and the predicted median (range) of half-life was 6.1 h
(4-22). The human oral absorption rate was assumed to be 6.0 h-1, based upon the average 
of the preclinical species (7.5 h-1). The predicted oral bioavailability median (range) was 
61% (39%-68%). A 100% bioavailability can be used as a conservative approach.
GSK3439171 was given orally to adult dogs for 6 weeks, and rats for 8 weeks starting 
dosing as juveniles on Postnatal Day (PND) 28 through maturity. Principal toxicities 
were a slight microscopic liver effect in the dog (inflammatory cell infiltrates in 


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periportal region) which was associated with elevations in liver enzyme activity, and 
adrenal gland and female reproductive tissue effects in the juvenile rat. In both species 
there was a sex difference in systemic exposure, with the females generally having higher 
exposure. For dogs with liver findings that were associated with increases in alanine 
aminotransferase activity (ALT), glutamate dehydrogenase (GLDH) or alkaline 
phosphatase (ALKP) activity, findings were dose and exposure-responsive with respect 
to magnitude, severity and incidence. Mixed inflammatory cell infiltrates in the liver 
combined with the increases in liver-related enzymes were considered adverse at 
≥100 mg/kg/day; thus, the NOAEL in dogs for 6 weeks duration was considered to be 
20 mg/kg/day with females having higher exposure (AUC: 11.0 µg.h/mL). Since the dog 
liver finding is monitorable in a clinical setting and not considered dose limiting, the 
male exposure at 600 mg/kg/day (AUC: 57.8 g.h/mL) is considered acceptable as a 
clinical single exposure limit for Part A. In juvenile rats, recoverable, dose-responsive 
findings were noted in the adrenal gland (cortical hypertrophy of the zona fasciculata) 
with associated increased adrenal weights, pale discoloration and/or enlargement in males 
given ≥100 mg/kg/day and females given ≥10 mg/kg/day. At 10 mg/kg, 1 of 10 female 
rats had pale discoloration and an increased adrenal gland weight, without a microscopic 
change. The rat adrenal findings may be considered potentially adverse, the NOEL for 
adrenal gland histologic effects was 10 mg/kg/day in male and female rats, with 
associated AUC (0-t) of 3.94 µg.h/mL. The lowest individual AUC at the lowest effected 
dose level (LOEL) of 100 mg/kg/day for male juvenile rat adrenal effects is 46 µg.h/mL.  
In a preliminary study, there were no adrenal macroscopic or microscopic effects in adult 
male rats after 7 days of dosing 1000 mg/kg/day (AUC in blood: 1130 µg.h/mL).  
In female juvenile rats, recoverable, dose responsive microscopic findings were also 
noted in the ovary (vacuolation of interstitial cells) and mammary gland (lobuloalveolar 
hypertrophy/hyperplasia) at ≥100 mg/kg/day; and pituitary (increased mitoses of cells in 
the pars distalis) at 600 mg/kg/day.   
Results of other nonclinical studies suggest that GSK3439171 does not present a 
genotoxic risk to humans. Additionally, there were no safety pharmacology findings of 
clinical concern at oral dog doses up to 1500 mg/kg. There were no changes considered 
related to GSK3439171 administration in the evaluation of spermatogenesis in either 
species. Thus, the nonclinical data support the conduct of clinical studies in men up to 
6 weeks duration up to the mean systemic exposure at the NOEL for adrenal gland 
histologic effects in the rat study (AUC: 3.94 g.h/mL) with appropriate monitoring in 
place, and for a shorter duration of 7 days up to the dog liver NOAEL exposure (AUC: 
11.0 µg.h/mL).  
Based on in vivo efficacy studies and mechanism of the H-PGDS pathway, the efficacy 
target was to maintain GSK3439171A concentrations above the IC50. A 10% inhibition of 
the H-PGDS enzyme (IC10) was considered as the minimal anticipated biological effect 
level (MABEL). The IC50 and IC10 were calculated from the H-PGDS recombinant 
enzyme inhibition assay and compared with in vivo studies (dystrophin deficient (mdx) 
and WT eccentric damage mouse models).
GSK3439171A in vitro inhibition was evaluated using a recombinant human H-PGDS 
enzyme assay. The data was fitted using an Emax model and the IC50 was 7.77 ng/mL and 


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the IC10 was 0.86 ng/mL. The target IC50 was compared to the in vivo efficacy studies in 
the WT eccentric damage mouse model and a dystrophin deficient (mdx) mouse model 
which is a commonly used preclinical model to mimic Duchenne muscular dystrophy. In 
these models, the corresponding ED50 (0.7 mg/kg/day and 0.6 mg/kg/day, respectively) 
and IC50 (5.5 ng/mL and 4.7 ng/mL, respectively) were comparable. Briefly, in these 
studies, 8-month old male mice were administered an initial dose of vehicle or 0.1, 0.3, 
1.0, 3.0, 10 and 30 mg/kg of GSK3439171A 10 minutes prior to a challenge of 60 
eccentric contraction repetitions, and then daily (BID, per oral (PO)) administration 
thereafter for 46 days. On day 45, serial blood samples were collected from a subset of 
animals (n=3) in each dose group and the steady state pharmacokinetic parameters were 
estimated. At varying intervals, maximal isometric limb torque was measured in vivo to 
assess functional recovery. Whereas vehicle-treated mdx mice exhibited prolonged 
recovery kinetics and never fully reached their starting (Baseline) function (~30% 
permanent force deficit), GSK3439171A-treated animals recovered significantly faster 
with significantly greater resolution of their force deficit. In the efficacy studies, 
longitudinal composite of muscle function pre-damage, and intermittently throughout the 
46-day study was obtained. GSK3439171A provided a significantly protective effect to 
the initial insult at doses ≥1 mg/kg. Limb recovery over time was normalized to Baseline 
from day 0 and was used as an integrated measure of the pharmacological effect to 
calculate an ED50 of 0.6 mg/kg/day with a 95% confidence interval ranging from 0.14 –
2.8 mg/kg/day. Thus, based on the H-PGDS enzyme inhibition evaluation, the target IC50
and IC10 values were 7.77 ng/mL and 0.86 ng/mL, respectively. 
PK simulations (100 replicates) were performed in a 70-kg human using an estimated 
median clearance (10.8 mL/min/kg) and volume of distribution (4.6 L/kg) with 30% 
between-subject variability assuming a 1-compartment model. Based on the results, a 37 
mg BID dose would achieve concentrations greater than the target IC50 in more than 90% 
of patients.
4.3.1.
Maximum Recommended Starting Dose (MRSD)
Using the FDA Guidance for estimation of the maximum safe starting dose, the NOAEL 
in female dogs was converted to the Human Equivalent Dose (HED) based on body 
surface area. After applying an uncertainty safety factor of 10 (guideline default) to the 
HED, the maximum recommended starting dose for a 60-kg adult is 66.7 mg. 
4.3.2.
Dose Predicted to Achieve the Therapeutic Exposure Target
The primary in vivo efficacy study was a dose-response evaluation of GSK3439171A on 
the H-PGDS recombinant enzyme and compared with data from the in vivo studies of 
muscle repair following injury in the mdx, WT eccentric damage mice.  Based on the 
predicted human clearance value range of 5.7-19.5 mL/min/kg, a preclinical exposure 
target of 0.176 μg·h/mL and a conservative oral bioavailability range of 39% to 100%, 
the dose to achieve the therapeutic exposure target ranged from 4 to 37 mg.  Based on the 
most conservative estimates, this AUC(0-t) value (0.176 μg·h/mL) is 63-fold and 328-
fold lower than the AUC(0-t) value of female dog NOAEL and single dose stopping 
limit, respectively. The predicted Cmax value from the 37 mg (higher dose: Pred 


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Cmax=0. 0925g/mL) is about 29-fold and 108-fold lower than the Cmax value of 
NOAEL and single dose stopping limit, respectively.
Assumptions were made on the following PK and PD parameters in order to bridge from 
animal to man: CL, V, F and in vivo ED50 of H-PGDS. These assumptions will be 
verified with lower dose data and if needed, adjustments will be made in subsequent dose 
selections.
4.3.3.
Minimum Anticipated Biological Effect Level (MABEL) Dose
A 10% inhibition of the H-PGDS enzyme (IC10) was considered as the MABEL and the 
PK of lower GSK3439171A was simulated in a 70-kg human using an estimated median 
clearance (CL) (10.8 mL/min/kg) and V (4.6 L/kg) with 30% between-subject variability 
assuming a 1-compartment model. A single dose of 5 mg was predicted to maintain IC10
levels (0.86 ng/mL) and a reasonable concentration is expected to be above the lower 
limit of quantification (LLOQ).  This predicted AUC(0-t) value for 5 mg dose (0.1 
μg·h/mL) is 110-fold lower than the NOAEL AUC(0-t) value and the predicted Cmax 
value (0.01 μg/mL) is about 270-fold lower than the NOAEL Cmax value.
4.3.4.
Dose Predicted to Achieve Exposure at the NOAEL Dose Level 
and Single Dose Stopping Limit
Based on the predicted human clearance value range of 5.7-19.5 mL/min/kg, a 
conservative range of oral bioavailability from 39% to 100%, and a NOAEL AUC(0-t) 
value of 11 μg·h/mL, the dose to achieve the female dog NOAEL exposure level ranges 
from 263 to 2310 mg. Also, the dose to achieve the Single Dose Stopping Limit exposure 
of 57.8 μg·h/mL ranges from 1384 to 12138 mg.
4.3.5.
Summary
The MRSD is 66.7 mg, the dose to achieve the therapeutic target is 37 mg BID, and dose 
to achieve the female dog NOAEL exposure level ranges from 263 to 2310 mg. Based on 
MABEL dosing, the starting dose will be 5 mg (13.34-fold lower than MRSD). Further 
dose escalation will be based on exposure, safety, and tolerability from the previous dose 
level. Based on the range of predicted H-PGDS inhibition and NOAEL exposure cover, 
the expected top dose may be 500 mg and the maximum dose that can be administered 
based on the Genotoxic Risk Assessment (GRA) is 3000 mg.
4.4.
End of Study Definition
A participant is considered to have completed the study if he/she has completed all 
phases of the study including or the last scheduled procedure shown in the SoA.
The end of the study is defined as the date of the last visit of the last participant in the 
study.


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5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be 18 to 65 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests, and cardiac monitoring. A 
participant with a clinical abnormality or laboratory parameter(s) not specifically 
listed in the exclusion or exclusion criteria that is outside the reference range for the 
population being studied may be included only if the investigator, in consultation 
with the Medical Monitor, agree and document that the finding is unlikely to 
introduce additional risk factors and will not interfere with the study procedures.
Weight
3.
Body weight ≥50.0 kg (110 lbs.) and body mass index (BMI) within the range 18.5 
to 31.0 kg/m2 (inclusive).
Sex
4.
Only males are eligible for this study
Contraceptive use should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies.
Male participants are eligible to participate if they agree to the following during their 
entire enrolment in the study plus an additional 5 days or 5 terminal half-lives (whichever 
is longer)

Refrain from donating sperm
PLUS either:

Be abstinent from sexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
OR

Must agree to use contraception/barrier as detailed below 
female partner to use an additional highly effective contraceptive method
with a failure rate of <1% per year as described in Appendix 4.


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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.
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, 
endocrine, hematological, or neurological disorders capable of significantly altering 
the absorption, metabolism, or elimination of drugs; constituting a risk when taking 
the study intervention; or interfering with the interpretation of data.
2.
Any clinically significant abnormal vital signs
3.
Lymphoma, leukemia, or any malignancy within the past 5 years except for basal 
cell or squamous epithelial carcinomas of the skin that have been resected with no 
evidence of metastatic disease for 3 years
4.
Alanine transaminase (ALT) >1.5x upper limit of normal (ULN) 
5.
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 
6.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones)
7.
QTc >450 msec
NOTES:

The QTc is the QT interval corrected for heart rate according to Fridericia’s 
formula (QTcF), machine-read or manually over-read.

The specific formula that will be used to determine eligibility and 
discontinuation for an individual subject should be determined prior to initiation 
of the study. In other words, several different formulae cannot be used to 
calculate the QTc for an individual subject and then the lowest QTc value used 
to include or discontinue the subject from the trial.
Prior/Concomitant Therapy
8.
Unable to refrain from the use of aspirin, NSAIDs, vitamins, herbal and dietary 
supplements (including St John’s Wort) within 10 days prior to the first dose of 
study medication (Specific medications listed in Section 6.5 may be allowed).


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Prior/Concurrent Clinical Study Experience
9.
Where participation in the study would result in loss of blood or blood products in 
excess of 500 mL within 56 days
10. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day.
11. Current enrolment or past participation within the last 30 days before signing of 
consent in this or any other clinical study involving an investigational study 
intervention or any other type of medical research. 
Diagnostic assessments
12. Presence of Hepatitis B surface antigen (HBsAg) at screening 
13. Positive Hepatitis C antibody test result at screening.
NOTE:  Subjects with positive Hepatitis C antibody due to prior resolved disease can be 
enrolled, only if a confirmatory negative Hepatitis C ribonucleic acid (RNA) test is 
obtained
14. Positive Hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study intervention
NOTE: Test is optional and subjects with negative Hepatitis C antibody test are not 
required to also undergo Hepatitis C RNA testing
15. Positive pre-study drug/alcohol screen
16. Positive human immunodeficiency virus (HIV) antibody test
Other Exclusions
17. Regular use of known drugs of abuse or positive urine drug test at screening or each 
in-house admission to the clinical research unit
18. Regular alcohol consumption within 6 months prior to screening and 5 days prior to 
admission defined as: 

An average weekly intake of > 14 units for males.  One unit is equivalent to 8 g 
of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) 
measure of 80 proof distilled spirits. 
19. Positive urinary cotinine test indicative of smoking history at screening or each in-
house admission to the clinical research unit or regular use of tobacco- or nicotine-
containing products (e.g. nicotine patches or vaporizing devices) within 6 months 
prior to screening.
20. Sensitivity to any of the study interventions, or components thereof, or drug or other 
allergy that, in the opinion of the investigator or medical monitor, contraindicates 
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5.3.
Lifestyle Considerations
5.3.1.
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
before the start of study intervention until after the final dose.

In Parts A and B, participants will fast at least 10 hours prior to dose and no food is 
allowed until 4 hours post-dosing. Meal times should be approximately uniform 
across all treatment periods. See the study reference manual (SRM) for additional 
details.

Water is allowed as desired except one hour before and after dosing.

In Part B, a subset of participants will undergo biliary metabolism testing using the 
Enterotest. The string device will be swallowed approximately 2 hours post-dose and 
removed at approximately 7 hours post-dose. At approximately 6 hours post-dose 
(i.e. ~1 hour prior to string withdrawal), a food cue will be used to stimulate gall 
bladder emptying and to encourage the release of bile onto the string:

Participants will be provided with visual images of food and asked to 
imagine eating the food for approximately 60 seconds.

Participants will then sniff a piece of orange peel/zest for 
approximately 30 seconds.

Participants will consume a high-fat food morsel (e.g. sausage 
sandwich) in order to stimulate gallbladder contraction
Additional details on this procedure are available in the SRM

In Part C, participants will be fed a standard FDA high fat/high calorie meal after at 
least 8 hours of fasting and completion of pre-dose assessments (see Table 1 for a 
description of the standard FDA high fat/high calorie meal.). The meal will be 
provided approximately 30 minutes prior to administration of study intervention.  
Study participants must consume the entire meal in 30 minutes or less. Non-
compliance will be recorded as well as the amount of the meal not eaten.   

The high fat/high calorie meal provided in the Fed arm of Part C should derive 
approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, 
respectively.  The caloric breakdown of the test meal will be outlined in the study 
report.  Substitutions in this test meal can be made as long as the meal provides a 
similar amount of calories from protein, carbohydrate, and fat and has comparable 
meal volume and viscosity.


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Table 1
Standard FDA High Fat, High Calorie Diet
Food
Quantity
Carbohydrate 
(g)
Protein 
(g)
Fat (g)
Calories
2 eggs fried in 
butter
2 eggs / 1 tsp 
butter
1.2
12.6
10 + 
7.6
213
Bacon
2 strips
0
8
10
121
Hash brown 
potatoes
4 oz
20
3
2
125
Whole milk
8 oz
12
8
8
145
Toast
2 slices
30
5
2
180
Pats of butter
2 tsp
0
0
15.2
136
Total
58.2
36.6
53.8
920
5.3.2.
Caffeine, Alcohol, and Tobacco

During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 24 
hours before the start of dosing until after collection of the final PK and/or PD
sample.

During each dosing session, participants will abstain from alcohol for 24 hours 
before the start of dosing until after collection of the final PK and/or PD sample. 

Participants will refrain from smoking or using tobacco or nicotine-containing 
products from at least 6 months prior to the Screening Visit through the last blood 
sample collected.
5.3.3.
Activity

Participants will abstain from strenuous exercise for 72 hours before each admission 
to the unit and throughout their stay in the unit. Participants may participate in light 
recreational activities during studies (e.g., watching television, reading). Participants 
will also abstain from strenuous exercise for 72 hours before their follow-up visit.
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse events 
(SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened only if the reason for screen failure is an ECG or lab value that, in the 
opinion of the investigator and/or Medical Monitor, is spurious or needs to be 
reconfirmed. Rescreened participants should be assigned a new participant number.


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Subjects who screen in one Part will not need to be rescreened for another Part, as long as 
they are within the 30 day screening window. A new subject number and rescreening will 
only be needed if they are outside the screening window.
6.
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
6.1.
Study Intervention(s) Administered
ARM Name
Experimental
Control
Intervention 
Name
GSK3439171A
Placebo
Type 
Drug
Drug
Dose 
Formulation
Oral solution (doses 0.5 mg up to 4.5
mg) 
capsule (doses 5 mg and upwards)
Oral solution to match experimental
(doses 0.5 mg up to 4.5 mg)
capsule (doses 5 mg and upwards)
Unit Dose 
Strength(s)
TBD
N/A
Dosage Level(s)
0.5 mg to not greater than 3000 mg 
(based on GRA limits) once or twice 
daily
Dosage and frequency to match 
experimental
Route of 
Administration
oral
oral
IMP and NIMP
IMP
NIMP
Sourcing
Provided centrally by the Sponsor 
Provided centrally by the Sponsor 
Packaging and 
Labeling
Study Intervention for solutions, will be 
provided in amber glass bottles with a 
child resistant cap. Each amber glass 
bottle will be labeled as required per 
country requirement.
Study Intervention for capsules, will be 
provided in HDPE bottles with a child 
resistant cap. Each HDPE bottle will be 
labeled as required per country 
requirement.
Study Intervention for solutions, will 
be provided in amber glass bottles 
with a child resistant cap. Each 
amber glass bottle will be labeled as 
required per country requirement.
Study Intervention for capsules, will 
be provided in HDPE bottles with a 
child resistant cap. Each HDPE 
bottle will be labeled as required per 
country requirement.


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6.2.
Preparation/Handling/Storage/Accountability
Details on storage, handling, and allowable excursions for GSK3439171A investigational 
product (IP), placebo, and solutions are provided in the Technical Agreement.
1.
A description of the detailed methods and materials required for preparation of 
GSK3439171A solution or capsule and placebo are provided in the Technical 
Agreement.
2.
The solution and capsules will be extemporaneously prepared at the clinical site as 
per instructions in the Technical Agreement that will be reviewed and approved by 
GSK prior to use.
3.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.
4.
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff.
5.
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).
6.
Further guidance and information for the final disposition of unused study 
intervention are provided in the Technical Agreement.

Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, Medical Monitor and/or 
GSK study contact.

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.
Precaution will be taken to avoid direct contact with the study intervention.  A MSDS
describing occupational hazards and recommended handling precautions will be provided 
to the investigator. In the case of unintentional occupational exposure notify the monitor, 
Medical Monitor and/or GSK study contact.


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6.3.
Measures to Minimize Bias: Randomization and Blinding
6.3.1.
Randomization
Study using 
Pre-Coded 
Randomization 
provided to site
Before treatment begins at the beginning of each part of the study, participants will be 
assigned a unique number (randomization number) in ascending numerical order at the
study site. The randomization number encodes the participant’s assignment to the 
respective arms of the study, according to the randomization schedule generated prior to 
the study by the Clinical Statistics Department at GSK. Each participant will be dispensed 
blinded study intervention, labeled with his/her unique randomization number throughout 
the study.
In Part A, approximately 9 participants in each cohort will be randomized to one of 3 
treatment sequences (AAP, APA & PAA, where A represents an active dose of 
GSK3439171 and P represents placebo).  Within each period, allocation of active (A) to 
placebo (P) treatment will be 2:1.   Within a cohort, an increasing dose of GSK3439171A
will be administered in each period as illustrated in the table below. Planned doses are 
provided in Section 6.6.   At each dose level, sentinel dosing will be employed, such that 
one subject is dosed with placebo and another with active dose of GSK3439171A and 
followed for 48 hr prior to the rest of the subjects receiving their randomized treatment.
Cohort
Sequence
Period 1
Period 2
Period 3
Cohort 1
AAP
APA
PAA
D1
D1
Placebo
D2
Placebo
D2
Placebo
D3
D3
Cohort 2
AAP
APA
PAA
D4
D4
Placebo
D5
Placebo
D5
Placebo
D6
D6
Cohort 3
AAP
APA
PAA
D7
D7
Placebo
D8
Placebo
D8
Placebo
D9
D9
In each cohort of Part B, approximately 12 participants will be randomized to receive 
either GSK3439171A or placebo in a parallel design using a 3:1 allocation ratio. 
Participants will receive a single dose followed by a 72 hr assessment period and then 
will receive daily repeat doses until the end of the study.


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Dose 
Cohort
Regimen
B1
R1 mg GSK3439171A or placebo QD or BID
B21
R2 mg GSK3439171A or placebo QD or BID 
B31
R3 mg GSK3439171A or placebo QD or BID 
1.
Dose levels for Cohorts will be determined based on real-time analysis of the safety, 
tolerability, PK, and preliminary PD data from Part A and therefore may be adjusted from 
predicted dose levels listed.
QD – Once daily
BID- Twice daily
Regimen
Period 1
Period 2
X
GSK3439171A1 administered in the fasted 
state
GSK3439171A1 administered after a high 
fat meal
Y
GSK3439171A1 administered after a high fat 
meal
GSK3439171A1 administered in the fasted 
state
1
Dose to be determined based on data from Part A of the study
In Part C, approximately 12 participants will be randomized 1:1 to receive 
GSK3439171A in one of two treatment sequences (Fed then Fasted or Fasted then Fed).
Participants who do not complete the study may be replaced at the discretion of the 
investigator in consultation with the sponsor.
6.3.2.
Blinding
Blind Break 
(Envelopes)
A sealed envelope that contains the study intervention assignment for each 
participant will be provided to the investigator. The sealed envelope will be 
retained by the investigator (or representative) in a secured area.
In case of an emergency, the investigator has the sole responsibility for 
determining if unblinding of a participant’s treatment assignment is warranted.
Participant safety must always be the first consideration in making such a 
determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact GSK prior to unblinding a 
participant’s treatment assignment unless this could delay emergency 
treatment of the participant. If a participant’s treatment assignment is unblinded 
GSK must be notified within 24 hours after breaking the blind.  The date and 
reason that the blind was broken must be recorded in the source 
documentation and electronic case report form (eCRF), as applicable.
Once the study is complete, all envelopes (sealed and opened) must be 
inventoried and returned to GSK.


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A participant may continue in the study if that participant’s intervention assignment is 
unblinded.  
Participants will be randomized to receive study intervention. Investigators and all site 
staff with the exception of the pharmacy staff will remain blinded to each participant’s 
assigned study intervention throughout the course of the study. In order to maintain this 
blind, unblinded site pharmacy staff will be responsible for the dispensation of all study 
intervention and will endeavour to ensure that there are no differences in time taken to 
dispense following randomization. The site staff will instruct the participant to avoid 
discussing the taste, dosing frequency, or packaging of the study intervention with the 
investigator.
Unblinded monitors and, in the event of a Quality Assurance audit, the auditor(s), will be 
allowed access to un-blinded study intervention records at the site to verify that
randomization/dispensing has been done accurately.
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 eCRF.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
intervention 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 intervention assignment, may be sent to investigators 
in accordance with local regulations and/or GSK policy.
Members of the GSK clinical study team will be unblinded for dose-escalation data 
reviews. This team may include but is not limited to the study statistician, programmers, 
physician project leader, Muscle Metabolism Discovery Performance Group leader, 
Clinical Investigation Lead, Operations Science Lead, Data Quality Lead, 
pharmacokineticist, DMPK analyst, safety review team, and other decision makers.  At 
the time of the data reviews, access to the randomization will be restricted to 
randomization numbers that have been assigned to participants in the cohort(s) under 
review.
6.4.
Study Intervention Compliance

When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff. 

When participants are dosed at the site, they will receive study intervention directly 
from the investigator or designee, under medical supervision.  The date and time of 
each dose administered in the clinic will be recorded in the source documents.  The 
dose of study intervention and study participant identification will be confirmed at 
the time of dosing by a member of the study site staff other than the person 
administering the study intervention.  Study site personnel will examine each 
participant’s mouth to ensure that the study intervention was ingested.


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6.5.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
Participants must abstain from taking prescription or nonprescription drugs, including 
vitamins and dietary or herbal supplements (including St. John’s Wort) within 10 days (or 
14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) 
before the start of study intervention until completion of the follow-up visit, unless, in the 
opinion of the investigator and sponsor, the medication will not interfere with the study. 
Due to potential effects on GSK3439171A’s related pathways, neither aspirin nor 
NSAIDS of any kind are permitted for use from 10 days prior to the start of the study 
through the follow-up visit. Acetaminophen or another medication selected by the 
investigator and the Medical monitor may be administered as prescribed (acetaminophen 
not to exceed 4,000 mg/24 hr per current guidelines) by attending study staff if simple 
analgesia is required during the study. Local anaesthesia will be used for muscle biopsy
procedures. Other concomitant medication may be considered on a case-by-case basis by 
the investigator in consultation with the Medical Monitor.
6.6.
Dose Modification
This protocol allows some alteration from the currently outlined dosing schedule, number 
of participants, and number of cohorts needed based on the emerging safety, PK, and PD 
data, but the maximum daily dose and/or (predicted) maximum/cumulative exposure will 
not exceed 3000 mg (based on GRA limit), 57.8 µg·h/ml  for single dose AUC exposure 
limit in Part A (based on  liver effects in dog at 600 mg/kg male dog), or 11.0 µg·h/ml for 
repeat dose AUC exposure limit in Part B (based on mean NOAEL exposure for liver
effects in 20 mg/kg female 6-week dog study) respectively.  The AUC stopping exposure 
limit of 11 µg.hr/mL s for the repeat dose phase were set by the rat adrenal toxicity is 
below (0.24 times) the lowest effect exposure for rat adrenal toxicity 
Information regarding dose escalation review processes is detailed in the Dose Escalation 
Plan. Briefly, the GSK medical monitor, in joint discussion with the participating 
investigator(s) (to remain blinded during the study), will be responsible for making dose 
escalation decisions. Prior to the dose escalation decision, the GSK clinical team, which 
includes but is not limited to, the medical monitor, clinical scientists, safety physician
and/or representative, and clinical pharmacokineticist, will review critical safety data 
defined in Section 8.2, Section 8.3, and in the Dose Escalation Plan. This includes review 
of all adverse events including non-dose-limiting toxicities, laboratory assessments and 


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other defined safety evaluations, as well as PK and PD data when appropriate. Quality 
control of critical safety data will also be described in the Dose Escalation Plan, which 
includes ongoing study monitoring visits, Sponsor review of the clinical database, and 
confirmation by site investigators and/or delegates that the data are accurate and 
complete.
The dose-escalation decision and rationale for each cohort will be discussed with the 
investigator(s) during teleconference(s) and documented in writing, with copies 
maintained at each study site and in the study master file.
The decision to proceed to the next higher dose level will be made by the clinical study 
team in consultation with the investigator(s) based on the evaluation of data from at least 
4 participants (Part A) or 6 participants (Part B) who received active treatment at the 
preceding lower dose.  Such decisions will be based on the safety and tolerability, as well 
as PK data observed at the lower dose level and the predicted exposure at the next dose 
level.  Some doses may be deleted and intermediate and/or higher/lower doses may be 
added as appropriate during the study as the results of safety/tolerability, PK, and PD 
assessments become available.
The details on the dose escalation committee can be found in Section 9.5.1
6.6.1.
Dose Escalation in Part A
In Part A, the decision to proceed to the next dose level of GSK3439171A will be made 
based on evaluation of the safety, tolerability and preliminary PK data as outlined in 
Section 4.1.
The primary preclinical exposure parameter that will guide dose escalation in Part A is 
based on single dose exposure limit in the male dog at 600 mg/kg/day (AUC(0-24h)) at 
steady state – 57.8 µg.h/mL described in Section 4.3. Assuming time-invariance, the Day 
1 AUC(0-inf) observed in each of the human participants in this study at each single dose 
will be compared to the above value in order to determine the magnitude of dose 
escalation. 
The following algorithm will be used for dose escalation in Part A:
1.
For each dose group, the human mean AUC (0-inf) on Day 1 will be calculated as 
percentage of the male dog at 600 mg/kg/day of AUC(0-24) steady-state (57.8
µg·h/mL). Example dose escalation based on single dose exposure limit exposures is 
provided below.  Some of the above doses may be deleted and intermediate and/or 
higher doses may be added as appropriate during the study as the results of 
safety/tolerability and PK assessments become available. The next dose level can 
then be determined as described in the example table below:


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Table 2
Mean simulated exposures at SD of GSK3439171A compared to 
single dose exposure limit set by male dog at 600 mg/kg/day 
exposures levels
Dose 
(mg)
Mean 
Simulated 
AUC(0-inf)
(μg*h/mL)
Fold cover 
from 600 mg/kg 
male dog 
AUC(0-24)1
Mean 
Simulated 
Cmax
(μg/mL)
Fold cover 
from 600
mg/kg male 
dog Cmax1
Simulated % H-
PGDS inhibition 
maintained for 24 
hours2
5
0.10
578
0.01
1000
10
20
0.39
158
0.05
200
20
50
0.99
58
0.12
83
40
100
1.97
29
0.24
42
60
300
5.91
10
0.72
14
80
500a
9.85
6
1.20
8
85
1 Compared to systemic exposure at 600 mg/kg/day in male dog steady-state AUC(0-24) and Cmax 
values (57.8 μg*h/mL and 10 μg/mL, respectively)
2 Represents the simulated mean GSK343171A concentrations maintained at different H-PGDS 
inhibition levels over 24 hours
Fewer or more dose levels may be explored based on emerging data from Part A.
2.
The highest dose in Part A will not exceed 3000 mg based on GRA limits.
3.
The highest predicted mean Day 1 AUC (0-inf) in Part A will not exceed 57.8
μg·h/ml.
Dosing in Part C (food effect) can be initiated after the exposures achieved with at least 
two dose levels administered in a fasted state are calculated. The dose levels chosen for 
Part C will ensure an adequate safety margin to allow for an increased exposure of 
GSK3439171A in the presence of food.
6.6.2.
Dose escalation in Part B
Part B can be initiated after the safety and PK data of at least four dose levels from Part A 
are evaluated. The decision to initiate Part B will be made by the clinical study team in 
conjunction with the investigator. 
Dose selection in Part B will be based on the safety/tolerability and PK data from Part A. 
The following rules will guide dose selection in Part B:
1. The starting daily dose in Part B will be selected such that its predicted exposure 
(mean AUC(0-24) and Cmax) on the last day of dosing is no higher than the Day 1 
exposure of a dose that has been found to be well tolerated and had no safety signals 
of concern in Part A. As the highest exposure with repeat dosing is expected on the 
last day of dosing (as a result of accumulation), this approach would select a daily 
dose which provides blood concentrations that, at any time during the period of 
dosing, are no higher than the ones already found to be well tolerated and had no 
safety signals of concern in Part A. The expected exposure on the last day of dosing 


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will be predicted based on the PK parameters for GSK3439171A established in Part 
A.
2. Subsequent doses in Part B may be selected using the criteria described above for the 
starting dose. Alternatively, a dose may also be selected even if it does not meet these 
criteria provided it is no more than 4-fold higher than a previous dose that has been 
found to be well tolerated and had no safety signals of concern upon repeat dosing in 
Part B.
3. The highest daily dose in Part B will not exceed the highest single dose that has been 
found to be well tolerated and had no safety signals of concern in Part A.
4. The highest predicted mean AUC(0-24) on the last day of dosing in Part B will not 
exceed 11.0 μg·h /ml (based on mean NOAEL exposure for liver effects in 20 mg/kg 
female 6-week dog study and is below (0.24 times) the lowest effect exposure for rat 
adrenal toxicity).
6.7.
Intervention after the End of the Study
Not applicable.
7.
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will
remain in the study and followed appropriately until resolution of the event or return of 
labs to acceptable levels. See the SOA for data to be collected at the time of 
discontinuation of study intervention.
7.1.1.
Liver Chemistry Stopping Criteria
Study intervention will be discontinued for a participant if liver chemistry stopping 
criteria are met:


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Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5*
Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse 
event; ULN = upper limit of normal.
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6
Liver chemistry stopping and increased monitoring criteria have been designed to assure 
participant safety and evaluate liver event etiology.
Discontinuation of study intervention 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 intervention discontinuation is in 
the best interest of the participant. 
7.1.1.1.
Study Intervention Restart or Rechallenge after liver stopping criteria 
met
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
7.1.2.
QTc Stopping Criteria

The QTcF 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.


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
For example, if a participant is eligible for the protocol based on QTcF, then 
QTcF must be used for discontinuation of this individual participant as well.

The QTcF formula must be used for a participant for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified 
ECGs are an exception.  

The QTc should be based on the average of triplicate ECG readings obtained over a 
brief (e.g., 5-10 minute) recording period.  
A participant that meets either bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from study intervention.  

QTcF >500 msec,

Change from Baseline: QTc >60 msec
See the SoA for data to be collected at the time of intervention discontinuation and 
follow-up and for any further evaluations that need to be completed.
7.1.3.
Individual Stopping Criteria

Any participant who experiences an SAE will be withdrawn from the study.  

Any participant who experiences an AE of moderate or severe intensity (as 
defined in CTCAE v5.0) that is considered attributable to dosing with 
GSK3439171A will be withdrawn from the study.  
7.1.4.
Dose Adjustment/Discontinuation Pharmacokinetic Criteria
In part A, any participant with observed AUC(0-inf) or Cmax values greater than the 
mean steady-state AUC(0-24) and Cmax values in male dog (57.8 µg·h/mL and 10
ug/mL, respectively) will be discontinued from study intervention.
In Part B, any participant with observed AUC(0-24) value greater than  the mean steady-
state AUC(0-24) observed in female dogs (11.0µg·h/mL) will be discontinued from study 
intervention.
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.
7.1.5.
Temporary Discontinuation
Temporary discontinuation of the study intervention is not allowed. 
7.1.6.
Study Stopping Criteria
7.1.6.1.
Safety Study Stopping Criteria
Dosing at the currently tested dose as well as escalation to higher doses will be stopped if 
either of the following occurs in the current dose group:


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
An SAE that is considered to be related to GSK3439171A in one or more 
participants on active treatment.

Similar AEs of moderate or severe intensity (as defined in CTCAE v5.0) that are 
considered to be related to GSK3439171A in two or more participants on active 
treatment.
Dosing at the current (or higher) dose may resume only if a safety review conducted by 
GSK in conjunction with the investigator determines that the observed SAEs or AEs are 
not related to GSK3439171 and such resumption is approved by the IRB/IEC.
7.1.6.2.
PK Study Stopping Criteria
The single dose PK stopping criteria are based on AUC(0-24) from the 600 mg/kg/day 
male dog due to liver findings. It is planned that for Part A, the predicted human mean 
GSK3439171A AUC(0-inf) or Cmax values will not exceed the mean GSK3439171A 
steady-state AUC(0-24) and Cmax values in male dog (57.8 ug·h/mL and 10 ug/mL, 
respectively). 
The repeat dose PK stopping criteria are based on AUC(0-24) from the 20 mg/kg/day 
female dog NOAEL due to liver findings. It is planned that for Part B, the predicted 
human mean GSK3439171A  AUC(0-24), value will not exceed the mean 
GSK3439171A steady-state AUC(0-24) values in dog at 20 mg/kg/day of 11.0 ug·h/mL.
7.2.
Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, compliance or administrative reasons. This is expected to be 
uncommon.

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 
intervention and from the study at that time.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.
7.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 


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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.
8.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. 

Protocol waivers or exemptions are not allowed 

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of ICF may be utilized for screening or 
Baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA.

The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 500 
mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
8.1.
Efficacy Assessments
Not applicable.


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8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
8.2.1.
Physical Examinations

A full 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 (height is only measured 
at screening).

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.
8.2.2.
Vital Signs

Oral temperature, pulse rate, respiratory rate, and blood pressure will be 
assessed.

Blood pressure and pulse measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device 
is not available.

Blood pressure and pulse measurements should be preceded by at least 5 
minutes of rest in a supine position for the participant in a quiet setting without 
distractions (e.g., television, cell phones).

Vital signs will be measured in a supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, and pulse and 
respiratory rate. Three readings of blood pressure and pulse will be recorded at 
intervals 1 to 2 minutes apart as specified in the SoA. The first reading should be 
rejected. The second and third readings should be averaged to give the 
measurement to be recorded in the case report form (CRF).
8.2.3.
Electrocardiograms

Triplicate 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) 
using an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, QT, and QTc intervals. Refer to Section 7 for QTc withdrawal criteria 
and additional QTc readings that may be necessary.

ECGs will be recorded whilst the participant is in a supine position, having 
rested in this position for at least 15 minutes.  Participants are permitted to make 
intermittent movement, if necessary, in preparation for procedures (e.g., to sit up 
to take study medication).  When ECGs are to be taken in triplicate, an interval 
of at least 5 minutes will be used between measures taken at screening or pre-
dose.  An interval of at least 1 minute is acceptable for any post-dose triplicate 
ECGs, when needed.


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
Various values from the ECG read-out will be entered into the eCRF (the 
average for some will be used for measures made in triplicate).

Any result falling outside the expected normal ranges as defined by the site will 
be repeated at the discretion of the investigator.  If any results falling outside of 
these expected normal ranges at the site are deemed not clinically significant by 
the investigator or an appropriately qualified designee, then this should be 
clearly stated on the hard copies of the ECG and signed and dated by the 
investigator. 

If the ECG trace indicates an abnormality that is measured by the equipment but 
is deemed normal by the investigator, then this should be clearly stated on the 
ECG tracing as normal and signed and dated by the investigator or appropriately 
qualified designee.  If the ECG tracing indicates an abnormality that is present 
but deemed as not clinically significant by the investigator or appropriately 
qualified designee, then this should be clearly stated on the ECG tracing as 
“NCS” and signed and dated by the investigator or appropriately qualified 
designee and stored with the source records for that participant.  If any results 
falling outside of the normal ranges are deemed clinically significant by the 
investigator or appropriately qualified designee then these should be recorded in 
the eCRF as an AE. 

ECGs will be stored electronically for manual measurement of intervals, if 
necessary. 

Whenever a 12-lead ECG is scheduled at the same nominal time as other study 
procedures (including vital signs, blood draws, or meals), the ECG should be 
obtained first followed by other procedures with timing planned so that the 
blood draw occurs at the exact nominal time.
8.2.4.
Telemetry
Telemetry will be performed during the study as outlined in the SoA. Additional details 
are available in the SRM.
8.2.5.
Holter Monitoring
Cardiac monitoring (24 hour) will be performed using continuous Holter monitoring 
during the study as shown in the SoA. 
Start date and time and stop date and time will be captured in the study database.  
Analysis of the Holter monitoring will consider the following:

Heart rate (HR) (brady and tachycardia).

Normal and aberrant beats.

Number of supraventricular contractions, premature atrial contractions, 
supraventricular tachycardias, premature ventricular contractions, couplets, 
triplets and ventricular tachycardias.

Atrio-ventricular conduction defects.


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
Atrial fibrillation and flutter.
8.2.6.
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 or within 14 days after the last dose of study 
intervention should be repeated until the values return to normal or Baseline or 
are no longer considered significantly abnormal by the investigator or medical 
monitor. Any lab or clinical assessment that is judged to be spurious by the 
Principal Investigator (PI) may be repeated.

If such values do not return to normal/Baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the SoA.

Samples collected for hematology, clinical chemistry, urinalysis, or hormone 
assays will be analysed at the unit’s local laboratory under the relevant Standard 
Operating Procedures (SOPs), GUIs and user manuals.  See user local laboratory 
manuals for details on methodology, processing, handling of specimens, and 
analyses.

Hematology, clinical chemistry, urinalysis and additional parameters to be tested 
are listed in Appendix 2.
8.2.7.
Hormone Monitoring
Based on preclinical findings in the rat Good Laboratory Practice (GLP) toxicology 
studies outlined in the IB, hormone monitoring will take place in Part B of the study only. 
Blood samples will be obtained as per the SoA and SRM and analysed for: 

Adrenal – ACTH, cortisol

Pituitary – LH, FSH, TSH, T3, and free T4 

Total Testosterone and DHT
All laboratory tests with values that are considered clinically significantly abnormal
during participation in the study or until the final follow up visit should be repeated until
the values return to normal or Baseline or are no longer considered significantly 
abnormal by the investigator or medical monitor. If such values do not return to normal 


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within a period judged reasonable by the investigator, the etiology should be identified 
and the sponsor notified.
8.2.8.
Suicidal Ideation and Behaviour Risk Monitoring
Not applicable.
8.3.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study intervention (see Section 7). 
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the start of intervention until the follow-up visit
at the time points specified in the SoA (Section 1.3). However, any SAEs 
assessed as related to study participation (e.g., study intervention, protocol-
mandated procedures, invasive tests, or change in existing therapy) or related to 
a GSK product will be recorded from the time a participant consents to 
participate in the study.

All AEs will be collected from the start of intervention until the follow-up visit
at the time points specified in the SoA (Section 1.3).

Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the CRF not the AE section.

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs after the conclusion 
of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the 
study, and he/she considers the event to be reasonably related to the study 
intervention or study participation, the investigator must promptly notify the 
sponsor.
8.3.2.
Method of Detecting AEs and SAEs

The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 3.


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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. 
8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is given in 
Appendix 3.
8.3.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information (e.g., summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
8.3.5.
Pregnancy

Details of all pregnancies in female partners of male participants will be collected 
after the start of study intervention and until follow-up.

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.
8.4.
Treatment of Overdose
For this study, any dose of GSK3439171A greater than 3000 mg within a 24-hour time 
period (1 hour) will be considered an overdose.


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Sponsor does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
GSK3439171A can no longer be detected systemically (at least 5 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.
8.5.
Pharmacokinetics
8.5.1.
Blood Sample Collection

Whole blood samples of approximately 2 mL will be collected for measurement 
of plasma concentrations of GSK3439171A as specified in the SoA. The timing 
of PK samples may be altered and/or PK samples may be obtained at additional 
time points to ensure thorough PK monitoring. Instructions for the collection and 
handling of biological samples will be provided by the sponsor. The actual date 
and time (24-hour clock time) of each sample will be recorded.

In Part B, at each sampling time point an additional 2 mL blood will be collected 
for metabolite profiling. Results will be reported under a separate PTS-Global 
Spectroscopy, GSK protocol.

Samples will be used to evaluate the PK of GSK3439171A. Samples collected for 
analyses of study intervention plasma concentration may also be used to evaluate 
safety or efficacy aspects related to concerns arising during or after the study.

Genetic analyses will not be performed on these whole blood samples [unless 
consent for this was included in the informed consent]. Participant confidentiality 
will be maintained. 
Details of blood sample processing, storage and shipping procedures are provided in the 
SRM or equivalent.
8.5.2.
Urine Sample Collection
In Part B only, urine samples will be collected as outlined in the SoA and urine PK 
calculations of GSK3439171A (including renal clearance), will be performed, as 
appropriate. These samples may also be analysed for additional metabolites of 
GSK3439171A as appropriate. The timing of urine samples may be altered and/or 
samples may be obtained at additional time points to ensure thorough PK monitoring.


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Prior to dosing on Day 1, urine samples will be collected for predose sampling as 
outlined in the SoA. Post-dose urine collection time points listed in the SoA table will 
begin immediately following dose administration.  The time will be recorded for each 
urine sample collected, and the total urine volume for each subject will be recorded over 
the collection time period. Subaliquots of these samples may be assessed for 
pharmacodynamics and results will be reported under a separate protocol. Details of urine 
sample processing, storage and shipping procedures are provided in the SRM or 
equivalent.
8.5.3.
Bile Sample Collection
The Entero-Test will be administered to the second or third dose cohort in Part B
(depending on PK results in Part A) as outlined in the SoA.  The Entero-Test is a gelatin 
capsule containing a weighted nylon line.  The Entero-Test will be swallowed 
approximately 2 hours after dosing by the fasted subject with one end taped to the face.  
Once the capsule has dissolved in the stomach, the weighted string will pass into the 
duodenum.  The weight will detach from the string and passed into stool.  During the 
post-dose period, bile flow will be promoted while the string is in the duodenum with a 
food stimulus at approximately 6 hours following the morning dose.  The string will be 
withdrawn from the oral cavity approximately 1 hour later.
The duodenal bile adsorbed to string will be eluted and analysed for drug-related peaks 
and the results reported under a separate PTS Global Spectroscopy, GSK protocol.  The 
Entero-Test bile sample collected from placebo-dosed subjects will be considered as the 
control.
Additional details of the bile sample collection procedure, processing, storage and 
shipping procedures are provided in the SRM or equivalent.
8.5.4.
Sample Analysis
Plasma, urine, and muscle (as appropriate) analysis will be performed under the control 
of PTS Bioanalysis, US, GlaxoSmithKline, the details of which will be included in the 
SRM.  Concentrations of GSK3439171A will be determined in plasma, urine, and muscle
samples using the currently approved bioanalytical methodology.  Raw data will be 
archived at the bioanalytical site (detailed in the SRM) or equivalent.
Plasma, bile and urine samples may be analyzed for other compound-related metabolites 
and the results reported under a separate PTS Global Spectroscopy, GlaxoSmithKline 
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.
8.6.
Pharmacodynamics
Under guidance of the SRM or equivalent, samples will be shipped to GlaxoSmithKline
or appropriate third-party vendors for analysis. 


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8.6.1.
Urine Pharmacodynamics Assessment
Subaliquots of the urine samples collected in Parts A and B will be designated for 
measurement of prostaglandin and/or inflammatory PD markers, including but not 
limited to tPGDM and tPGEM, at the time points outlined in the SoAs in Section 1. See 
SRM (or equivalent) for details on sample collection, processing, and storage.
8.6.2.
Muscle Biopsy
Muscle biopsies will be obtained in order to examine PK/PD of GSK3439171A as well as 
H-PGDS inhibition in a tissue of potential relevance. Information gained from these 
biopsies will also help in determining dose selection for future studies. Under local 
anesthesia, skeletal muscle biopsies will be obtained from the vastus lateralis at the time 
points indicated in Part B of the SoA. See SRM or equivalent for details on the 
procedure, sample collection, and storage.
8.7.
Genetics
A 6 mL blood sample for deoxyribonucleic acid (DNA) isolation will be collected from 
participants who have consented to participate in the genetics analysis component of the 
study. Participation is optional. Participants who do not wish to participate in the genetic 
research may still participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in the SRM or 
equivalent.
8.8.
Biomarkers
Collection of samples for other biomarker research is also part of this study. Refer to the 
SoA and SRM (or equivalent) for details on timings.
These samples may be used for research to develop methods, assays, prognostics and/or 
companion diagnostics related to prostaglandin and/or inflammatory-mediated diseases.
Samples may be stored for a maximum of 15 years (or according to local regulations) 
following the last participant’s last visit for the study at a facility selected by the sponsor 
to enable further analysis of biomarker responses to GSK3439171A. 
8.9.
Health Economics or Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.


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9.
STATISTICAL CONSIDERATIONS
9.1.
Statistical Hypotheses
The primary objectives of this study are to evaluate safety and tolerability of single and 
repeat doses of GSK3439171A and to characterize the PK of GSK3439171A. No formal 
statistical hypotheses will be tested.  Descriptive statistics will be used to assess safety 
and tolerability objectives.  Treatment comparisons with placebo will be based on review 
of descriptive statistics and individual participant data.  An estimation approach will be 
used to address the PK objectives where point estimates and corresponding 90% 
confidence intervals (CIs) will be constructed as appropriate for the assessment of dose-
proportionality, steady-state, time invariance and food effect.
Estimation of effects of GSK3439171A on PD/biomarkers is an exploratory objective.  
No formal statistical hypotheses will be tested.  An estimation approach will be used to 
address these objectives, where point estimates and corresponding CIs will be constructed 
as appropriate.
Unblinded, in-stream data reviews will be performed for Parts A and B in order to inform 
dose-escalation decisions. Final results for each study part (A, B, C) may be reported as 
each part completes rather than after completion of all study parts.
9.2.
Sample Size Determination
The sample size for the study is not based on statistical considerations.  The sample size 
for Part A (single dose, dose-escalation) has been selected to provide sufficient safety, 
tolerability and PK data to support escalation to the next single dose level in Part A and 
to support selection of dose levels for Part B while minimizing the number of participants 
exposed to study drug.  Similarly, the sample size for Part B (repeat dose, dose-
escalation) has been selected to provide sufficient safety, tolerability and PK data to 
support escalation to the next repeat dose level in Part B and to support dose selection for 
subsequent studies.
The sample size for Part C (food effect) was selected in the absence of estimates of 
variability for PK parameters as the minimum needed to adequately estimate food effect 
and may be re-estimated based on the observed PK variability from Part A.
Approximately 150 participants will be screened to achieve 75 randomly assigned to 
study intervention and 75 evaluable participants for an estimated total of 27 evaluable 
participants in Part A (6 active: 3 placebo per cohort), 36 evaluable participants in Part B 
(9 active:3 placebo per cohort), and 12 evaluable participants in Part C. 
9.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:


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Population
Description
Enrolled
All participants who sign the ICF
Randomized
All participants who were randomized
Evaluable
All randomized participants who take at least 1 dose of study 
intervention and undergo at least one set of assessments.
Safety
All participants who take at least 1 dose of study intervention. 
Participants will be analyzed according to the intervention they 
actually received.
PK
Participants in the Safety population for whom a PK sample was 
taken and analyzed for GSK3439171A and result reported
PD
Participants in the Safety population with Baseline and at least one 
post-Baseline PD measure.
9.4.
Statistical Analyses
Pharmacokinetic Analyses
PK analysis will be the responsibility of the Clinical Pharmacology Modeling and 
Simulation Department, CPMS, GlaxoSmithKline. Plasma GSK3439171A concentration-
time data will be analyzed by non-compartmental methods with WinNonlin 5.2 or higher.  
Calculations will be based on the actual sampling times recorded during the study.  
From the plasma concentration-time data, the following PK parameters will be 
determined, as data permit: 

Apparent Clearance (CL/F)

maximum observed blood concentration (Cmax), 

time to Cmax (tmax), 

area under the plasma concentration-time curve [AUC(0-t), AUC(0-inf) and 
AUC(0-τ)]

apparent terminal phase half-life (t1/2)

trough concentration (C).  
AUC(0-∞) or AUC(0-τ) and Cmax following single and repeat doses may be used for 
assessment of dose proportionality.  Trough concentration (C) samples collected on the 
specified days will be used to assess attainment of steady state and the steady state ratio 


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(Rss) will be calculated (Day 16 AUC(0-τ)/Day 1 AUC(0-inf)). To estimate the extent of 
accumulation after repeat dosing, the observed accumulation ratio (Ro: Day 13 or 17
AUC(0-)/Day 1 AUC(0-); and RCmax: Day 13 or 17 Cmax/Day 1 Cmax)  will be 
determined.
PK data will be presented in graphical and/or tabular form and will be summarized 
descriptively.
Statistical analyses of the PK parameter data will be the responsibility of Clinical 
Statistics, GlaxoSmithKline. Distributional assumptions underlying the statistical 
analyses will be assessed by visual inspection of residual plots. Normality will be 
examined by normal probability plots, while homogeneity of variance will be assessed by 
plotting the residuals against the predicted values for the model. If there are any 
important departures from the distributional assumptions, alternative models may be 
explored using appropriately transformed data. Full details on the statistical aspects will 
be described in the Reporting and Analysis Plan (RAP).
Dose Proportionality (Parts A and B: Single and Repeat Dose Study Phases)
Dose proportionality will be assessed following single doses of GSK3439171A (Part A) 
via analyses of AUC(0-t), AUC(0-inf), and Cmax. Dose proportionality following 
repeated dosing (Part B) will be assessed using AUC(0-τ) and Cmax.
A statistical analysis will be performed for each parameter separately using the power 
model with the log-transformed PK parameter as the dependent variable and log(dose) as 
a fixed effect. For Part A, the intercept and slope will be fit as random effects.  In 
addition, effects for cohort and cohort by log(dose) may be included in the model to 
examine differences in slopes across cohorts. Estimates of the slopes will be reported 
along with corresponding 90% CIs (slope≈1 implies dose proportionality).
Food Effect (Part C: Single Dose Study)
The effect of food on the PK of GSK3439171A (AUC(0-inf), Cmax, and t1/2) will be 
examined. An analysis of variance model will be fitted separately to each of the log-
transformed PK parameters with period and treatment (fed or fasted) as fixed effects and 
participant as a random effect. Point estimates for the differences in means 
(GSK3439171A fed – GSK3439171A fasted) and corresponding 90% CIs will be 
constructed from the least squares means, using the residual variance. These will then be 
back-transformed to provide point estimates and corresponding 90% CIs for the ratio of 
geometric means fed:fasted.
Accumulation (Part B: Repeat Dose Study Phase)
The extent of accumulation of GSK3439171A will be based on AUC (Ro) and Cmax 
(RCmax). 
Statistical analysis of log-transformed AUC(0-) and Cmax will be performed separately 
and by dose using an ANOVA model with a fixed, categorical effect for day and a 
random effect for participant. The accumulation ratios (Ro and RCmax) of 


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GSK3439171A will be evaluated for each dose by exponentiating the difference in least 
squares means (Day 13 or 17 – Day 1) and the associated 90% CI. 
Time Invariance
Assessment of the achievement of steady state will be based on the AUC (Rss).  The time 
invariance ratio will be calculated as the ratio of AUC(0-) on Day 13 or 17 over AUC(0-
inf) on Day 1. The time invariance ratio will be listed and summarized along with other 
PK parameters. 
Statistical analysis of the log-transformed AUCs will be performed separately for each 
dose using an ANOVA model with a fixed, categorical effect for day and a random effect 
for participant. The time invariance ratio of GSK3439171A will be evaluated for each 
dose by exponentiating the difference in least squares means (Day 17 – Day 1) and the 
associated 90% CI. The values of AUC used in the analysis will be AUC(0-inf) on Day 1 
and AUC(0-) on Day 13 or 17.
Achievement of Steady State (Part B: Repeat Dose Study Phase)
Steady-state will be assessed visually by plotting trough concentration levels, Cτ, 
collected pre-morning dose versus collection day by dose.  In addition, statistical analysis 
of trough concentration levels (e.g., Days 6,7,9, and 10 (7 day repeat dosing period) or 6-
7, 16-17 (14 day repeat dosing period) will be performed after log-transformation of the 
concentrations. A mixed effects ANOVA model will be fit with day (continuous variable) 
as a fixed effect and subject as a random effect for each dose level separately.  The 
coefficient for the slope of the day effect on the log-scale will be used to evaluate steady 
state for each dose.  The 90% confidence intervals for the slope will be calculated.


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9.4.1.
Safety Analyses
All safety analyses will be performed on the Safety Population. 
Endpoint
Statistical Analysis Methods
Primary
Descriptive statistics will be used to assess safety and tolerability objectives.  No 
formal statistical analyses of safety data are planned. Data will be summarized 
according to GSK Integrated Data Standards Library (IDSL) standards. In 
addition, individual participant data will be reviewed. Treatment comparisons with 
placebo will be based on review of descriptive statistics and individual participant 
data.
9.4.2.
Other Analyses
In Parts A and B, dose-response modelling of urinary tPGDM/tPGEM will be 
undertaken, data permitting. Details will be described in the reporting and analysis plan.
The population PK analysis and pharmacodynamic analyses may be presented separately 
from the main clinical study report (CSR). 
9.5.
Interim Analyses
There will be no formal statistical interim analysis.  However, preliminary safety, PK, 
and PD/biomarker data will be reviewed in-stream by the GSK study team members prior 
to each dose escalation.  Data for these reviews will be cumulative and can include 
individual participant data, summaries by treatment group and graphical displays.  This is 
a sponsor unblinded trial and GSK staff will be unblinded for these reviews (see Section 
6.3).
Preliminary results from available safety data may be reported prior to database freeze for 
the purposes of safety review by GSK, and where required by regulatory bodies.
Other selected preliminary data may be unblinded and reported prior to database freeze 
for internal decision making. 
In each case described above, the study will not be officially unblinded and access to the 
randomization will be restricted.
9.5.1.
Data Monitoring Committee (DMC)
Dose modifications, including dose escalations, will be reviewed by the dose escalation 
committee. This committee includes, but is not limited to, the medical monitor, principal 
investigator, clinical scientists, safety physician and/or representative, and clinical 
pharmacokineticist. Dose escalation decisions will be made as outlined in Section 4.1 and 
Section 6.6 and in the Dose Escalation Plan.


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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
10.1.2.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.


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10.1.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
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.
10.1.4.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.


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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.
10.1.5.
Dissemination of Clinical Study Data

Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the 
study subjects, as appropriate.

GSK will provide the investigator with the randomization codes for their site 
only after completion of the full statistical analysis.

The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK Policy.

GSK intends to make anonymized patient-level data from this trial available to 
external researchers for scientific analyses or to conduct further research that 
can help advance medical science or improve patient care. This helps ensure the 
data provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding

A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge.
10.1.6.
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. 


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
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, 
or on-site monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations).

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. 
10.1.7.
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 Source Document 
Agreement.


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10.1.8.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
10.1.9.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.


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10.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 3 will be performed by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

Pregnancy Testing 
Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria.
Table 3
Protocol-Required Safety Laboratory Assessments
Hematology
Platelet Count
RBC Indices:
Automated WBC Differential:
RBC Count
MCV
Neutrophils
WBC Count (absolute) 
MCH
Lymphocytes
Reticulocyte Count
MCHC
Monocytes
Hemoglobin
Prothrombin time (with and without INR)
Eosinophils
Hematocrit
Activated partial thromboplastin time
Basophils
Clinical Chemistry
BUN
Potassium
AST (SGOT)
Total and direct bilirubin
Creatinine
Chloride
ALT (SGPT)
Uric Acid
Glucose
Total CO2
GGT
Albumin
Sodium
Calcium
Alkaline phosphatase
Total Protein
Creatine Phosphokinase (Total)
Hormone Assessments
Luteinizing hormone 
(LH)
Total Testosterone
Adrenocorticotropic 
hormone (ACTH
cortisol
Free T4
Follicle stimulating 
hormone (FSH)
Dihydrotestosterone 
(DHT)
Thyroid stimulating 
hormone (TSH)
T3
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)


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Other screening tests
HIV
Hepatitis B (HBsAg)
Hepatitis C (Hep C antibody -- if second generation Hepatitis C antibody positive, a hepatitis C antibody 
Chiron RIBAimmunoblot assay (or other third generation immunoassay) should be reflexively performed on 
the same sample to confirm the result) 
Cotinine, Serum Alcohol, and drug screen (to include at minimum: amphetamines, barbiturates, cocaine, 
opiates, cannabinoids and benzodiazepines).
NOTES :
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver 
stopping or monitoring event are given in Section 7.1 and Appendix 7 All events of ALT 3 × upper 
limit of normal (ULN) and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and 
international normalized ratio (INR) >1.5, if INR measured, which may indicate severe liver injury 
(possible Hy’s Law), must be reported as an SAE (excluding studies of hepatic impairment or 
cirrhosis).
2
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC.
Local urine testing will be standard for the protocol unless serum testing is required by 
local regulation or IRB/IEC.
Laboratory/analyte 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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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.3.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study intervention, whether or not considered related to 
the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from Baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related 
to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 


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assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
10.3.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
o
Results in death
o
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
Baseline is not considered an AE.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 


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and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3.
Recording and Follow-Up of AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.


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
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 


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findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
10.3.4.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in Study Reference Manual.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the Study Reference Manual.


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10.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information
10.4.1.
Contraception Guidance:

CONTRACEPTIVESa ALLOWED FOR FEMALE PARTNERS OF PARTICIPANTS 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
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 intervention. 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.
c.
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive 
methods are limited to those which inhibit ovulation as the primary mode of action.
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)


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10.4.2.
Collection of Pregnancy Information:
Male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to male participants who receive GSK3439171A.

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. 


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10.5.
Appendix 5: Genetics
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility, severity and progression of disease. Variable response to study 
intervention may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion; mechanism of action of the drug; disease 
etiology; and/or molecular subtype of the disease being treated. Therefore, where 
local regulations and IRB/IEC allow, a blood sample will be collected for DNA 
analysis

DNA samples will be used for research related to GSK3439171A or prostaglandin or 
inflammation-mediated disease. They may also be used to develop tests/assays 
including diagnostic tests) related to GSK3439171A or study interventions of this 
drug class and prostaglandin or inflammation-mediated disease. Genetic research 
may consist of the analysis of one or more candidate genes or the analysis of genetic 
markers throughout the genome or analysis of the entire genome (as appropriate)

DNA samples will be analyzed if it is hypothesized that this may help further 
understand the clinical data. 

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to GSK3439171A or study interventions of this class. The 
results of genetic analyses may be reported in the clinical study report or in a 
separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained while research on GSK3439171A (or study 
interventions of this class) or prostaglandin or inflammation-mediated disease
continues but no longer than 15 years after the last subject last visit or other period as 
per local requirements.


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10.6.
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 intervention

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, 
aspartate transaminase [AST], alkaline 
phosphatase, bilirubin and INR) and perform 
liver event follow up assessments within 24 
hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilise or return to 
within Baseline

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN and INR 
≤1.5:

Repeat liver chemistries (include ALT, AST, 

Viral hepatitis serology3

Obtain international normalized ratio (INR) 
and recheck with each liver chemistry 
assessment until the transaminases values 
show downward trend

Obtain blood sample for pharmacokinetic 
(PK) analysis, obtained within 7 days 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 


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alkaline phosphatase, bilirubin and INR) and 
perform liver event follow up assessments 
within 24-72 hrs

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 intervention for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, which 
may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis); the threshold value stated will not apply to subjects receiving anticoagulants
3.
Includes: Hepatitis A immunoglobulin (gM) antibody; HBsAg and HBcAb; Hepatitis C RNA; Cytomegalovirus IgM 
antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or 
monospot testing) and Hepatitis E IgM antibody 
4.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator interventions.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study intervention 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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10.7.
Appendix 7: Abbreviations and Trademarks
Abbreviations
µg
microgram
ACTH
Adrenocorticotropic Hormone
AE
adverse event
ALKP
Alkaline Phosphatase
ALT
Alanine Transferase
ANOVA
Analysis of Variance
AST 
Aspartate Aminotransferase
AUC
Area Under the Curve
BID
Twice Daily
BMI
Body Mass Index
BP
Blood Pressure
BUN
Blood Urea Nitrogen
CIOMS
Council for International Organizations of Medical Sciences
Cmax
Maximum Concentration
CO2
Carbon Dioxide
CONSORT
Consolidated Standards of Report Trials
COX
Cyclooxygenase
CPMS
Clinical Pharmacology Modelling and Simulation
CRF
Case Report Form
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CTFF
Clinical Trial Facilitation Group
Cτ
Trough Concentration
CV
Cardiovascular
D
Dose
DHT
Dihydrotestosterone
DMPK
Drug Metabolism and Pharmacokinetics
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
ED50
Median Effective Dose
Emax
Maximum Efficacy
FDA
Food and Drug Administration
FSH
Follicle-stimulating Hormone
FTIH
First Time In Human
g
Gram
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GGT
Gamma-glutamyl Transferase
GLDH
Glutamate Dehydrogenase


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GLP
Good Laboratory Practice
GRA
Genotoxic Risk Assessment
GSK
GlaxoSmithKline
GUIs
Guidances
HBCAb
Hepatitis B Core Antibody
HBSAg
Hepatitis B Surface Antigen
HED
Human Equivalent Dose
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
H-PGDS
Hematopoietic Prostaglandin D2 Synthase
hr
hours
hr-1
Per hour
HR
Heart Rate
IB
Investigator's Brochure
IC
Inhibitory Concentration
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Internal Ethics Committee
IgM
Immunoglobulin M
IMP
Investigational Medicinal Product
INR
International Normalized Ratio
IRB
Internal Review Board
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
kg
Kilogram
KO
Knockout
L
Liter
LAM
Lactational Amenorrhea Method
lb
pound
LBF
Liver Blood Flow
LH
Luteinizing Hormone
m2
Square Meter
MABEL
Minimum Anticipated Biological Effect Level
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
mg
milligram
min
minute
mL
Milliliter
MRSD
Maximum Recommended Starting Dose
MSDS
Material Safety Data Sheet
NCS
Not Clinically Significant


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ng
nanogram
NIMP
Non-Investigational Medicinal Product
NOAEL
No Adverse Effect Level
NOEL
No Effect Level
NSAID
Non-steroidal Anti-inflammatory Drug
PBPK
Physiologically-based Pharmacokinetics
PD
Pharmacodynamics
PG
Prostaglandin
PGD2
Prostaglandin D2
PGE2
Prostaglandin E2
PGF2A
Prostaglandin F2a
PGG2
Prostaglandin G2
PGH2
Prostaglandin H2
pH
Potential of Hydrogen
PI
Principal Investigator
PK
Pharmacokinetics
PND
Post-Natal Day
PO
Per Oral
QT
QT Interval
QTc
Corrected QT Interval
QTcF
QT interval corrected according to Fridericia's formula
RAP
Reporting and Analysis Plan
RBC
Red Blood Cells
RCmax
Ratio of Cmax
RD
Repeat Dose
RNA
Ribonucleic Acid
Rss
Steady-state Ratio
SAE
Serious Adverse Event
SGOT
Serum Glutamic-oxaloacetic Transaminase
SGPT
Serum Glutamic-Pyruvic Transaminase
SD
Single Dose
SOA
Schedule of Activities
SOPs
Standard Operating Procedures
SRM
Study Reference Manual
SUSAR
Suspected Unexpected Serious Adverse Reaction
t1/2
terminal half-life
T3
Triiodothyronine
T4
Thyroxine
Th2
T Helper 2 
tPGDM
11,15-Dioxo-9α-hydroxy-2,3,4,5-tetranorprostan-1,20-dioic acid
tPGEM
9,15-dioxo-11α-hydroxy-13,14-dihydro-2,3,4,5-tetranorprostan-
1,20-dioic acid
tmax
Time to Maximum Observed Concentration


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TSH
Thyroid Stimulating Hormone
TXA2
Thromboxane A2
ULN
Upper Limit of Normal
WBC
White Blood Cell
WT
Wildtype
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
PK Predictor Pro
GastroPlus
WinNonlin


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10.8.
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).
Amendment 1: 31-AUG-2018
Overall Rationale for the Amendment:  Updates to the PK exposure limits for Parts A 
and B, stopping criteria, and safety review language have been modified based on FDA 
recommendations. Day -2 has also been removed from Part C of the SoA as it is not 
necessary. Information around Holter Monitoring has been altered to reflect the intent of 
collecting but not analyzing Holter Monitoring data in this study.
Section # and Name
Description of Change
Brief Rationale
1.3 Schedule of Activities 
(SoA
Removal of Day -2 from Part 
C SoA
Participants will not be undergoing 
PD assessments in Part C and 
therefore Day -2 admission is not 
required
2.3 Benefit/Risk 
Assessment
Addition of clarification of 
minimum number and type of 
participants data for dose 
escalation review
A minimum of 4 participants on 
active treatment will complete all 
assessments as outlined. All 
available safety and PK data from all 
participants will be reviewed.
2.3.1 Risk Assessment
Update of information 
describing dose-limiting 
findings in preclinical species
The FDA has recommended a 
higher single dose limit above the 
dog NOAEL as the effects are 
monitorable in a clinical setting
4.3 Justification for Dose
Updates to dose exposure 
limits based on preclinical 
species data and resulting 
changes in MRSD and 
exposure limits for Parts A 
and B of the study
The acceptable exposure limits have 
been increased for Part A and 
decreased for Part B based on 
interpretation and clinical 
management of preclinical findings 
and pharmacokinetic modelling.


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Section # and Name
Description of Change
Brief Rationale
6.6 Dose Modification
Changes to human exposure 
limits and planned doses 
updated 
The acceptable exposure limits have 
been increased for Part A and 
decreased for Part B based on 
interpretation and clinical 
management of preclinical findings 
and pharmacokinetic modelling.
7.1.3 Individual Stopping 
Criteria
Stopping criteria described 
separately for both SAEs and 
AEs
Differences between SAEs, AEs, 
and automatic withdrawal from the 
study needed to be more discretely 
defined.
7.1.4 Dose 
Adjustment/Discontinuation 
Pharmacokinetic Criteria
PK stopping criteria updated 
based on updated exposure 
limits
The acceptable exposure limits have 
been increased for Part A and 
decreased for Part B based on 
interpretation and clinical 
management of preclinical findings 
and pharmacokinetic modelling.
7.1.7.1 Safety Study 
Stopping Criteria
Study Stopping criteria 
described separately for both 
SAEs and AEs
Differences between SAEs, AEs 
criteria for stopping the study need 
to be more discretely defined.
7.1.7.2 PK Study Stopping 
Criteria
PK study stopping criteria 
updated based on updated 
exposure limits
The acceptable exposure limits have 
been increased for Part A and 
decreased for Part B based on 
interpretation and clinical 
management of preclinical findings 
and pharmacokinetic modelling.
8.2.5 Holter Monitoring
Removal of data points from 
section
As Holter Monitoring will be collected 
and not analysed in this study, 
interpretation and nature of 
abnormalities will not be captured in 
the study database
Throughout
Minor editorial and document 
formatting revisions 
Updated the abbreviation 
table.
Minor, therefore have not been 
summarized
Corrections/clarifications
Amendment 2: 13-MAR-2019
Overall Rationale for the Amendment: The safety study stopping criteria language has 
been updated to reflect the intention for the two or more AEs of moderate or severe 
intensity to be of similar kind. In addition, we have aligned the protocol to a previous 


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Note To File (NTF) updating the Schedule of Activities (SoAs), study design, statistical 
analyses and objectives and endpoints based on emerging PK data gathered during this 
study.
Section # and Name
Description of Change
Brief Rationale
1.1 Synopsis- Objectives
Addition of Ctrough 
concentrations at Dose 3 and 
4
The PK of GSK3439171 is different 
than the initial preclinical predictions, 
leading to alterations of study 
assessment windows and PK 
timings that have previously been 
captured in a NTF
1.3 Schedule of Activities
Update to reflect changes 
made to study assessments 
based on emerging PK data
The PK of GSK3439171 is different 
than the initial preclinical predictions, 
leading to alterations of study 
assessment windows and PK 
timings that have previously been 
captured in a NTF
3 Objectives and 
Endpoints
Update to reflect changes 
made to study assessments
based on emerging PK data
The PK of GSK3439171 is different 
than the initial preclinical predictions, 
leading to alterations of study 
assessment windows and PK 
timings that have previously been 
captured in a NTF
4 Study Design
Update to reflect changes 
made to study assessments 
based on emerging PK data
The PK of GSK3439171 is different 
than the initial preclinical predictions, 
leading to alterations of study 
assessment windows and PK 
timings that have previously been 
captured in a NTF
7.1 Discontinuation of 
Study Intervention and 
Participant 
Discontinuation/Withdrawal
Update to language to 
specify occurrence of similar 
AEs
Safety study stopping criteria was 
intended to reflect the occurrence of 
similar AEs of moderate or severe 
intensity occurring in two or more 
participants.
9.4 Statistical Analyses
Update to reflect changes 
made to study assessments 
based on emerging PK data
The PK of GSK3439171 is different 
than the initial preclinical predictions, 
leading to alterations of study 
assessment windows and PK 
timings that have previously been 
captured in a NTF


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11.
REFERENCES
Abe H, et al. Molecular cloning, chromosome mapping and characterization of the mouse 
CRTH2 gene, a putative member of the leukocyte chemoattractant receptor family. Gene 
1999; 227:71-77.
Boie Y, Sawyer N, Slipetz DM, Metters KM, and Abramovitz M. Molecular cloning and 
characterization of the human prostanoid DP receptor. J Biol Chem 1995; 270:18910-
18916.
Cohen DB, Kawamura S, Ehteshami JR, Rodeo SA. Indomethacin and Celecoxib impair 
rotator cuff tendon-to-bone healing. Amer J Sports Med 2006; 34: 362-369.
Connizzo, BK et al. The detrimental effects of systemic ibuprofen delivery on tendon 
healing are time dependent. Clin Orthop Relat Res 2014; 472:2433-2439.
Figueiredo-Pereira ME, Rockwell P, Schmidt-Glenewinkel T, Serrano P.  
Neuroinflammation and J2 prostaglandins: linking impairment of the ubiquitin-
proteasome pathway and mitochondria to neurodegeneration.  Frontiers in Molecular 
Neuroscience, 2015(7); article 104.
GlaxoSmithKline Document Number 2018N359817_00. Investigator’s Brochure for 
GSK3439171A, June 2018.
Hirata T and Narumiya S. Prostanoid Receptors. Chem Rev 2011. 111; 6209-6230.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Korotkova M, Lundberg IE. The skeletal muscle arachidonic acid cascade in health and 
inflammatory disease. Nat Rev Rheumatol 2014; 10: 295-303.
Lewis RA, Soter NA, Diamond PT, Austen KF, Oates JA, and Roberts LJ. Prostaglandin 
D2 generation after activation of rat and human mast cells with anti-IgE. J Immun 1982; 
129:1627-1631.
Mohri I et al. Inhibition of prostaglandin D synthase suppresses muscular necrosis. Amer 
J Pathol 2009; 174: 1735-1744.
Smith WL, Urade Y, Jakobsson PJ. Enzymes of the cyclooxygenase pathways of 
prostanoid biosynthesis. J Chem Rev 2011; 11: 5821-5865.
Urade Y and Hayaishi O. Prostaglandin D synthase structure and function. Vitamins and 
Hormones 2000; 58,89-120.

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
209275
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for A Three-Part FTIH Study to 
Evaluate Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of Single and Repeat Oral Doses of
GSK3439171A, in a Randomized, Double-Blind (sponsor 
unblinded), Placebo- Controlled, Dose Escalation study and 
to Evaluate the Effect of Food on a Single Oral Dose of 
GSK3439171A in Healthy Adult Participants
Compound Number 
:
GSK3439171
Effective Date 
:
09-Oct-2019
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 209275.

This RAP is intended to describe the safety, tolerability, pharmacokinetic and 
pharmacodynamic analyses required for the study.

This RAP will be provided to the study team members to convey the content of the 
reporting efforts, specifically Statistical Analysis Complete (SAC).
Author(s):
Author 
Date
Lead
04-Oct- 2019
Senior Statistician (FPD, Clinical Statistics)
Co-Authors
04-Oct- 2019
Clinical Pharmacologist (Clinical Pharmacology Modeling and 
Simulation)
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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RAP Team Review Confirmations 
(Method: E-mail)
Reviewer
Date
Director, Clinical Statistics (FPD, Biostatistics)
03-Oct- 2019
 
Principal Statistician (FPD Clinical Statistics)
04-Oct- 2019
 
Director, Clinical Development (Disc Med)
04-Oct- 2019
04-Oct- 2019
Clinical Team Leader (FPD, Muscle Metabolism DPU)
04-Oct- 2019
Clinical Research Scientist (Global Clinical Sciences and Delivery, 
Clinical Projects and Quantitative Sciences)
Director, Clinical Development (Disc Med)
04-Oct- 2019
Medical Director, (Safety/ Pharmacovigilance)
04-Oct- 2019
04-Oct- 2019
Principal Data Manager (FPD, Global Clinical & Data Operations)
06-Oct- 2019
Biostatistics and Programming Manager (FPD, Biostatistics India)
Clinical Statistics & Clinical Programming Line Approvals 
(Method: Pharma TMF eSignature)
Approver
Date
09-Oct-2019
Biostatistics and Programming Manager (FPD, Biostatistics India)
09-Oct-2019
Senior Manager - Biostatistics and Programming (FPD, Biostatistics 
India)
.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Objective(s) and Endpoint(s)...............................................................7
2.3.
Study Design ................................................................................................9
2.4.
Statistical Hypotheses / Statistical Analyses ...............................................11
3.
PLANNED ANALYSES ..........................................................................................12
3.1.
Interim Analyses .........................................................................................12
3.2.
Final Analyses ............................................................................................12
4.
ANALYSIS POPULATIONS ...................................................................................13
4.1.
Protocol Deviations.....................................................................................13
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................14
5.1.
Study Treatment & Sub-group Display Descriptors.....................................14
5.2.
Baseline Definitions ....................................................................................15
5.3.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................17
6.
STUDY POPULATION ANALYSES .......................................................................18
6.1.
Overview of Planned Study Population Analyses........................................18
7.
SAFETY ANALYSES .............................................................................................19
7.1.
Adverse Events Analyses ...........................................................................19
7.2.
Clinical Laboratory Analyses.......................................................................19
7.3.
Other Safety Analyses ................................................................................19
8.
PHARMACOKINETIC ANALYSES.........................................................................20
8.1.
Primary Pharmacokinetic Analyses.............................................................20
8.1.1.
Endpoint / Variables.....................................................................20
8.1.1.1.
Drug Concentration Measures....................................20
8.1.1.2.
Derived Pharmacokinetic Parameters.........................20
8.1.2.
Summary Measure ......................................................................21
8.1.3.
Population of Interest...................................................................21
8.2.
Secondary Pharmacokinetic Analyses........................................................21
8.2.1.
Endpoint / Variables.....................................................................21
8.2.1.1.
Drug Concentration Measures....................................22
8.2.1.2.
Derived Pharmacokinetic Parameters.........................22
8.2.2.
Summary Measure ......................................................................22
8.2.3.
Population of Interest...................................................................22
8.2.4.
Statistical Analyses / Methods .....................................................22
8.2.4.1.
Statistical Methodology Specification..........................23


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8.2.4.1.1.
Statistical Methodology 
Specification for Part A (Single 
Dose)......................................................23
8.2.4.1.2.
Statistical Methodology 
Specification for Part B ...........................24
8.2.4.1.3.
Statistical Methodology 
Specification for Part C...........................27
8.3.
Exploratory Pharmacokinetic Analyses .......................................................28
9.
PHARMACOKINETIC (POPPK) ANALYSES .........................................................29
10. PHARMACODYNAMIC (AND / OR BIOMARKER) ANALYSES .............................29
10.1.
Exploratory Pharmacodynamic and Biomarker Analyses............................29
10.1.1.
Endpoint / Variables.....................................................................29
10.1.1.1.
Drug Concentration Measures....................................31
10.1.2.
Summary Measure ......................................................................31
10.1.3.
Population of Interest...................................................................31
10.1.4.
Statistical Analyses / Methods .....................................................31
10.1.4.1.
Statistical Methodology Specification..........................31
10.1.4.1.1.
Statistical Methodology 
Specification for Part A (Single 
Dose)......................................................31
10.1.4.1.2.
Statistical Methodology 
Specification for Part B (Repeat 
Dose)......................................................32
11. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES .................................33
12. REFERENCES.......................................................................................................34
13. APPENDICES........................................................................................................35
13.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................35
13.2.
Appendix 2: Schedule of Activities ..............................................................36
13.2.1.
Protocol Defined Schedule of Events...........................................36
13.3.
Appendix 3: Assessment Windows .............................................................73
13.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................74
13.4.1.
Study Phases ..............................................................................74
13.4.1.1.
Study Phases for Concomitant Medication .................74
13.5.
Appendix 5: Data Display Standards & Handling Conventions....................75
13.5.1.
Reporting Process .......................................................................75
13.5.2.
Reporting Standards....................................................................75
13.5.3.
Reporting Standards for Pharmacokinetic....................................76
13.6.
Appendix 6: Derived and Transformed Data ...............................................79
13.6.1.
General........................................................................................79
13.6.2.
Study Population..........................................................................80
13.6.3.
Safety ..........................................................................................81
13.6.4.
Pharmacokinetic ..........................................................................82
13.7.
Appendix 7: Reporting Standards for Missing Data.....................................83
13.7.1.
Premature Withdrawals................................................................83


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13.7.2.
Handling of Missing Data.............................................................83
13.7.2.1.
Handling of Missing and Partial Dates ........................83
13.7.2.2.
Handling of PK Concentration Data............................84
13.7.2.3.
Handling of Missing Data for Statistical 
Analysis......................................................................84
13.8.
Appendix 8: Values of Potential Clinical Importance ...................................85
13.8.1.
Laboratory Values........................................................................85
13.8.2.
ECG.............................................................................................86
13.8.3.
Vital Signs....................................................................................86
13.9.
Appendix 9: Population Pharmacokinetic (PopPK) Analyses ......................87
13.10. Appendix 10: Pharmacokinetic / Pharmacodynamic Analyses ....................88
13.11. Appendix 11: Abbreviations & Trade Marks ................................................89
13.11.1. Abbreviations...............................................................................89
13.11.2. Trademarks .................................................................................90
13.12. Appendix 12: List of Data Displays..............................................................91
13.12.1. Data Display Numbering..............................................................91
13.12.2. Mock Example Shell Referencing ................................................91
13.12.3. Deliverables.................................................................................92
13.12.5. Safety Tables...............................................................................96
13.12.6. Safety Figures ...........................................................................108
13.12.7. Pharmacokinetic Tables.............................................................113
13.12.8. Pharmacokinetic Figures ...........................................................116
13.12.9. Pharmacodynamic (and / or Biomarker) Tables .........................118
13.12.10.Pharmacodynamic (and / or Biomarker) Figures........................123
13.12.11.ICH Listings ...............................................................................139
13.12.12.Non-ICH Listings........................................................................155
13.12.13.Other Listings ............................................................................157
13.13. Example Mock Shells for Data Displays....................................................158


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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 209275:
Revision Chronology:
2018N361438_00
03-JUL-2018
Original
2018N361438_01
27-AUG-2018
Updates to the PK exposure limits for Parts A and B, stopping 
criteria, and safety review language have been modified 
based on FDA recommendations. Day -2 has also been 
removed from Part C of the SoA as it is not
necessary. Information around Holter Monitoring has been 
altered to reflect the intent of collecting but not analyzing 
Holter Monitoring data in this study.
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan

Detail to Include: Outline & fully justify (where applicable) changes to the 
planned protocol analysis.
o
If there are no changes or deviations from the protocol, then specify within 
this section.
Changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1.
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes

Analysis population: Enrolled 
population has been removed 
from the population definitions.

Analysis population: 
Screened population 
definition has been added 
to the population definitions.

More specific definition 
according to the new RAP 
template

Analysis population: Evaluable 
population has been removed 
from the population definitions.


This population will be 
equivalent to the PK/PD 
population which are 
already included


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2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints
To assess the safety and tolerability 
of GSK3439171A following single 
and repeat doses in healthy 
participants
Adverse events (AE), Serious Adverse Events 
(SAE), clinical laboratory values, vital signs, and 
electrocardiograms (ECG)
To characterize the PK of
GSK3439171A, following single 
and repeat doses in healthy 
participants
Derived PK parameters for GSK3439171A 
including area under the plasma drug concentration 
versus time curve (AUC(0-t), AUC(0-inf), 
maximum observed plasma drug concentration 
(Cmax), time to maximum observed plasma drug 
concentration (tmax), and apparent terminal half-
life (t1/2) as appropriate
Secondary Objectives
Secondary Endpoints
To assess the effect of food on the 
PK of GSK3439171A following an 
oral dose in healthy participants
Derived PK parameters for GSK3439171A 
including area under the plasma drug concentration 
versus time curve (AUC(0-t), AUC(0-inf), 
maximum observed plasma drug concentration 
(Cmax), time to maximum observed plasma drug 
concentration (tmax), and apparent terminal half-
life (t1/2) as appropriate
To assess preliminary dose
proportionality of GSK3439171A 
following single and repeat oral 
doses, as data permit
AUC(0-t), AUC(0-inf), and Cmax following single 
dose and AUC(0-τ) and Cmax following repeat 
dose for the assessment of dose proportionality
To examine the extent of 
accumulation and achievement of 
steady-state following repeat oral 
doses of GSK3439171A, as data 
permits

Determine observed accumulation based on 
AUC(Ro) and Cmax (RCmax) and 
determine the steadystate ratio (Rss)

Trough plasma concentrations at the
end of the dosing interval (Cτ) collected 
pre-dose for repeat doses 12, 13 and 14* to 
assess the achievement of steady-state of 
GSK3439171A
Exploratory Objectives
Exploratory Endpoints
To evaluate the PD properties of 
GSK3439171A
Levels of mediators on prostaglandin and/or 
inflammatory metabolic pathways such as, but not 
limited to, PGD2, and PGE2.
To assess the effect of
GSK3439171A on QTc in healthy 
adult volunteers
Holter monitor data collection and storage for 
evaluation of the correlation between plasma levels 
of GSK3439171A and changes in the QTc interval 
in the future, if appropriate
To evaluate additional biomarkers
of GSK3439171A target 
Levels of change in novel biomarkers in blood, 
muscle, or urine, such as, but not limited to, urine 


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Objectives
Endpoints
engagement after single and repeat 
doses.
tetranor PGDM and PGEM (tPGDM, tPGEM), 
PGD2, and PGE2
To investigate the plasma, urinary 
and biliary (Part B) metabolic 
pathways of GSK3439171A in 
healthy subjects
GSK3439171-related material in plasma, urine and 
bile
* 12, 13 and 14 changed to 6,7,9,10, 11, 15,16, and 17


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2.3.
Study Design
Overview of Study Design and Key Features
Part A: Single Ascending Dose
Within a cohort, participants will be randomized to one of 3 treatment sequences such
that each participant receives 2 active doses and 1 placebo dose resulting in each active
dose being administered to 6 participants and placebo to 3 participants
● Starting dose (Dose 1) = 5 mg
● Subsequent dose escalations will be determined based on safety and PK data
● Maximum predicted dose = 500 mg (Genotoxic Risk Assessment Limit= 3000mg)
● Washout= 7 days or 5 half-lives, whichever is longer
= Dose escalation meeting
PBO= Placebo
*Note: dosing strategy is for illustrative purposes and does not represent the randomization
strategy
Part B: Single and Repeat Dose 14-day dose-rising
Part C: Food Effect


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Overview of Study Design and Key Features
Design 
Features

Part A is a randomized, double blind, placebo-controlled, crossover, 
single dose escalation study in healthy participants. Participants will be 
randomized to placebo or active study intervention groups after 
screening.

Part B is a randomized, double blind, placebo-controlled, parallel group, 
repeat dose escalation study in healthy participants. Participants will be 
randomized to placebo or active study intervention groups after 
screening.

Part C is a randomized, open label, crossover, food effect study in 
healthy participants. Participants will be randomized to fed or fasted 
groups after screening.
Dosing

Part A: Each participant will participate in 3 dosing periods and will receive 2 
doses of GSK3439171A and 1 dose of placebo in a randomized fashion. There 
will be an approximately 7 day (or 5 half-lives, whichever is longer) washout 
period between dosing in each session. Each active dose level will be 
administered initially to a smaller group of participants (1on active and 1 on 
placebo) and will be followed clinically for 48 hr (or 5 half-lives, whichever is 
longer) to allow for adequate observation of safety. If no acute safety issues are 
observed in this smaller group of sentinel participants, then the remaining 
participants (approximately 5 participants on active and 2 participants on placebo) 
will receive the dose.

Part B: In each cohort of Part B of the study, approximately twelve participants 
will be randomized to either one dose level of GSK3439171A or placebo 
according to a randomization schedule prepared prior to the start of the study. 
The study will be conducted sequentially starting with Dose 1 Cohort B1.
Participants will receive a single dose followed by a 48 hr assessment period and 
then will receive daily repeat doses until the end of the study.

Part C: In this crossover design, approximately 12 participants will take part in two 
periods with dosing in each period separated by approximately 7 days (or 5 half-
lives of the study intervention, whichever is longer). In each study session, 
participants will be admitted to the clinical unit and receive a single dose of 
GSK3439171A either in the fasted state or after a high fat meal.
Time & 
Events

Refer to Appendix 2: Schedule of Activities
Treatment 
Assignment
Participants will be randomized to receive study intervention. Randomization schedule 
generated using RandAll NG prior to the study by the Clinical Statistics Department at 
GSK will be sent to the site and the site pharmacist randomizes the participants according 
to the randomization schedule. Investigators and all site staff with the exception of the 
pharmacy staff will remain blinded to each participant’s assigned study intervention 
throughout the course of the study.

Part A: approximately 9 participants in each cohort will be randomized to one of 3 
treatment sequences for 3 cohorts. Within each period, allocation of active (A) to
placebo (P) treatment will be 2:1. Within a cohort, an increasing dose of 
GSK3439171A will be administered in each period.

Part B: In each cohort of, approximately 12 participants will be randomized to 
receive either GSK3439171A or placebo in a parallel design using a 3:1 allocation 
ratio.

Part C: Approximately 12 participants will be randomized 1:1 to receive


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Overview of Study Design and Key Features
GSK3439171A in one of two treatment sequences (Fed then Fasted or Fasted 
then Fed).
Interim 
Analysis
There will be no formal statistical interim analysis. However, preliminary safety, PK, 
and PD/biomarker data will be reviewed in-stream by the GSK study team 
members prior to each dose escalation. Data for these reviews will be cumulative 
and can include individual participant data, summaries by treatment group and 
graphical displays. This is a sponsor unblinded trial and GSK staff will be unblinded 
for these reviews.
2.4.
Statistical Hypotheses / Statistical Analyses
The primary objectives of this study are to evaluate safety and tolerability of single and 
repeat doses of GSK3439171A and to characterize the PK of GSK3439171A. No formal 
statistical hypotheses will be tested. Descriptive statistics will be used to assess safety and 
tolerability objectives. Treatment comparisons with placebo will be based on review of 
descriptive statistics and individual participant data. An estimation approach will be used 
to address the PK objectives where point estimates and corresponding 90% confidence 
intervals (CIs) will be constructed as appropriate for the assessment of dose 
proportionality, steady-state, time invariance and food effect.


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3.
PLANNED ANALYSES
3.1.
Interim Analyses
There will be no formal statistical interim analysis. However, preliminary safety, PK, and 
PD/biomarker data will be reviewed in-stream by the GSK study team members and 
investigational site (PAREXEL) team prior to each dose escalation. This data review is 
conducted in two steps: First GSK staff will review the unblinded data, as this is a 
sponsor unblinded trial and then the blinded data will be presented to investigational site 
team in another meeting. Data for these reviews will be cumulative and can include 
individual participant data, summaries by treatment group and graphical displays.
Preliminary results from available safety data may be reported prior to database freeze for 
the purposes of safety review by GSK, and where required by regulatory bodies. Other 
selected preliminary data may be unblinded and reported prior to database freeze for 
internal decision making. In each case described above, the study will not be officially 
unblinded and access to the randomization will be restricted.
After completing Part A and cohort 1&2 for Part B there was a safety review of the 
unblinded data to decide if higher dose can be administered for cohort 3 in Part B. 
Summaries and figures for Clinical chemistry, Hematology and Hormone level were 
created for the safety review (The displays that were created are indicated in list of data 
displays). Unblinded results were produced for an IB update, which was a subset of Study 
population, Safety and PK concentration displays, more details of the results submitted 
will be documented in IB update documentation.
Summaries and graphical displays for in-stream reviews will not be provided by Statistics 
and Programming and as such, no details on these summaries are provided in the RAP.
3.2.
Final Analyses
Final analyses will be reported when all subjects in all cohorts have completed their final 
scheduled visits and the following sequential steps have occurred:
1.
All participants have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management.
3.
All criteria for unblinding the randomization codes have been met. 
4.
Randomization codes have been distributed according to RandAll NG procedures.


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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened 
All participants who were screened for eligibility
Screen Failures
Randomized 
All participants who were randomized
Study Population
Safety
All participants who take at least 1 dose of study 
intervention.
Participants will be analyzed according to the 
intervention they actually received.
Study Population
Safety
PK
Participants in the Safety population for whom a 
PK sample was taken and analyzed for 
GSK3439171A and result reported
PK
PD
Participants in the Safety population with at least 
one PD measure.
PD/Biomarker
Refer to Appendix 12: List of Data Displays which details the population used for each display.
Metabolite ID work will be reported in a separate GSK report
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan.
o Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised on the protocol deviations dataset. 
o This dataset will be the basis for the summaries and listings of protocol 
deviations.
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the ClinBase. 


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
•
There are no planned adjustments made for multiple centres in this study.
•
There are no planned adjustments for multiple comparisons or multiplicity.
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG
Data Displays for Reporting 
Code
Description
Description
Order in TLF 
Part A
D1
GSK3439171A Dose 1 
5 mg
2
D2
GSK3439171A Dose 2
10 mg
3
D3
GSK3439171A Dose 3
30 mg
4
D4
GSK3439171A Dose 4
60 mg
5
D5
GSK3439171A Dose 5
120 mg
6
D6
GSK3439171A Dose 6
180 mg
7
PA
Placebo Part A 
Placebo
1
Part B
DD1
GSK3439171A R1 mg QD or 
BID
5 mg
10
DD2
GSK3439171A R2 mg QD or 
BID
11 mg
11
DD3
GSK3439171A R3 mg QD or 
BID
40 mg
12
PB
Placebo Part B 
Placebo
8
PB3
Placebo Part B Cohort 3
Placebo Cohort 3
9


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Treatment Group Descriptions
RandAll NG
Data Displays for Reporting 
Code
Description
Description
Order in TLF 
Part C
C1
GSK3439171A fasted 
60 mg Fasted
13
C2
GSK3439171A fed
60 mg Fed
14
Note: If additional dose levels are explored in either Part A or B, then they will follow in 
a sequential order in the table
Treatment comparisons will be displayed as follows using the descriptors as specified:
1.
Day 17 vs Day 1 (e.g.; Ro, RCmax and Rss)
2.
Dose X.X mg vs Placebo
3.
Repeat Dose X.X mg vs Placebo
4.
Fasted vs Fed
5.2.
Baseline Definitions
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment with a non-missing value, including those from unscheduled 
visits. For the parameters having multiple assessments, mean value of the assessments 
will be considered as baseline value. 
Baseline Definitions – Part A
Parameter
Study Assessments Considered as Baseline
Baseline Used 
in Data Display
Screening
Day -2
Day -1
Day 1 (Pre-
Dose)
Safety Assessments
Lab results, 12-
lead
Electrocardiogram
(ECG) & Vital 
Signs
X
X
X
Day 1
Routine Urinalysis
X
X
Day 1
Telemetry
X
Day 1 
30 min (10 
min) 
Pharmacodynamics
parameters
X
X
Day -1 #


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# Postdose value will be collected on intervals 0-2, 2-4, 4-6, 6-8, 8-12 and 12-24 hr.
Time matched predose value for each of these intervals (24-22, 22-20, 20-18, 18-16, 16-
12 and 12-0 respectively), predose aggregate value of 24-12hr (for post dose aggregate of 
0-12 hrs) and predose aggregate value of 12-0 hr (for post dose aggregate of 12-24 hrs) 
will be considered as baseline for different pharmacodynamic parameters
Baseline Definitions – Part B
Parameter
Study Assessments Considered as Baseline
Baseline Used in 
Data Display
Screening
Day -2
Day -1
Day 1 (Pre-
Dose)
Safety Assessments
Lab results
X
X
X
X
Day 1
Hormone 
monitoring
X
Day -1†
Routine Urinalysis, 
12-lead
Electrocardiogram
(ECG) & Vital 
Signs
X
X
X
Day 1
Telemetry
X
Day 1 
30 min (10 
min)
Pharmacodynamics
parameters
X
X
Day -1 #
Blood sampling for
metabolite 
profiling
X
Day 1 (pre-
dose)
Muscle Biopsy
X
Day -1
† There will be 2 individual baseline values (samples from midnight and 9am) for ACTH 
and Cortisol hormones. Both values may be used to calculate change from baseline for 
post dose measurements.
#  Postdose value will be collected on intervals 0-2, 2-4, 4-6, 6-8, 8-12 and 12-24hr. Time 
matched predose value for each of these intervals (24-22, 22-20, 20-18, 18-16, 16-12 and 
12-0 respectively), predose aggregate value of 24-12hr (for post dose aggregate of 0-12 
hrs) and predose aggregate value of 12-0 hr (for post dose aggregate of 12-24 hrs) will be 
considered as baseline for different pharmacodynamic parameters


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Baseline Definitions – Part C
Parameter
Study Assessments Considered as Baseline
Baseline Used 
in Data Display
Screening
Day -1
Day 1 (Pre-Dose)
Safety Assessments
Lab results, 12-lead
Electrocardiogram
(ECG) & Vital Signs
X
X
Day 1
Routine Urinalysis
X
X
Day 1
Telemetry
X
Day 1 
30 min (10 
min)
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing.
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
13.3
Appendix 3: Assessment Windows
13.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
13.5
Appendix 5: Data Display Standards & Handling Conventions
13.6
Appendix 6: Derived and Transformed Data
13.7
Appendix 7: Reporting Standards for Missing Data
13.8
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 randomised 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.  
Details of the planned displays are presented in Appendix 12: List of Data Displays.


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7.
SAFETY ANALYSES
The safety analyses will be based on the safety population, unless otherwise specified.
Descriptive statistics will be used to assess safety and tolerability objectives. No formal 
statistical analyses of safety data are planned. Data will be summarized according to GSK 
Integrated Data Standards Library (IDSL) standards for Part A, Part B and Part C 
separately. In addition, individual participant data will be reviewed. Treatment 
comparisons with placebo will be based on review of descriptive statistics and individual 
participant data.
7.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious adverse 
events (SAEs) and other significant AEs will be based on GSK Core Data Standards. 
7.2.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, Liver chemistries and Hormone assessment tests will be 
based on GSK Core Data Standards. Hormone assessment tests will be done in Part B 
only and all the other laboratory evaluations will be done for all the 3 parts (A, B & C) of 
the study.
7.3.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs vital signs and 
Telemetry will be based on GSK Core Data Standards, unless otherwise specified. 


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8.
PHARMACOKINETIC ANALYSES
8.1.
Primary Pharmacokinetic Analyses
8.1.1.
Endpoint / Variables
Pharmacokinetic parameters will be determined from the plasma concentration-time data, 
as data permits.
PK parameters: Maximum observed blood concentration (Cmax), time to Cmax (tmax), 
area under the plasma concentration-time curve [AUC(0-t), AUC(0-24), AUC(0-inf) and 
AUC(0-τ)], Pre-dose observed concentration (Cτ), apparent terminal phase half-life (t1/2)
will be determined, as data permit.
8.1.1.1.
Drug Concentration Measures
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 13.5.3.
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 Phoenix 64. All calculations of non-
compartmental parameters will be based on actual sampling times. Pharmacokinetic 
parameters listed will be determined from the plasma concentration-time data, as data 
permits.
Table 2
Derived Pharmacokinetic Parameters (Primary end points)
Parameter
Parameter Description
Part A
Part B
Part C
AUC(0-t)
Area under the concentration-time curve 
from time zero to the time of the last 
quantifiable concentration (C(t)) which 
will be calculated using the linear 
trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for 
each decremental trapezoid.
X
X1
X
AUC(0-∞)
Area under the concentration-time curve 
extrapolated to infinity calculated as 
AUC(0-∞)= AUC(0-t) + C(t)/lambda_z
X
X1
X
AUC(0-24)
Area under the concentration-time curve 
from time zero to 24 hours post-dose which 
will be calculated using the linear 
trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for 
each decremental trapezoid.
X
X1,2


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Parameter
Parameter Description
Part A
Part B
Part C
tmax
Time to reach Cmax, determined directly 
from the concentration-time data.
X
X1,2
X
t1/2
Apparent terminal half-life will be 
calculated as:
t½ = ln2 / lambda_z
X
X1,2
X
Ae
Urinary excretion of unchanged drug
X1,2
Clr
Renal clearance
X1,2
Fe
Fraction of the dose excreted in the urine
X1,2
Cmax
Maximum observed concentration, 
determined directly from the 
concentration-time data.
X
X1,2
X
Cτ
Pre-dose observed concentration (trough)
for repeat doses on Days 6,7,9,10, 11, 
15,16, and 17 (6, 7, 9 & 10 for 7 day repeat 
dosing) which will be obtained directly 
from the concentration-time data.
X1,2
Additional parameters may be calculated as required.
Lambda_z is the terminal phase rate constant.
1Determined for dose 1
2Determined at SS (following 14 days of consecutive dosing)
8.1.2.
Summary Measure
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively by dose group for each study part separately.
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 13.5.3.
Reporting Standards for Pharmacokinetic)
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modelling and Simulation Department, CPMS, GlaxoSmithKline and Statistical analyses 
of the pharmacokinetic parameter data will be the responsibility of Clinical Statistics &
Programming, GlaxoSmithKline.
8.1.3.
Population of Interest 
The primary pharmacokinetic analyses will be based on the Pharmacokinetic population, 
unless otherwise specified.
8.2.
Secondary Pharmacokinetic Analyses
8.2.1.
Endpoint / Variables
Observed accumulation ratio AUC(Ro), predicted accumulation ratio AUC(Rp), observed 
accumulation ratio for Cmax (RCmax) and steady state ratio (Rss).


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8.2.1.1.
Drug Concentration Measures 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 13.5.3
Reporting Standards for Pharmacokinetic)
8.2.1.2.
Derived Pharmacokinetic Parameters
Table 3
Derived Pharmacokinetic Parameters (Secondary end points)
Parameter
Parameter Description
Part A
Part B
Part C
% AUCex
The percentage of AUC (0-∞) obtained by 
extrapolation (%AUCex) will be calculated as: 
AUC(0-∞)- AUC(0-t)/AUC(0- ∞) x 100
X
X
X
AUC(Ro)
Observed accumulation ratio (Ro) for AUC will 
be calculated as follows:
Day 17 AUC(0- τ)/Day 1 AUC(0- τ)
X1
AUC(Rp)
Predicted accumulation ratio will be calculated 
as follows:
Day 1 AUC(0- ∞)/Day 1 AUC(0- 24)
X
X1
X
Rss
Steady state accumulation ratio (Rss) will be 
calculated as follows:
Day 17 AUC(0- τ)/Day 1 AUC(0-∞)
X1
RCmax
Observed accumulation ratio for Cmax (Rcmax) 
will be calculated as follows:
Day 17 Cmax/Day 1 Cmax
X1
1Day 10 AUC will be considered instead of Day 17 for the reduced treatment period cohort (Part B 
cohort3).
8.2.2.
Summary Measure
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 13.5.2.
Reporting Standards for Pharmacokinetic)
8.2.3.
Population of Interest 
The secondary pharmacokinetic analyses will be based on the Pharmacokinetic 
population, unless otherwise specified.
8.2.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 8.2.1.2 will be
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.


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8.2.4.1.
Statistical Methodology Specification
8.2.4.1.1.
Statistical Methodology Specification for Part A (Single Dose)
Pharmacokinetic Statistical Analyses – ANOVA – Single Dose (Part A)
Endpoint / Variables
AUC(0-t), AUC(0-24), AUC(0-∞), Cmax, Cτ, t1/2, AUC(Rp)
Model Specification
Actual value of t1/2 and loge-transformed values of rest of the endpoints will be statistically 
analyzed using Mixed Model (MM) ANOVA.

Fixed effect: dose

Random effect: Subject 
An unstructured covariance structure for the G matrix will be used.

If this model fails to converge, alternative covariance structures may be considered.

Akaike’s Information Criteria (AIC) will be used to assist with the selection of covariance 
structure.
Analyses will be done with the MIXED Procedure in SAS, using the Kenward-Roger option to 
estimate denominator degrees of freedom and standard errors
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.
Model Results Presentation
LSmeans and 90% CI are estimated for each dose as well as overall estimate of within-subject CV
Note: AUC(0-t) is only reported when AUC(0-∞) is not reportable
Pharmacokinetic Statistical Analyses - Dose Proportionality (Power Model) – Single Dose 
(Part A) 
Endpoint / Variables
Single Dose: AUC(0-t), AUC(0-∞) and Cmax
Model Specification
Will be statistically analyzed using the power model
y = α* doseβ


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Where y =PK parameter being analyzed and α= subject
Loge transformed data will be analyzed by fitting the following terms in the mixed effect model:

Fixed effect: loge (dose) 

Random effect: Subject (Intercept only)
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.
Model Results Presentation
Estimates of the mean slopes of loge (dose) will be reported along with corresponding 90% 
confidence intervals (slope≈1 implies dose proportionality)
Note: AUC(0-t) is only reported when AUC(0-∞) is not reportable
8.2.4.1.2.
Statistical Methodology Specification for Part B
Pharmacokinetic Statistical Analyses – ANOVA (Accumulation & Time Invariance) – Repeat 
Dose (Part B)
Endpoint / Variables
AUC(0- τ), AUC(0-∞), Cmax, Cτ, AUC Rss, t1/2, AUC (Ro), RCmax
Model Specification
Actual value of t1/2 and loge-transformed values of all other will be statistically analyzed using 
Mixed Model (MM) ANOVA.

Fixed effect: day, dose, day*dose

Random effect: Subject 
An unstructured covariance structure for the G matrix will be used.

If this model fails to converge, alternative covariance structures may be considered.

Akaike’s Information Criteria (AIC) will be used to assist with the selection of covariance 
structure.
Analyses will be done with the MIXED Procedure in SAS, using the Kenward-Roger option to 
estimate denominator degrees of freedom and standard errors


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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.
Model Results Presentation
LSmeans and 90% CI are estimated for each dose as well as overall estimate of within-subject CV.
For AUC(0- τ), Cmax and AUC-Rss, estimates of ratio of Day 17to Day 1 will be evaluated for each 
dose by exponentiating the difference in least squares means (Day 17– Day 1) and the associated 
90% CI.  Such that ratios of Day 17 to Day 1 for AUC(0- τ), Cmax and AUC-Rss provide estimates 
of Ro, RCmax and Rss, respectively
Note: For AUC-Rss, Day 17 AUC(0- τ) and Day 1 AUC(0-∞) should be considered.
Note: Day 10 values will be considered instead of Day 17 for the reduced treatment period cohort
(cohort 3)
Pharmacokinetic Statistical Analyses - Dose Proportionality (Power Model) – Repeat Dose 
(Part B)
Endpoint / Variables
Repeat Dose: AUC(0-τ) and Cmax
Model Specification
Will be statistically analyzed using the power model
y = α* doseβ
Where y =PK parameter being analyzed and α= subject
Loge transformed data will be analyzed by fitting the following terms in the mixed effect model:

Fixed effect: loge (dose)

Random effect: Subject (Intercept only)
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. 


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•
Non-parametric analyses will be conducted if the normality assumption does not hold.
Model Results Presentation
Estimates of the mean slopes of loge (dose) will be reported along with corresponding 90% 
confidence intervals (slope≈1 implies dose proportionality)
Pharmacokinetic Statistical Analyses - Achievement of Steady State – Repeat Dose (Part B) 
Endpoint / Variables
Trough plasma concentrations at the end of the dosing interval (Cτ) for repeat doses Days 
6,7,9,10, 11, 15,16, and 17 (6, 7, 9 & 10 for reduced treatment period cohort)
Model Specification
Loge-transformed values of the endpoint will be statistically analyzed separately by dose using 
Mixed Model (MM) ANOVA.

Fixed effect: day as continuous variable, dose, day*dose

Random effect: Subject
An unstructured covariance structure for the G matrix will be used.

In the event that this model fails to converge, alternative covariance structures may be 
considered.

Akaike’s Information Criteria (AIC) will be used to assist with the selection of covariance 
structure.
Analyses will be done with the MIXED Procedure in SAS, using the Kenward-Roger option to 
estimate denominator degrees of freedom and standard errors
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.
Model Results Presentation
The coefficient for the slope of the day effect on the log-scale will be used to evaluate steady state 
for each dose. The 90% confidence intervals for the slope will be
calculated.
Steady-state will be assessed visually by plotting trough concentration levels, Cτ, collected pre-
morning dose versus collection day by dose.


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8.2.4.1.3.
Statistical Methodology Specification for Part C
Pharmacokinetic Statistical Analyses - Food Effect -Single Dose (Part C) 
Endpoint / Variables
AUC(0-t), AUC(0-∞), Cmax and t1/2
Model Specification
Loge-transformed values of AUC(0-t) and AUC(0-∞) and actual value of t1/2 will be statistically 
analyzed using Mixed Model (MM) ANOVA.

Fixed effect: period, treatment(fed/fasted)

Random effect: Subject
An unstructured covariance structure for the G matrix will be used.

If this model fails to converge, alternative covariance structures may be considered.

Akaike’s Information Criteria (AIC) will be used to assist with the selection of covariance 
structure.
Analyses will be done with the MIXED Procedure in SAS, using the Kenward-Roger option to 
estimate denominator degrees of freedom and standard errors
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.
Model Results Presentation
Point estimates for the differences in means (GSK3439171A fed – GSK3439171A fasted) and 
corresponding 90% CIs will be constructed from the least squares means, using the residual 
variance. These will then be back-transformed to provide point estimates and corresponding 90% 
CIs for the ratio of geometric means fed:fasted.
Endpoint(s)
Tmax
Note: This endpoint will not be log transformed for analysis
Model Specification
Wilcoxon matched pair test
Model Results Presentation
Point estimate and 90% confidence interval for the median difference (fed – fasted)
Note: AUC(0-t) is only reported when AUC(0-∞) is not reportable Population


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8.3.
Exploratory Pharmacokinetic Analyses
If data permits, PK data of metabolites will be analyzed in the similar way as for drug 
substance and similar output will be generated.


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9.
PHARMACOKINETIC (POPPK) ANALYSES
PopPK will be performed under a separate RAP and will be reported separately.
10.
PHARMACODYNAMIC (AND / OR BIOMARKER)
ANALYSES
10.1.
Exploratory Pharmacodynamic and Biomarker Analyses
10.1.1.
Endpoint / Variables
Following table describes the pharmacodynamic/biomarker end points:
Parameter
Parameter Description/Derivation
Part A
Part B
PGD2
X
PGE2
X
Creatinine #
X
X
tPGDM #
X
X
tPGEM #
X
X
6-keto-PGF1A
X
PGF2A
X
TXB2
X
Creatinine corrected 
data for tPGDM and 
tPGEM #
Three versions of data to be considered:
1.Raw data(mass) 
2. Aggregated data 0-12hrs 
3. Aggregated data 12-24hr
4. Aggregated data 24-48hrs
Each version of data(mass) divided by time 
matched creatinine(mass) 
X
X
Baseline corrected 
urinary tetranor data 
for tPGDM and 
tPGEM #
Post dose data divided by time matched baseline 
data
Three versions of data to be considered:
1.Creatinine corrected raw data 
2. Creatinine corrected aggregated data 0-12hrs 
3. Creatinine corrected aggregated data 12-24hrs
X
X
Baseline corrected 
urinary tetranor data 
for creatinine #
Post dose data divided by time matched baseline 
data
Three versions of data to be considered:
1.Raw data 
2. Aggregated data 0-12hrs 
3. Aggregated data 12-24hrs
X
X


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Parameter
Parameter Description/Derivation
Part A
Part B
Placebo corrected 
data for tPGDM and
tPGEM #
Creatinine corrected data from active dose 
divided by time matched placebo data and then 
find ratio to baseline.
Three versions of data to be considered:
1.Creatinine corrected raw data 
2. Creatinine corrected aggregated data 0-12hrs 
3. Creatinine corrected aggregated data 12-24hrs
X
Placebo corrected 
data for creatinine #
Data from active dose divided by time matched 
placebo data and then find ratio to baseline.
Three versions of data to be considered:
1.Raw data 
2. Aggregated data 0-12hrs 
3. Aggregated data 12-24hrs
X
Time matched PK 
Concentration for 
urinary tetranor data 
for tPGDM and
tPGEM
For each PD marker interval, use the upper bound 
as target time; e.g. for 0-2hr interval, 2hr is the 
target time
Identify PK concentration with nominal time at the 
target time;
If there is no PK sample taken at target time, use 
the PK concentration data with nominal time 
before but closest to target time;
Use 0 PK concentration for placebo
X
X
Ratio of 
tPGDM/tPGEM  #
Time matched ratio for tPGDM/tPGEM  
Three versions of data to be considered:
1.Creatinine corrected raw data 
2. Creatinine corrected aggregated data 0-12hrs 
3. Creatinine corrected aggregated data 12-24hrs
4. Aggregated data 24-48hrs
X
X
# Urine tetranor and urine creatinine data should be considered as mass 
(Mass=Concentration*Volume). 
Raw data – Mass data for each of the intervals 0-2, 2-4, 4-6, 6-8, 8-12 &12-24. (predose and postdose)
Aggregated data 0-12hrs  - Add the mass from each interval till 12 hrs (predose and postdose)
Aggregated data 12-24hrs  - Mass from 12-24hr interval  (predose and postdose)
Aggregated data 124-48hrs  - Mass from 24-48hr interval  (postdose)


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10.1.1.1.
Drug Concentration Measures 
Refer to Appendix 5: Data Display Standards & Handling Conventions 
10.1.2.
Summary Measure
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 13.5.3.
Reporting Standards for Pharmacokinetic)
10.1.3.
Population of Interest 
The exploratory pharmacodynamics (and / or biomarker) analyses will be based on the 
PD population, unless otherwise specified.
10.1.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables will be summarised using descriptive 
statistics, graphically presented (where appropriate) and listed.
10.1.4.1.
Statistical Methodology Specification
10.1.4.1.1. Statistical Methodology Specification for Part A (Single Dose)
Pharmacodynamic Statistical Analyses – Mixed Effect Model – Single Dose (Part A)
Endpoint / Variables
tPGDM, tPGEM, Creatinine, Creatinine corrected tPGDM and Creatinine corrected tPGEM
(Aggregated values for predose 24-12hr & 12-0hr and postdose 0-12 hr, 12-24 hr & 24-48 hr)
Model Specification
Loge transformed values of the endpoints will be statistically analyzed using Mixed Model (MM).

Fixed effect: dose, timepoint, dose*timepoint

Random effect: Subject 
An unstructured covariance structure for the G matrix will be used.

If this model fails to converge, alternative covariance structures may be considered.

Akaike’s Information Criteria (AIC) will be used to assist with the selection of covariance 
structure.
Analyses will be done with the MIXED Procedure in SAS, using the Kenward-Roger option to 
estimate denominator degrees of freedom and standard errors
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 


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Pharmacodynamic Statistical Analyses – Mixed Effect Model – Single Dose (Part A)
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.
Model Results Presentation
LS Geometric means and 90% CI are estimated for each dose as well as the estimate (90% CI) of 
change from baseline for each timepoint, using the time matched baseline. 
Note: For post dose 24-48hrs baseline (predse) is not available
10.1.4.1.2. Statistical Methodology Specification for Part B (Repeat Dose)
Pharmacodynamic Statistical Analyses – Mixed Effect Model – Repeat Dose (Part B)
Endpoint / Variables
tPGDM, tPGEM, Creatinine, Creatinine corrected tPGDM and Creatinine corrected tPGEM
(Aggregated values for predose 24-12hr & 12-0hr and postdose 0-12 hr, 12-24 hr & 24-48 hr)
Model Specification
Loge transformed values of the endpoints will be statistically analyzed using Mixed Model (MM).

Fixed effect: timepoint, dose, timepoint*dose

Random effect: Subject 
An unstructured covariance structure for the G matrix will be used.

If this model fails to converge, alternative covariance structures may be considered.

Akaike’s Information Criteria (AIC) will be used to assist with the selection of covariance 
structure.
Analyses will be done with the MIXED Procedure in SAS, using the Kenward-Roger option to 
estimate denominator degrees of freedom and standard errors
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.
Model Results Presentation
LS Geometric means and 90% CI are estimated for each dose as well as the estimate (90% CI) of 
change from baseline for each timepoint, using the time matched baseline. 
Note: For post dose 24-48hrs baseline (predose) is not available
Consider Day -1(predose), Day1, Day 7, Day 10, Day 17


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11.
PHARMACOKINETIC / PHARMACODYNAMIC
ANALYSES
A detailed population PK/PD data analysis plan will be prepared in a separate RAP. 


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12.
REFERENCES
GlaxoSmithKline Document Number 2018N361438_03: Study Protocol of 209275, A Three-Part 
FTIH Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single 
and Repeat Oral Doses of GSK3439171A, in a Randomized, Double-Blind (sponsor unblinded), 
Placebo Controlled, Dose Escalation study and to Evaluate the Effect of Food on a Single Oral 
Dose of GSK3439171A in Healthy Adult Participants


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13.
APPENDICES
13.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
As Per Protocol Population is not defined, this section is not applicable.


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13.2.
Appendix 2: Schedule of Activities
13.2.1.
Protocol Defined Schedule of Events
SoA – Part A
Part A- Single Dose 
Procedure
Screening 
(up to 30 
days 
before Day 
1)
Treatment Period [Days] (for each dosing period)
Follow-
up
(~14±1 
days 
post last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
-1
1
2
3
4
E.D.
Informed consent
X
Inclusion and 
exclusion criteria 
(including drug 
screens)
X
X
Recheck clinical status before 
randomization and/or 1st dose of 
study medication.
Demography
X
Physical examination 
including height and 
weight
F
B
B
(B)
F
F: Full exam; B: Brief Exam; height 
is only taken once at screening


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Part A- Single Dose 
Procedure
Screening 
(up to 30 
days 
before Day 
1)
Treatment Period [Days] (for each dosing period)
Follow-
up
(~14±1 
days 
post last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
-1
1
2
3
4
E.D.
Medical history 
(includes substance 
usage and family 
history of premature 
cardiovascular (CV) 
disease and any 
changes in health 
status occurring 
between screening 
and admission to the 
unit)
X
X
Substances: Drugs, Alcohol, 
tobacco, and caffeine
Past and current 
medical conditions  
X
X
Human 
Immunodeficiency 
Virus (HIV), Hepatitis 
B and C screening
X
If test otherwise performed within 3 
months prior to first dose of study 
intervention, testing at screening is 
not required
Admission to Clinical 
Unit
X
Safety Laboratory 
assessments 
(include liver 
chemistries)
X
X
X
X
X
X
(X)
X
Predose; 8 hr, 24 hr, and, 48 hr, and 
72 hr post-dose and at follow-up visit
Routine Urinalysis
X
X
X
X
X
(X)
X
Predose; 8 hr, 24 hr, 48 hr, and 72 
hr post-dose and at follow-up visit 


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Part A- Single Dose 
Procedure
Screening 
(up to 30 
days 
before Day 
1)
Treatment Period [Days] (for each dosing period)
Follow-
up
(~14±1 
days 
post last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
-1
1
2
3
4
E.D.
12-lead 
Electrocardiogram 
(ECG)
X
X
======================X=====================
(X)
X
ECGs assessed at screening 
(triplicate) and admission (single).  
During treatment period ECGs 
assessed predose (triplicate at least 
5 minutes (min) intervals) and 
single measurements postdose 
every 30 min for 1 hr, hourly up to 6 
hr, and at 12 hr, 24 hr, 36 hr and 48 
hr and 72 hr post-dose 
Vital signs (pulse 
rate, blood pressure 
(bp), respiratory rate, 
and oral 
temperature)
X
X
======================X======================
(X)
X
Vitals assessed at screening 
(triplicate measurements for pulse 
and (bp)) (and admission (single 
measurements).  During treatment 
period vitals assessed predose 
(triplicate measurements for pulse 
and bp) and postdose (single 
measurements) every 15 min for 1 
hr, hourly up to 6 hr, then at 12 hr, 
24 hr, 36 hr, 48 hr, and 72 hr post-
dose.
See Section 8.2.2 for further
information
Randomization
X
Randomization will occur before 
first dose in period 1.


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Part A- Single Dose 
Procedure
Screening 
(up to 30 
days 
before Day 
1)
Treatment Period [Days] (for each dosing period)
Follow-
up
(~14±1 
days 
post last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
-1
1
2
3
4
E.D.
Genetic sample
X
Any time predose on Day 1. 
This research may be described in 
a separate Informed Consent Form 
(ICF) or as part of a combined ICF.  
A separate signature is required 
where participant participation is 
optional
Study intervention
X
Telemetry
X
Telemetry performed starting 30 
min (10 min) pre-dose to 12 hr 
(20 min) post-dose
Adverse Event (AE) 
review
=======================X====================
(X)
X
Serious Adverse 
Event (SAE) review
X
===========================X=============================
(X)
X
Concomitant 
medication review
X
======================X=====================
(X)
X


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Part A- Single Dose 
Procedure
Screening 
(up to 30 
days 
before Day 
1)
Treatment Period [Days] (for each dosing period)
Follow-
up
(~14±1 
days 
post last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
-1
1
2
3
4
E.D.
24hr urine sampling 
for 
Pharmacodynamics 
(PD)
X1
X2
X3
X3
(X)
1combined void for windows of 24-
22 hr, 22-20 hr, 20-18 hr, 18-16 hr, 
16-12 hr, and 12-0 hr predose.
2 combined void for windows of 0-2 
hr, 2-4 hr, 4-6 hr, 6-8 hr 8-12 hr, 
and 12-24 hr post-dose 
3combined void for 24 hr
Blood sampling for 
Pharmacokinetics 
(PK)
======================X=====================
(X)
Predose, 5min, 30min, 1 hr, 1.5 hr, 
2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 10 hr, 12 
hr, 18 hr, 24 hr, 36 hr, and 48 hr, 60 
hr, and 72 hr post-dose
24 hr Holter 
Monitoring
X
Predose through 24 hr post-dose
Discharge from 
Clinical Unit
X
(X)


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The timing and number of planned study assessments, including safety, PK, PD/biomarker 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 as the result of emerging 
pharmacokinetic/pharmacodynamic data from this study must be documented and approved by the relevant study team member and then 
archived in the sponsor and site study files, but will not constitute a protocol amendment. The Competent Authority (CA) and ethics 
committee (EC) will be informed of any safety issues that constitute a substantial amendment and require alteration of the safety 
monitoring scheme or amendment of the ICF. The changes will be approved by the CA and the EC before implementation.


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SoA – Part B
Part B – Repeat Dose 
Procedure
Screening 
(up to 30 
days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5-7
8
9-11
12
13-14
15
16
17
18
19
20
Informed consent
X
Inclusion and 
exclusion criteria 
(including drug 
screens)
X
X
Recheck clinical status 
before randomization and 
prior to muscle biopsy/or 
1st dose of study 
medication.
Demography
X
Full physical 
examination 
including height 
and weight
F
B
B
(B)
F
F: Full exam; B: Brief 
exam; height is only taken 
once at screening
Medical history 
(includes 
substance usage 
and family history 
of premature CV 
disease and any 
changes in health 
status occurring 
between screening 
and admission to 
the unit)
X
X
Substances: Drugs, 
Alcohol, tobacco, and 
caffeine


CONFIDENTIAL
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43
Part B – Repeat Dose 
Procedure
Screening 
(up to 30 
days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5-7
8
9-11
12
13-14
15
16
17
18
19
20
Past and current 
medical conditions  
X
X
HIV, Hepatitis B 
and C screening
X
If test otherwise 
performed within 3 
months prior to first dose 
of study intervention, 
testing at screening is not 
required
Admission to 
Clinical Unit
X
Safety Laboratory 
assessments 
(include liver 
chemistries)
X
X
X
X1
X1
X1
X
(X)
X1
Pre-randomization 
assessments for eligibility 
must be performed 
PRIOR to predose muscle 
biopsy
Predose, 24 hr, and 48, 
and 72 hr post-Day 1 
dose; additional 
timepoints may be added 
based on findings in Part 
A
1Days 7, 11, 17, 20,  and 
follow-up


CONFIDENTIAL
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44
Part B – Repeat Dose 
Procedure
Screening 
(up to 30 
days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5-7
8
9-11
12
13-14
15
16
17
18
19
20
Routine urinalysis
X
X
X
X2
X2
X2
X2
(X)
X2
Predose, 24 hr, 48 hr, and 
72 hr post-Day 1 dose; 
additional timepoints may 
be added based on 
findings in Part A
2Days 7, 11,17, 20, and 
follow-up


CONFIDENTIAL
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45
Part B – Repeat Dose 
Procedure
Screening 
(up to 30 
days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5-7
8
9-11
12
13-14
15
16
17
18
19
20
Hormone 
monitoring 
X
X
(X)
Samples to be taken at 
midnight and 9am (10 
min) on Days -1 and 17 
Samples taken at midnight 
will be analysed for 
adrenocorticotropic 
hormone (ACTH) and 
cortisol
Samples taken at 9am will 
be analysed for ACTH, 
cortisol, luteinizing 
hormone (LH), follicle 
stimulating hormone 
(FSH), thyroid stimulating 
hormone (TSH), total 
testosterone, 
dihydrotestosterone (DHT), 
triiodothyronine (T3), and 
free thyroxine (free T4) 
See Section 8.2.7. in 
Protocol for information 
regarding monitoring of 
abnormal hormone results


CONFIDENTIAL
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46
Part B – Repeat Dose 
Procedure
Screening 
(up to 30 
days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5-7
8
9-11
12
13-14
15
16
17
18
19
20
12-lead ECG
X
X
=====X5=====
X5
X5
X5
X5
X5
(X)
X
ECGs assessed at 
screening (triplicate 
measure) and admission 
(single measure).  During 
treatment period ECGs 
assessed predose 
(triplicate measure at at 
least 5 min intervals) and 
post-dose (single 
measure) every 30 min for 
1 hr, hourly up to 6 hr, at 
12 hr post-dose then at 24 
hr, 36 hr, 48 hr, and 72 hr 
post-dose 
5 Days 7,11, 15, and 17, 
and 20 Post-dose at 
Cmax based on observed 
Cmax in Part A (currently 
estimated to occur at ~2 
hr post dose), except for 
Day 20. Day 20 ECG to 
occur any time before 
Discharge


CONFIDENTIAL
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47
Part B – Repeat Dose 
Procedure
Screening 
(up to 30 
days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5-7
8
9-11
12
13-14
15
16
17
18
19
20
Vital signs (pulse 
rate, bp, respiratory 
rate, and oral 
temperature)
X
X
X6
X7
X6
(X)
X
6Vitals assessed at 
screening (triplicate 
measurements for pulse 
and bp) and admission 
(single measurements).  
During treatment period 
vitals assessed predose 
(triplicate measurements 
for pulse and bp) and 
postdose (single 
measurements) every 15 
min for 1 hr, hourly up to 6 
hr, and at 12 hr, 24 hr, 36 
hr, 48 hr, and 72 hr post-
dose
7Vitals assessed once 
every 24 hr
See Section 8.2.2. in 
Protocol for further 
information
Randomization
X


CONFIDENTIAL
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48
Part B – Repeat Dose 
Procedure
Screening 
(up to 30 
days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5-7
8
9-11
12
13-14
15
16
17
18
19
20
Genetic sample
X
Any time predose on Day 
1
This research may be 
described in a separate 
ICF or as part of a 
combined ICF.  A 
separate signature is 
required where participant 
participation is optional
Study intervention
X
====================X======================
Telemetry
X
Telemetry performed 
starting 30 (10 min) pre-
dose to 12 hr (20 min) 
post-dose
AE review
=============================X==============================
SAE review
=========================================X========================================
Concomitant 
medication review
=========================================X========================================


CONFIDENTIAL
209275
49
Part B – Repeat Dose 
Procedure
Screening 
(up to 30 
days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5-7
8
9-11
12
13-14
15
16
17
18
19
20
Urine sampling PD
X8
X9
X9
X9, 10
X9
(X)
8combined void for 
windows of 24-22 hr, 22-
20 hr, 20-18 hr, 18-16 hr, 
16-12 hr, and 12-0 hr 
predose. 
9combined void for 
windows of 0-2 hr, 2-4 hr, 
4-6 hr, 6-8 hr, 8-12 hr, 
and 12-24 hr post-dose 
10 Day 10 only
Aliquots will be removed 
prior to pooling for urine 
PK. Total urine volume 
will be recorded before 
aliquots for PD are 
removed.


CONFIDENTIAL
209275
50
Part B – Repeat Dose 
Procedure
Screening 
(up to 30 
days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5-7
8
9-11
12
13-14
15
16
17
18
19
20
24h urine sampling 
for PK and 
metabolite profiling
X
X
X
X
(X)
Voids from urine 
pharmacodynamic (PD) 
sampling windows will be 
combined into 0-24 hr 
pools on Day -1,1, and 17 
after aliquoting for PD. 
These voids will be 
combined for 
PK/metabolite analysis 
only after aliquots for 
urine PD are removed
See study reference 
manual (SRM) for details 
on samples and 
processing


CONFIDENTIAL
209275
51
Part B – Repeat Dose 
Procedure
Screening 
(up to 30 
days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5-7
8
9-11
12
13-14
15
16
17
18
19
20
Blood sampling for 
PK
X11
X12
X12
X12
X11
(X)
11Day 1 and Day 17: 
Predose, 5 min, 30 min, 1 
hr, 1. 5hr, 2 hr, 3 hr, 4 hr, 
6 hr, 8 hr, 10 hr, 12 hr, 18 
hr, 24 hr, 36 hr, 48 hr, 60 
hr, and 72 hr post-dose
12pre-dose samples 
collected on days 6,7, 9-
11 and 15-16
Blood sampling for 
metabolite profiling
X
X
Day 1 and Day 17: 
Predose, 5 min, 30 min, 1 
hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 
6 hr, 8 hr, 10 hr, 12 hr, 18 
hr, 24 hr, 36 hr, 48 hr, 60 
hr, and 72 hr post-dose
Blood sampling for 
Pharmacodynamics 
and biomarkers
X13
X13
X14
X14
(X)
13Predose and 24 hr post-
dose on Day 1  
14Predose Days 10 and 
17


CONFIDENTIAL
209275
52
Part B – Repeat Dose 
Procedure
Screening 
(up to 30 
days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5-7
8
9-11
12
13-14
15
16
17
18
19
20
Muscle Biopsy
X15
X16
(X)
Muscle biopsies must be 
performed AFTER clinical 
safety assessments on 
the corresponding days
15Day -1 muscle biopsy to 
occur 1-6 hr after 
estimated timing of initial 
dose on Day 1. Time of 
sample collection to be 
recorded
16Muscle Biopsy 
performed any time during 
pre-dose period; Day 17 
muscle biopsy to occur 
within 1-6 hr after last 
dose administered
Time of sample collection 
to be recorded. Muscle 
biopsy can be performed 
at any time during pre-
dose period.


CONFIDENTIAL
209275
53
Part B – Repeat Dose 
Procedure
Screening 
(up to 30 
days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–2
–1
1
2
3
4
5-7
8
9-11
12
13-14
15
16
17
18
19
20
Enterotest (bile 
sample collection)
X
For second or third dose-
level only (depending on 
PK results in Part A)
Enterotest capsule to be 
swallowed ~2 hr after 
dosing and removed ~7 hr 
after dosing (~1 hr after 
food cue)
Enterotest food cue
X
For second or third dose-
level only (depending on 
PK results in Part A)
Food cue will be given 6 
hr post-dose
Discharge from 
Clinical Unit
X
(X)

The time to start the second dose in Part B can be modified based on the estimates of half-life from Part A.

Duration of dosing in Part B can be modified based on the estimates of half-life from Part A.


CONFIDENTIAL
209275
54

The timing and number of planned study assessments, including safety, PK, PD/biomarker 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 as the result of emerging 
pharmacokinetic/pharmacodynamic data from this study must be documented and approved by the relevant study team member and then 
archived in the sponsor and site study files, but will not constitute a protocol amendment. The CA and EC will be informed of any safety 
issues that constitute a substantial amendment and require alteration of the safety monitoring scheme or amendment of the ICF. The 
changes will be approved by the CA and the EC before implementation.


CONFIDENTIAL
209275
55
Part B .2– 7 Day Repeat Dose 
Procedure
Screenin
g 
(up to 30 
days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawa
l
–2
–1
1
2
3
4
5
6
7
8
9
10
11
12
13
Informed consent
X
Inclusion and 
exclusion criteria 
(including drug 
screens)
X
X
Recheck clinical status 
before randomization and 
prior to muscle biopsy/or 
1st dose of study 
medication.
Demography
X
Full physical 
examination 
including height 
and weight
F
B
B
(B)
F
F: Full exam; B: Brief 
exam; height is only taken 
once at screening
Medical history 
(includes 
substance usage 
and family history 
of premature CV 
disease and any 
changes in health 
status occurring 
between screening 
and admission to 
the unit)
X
X
Substances: Drugs, 
Alcohol, tobacco, and 
caffeine


CONFIDENTIAL
209275
56
Part B .2– 7 Day Repeat Dose 
Procedure
Screenin
g 
(up to 30 
days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawa
l
–2
–1
1
2
3
4
5
6
7
8
9
10
11
12
13
Past and current 
medical conditions  
X
X
HIV, Hepatitis B 
and C screening
X
If test otherwise 
performed within 3 
months prior to first dose 
of study intervention, 
testing at screening is not 
required
Admission to 
Clinical Unit
X
Safety Laboratory 
assessments 
(include liver 
chemistries)
X
X
X
X1
X1
X1
(X)
X1
Pre-randomization 
assessments for eligibility 
must be performed 
PRIOR to predose 
muscle biopsy
Predose, 24 hr, and 48, 
and 72 hr post-Day 1 
dose; additional 
timepoints may be added 
based on findings in Part 
A
1Days 7, 10, 13, and 
follow-up


CONFIDENTIAL
209275
57
Part B .2– 7 Day Repeat Dose 
Procedure
Screenin
g 
(up to 30 
days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawa
l
–2
–1
1
2
3
4
5
6
7
8
9
10
11
12
13
Routine urinalysis
X
X
X
X2
X2
X2
(X)
X2
Predose, 24 hr, 48 hr, 
and 72 hr post-Day 1 
dose; additional 
timepoints may be added 
based on findings in Part 
A
2Days 7, 10, 13, and 
follow-up


CONFIDENTIAL
209275
58
Part B .2– 7 Day Repeat Dose 
Procedure
Screenin
g 
(up to 30 
days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawa
l
–2
–1
1
2
3
4
5
6
7
8
9
10
11
12
13
Hormone 
monitoring 
X
X
Samples to be taken at 
midnight and 9am (10 
min) on Days -1 and 10 
Samples taken at midnight 
will be analysed for 
adrenocorticotropic 
hormone (ACTH) and 
cortisol
Samples taken at 9am will 
be analysed for ACTH, 
cortisol, luteinizing 
hormone (LH), follicle 
stimulating hormone 
(FSH), thyroid stimulating 
hormone (TSH), total 
testosterone, 
dihydrotestosterone 
(DHT), triiodothyronine 
(T3), and free thyroxine 
(free T4) 
See Section 8.2.7. in 
Protocol for information 
regarding monitoring of 
abnormal hormone results


CONFIDENTIAL
209275
59
Part B .2– 7 Day Repeat Dose 
Procedure
Screenin
g 
(up to 30 
days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawa
l
–2
–1
1
2
3
4
5
6
7
8
9
10
11
12
13
12-lead ECG
X
X
=====X=====
X5
X5
X5
(X)
X5
ECGs assessed at 
screening (triplicate 
measure) and admission 
(single measure).  During 
treatment period ECGs 
assessed predose 
(triplicate measure at at 
least 5 min intervals) and 
post-dose (single 
measure) every 30 min 
for 1 hr, hourly up to 6 hr, 
at 12 hr post-dose then at 
24 hr, 36 hr, 48 hr, and 
72 hr post-dose 
5 Days 7,10, 13, and 
Follow-up Post-dose at 
Cmax based on observed 
Cmax in Part A (currently 
estimated to occur at ~2 
hr post dose), except for 
Day 13 . Day 13 ECG to 
occur any time before 
Discharge


CONFIDENTIAL
209275
60
Part B .2– 7 Day Repeat Dose 
Procedure
Screenin
g 
(up to 30 
days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawa
l
–2
–1
1
2
3
4
5
6
7
8
9
10
11
12
13
Vital signs (pulse 
rate, bp, respiratory 
rate, and oral 
temperature)
X
X
X6
X7
X6
(X)
X
6Vitals assessed at 
screening (triplicate 
measurements for pulse 
and bp) and admission 
(single measurements).  
During treatment period 
vitals assessed predose 
(triplicate measurements 
for pulse and bp) and 
postdose (single 
measurements) every 15 
min for 1 hr, hourly up to 
6 hr, and at 12 hr, 24 hr, 
36 hr, 48 hr, and 72 hr 
post-dose
7Vitals assessed once 
every 24 hr
See Section 8.2.2.  in 
Protocol for further 
information
Randomization
X


CONFIDENTIAL
209275
61
Part B .2– 7 Day Repeat Dose 
Procedure
Screenin
g 
(up to 30 
days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawa
l
–2
–1
1
2
3
4
5
6
7
8
9
10
11
12
13
Genetic sample
X
Any time predose on Day 
1
This research may be 
described in a separate 
ICF or as part of a 
combined ICF.  A 
separate signature is 
required where participant 
participation is optional
Study intervention
X
==================X===================
Telemetry
X
Telemetry performed 
starting 30 (10 min) pre-
dose to 12 hr (20 min) 
post-dose
AE review
=========================================X==========================================
SAE review
====================================================X========================================================
Concomitant 
medication review
========================================================X================================================


CONFIDENTIAL
209275
62
Part B .2– 7 Day Repeat Dose 
Procedure
Screenin
g 
(up to 30 
days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawa
l
–2
–1
1
2
3
4
5
6
7
8
9
10
11
12
13
Urine sampling PD
X8
X9
X9
X9
(X)
8combined void for 
windows of 24-22 hr, 22-
20 hr, 20-18 hr, 18-16 hr, 
16-12 hr, and 12-0 hr 
predose. 
9combined void for 
windows of 0-2 hr, 2-4 hr, 
4-6 hr, 6-8 hr, 8-12 hr, 
and 12-24 hr post-dose 
Aliquots will be removed 
prior to pooling for urine 
PK. Total urine volume 
will be recorded before 
aliquots for PD are 
removed.


CONFIDENTIAL
209275
63
Part B .2– 7 Day Repeat Dose 
Procedure
Screenin
g 
(up to 30 
days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawa
l
–2
–1
1
2
3
4
5
6
7
8
9
10
11
12
13
24h urine sampling 
for PK and 
metabolite profiling
X
X
X
(X)
Voids from urine 
pharmacodynamic (PD) 
sampling windows will be 
combined into 0-24 hr 
pools on Day -1,1, and 10 
after aliquoting for PD. 
These voids will be 
combined for 
PK/metabolite analysis 
only after aliquots for 
urine PD are removed
See study reference 
manual (SRM) for details 
on samples and 
processing


CONFIDENTIAL
209275
64
Part B .2– 7 Day Repeat Dose 
Procedure
Screenin
g 
(up to 30 
days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawa
l
–2
–1
1
2
3
4
5
6
7
8
9
10
11
12
13
Blood sampling for 
PK
X10
X11
X11
X11
X10
(X)
10Day 1 and Day 10: 
Predose, 5 min, 30 min, 1 
hr, 1. 5hr, 2 hr, 3 hr, 4 hr, 
6 hr, 8 hr, 10 hr, 12 hr, 18 
hr, 24 hr, 36 hr, 48 hr, 60 
hr, and 72 hr post-dose
11pre-dose samples 
collected on days 6, 7, 
and 9 
Blood sampling for 
metabolite profiling
X
X
Day 1 and Day 10
Predose, 5 min, 30 min, 1 
hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 
6 hr, 8 hr, 10 hr, 12 hr, 18 
hr, 24 hr, 36 hr, 48 hr, 60 
hr, and 72 hr post-dose
Blood sampling for 
Pharmacodynamic
s and biomarkers
X12
X12
X13
X13
(X)
12Predose and 24 hr post-
dose on Day 1  
13Predose Days 7 and 10


CONFIDENTIAL
209275
65
Part B .2– 7 Day Repeat Dose 
Procedure
Screenin
g 
(up to 30 
days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawa
l
–2
–1
1
2
3
4
5
6
7
8
9
10
11
12
13
Muscle Biopsy
X14
X15
(X)
Muscle biopsies must be 
performed AFTER clinical 
safety assessments on 
the corresponding days
14Day -1 muscle biopsy to 
occur 1-6 hr after 
estimated timing of initial 
dose on Day 1. Time of 
sample collection to be 
recorded
15Day 10  muscle biopsy 
to occur within 1-6 hr after 
last dose administered
Time of sample collection 
to be recorded. Muscle 
biopsy can be performed 
at any time during pre-
dose period.


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Part B .2– 7 Day Repeat Dose 
Procedure
Screenin
g 
(up to 30 
days 
before 
Day 1)
Intervention Period [Days] (for each dosing cohort)
E.D
Follow-
up
(~14±1 
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawa
l
–2
–1
1
2
3
4
5
6
7
8
9
10
11
12
13
Discharge from 
Clinical Unit
X
(X)

The time to start the second dose in Part B can be modified based on the estimates of half-life from Part A.

Duration of dosing in Part B can be modified based on the estimates of half-life from Part A.

The timing and number of planned study assessments, including safety, PK, PD/biomarker 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 as the result of emerging 
pharmacokinetic/pharmacodynamic data from this study must be documented and approved by the relevant study team member 
and then archived in the sponsor and site study files, but will not constitute a protocol amendment. The CA and EC will be 
informed of any safety issues that constitute a substantial amendment and require alteration of the safety monitoring scheme or 
amendment of the ICF. The changes will be approved by the CA and the EC before implementation.


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Part C- Food Effect 
Screening 
(up to 30
days 
before Day 
1)
Treatment Period [Days] (with or without food)
Follow-
up
(~14±1
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–1
1
2
3
4
E.D.
Informed 
consent
X
Inclusion and 
exclusion criteria 
(including drug 
screens)
X
X
Recheck clinical status 
before randomization and/or 
1st dose of study medication.
Demography
X
Physical 
examination 
including height 
and weight
F
B
B
(B)
F
F: Full exam; B: Brief Exam; 
height is only taken once at 
screening


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Part C- Food Effect 
Screening 
(up to 30
days 
before Day 
1)
Treatment Period [Days] (with or without food)
Follow-
up
(~14±1
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–1
1
2
3
4
E.D.
Medical history 
(includes 
substance 
usage and 
family history of 
premature CV 
disease and any 
changes in 
health status 
occurring 
between 
screening and 
admission to the 
unit)
X
X
Substances: Drugs, Alcohol, 
tobacco, and caffeine
Past and current 
medical 
conditions  
X
X
HIV, Hepatitis B 
and C screening
X
If test otherwise performed 
within 3 months prior to first 
dose of study intervention, 
testing at screening is not 
required
Admission to 
Clinical Unit
X


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Part C- Food Effect 
Screening 
(up to 30
days 
before Day 
1)
Treatment Period [Days] (with or without food)
Follow-
up
(~14±1
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–1
1
2
3
4
E.D.
Safety 
Laboratory 
assessments 
(including liver 
chemistries)
X
X
X
X
X
X
(X)
X
Predose; 8 hr, 24 hr, 48 hr, 
and 72 hr post-dose and at 
follow-up visit
Routine 
Urinalysis
X
X
X
X
X
(X)
X
Predose; 8 hr, 24 hr, 48 hr, 
and 72hr post-dose and at 
follow-up visit
12-lead ECG
X
X
===========================X===============================
(X)
X
ECGs assessed at screening 
(triplicate) and admission 
(single).  During treatment 
period ECGs assessed 
predose (triplicate at least 5 
min intervals) and single 
measurements postdose 
every 30 min for 1 hr, hourly 
up to 6 hr, and at 12 hr, 24 
hr, 36 hr, 48 hr, and 72 hr 
post-dose 


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Part C- Food Effect 
Screening 
(up to 30
days 
before Day 
1)
Treatment Period [Days] (with or without food)
Follow-
up
(~14±1
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–1
1
2
3
4
E.D.
Vital signs (pulse 
rate, bp, 
respiratory rate, 
and oral 
temperature)
X
X
=======================X=======================
(X)
X
Vitals assessed at screening 
(triplicate measurements for 
pulse and bp) and admission 
(single measurements).  
During treatment period vitals 
assessed predose (triplicate 
measurements for pulse and 
bp) and postdose (single 
measurements) every 15 min 
for 1 hr, hourly up to 6 hr, and 
at 12 hr, 24 hr, 36 hr, 48 hr, 
and 72 hr post-dose
See Section 8.2.2. in Protocol
for further information
Randomization
X


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Part C- Food Effect 
Screening 
(up to 30
days 
before Day 
1)
Treatment Period [Days] (with or without food)
Follow-
up
(~14±1
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–1
1
2
3
4
E.D.
Genetic sample
X
Sample can be obtained at 
any point during dosing. This 
research may be described in 
a separate ICF or as part of a 
combined ICF.  A separate 
signature is required where 
participant participation is 
optional
Test Meal
X
Fed Arm only. See Section 
5.3.1. in Protocol for timings 
regarding meals, fasting, and 
treatment administration
Study 
intervention
X
Telemetry
X
Telemetry performed starting 
30 min (10 min) pre-dose to 
12hrs (20 min) post-dose
AE review
===================X===================
(X)
X
SAE review
X
             ================================X==============================
(X)


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Part C- Food Effect 
Screening 
(up to 30
days 
before Day 
1)
Treatment Period [Days] (with or without food)
Follow-
up
(~14±1
days 
post 
last 
dose)
Notes
E.D = early 
discontinuation/withdrawal
–1
1
2
3
4
E.D.
Concomitant 
medication 
review
X
================================X==============================
(X)
X
Blood sampling 
for PK
======================X=====================
(X)
3Predose, 5 min, 30 min, 1 
hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 
hr, 8 hr, 10 hr, 12 hr, 18 hr, 
24 hr, 36 hr, and 48 hr, 60 hr, 
and 72 hr post-dose
Discharge from 
Clinical Unit
X
(X)

Duration of dosing in Part C can be modified based on the estimates of half-life from Part A.

The timing and number of planned study assessments, including safety, PK, PD/biomarker 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 as the result of emerging 
pharmacokinetic/pharmacodynamic data from this study must be documented and approved by the relevant study team member and then 
archived in the sponsor and site study files, but will not constitute a protocol amendment. The CA and EC will be informed of any safety 
issues that constitute a substantial amendment and require alteration of the safety monitoring scheme or amendment of the ICF. The 
changes will be approved by the CA and the EC before implementation.


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13.3.
Appendix 3: Assessment Windows
Nominal time will be used for all analysis except PK analysis where planned and actual
time will be used.


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13.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
13.4.1.
Study Phases
Assessments and events will be classified according to the time of occurrence relative to 
study treatment
Study Phase
Definition
Pre-Treatment 
Date ≤ Study Treatment Start Date
On-Treatment
Study Treatment Start Date < Date ≤ Study Treatment Stop Date + 3 days
Post-Treatment
Date > Study Treatment Stop Date + 3 days
Note: Estimated half-life of GSK3439171 is approx. 13 hours. The maximum of (5 
halflives ~ 65 hours ~ 3days) and after the Study Treatment End Date, lag time have been 
considered to be 3 days to define the end of treatment phase.
13.4.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before 28 days, prior to screening visit
Concomitant
Any medication that is not a prior
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.


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13.5.
Appendix 5: Data Display Standards & Handling Conventions
13.5.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: us1salx00259
HARP Compound
: /arenv/arprod/gsk3439171/mid209275/final_01
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG Version 1.0
Generation of RTF Files

RTF files will be generated for SAC.
13.5.2.
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.


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
The reported precision from non eCRF sources will follow the IDSL statistical principles but may be adjusted to a clinically interpretable number of DP’s.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days on the analyses and interpretation of the results will be 
assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 
Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or figures. However, for baseline consideration if the latest predose is an unscheduled visit, then as 
per the baseline definition, this will be considered as baseline. And unscheduled visits will be taken into consideration for calculating worst-case post baseline 
value in ECG displays as well.

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.
13.5.3.
Reporting Standards for Pharmacokinetic
Concentration Data
Descriptive 
Summary Statistics
Refer to IDSL Statistical Principle 6.06.1
Assign zero to NQ values (Refer to GUI_51487 for further details)
Pharmacokinetic Parameters
Descriptive 
Summary Statistics 
(Log Transformed)
N, n, geometric mean, 90% CI of geometric mean, standard deviation (SD) of logged data and between geometric coefficient of variation 
(CVb (%)) will be reported.


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CVb (%) = √ (exp(SD2) - 1) * 100 [NOTE: SD = SD of loge transformed    data]
Following steps can be used to calculate 90% CI for PK parameters:
Standard Error = [(Geometric Stdev-1)/Sqrt(N)],
Margin of Error = [Standard Error * 1.645], and
CI = [Geometric Mean Margin of Error]
Parameters Not 
Being Log 
Transformed
tmax, t½
Summary Tables
Cmax, tmax, AUC(0-τ), AUC(0-t), AUC (0-∞), AUC (Ro),
Rcmax, Cτ, t1/2, Rss, Ae, fe, CLr, as data permit
Listings
Include PK Parameters Cmax, tmax, AUC(0-τ), AUC(0-t), AUC
(0-∞), AUC (Ro), Rcmax, Cτ, t1/2, Rss, Ae, fe, CLr, as data
Permit
Graphical Displays
Refer to IDSL Statistical Principles 7.01 to 7.13 and Standards for the Transfer and
Reporting of PK Data using HARP.


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Pharmacokinetic Concentration Data
PC Windows Non-
Linear (WNL) File
PC WNL file (CSV format) for the noncompartmental analysis by Clinical Pharmacology Modelling and Simulation function will be
created according to [Insert document name]. 
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
The following PK parameters will be derived by the Programmer: [Insert PK parameters, e.g. C24, C12, AUC/Dose]
Pharmacokinetic Parameter Data
Is NQ impacted PK 
Parameters Rule 
Being Followed
No. 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.


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13.6.
Appendix 6: Derived and Transformed Data
13.6.1.
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.

If there are two values within a time window the value closest to the target day for that window will be used. If values are the same distance from the target, then 
the mean will be taken.

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 and C, 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 in the period

Ref Data ≥ First Dose Date in the period→ Period Study Day = Ref Date – First Dose Date in the period + 1
In Part A, B & C: 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    
Change from baseline and Percentage change from baseline definition
Change from Baseline = Post-Dose Visit Value – Baseline (For Part A & C, corresponding period baseline should be considered as baseline)
Percentage Change from Baseline = ((Post-Dose Visit Value – Baseline)/Baseline)*100 (For Part A & C, corresponding period baseline should be 
considered as baseline)

Unless otherwise specified, the baseline definitions specified in Section 5.2 Baseline Definition will be used for derivations for endpoints / parameters and indicated on summaries
and listings

Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing
Displays


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
Compound ID should be used as GSK3439171 for the displays

Listings: Since it is single site study, site id and investigator id will be included in ‘Listing of Planned and Actual Treatment’ and will be excluded 
from other Listings.

Safety summaries and figures:
o
Part A and B, ‘All treatment’ total (Subjects on treatment except placebo) should be included and footnote to indicate this. Part C overall 
‘Total’ should be included.
o
Part A and C, in Lab, Vitals and ECG displays, Day -2 and -1(if available) should be included for absolute value displays. 
o
Part B in Lab, Vitals and ECG displays, Day -2 and -1(if available) should be included for absolute value displays along with screening 
and follow up data. And for change from baseline and percentage change from baseline displays follow up data should be included
13.6.2.
Study Population
Treatment Compliance

Treatment compliance will be calculated based on the formula:  
Treatment Compliance = Number of Actual Doses / (Planned Treatment Duration in Days * Frequency)

Frequency is 2 for BID and 1 for QD. Treatment compliance could be greater than 100% if there are events of overdose. Cumulative compliance (since Day 1) at 
each visit will be calculated.
Extent of Exposure

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. 

The cumulative dose will be based on the formula:
Cumulative Dose = Sum of (Number of Days x Total Daily Dose)

If there are any treatment breaks during the study, exposure data will be adjusted accordingly.


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13.6.3.
Safety
Laboratory Parameters

If a laboratory value which is expected to have a numeric value for summary purposes, has a non-
detectable level reported in the database, where the numeric value is missing, but typically a character 
value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the comment field) is 
present, the number of significant digits in the observed values will be used to determine how much to 
add or subtract in order to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01
o
Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1    
ECG Parameters
RR Interval

If RR interval (msec) is not provided directly, then RR can be derived as:
[1] If QTcF is machine read, then: 

If ECGs are manually read, the RR value preceding the measurement QT interval should be a collected 
value. THEN do not derive.
Corrected QT Intervals

When not entered directly in the ClinBase, corrected QT intervals by Fredericia’s (QTcF) formula will be 
calculated in msec, depending on the availability of other measurements.

IF RR interval (msec) is provided then missing QTcF will be derived as: 


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13.6.4.
Pharmacokinetic
PK Parameters
The PK Population will include all subjects who undergo PK sampling and have evaluable PK assay results.

See Table 2. Derived Pharmacokinetic Parameters (Primary end points) and Table 3. Derive
d Pharmacokinetic Parameters (Secondary end points) for derived Pharmacokinetic parameters


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13.7.
Appendix 7: Reporting Standards for Missing Data
13.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as ‘A 
participant is considered to have completed the study if he/she has completed all 
phases of the study including or the last scheduled procedure shown in the SoA.’

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.
13.7.2.
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:
o
These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
13.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse Events

The Clinbase allows for the possibility of partial dates (i.e., only month and year) 
to be recorded for AE start and end dates; that is, the day of the month may be 
missing. In such a case, the following conventions will be applied for calculating 
the time to onset and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is before the 
start date of study treatment; in this case the study treatment start date will 
be used and hence the event is considered On-treatment as per Appendix 
4: Study Phases 
o
Missing Stop Day: Last day of the month will be used, unless this is after 
the stop date of study treatment; in this case the study treatment stop date 
will be used.

Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be 
missing.
Concomitant 
Medications/Medical 
History

Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 


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Element
Reporting Detail
(dependent on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.

For each period in crossover design:
o
If start date is completely missing, then we assume the medication 
has been taken from the beginning of the study
o
If stop date is completely missing, then we assume the medication 
has been taken until the end of the study
13.7.2.2.
Handling of PK Concentration Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument.

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.

Answers such as “Not applicable” and “Not evaluable” are not considered to be missing 
data and should be displayed as such.
Outliers
Any subjects excluded from the summaries and/or statistical analyses will be documented 
along with the reason for exclusion in the clinical study report.
13.7.2.3.
Handling of Missing Data for Statistical Analysis
Element
Reporting Detail
Imputation
o
No imputation will be performed for missing data


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13.8.
Appendix 8: Values of Potential Clinical Importance
13.8.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 
1
Male
0.54
Female
0.54
∆from BL
↓0.075
Haemoglobin 
g/L
Male
180
Female
180
∆from BL
↓25
Lymphocytes 
x109/ L
0.8
Neutrophil Count 
x109/ L
1.5
Platelet Count 
x109/ L
100
550
While Blood Cell Count (WBC)
x109/ L
3
20
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Albumin 
g/L
30
Calcium
mmol/L
2
2.75
Creatinine
umol/L
∆from BL
↑ 44.2
Glucose
mmol/L
3
9
Magnesium
mmol/L
.5
1.23
Phosphorus
mmol/L
.8
1.6
Potassium
mmol/L
3
5.5
Sodium
mmol/L
130
150
Creatine Kinase (CK)
>500 U/I
Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
≥ 2x ULN
AST/SGOT 
U/L
High
≥ 2x ULN
AlkPhos 
U/L
High
≥ 2x ULN
T Bilirubin 
µmol/L
High
≥ 1.5x ULN
T. Bilirubin + ALT
µmol/L
High
1.5xULN T. Bilirubin
+
≥ 2x ULN ALT
U/L


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13.8.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
>450
Absolute PR Interval
msec
<110
>220
Absolute QRS Interval
msec
<75
>110
Change from Baseline
Increase from Baseline QTc
msec
>60
13.8.3.
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


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13.9.
Appendix 9: Population Pharmacokinetic (PopPK) Analyses
PopPK will be performed under a separate RAP and will be reported separately


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13.10.
Appendix 10: Pharmacokinetic / Pharmacodynamic 
Analyses
A detailed population PK/PD data analysis plan will be prepared in a separate RAP.


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13.11.
Appendix 11: Abbreviations & Trade Marks
13.11.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GSK
GlaxoSmithKline
IA
Interim Analysis
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
MMRM
Mixed Model Repeated Measures
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SDSP
Study Data Standardization Plan


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Abbreviation
Description
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
SR
Safety Review
13.11.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
NONMEM
SAS
WinNonlin


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13.12.
Appendix 12: List of Data Displays

PROGRAMMING NOTES: Where applicable, programming notes can be included to 
supplement and/or highlight specific information to aid with display generation.
o
Consideration should be given to any changes to the standard GSK IDSL displays 
or inclusion of optional columns for safety reporting.
o
If applicable, provide additional information to aid generation of graphical displays 
(e.g. if a multiple panel plot is being generated then details such as the number of 
rows / columns, panel by variable, legend variable etc may be included).
o
Consideration should be given for additional level of instructions for any outsourced 
studies, so as to ensure clarity for generating each display to the expected 
specifications.
o
Note: Small studies (e.g. early phase studies) or where sample sizes or event rates 
are small, study teams may choose to omit certain summary tables where a listing of 
the data would be sufficient (See IDSL Principle 4.21 Minimal Analysis). The lead 
RAP author / RAP Team should consult and get agreement from medical writing / 
CSR writer that listings would be sufficient for the study.
13.12.1.
Data Display Numbering

NOTE: The numbering of data displays is now driven by best practices outlined for the 
development of the Clinical Study Report but the numbering scheme should be utilised 
for all reporting efforts. For listings utilise sequential numbering for ICH and Other 
Listings. 

Automation: Numbering of data displays is automated within tables. If rows are added or 
deleted, the numbering of displays will be automatically updated. Therefore, when 
updating sections based on the order of objectives / endpoints in the protocol, rename 
section headings rather than rearranging sections using cut and paste options.
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.33
-
Safety
3.1 to 3.67
3.1 to 3.28
Pharmacokinetic
4.1 to 4.26
4.1 to 4.15
Pharmacodynamic and / or Biomarker
6.1 to 6.9
6.1 to 6.16
Section
Listings
ICH Listings
1 to 110
Non-ICH Listings
111 to 134
Other Listings
135
13.12.2.
Mock Example Shell Referencing

Mock Example Shells: Only to be provided if not covered by GSK IDSL, or if there are 
major changes to the standard data displays. 


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o
Alternately, provide an appropriate GSK IDSL data standard reference and include 
details in the programming notes column for the display to be generated.
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Section 13.13: 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
Pharmacodynamic / Biomarker
PD_Fn
PD_Tn
PD_Ln

Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
13.12.3.
Deliverables

Delivery Priority: If applicable, can provide information on whether specific outputs are 
required at times other than statistical analysis complete (SAC) or to provide an order of 
displays to be generated so as to facilitate and manage reporting. 

Example where the deliverable priority may be used are: 
o
Decision Critical Data Reporting: For example, this may include endpoints 
reported prior to SAC that are required for making critical decisions for the 
compound.
o
Partial Data Reporting: For example, this may include a study conducted in 
multiple parts where there will be unblinding and reporting of one or more parts of 
the study prior to database freeze.
o
Exploratory Data Reporting: For example, this may include endpoints that are 
potentially analysed post SAC (e.g. TAQMAN data). These may not be intended 
for the CPSR report and as such would not need to have a table or figure number.
o
Output for Presentation Purposes Only: For example, this may include 
combining output with data from other sources for presentation purposes. These 
would not be intended for the CPSR report and as such would not need to have a 
display number.
Delivery [Priority] [1]
Description
SR
Safety Review (after completing Part A and Part B cohort 1& 2)
SAC 
Final Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort


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13.12.4.
Study Population Tables

The requirements for each display (i.e. IDSL, ICH etc.) specified in the programming notes may be retained, all other red 
reference notes should be deleted.

Select appropriate standard based on study design (i.e. parallel vs cross-over), when applicable.

The ADaM datasets for the Core Study Population/Safety displays can be found in the IDSL Library under Reference Statistical 
Displays ADaM Datasets for Core RAP Displays
Study Population Tables
No.
Populatio
n
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
Safety
CP_ES1
Summary of Subject Status and Reason for Study Withdrawal -
Part A
by Cohort
SAC 
1.2.
Safety
CP_ES1
Summary of Subject Status and Reason for Study Withdrawal -
Part B
by Cohort
SAC 
1.3.
Safety
CP_ES1
Summary of Subject Status and Reason for Study Withdrawal -
Part C
By Cohort- since only one cohort, 
‘Total’ column
SAC 
1.4.
\
Safety
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment – Part B
By Dose
SAC
1.5.
Safety
ES4
Summary of Participant Disposition at Each Study Epoch - Part 
A
By Cohort
SAC


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Study Population Tables
No.
Populatio
n
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.6.
Safety
ES4
Summary of Participant Disposition at Each Study Epoch - Part 
C
By Cohort
SAC
1.7.
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure -
Part A
by Cohort
SAC 
1.8.
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure -
Part B
by Cohort
SAC 
1.9.
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure -
Part C
By Cohort- since only one cohort, 
‘Total’ column
SAC 
Protocol Deviation
1.10.
Safety
DV1
Summary of Important Protocol Deviations - Part A
By dose
SAC
1.11.
Safety
DV1
Summary of Important Protocol Deviations - Part B
By Dose 
SAC
1.12.
Safety
DV1
Summary of Important Protocol Deviations - Part C
By Dose 
SAC
Population Analysed
1.13.
1
Screened
SP1 
Summary of Study Populations by Dose- Part A
By Dose and ‘All Treatment’ column
(Subjects on treatment except placebo)
should be included instead of ‘Total’ 
column           
SAC
1.14.
Screened
SP1
Summary of Study Populations by Cohort- Part A
By Cohort 
SAC
1.15.
Screened
SP1 
Summary of Study Populations by Dose- Part B
By Dose and ‘All Treatment’ column 
(Subjects on treatment except placebo) 
should be included instead of ‘Total’ 
column           
SAC
1.16.
Screened
SP1
Summary of Study Populations by Cohort- Part B
By Cohort 
SAC
1.17.
Screened
SP1 
Summary of Study Populations - Part C
By Dose and ‘Total’  column
SAC


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Study Population Tables
No.
Populatio
n
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Demographic and Baseline Characteristics
1.18.
Safety
DM3
Summary of Demographic Characteristics - Part A
By cohort
SAC
1.19.
Safety
DM1 
Summary of Demographic Characteristics - Part B
By cohort
SAC
1.20.
Safety
DM3
Summary of Demographic Characteristics - Part C
SAC
1.21.
Randomiz
ed
DM11
Summary of Age Ranges – Part A
EudraCT, Disclosure display
SAC
1.22.
Randomiz
ed
DM11
Summary of Age Ranges – Part B
EudraCT,  Disclosure display
SAC
1.23.
Randomiz
ed
DM11
Summary of Age Ranges – Part C
EudraCT,  Disclosure display
Add ‘Total’ column
SAC
1.24.
Safety
DM5
Summary of Race and Racial Combinations - Part A
ICH E3, FDA, FDAAA, EudraCT, 
Disclosure display
Add ‘Total’ column
SAC
1.25.
Safety
DM5
Summary of Race and Racial Combinations - Part B
ICH E3, FDA, FDAAA, EudraCT,
Disclosure display
SAC
1.26.
Safety
DM5
Summary of Race and Racial Combinations - Part C
ICH E3, FDA, FDAAA, EudraCT, 
Disclosure display
Add ‘Total’ column
SAC
Prior and Concomitant Medications
1.27.
Safety
MH1
Summary of Current/Past Medical Conditions - Part A
by Cohort
SAC
1.28.
Safety
MH1
Summary of Current/Past Medical Conditions - Part B
by Cohort
SAC


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Study Population Tables
No.
Populatio
n
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.29.
Safety
MH1
Summary of Current/Past Medical Conditions - Part C
By Cohort- since only one cohort, 
‘Total’ column
SAC
1.30.
Safety
CP_CM1
Summary of Concomitant Medications - Part A
by Cohort
SAC
1.31.
Safety
CP_CM1
Summary of Concomitant Medications - Part B
by Cohort
SAC
1.32.
Safety
CP_CM1
Summary of Concomitant Medications - Part C
By Cohort- since only one cohort, 
‘Total’ column
SAC
Exposure and Treatment Compliance
1.33.
Safety
EX1
Summary of Exposure to Study Treatment - Part B
ICH E3
Dose and/or time on treatment, 
as applicable. 
Many possible considerations; 
defer to therapy area standards 
where available. 
For ClinPharm, a listing often 
substitutes for a table.
SAC
13.12.5.
Safety Tables

The requirements for each display (i.e. IDSL, ICH, FDAAA etc) specified in the programming notes may be retained, all other red reference 
notes should be deleted.

Select appropriate standard based on study design (i.e. parallel vs cross-over), when applicable. 

Suggested IDSL shells are noted in the third column, but other IDSL shells may be used, as appropriate 


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
The ADaM datasets for the Core Study Population/Safety displays can be found in the IDSL Library under Reference Statistical Displays 
ADaM Datasets for Core RAP Displays
Safety: Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.1.
Safety
CP_AE1x
Summary of All Adverse Events by System Organ Class and 
Preferred Term - Part A
SAC
3.2.
Safety
CP_AE1p 
Summary of All Adverse Events by System Organ Class and 
Preferred Term - Part B
SAC
3.3.
Safety
CP_AE1p 
Summary of All Adverse Events by System Organ Class and 
Preferred Term by Study Phase - Part B
SAC
3.4.
Safety
CP_AE1x 
Summary of All Adverse Events by System Organ Class and 
Preferred Term - Part C
SAC
3.5.
Safety
AE5B
Summary of All Adverse Events by Maximum Grade by System 
Organ Class and Preferred Term – Part A
SAC
3.6.
Safety
AE5B
Summary of All Adverse Events by Maximum Grade by System 
Organ Class and Preferred Term – Part B
SAC
3.7.
Safety
AE5B
Summary of All Adverse Events by Maximum Grade by System 
Organ Class and Preferred Term – Part C
SAC
3.8.
Safety
             
CP_AE1x  
Summary All Drug-Related Adverse Events by System Organ 
Class and Preferred Term- Part A
SAC
3.9.
Safety
             
CP_AE1p  
Summary All Drug-Related Adverse Events by System Organ 
Class and Preferred Term - Part B
As 3.1 notes.
SAC


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Safety: Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.10.
Safety
             
CP_AE1x  
Summary All Drug-Related Adverse Events by System Organ 
Class and Preferred Term - Part C
As 3.1 notes.
SAC
3.11.
Safety
AE15
Summary of Common (>=10%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Participant 
and Occurrences) – Part A
FDAAA, EudraCT
Disclosure display
Common’ to be defined by 
study/project team. For studies 
with very few 
events/participants, listing is 
sufficient: discuss this option 
with your disclosure 
representative.
SAC
3.12.
Safety
AE15
Summary of Common (>=10%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Participant 
and Occurrences) – Part B
FDAAA, EudraCT
Disclosure display
‘Common’ to be defined by 
study/project team. For studies 
with very few 
events/participants, listing is 
sufficient: discuss this option 
with your disclosure 
representative.
SAC


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Safety: Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.13.
Safety
AE15
Summary of Common (>=10%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Participant 
and Occurrences) – Part C
FDAAA, EudraCT
Disclosure display
‘Common’ to be defined by 
study/project team. For studies 
with very few 
events/participants, listing is 
sufficient: discuss this option 
with your disclosure 
representative.
SAC
Serious and Other Significant Adverse Events
3.14.
Safety
AE16
Summary of Serious Adverse Events by System Organ Class and 
Preferred Term (Number of Participants and Occurrences) - Part A
FDAAA, EudraCT
By dose
For studies with few 
events/participants listing is 
sufficient: discuss this option 
with your disclosure 
representative.
SAC
3.15.
Safety
AE16
Summary of Serious Adverse Events by System Organ Class and 
Preferred Term (Number of Participants and Occurrences) - Part B
FDAAA, EudraCT
For studies with few 
events/participants listing is 
sufficient: discuss this option 
with your disclosure 
representative.
SAC


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Safety: Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.16.
Safety
AE16
Summary of Serious Adverse Events by System Organ Class and 
Preferred Term (Number of Participants and Occurrences) - Part C
FDAAA, EudraCT
For studies with few 
events/participants listing is 
sufficient: discuss this option 
with your disclosure 
representative.
SAC
Laboratory: Chemistry 
3.17.
Safety
LB1
Summary of Clinical Chemistry Values – Part A
By dose Includes Baseline values.
Includes pre-specified 
parameters repeated in 
conventional units.
SR, SAC
3.18.
Safety
LB1
Summary of Clinical Chemistry Values – Part B
By dose
Includes Baseline values.
Includes pre-specified 
parameters repeated in 
conventional units.
SR, SAC
3.19.
Safety
LB1
Summary of Clinical Chemistry Values – Part C
By treatment group (fed/fasted) 
Includes Baseline values.
Includes pre-specified 
parameters repeated in 
conventional units.
SAC
3.20.
Safety
LB1
Summary of Chemistry Changes from Baseline - Part A
By dose and ‘All Treatment’ for all 
parameters mentioned in the protocol
Includes Baseline values.
Includes pre-specified 
parameters repeated in 
conventional units.
SR, SAC


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Safety: Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.21.
Safety
LB1
Summary of Chemistry Changes from Baseline - Part B
By dose for all parameters mentioned in 
the protocol Includes Baseline 
values.
Includes pre-specified 
parameters repeated in 
conventional units.
SR, SAC
3.22.
Safety
LB1
Summary of Chemistry Changes from Baseline - Part C
By treatment group (fed/fasted) and 
‘Total’ for all parameters mentioned in 
the protocol Includes Baseline 
values.
Includes pre-specified 
parameters repeated in 
conventional units.
SAC
3.23.
Safety
LB1
Summary of Chemistry Percent Changes from Baseline - Part A
By dose and ‘All Treatment’ for all 
parameters mentioned in the protocol
Includes Baseline values.
Baseline values are required
Includes pre-specified 
parameters repeated in 
conventional units.
SAC
3.24.
Safety
LB1
Summary of Chemistry Percent Changes from Baseline - Part B
By dose for all parameters mentioned in 
the protocol Includes Baseline 
values.
Baseline values are required
Includes pre-specified 
parameters repeated in 
conventional units.
SAC


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Safety: Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.25.
Safety
LB1
Summary of Chemistry Percent Changes from Baseline - Part C
By treatment group (fed/fasted) and 
‘Total’ for all parameters mentioned in 
the protocol Includes Baseline 
values.
Baseline values are required
Includes pre-specified 
parameters repeated in 
conventional units.
SAC
Laboratory: Haematology
3.26.
Safety
LB1
Summary of Haematology Values – Part A
By dose for all parameters mentioned in 
the protocol
SR, SAC
3.27.
Safety
LB1
Summary of Haematology Values – Part B
By dose for all parameters mentioned in 
the protocol
SR, SAC
3.28.
Safety
LB1
Summary of Haematology Values – Part C
By treatment group (fed/fasted) and 
‘Total’ for all parameters mentioned in 
the protocol
SAC
3.29.
Safety
LB1
Summary of Haematology Changes from Baseline - Part A
By dose and ‘All Treatment’ (treatment 
vs placebo) for all parameters 
mentioned in the protocol
SR, SAC
3.30.
Safety
LB1
Summary of Haematology Changes from Baseline - Part B
By dose for all parameters mentioned in 
the protocol
SR, SAC
3.31.
Safety
LB1
Summary of Haematology Changes from Baseline - Part C
By treatment group (fed/fasted) and 
‘Total’ for all parameters mentioned in 
the protocol
SAC


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Safety: Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.32.
Safety
LB1
Summary of Haematology Percent Changes from Baseline - Part A
By dose and ‘All Treatment’ (treatment 
vs placebo) for all parameters 
mentioned in the protocol
Baseline values are required
SAC
3.33.
Safety
LB1
Summary of Haematology Percent Changes from Baseline - Part B
By dose for all parameters mentioned in 
the protocol
Baseline values are required
SAC
3.34.
Safety
LB1
Summary of Haematology Percent Changes from Baseline - Part C
By treatment group (fed/fasted) and 
‘Total’ for all parameters mentioned in 
the protocol
Baseline values are required
SAC
Hormone Assessment
3.35.
Safety
LB1
Summary of Hormone Assessment Values – Part B
By dose for all parameters mentioned in 
the protocol
SR, SAC
3.36.
Safety
LB1
Summary of Hormone Assessment Changes from Baseline - Part 
B
By dose for all parameters mentioned in 
the protocol
SR, SAC
3.37.
Safety
LB1
Summary of Hormone Assessment Percent Changes from 
Baseline - Part B
By dose for all parameters mentioned in 
the protocol
Baseline values are required
SR, SAC
Laboratory: Urinalysis
3.38.
Safety
UR3b
Summary of Urinalysis Dipstick Results – Part A
ICH E3
Page by test Includes Baseline 
values.
SAC
3.39.
Safety
UR3b
Summary of Urinalysis Dipstick Results – Part B
ICH E3
Page by test Includes Baseline 
values.
SAC


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Safety: Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.40.
Safety
UR3b
Summary of Urinalysis Dipstick Results – Part C
ICH E3
Page by testIncludes Baseline 
values.
SAC
Laboratory: Liver Function
3.41.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting – Part A
IDSL
SAC
3.42.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting – Part B
IDSL
SAC
3.43.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting – Part C
IDSL
SAC
3.44.
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities – Part A
IDSL
Listing may be sufficient if few 
events.
SAC
3.45.
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities – Part B
IDSL
Listing may be sufficient if few 
events.
SAC
3.46.
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities – Part C
IDSL
Listing may be sufficient if few 
events.
SAC
ECG
3.47.
Safety
EG1
Summary of ECG Findings – Part A 
IDSL
As above for Chemistry, using 
ECG findings categories (and 
change from baseline 
categories, if applicable).
SAC


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Safety: Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.48.
Safety
EG1
Summary of ECG Findings – Part B
IDSL
As above for Chemistry, using 
ECG findings categories (and 
change from baseline 
categories, if applicable).
SAC
3.49.
Safety
EG1
Summary of ECG Findings – Part C
IDSL
As above for Chemistry, using 
ECG findings categories (and 
change from baseline 
categories, if applicable).
SAC
3.50.
Safety
EG2
Summary of Change from Baseline in ECG Values – Part A
IDSL
Includes Baseline values.
SAC
3.51.
Safety
EG2
Summary of Change from Baseline in ECG Values – Part B
IDSL
Includes Baseline values.
SAC
3.52.
Safety
EG2
Summary of Change from Baseline in ECG Values – Part C
IDSL
Includes Baseline values.
SAC
3.53.
Safety
EG10
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category – Part A
IDSL
Recommended for studies with 
sufficiently large sample size or 
frequency of values of interest.
SAC
3.54.
Safety
EG10
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category – Part B
IDSL
Recommended for studies with 
sufficiently large sample size or 
frequency of values of interest.
SAC


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Safety: Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.55.
Safety
EG10
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category – Part C
IDSL
Recommended for studies with 
sufficiently large sample size or 
frequency of values of interest.
SAC
3.56.
Safety
EG11
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category – Part A
IDSL
Recommended for studies with 
sufficiently large sample size or 
frequency of values of interest.
SAC
3.57.
Safety
EG11
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category – Part B
IDSL
Recommended for studies with 
sufficiently large sample size or 
frequency of values of interest.
SAC
3.58.
Safety
EG11
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category – Part C
IDSL
Recommended for studies with 
sufficiently large sample size or 
frequency of values of interest.
SAC
Vital Signs
3.59.
Safety
VS1
Summary of Vital Signs – Part A
ICH E3
Includes Baseline values.
SAC
3.60.
Safety
VS1
Summary of Vital Signs – Part B
ICH E3
Includes Baseline values.
SAC
3.61.
Safety
VS1
Summary of Vital Signs – Part C
ICH E3
Includes Baseline values.
SAC
3.62.
Safety
VS1
Summary of Change from Baseline in Vital Signs – Part A
ICH E3
Includes Baseline values.
SAC


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Safety: Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.63.
Safety
VS1
Summary of Change from Baseline in Vital Signs – Part B
ICH E3
Includes Baseline values.
SAC
3.64.
Safety
VS1
Summary of Change from Baseline in Vital Signs – Part C
ICH E3
Includes Baseline values.
SAC
3.65.
Safety
VS1
Summary of Percent Change from Baseline in Vital Signs – Part A
ICH E3
Includes Baseline values.
SAC
3.66.
Safety
VS1
Summary of Percent Change from Baseline in Vital Signs – Part B
ICH E3
Includes Baseline values.
SAC
3.67.
Safety
VS1
Summary of Percent Change from Baseline in Vital Signs – Part C
ICH E3
Includes Baseline values.
SAC


CONFIDENTIAL
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13.12.6.
Safety Figures

The requirements for each display (i.e. IDSL, ICH etc) specified in the programming notes may be retained, all other reference notes can be 
deleted.

Select appropriate standard based on study design (i.e. parallel vs cross-over), when applicable. 

The ADaM datasets for the Core Study Population/Safety displays can be found in the IDSL Library under Reference Statistical Displays 
ADaM Datasets for Core RAP Displays.


CONFIDENTIAL
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109
Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory: Chemistry
3.1.
Safety
LB_PLOT1
Individual Plot of Clinical Chemistry Parameters Over Time by 
Dose – Part A
By dose 
SAC
3.2.
Safety
LB_PLOT1
Individual Plot of Clinical Chemistry Parameters Over Time by 
Dose – Part B
By dose 
SAC
3.3.
Safety
LB_PLOT1
Individual Plot of Clinical Chemistry Parameters Over Time by 
Dose – Part C
By dose 
SAC
3.4.
Safety
LB_PLOT1
Individual Plot of Clinical Chemistry Parameters Over Time by 
Subject – Part A
By subject
SAC
3.5.
Safety
LB_PLOT1
Individual Plot of Clinical Chemistry Parameters Over Time by 
Subject – Part C
By subject
SAC
3.6.
Safety
LB_PLOT2
Mean ±SD Plot of Change from Baseline for Clinical Chemistry 
Parameters Over Time by Dose – Part A
By dose and treatment (treatment vs 
placebo) for all parameters mentioned 
in the protocol
SAC
3.7.
Safety
LB_PLOT2
Mean ±SD Plot of Change from Baseline for Clinical Chemistry 
Parameters Over Time by Dose – Part B
By dose for all parameters mentioned in 
the protocol
SAC
3.8.
Safety
LB_PLOT2
Mean ±SD Plot of Change from Baseline for Clinical Chemistry 
Parameters Over Time by Dose – Part C
By treatment group (fed/fasted) for all 
parameters mentioned in the protocol
SAC
3.9.
Safety
LB_PLOT2
Mean ±SD Plot of Percent Change from Baseline for Clinical 
Chemistry Parameters Over Time by Dose – Part A
By dose and treatment (treatment vs 
placebo) for all parameters mentioned 
in the protocol
SAC
3.10.
Safety
LB_PLOT2
Mean ±SD Plot of Percent Change from Baseline for Clinical 
Chemistry Parameters Over Time by Dose – Part B
By dose for all parameters mentioned in 
the protocol
SAC


CONFIDENTIAL
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Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.11.
Safety
LB_PLOT2
Mean ±SD Plot of Percent Change from Baseline for Clinical 
Chemistry Parameters Over Time by Dose – Part C
By treatment group (fed/fasted) for all 
parameters mentioned in the protocol
SAC
Laboratory: Haematology
3.12.
Safety
LB_PLOT1
Individual Plot of Haematology Parameters Over Time by Dose 
– Part A
By dose 
SAC
3.13.
Safety
LB_PLOT1
Individual Plot of Haematology Parameters Over Time by Dose 
– Part B
By dose 
SAC
3.14.
Safety
LB_PLOT1
Individual Plot of Haematology Parameters Over Time by Dose 
– Part C
SAC
3.15.
Safety
LB_PLOT1
Individual Plot of Haematology Parameters Over Time by 
Subject – Part A
By Subject
SAC
3.16.
Safety
LB_PLOT1
Individual Plot of Haematology Parameters Over Time by 
Subject – Part C
By Subject
SAC
3.17.
Safety
LB_PLOT2
Mean ±SD Plot of Change from Baseline for Haematology 
Parameters Over Time by Dose – Part A
By dose and treatment (treatment vs 
placebo) for all parameters mentioned 
in the protocol
SAC
3.18.
Safety
LB_PLOT2
Mean ±SD Plot of Change from Baseline for Haematology 
Parameters Over Time by Dose – Part B
By dose for all parameters mentioned in 
the protocol
SAC
3.19.
Safety
LB_PLOT2
Mean ±SD Plot of Change from Baseline for Haematology 
Parameters Over Time by Dose – Part C
By treatment group (fed/fasted) for all 
parameters mentioned in the protocol
SAC
3.20.
Safety
LB_PLOT2
Mean ±SD Plot of Percent Change from Baseline for 
Haematology Parameters Over Time by Dose – Part A
By dose and treatment (treatment vs 
placebo) for all parameters mentioned 
in the protocol
SAC


CONFIDENTIAL
209275
111
Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.21.
Safety
LB_PLOT2
Mean ±SD Plot of Percent Change from Baseline for 
Haematology Parameters Over Time by Dose – Part B
By dose for all parameters mentioned in 
the protocol
SAC
3.22.
Safety
LB_PLOT2
Mean ±SD Plot of Percent Change from Baseline for 
Haematology Parameters Over Time by Dose – Part C
By treatment group (fed/fasted) for all 
parameters mentioned in the protocol
SAC
Hormone Assessment
3.23.
Safety
LB_PLOT1
Individual Plot of Hormone Assessment Parameters Over Time 
by Dose – Part B
By dose 
SAC
3.24.
Safety
LB_PLOT2
Mean ±SD Plot of Change from Baseline for Hormone 
Assessment Parameters Over Time by Dose – Part B
By dose for all parameters mentioned in 
the protocol
SAC
3.25.
Safety
LB_PLOT2
Mean ±SD Plot of Percent Change from Baseline for Hormone 
Assessment Parameters Over Time by Dose – Part B
By dose for all parameters mentioned in 
the protocol
SAC
Laboratory: Liver Function
3.26.
Safety
LIVER14
Scatter Plot of Maximum vs. Baseline for ALT – Part A
Recommended for larger 
studies, but not required for 
smaller studies.
SAC
3.27.
Safety
LIVER14
Scatter Plot of Maximum vs. Baseline for ALT – Part B
Recommended for larger 
studies, but not required for 
smaller studies.
SAC


CONFIDENTIAL
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112
Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.28.
Safety
LIVER14
Scatter Plot of Maximum vs. Baseline for ALT – Part C
Recommended for larger 
studies, but not required for 
smaller studies.
SAC


CONFIDENTIAL
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113
13.12.7.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK concentration
4.1.
PK
PK01
Summary of Plasma GSK3439171 Pharmacokinetic 
Concentration-Time Data (ng/mL) – Part A
SAC
4.2.
PK
PK01
Summary of Plasma GSK3439171 Pharmacokinetic 
Concentration-Time Data (ng/mL) – Part B
SAC
4.3.
PK
PK01
Summary of Plasma GSK3439171 Pharmacokinetic 
Concentration-Time Data (ng/mL) – Part C
SAC
PK Urine
4.4.
PK
PK02
Summary of Pharmacokinetic Urine Excretion Rate-Time
Data – Part B
SAC
PK derived parameters
4.5.
PK
PK03
Summary Statistics of Derived Plasma GSK3439171
Pharmacokinetic Parameters – Part A
SAC
4.6.
PK
PK03
Summary Statistics of Derived Plasma GSK3439171
Pharmacokinetic Parameters – Part B
SAC
4.7.
PK
PK03
Summary Statistics of Derived Plasma GSK3439171
Pharmacokinetic Parameters – Part C
SAC
4.8.
PK
PK05
Summary Statistics of Log-Transformed Derived Plasma 
GSK3439171 Pharmacokinetic Parameters – Part A
SAC
4.9.
PK
PK05
Summary Statistics of Log-Transformed Derived Plasma 
GSK3439171 Pharmacokinetic Parameters – Part B
SAC


CONFIDENTIAL
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114
Pharmacokinetic: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.10.
PK
PK05
Summary Statistics of Log-Transformed Derived Plasma 
GSK3439171 Pharmacokinetic Parameters – Part C
SAC
4.11.
PK
PK_T1
Statistical Analysis of Plasma GSK3439171 Pharmacokinetic 
Parameters: Analysis of Variance (ANOVA) – Part A
t1/2
SAC
4.12.
PK
PK_T1
Statistical Analysis of Plasma GSK3439171 Pharmacokinetic 
Parameters: Analysis of Variance (ANOVA) – Part B
t1/2
Include ‘Visit’ as first column
SAC
4.13.
PK
PK_T1
Statistical Analysis of Plasma GSK3439171 Pharmacokinetic 
Parameters: Analysis of Variance (ANOVA) – Part C
t1/2
SAC
4.14.
PK
PK_T2
Statistical Analysis of Log-Transformed Plasma
GSK3439171 Pharmacokinetic Parameters: Analysis of 
Variance (ANOVA) – Part A
AUC(0-t), AUC(0-24), AUC(0-∞), 
Cmax, Cτ, AUC(Rp)
SAC
4.15.
PK
PK_T2
Statistical Analysis of Log-Transformed Plasma
GSK3439171 Pharmacokinetic Parameters: Analysis of 
Variance (ANOVA) – Part B
AUC(0- τ), AUC(0-∞), Cmax, Cτ
Include ‘Visit’ as first column
SAC
4.16.
PK
PK_T2
Statistical Analysis of Log-Transformed Plasma
GSK3439171 Pharmacokinetic Parameters: Analysis of 
Variance (ANOVA) – Part C
AUC(0-t), AUC(0-∞), Cmax 
SAC
4.17.
PK
PK_T5
Statistical Analysis of Log-Transformed Plasma
GSK3439171 Pharmacokinetic Parameters Assessing 
Accumulation Ratio and Time Invariance – Part B
SAC
4.18.
PK
PK_T6
Statistical Analysis of Log-Transformed Plasma
GSK3439171 Pharmacokinetic Parameters Assessing 
Achievement of Steady State – Part B
SAC


CONFIDENTIAL
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115
Pharmacokinetic: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.19.
PK
PK_T3
Statistical Analysis of Log-Transformed Plasma
GSK3439171 Pharmacokinetic Parameters Assessing Dose
Proportionality (Power Model) – Part A
AUC(0-t), AUC(0-∞) and Cmax
SAC
4.20.
PK
PK_T4
Statistical Analysis of Log-Transformed Plasma
GSK3439171 Pharmacokinetic Parameters Assessing Dose
Proportionality (Power Model) – Part B
AUC(0-τ) and Cmax
By timepoint
SAC
Pharmacogenetic
4.21.
PK
GN1
Summary of Subject Accountability – Part A
By cohort
SAC
4.22.
PK
GN1
Summary of Subject Accountability – Part B
SAC
4.23.
PK
GN1
Summary of Subject Accountability – Part C
SAC
4.24.
PK
GN2
Summary of Genetic Consent Not Obtained/Withdrawn – Part A
By cohort
SAC
4.25.
PK
GN2
Summary of Genetic Consent Not Obtained/Withdrawn – Part B
SAC
4.26.
PK
GN2
Summary of Genetic Consent Not Obtained/Withdrawn – Part C
SAC


CONFIDENTIAL
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116
13.12.8.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Individual Concentration Plots
4.1.
PK
PK16b
Individual Plasma GSK3439171 Concentration-time Plot
(Linear and Semi-log) by Subject – Part A
      SAC
4.2.
PK
PK16a
Individual Plasma GSK3439171 Concentration-time Plot
(Linear and Semi-log) by Subject – Part B
       SAC
4.3.
PK
PK16b
Individual Plasma GSK3439171 Concentration-time Plot
(Linear and Semi-log) by Subject – Part C
       SAC
4.4.
PK
PK24
Individual Plasma GSK3439171 Concentration-time Plot
(Linear and Semi-log) by Treatment – Part A
SAC
4.5.
PK
PK24
Individual Plasma GSK3439171 Concentration-time Plot
(Linear and Semi-log) by Treatment – Part B
SAC
4.6.
PK
PK24
Individual Plasma GSK3439171 Concentration-time Plot
(Linear and Semi-log) by Treatment – Part C
SAC
4.7.
PK
PK17
Mean Plasma GSK3439171 Concentration-Time Plots
(Linear and Semi-log) – Part A
SAC
4.8.
PK
PK17
Mean Plasma GSK3439171 Concentration-Time Plots
(Linear and Semi-log) – Part B
SAC
4.9.
PK
PK17
Mean Plasma GSK3439171 Concentration-Time Plots
(Linear and Semi-log) – Part C
SAC
4.10.
PK
PK18
Median Plasma GSK3439171 Concentration-Time Plots
(Linear and Semi-log) – Part A
SAC


CONFIDENTIAL
209275
117
Pharmacokinetic: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.11.
PK
PK18 
Median Plasma GSK3439171 Concentration-Time Plots
(Linear and Semi-log) – Part B
SAC
4.12.
PK
PK18 
Median Plasma GSK3439171 Concentration-Time Plots
(Linear and Semi-log) – Part C
SAC
4.13.
PK
PK21 
Individual GSK3439171 Urine Excretion Rate-Time Plots 
(Linear and Semi-log) – Part B
SAC
4.14.
PK
PK22 
Mean GSK3439171 Urine Excretion Rate-Time Plots (Linear 
and Semi-log) – Part B
SAC
4.15.
PK
PK23 
Median GSK3439171 Urine Excretion Rate-Time Plots 
(Linear and Semi-log) – Part B
SAC


CONFIDENTIAL
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118
13.12.9.
Pharmacodynamic (and / or Biomarker) Tables
Pharmacodynamic (and or Biomarker): Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Urinary Tetranor and Urinary Creatinine
6.1.
PD
PK03
Summary Statistics of Urinary Tetranor and Urinary Creatinine
Concentration Data– Part A 
SAC


CONFIDENTIAL
209275
119
Pharmacodynamic (and or Biomarker): Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.2.
PD
PK03
Summary Statistics of Urinary Tetranor and Urinary Creatinine
Parameters – Part A 
PD parameters: tPGDM, tPGEM 
End points #: 

1)Raw data (mass) 
2)Creatinine corrected raw 
data, 3)Creatinine corrected 
aggregated data 0-12hrs, 
4)Creatinine corrected 
aggregated data 12-24hrs 
5)Creatinine corrected 
aggregated data 24-48hrs

Baseline corrected value, 
Placebo corrected value and 
ratio of tPGDM/tPGEM for 
version 2,3 & 4 of the data 
mentioned above
PD parameters: Creatinine
End points #: 

1)Raw data (mass), 
2)Aggregated data 0-12hrs & 
3)Aggregated data 12-24hrs
4) Aggregated data 24-48hrs
Baseline corrected value and Placebo 
corrected value for version 2,3 & 4 of 
the data mentioned above
SAC
6.3.
PD
PK03
Summary Statistics of Urinary Tetranor and Urinary Creatinine
Concentration Data – Part B 
SAC


CONFIDENTIAL
209275
120
Pharmacodynamic (and or Biomarker): Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.4.
PD
PK03
Summary Statistics of Urinary Tetranor and Urinary Creatinine
Parameters – Part B 
PD parameters: tPGDM, tPGEM 
End points #: 

1)Raw data (mass) 
2)Creatinine corrected raw 
data, 3)Creatinine corrected 
aggregated data 0-12hrs, 
4)Creatinine corrected 
aggregated data 12-24hrs 
5)Creatinine corrected 
aggregated data 24-48hrs 

Baseline corrected value and 
ratio of tPGDM/tPGEM for 
version 3,4 & 5 of the data 
mentioned above
PD parameters: Creatinine
End points #: 

1)Raw data (mass)
2)Aggregated data 0-12hrs & 
3)Aggregated data 12-24hrs 
4)Aggregated data 24-48hrs
Baseline corrected value and Placebo 
corrected value for version 2,3 & 4 of 
the data mentioned above
SAC


CONFIDENTIAL
209275
121
Pharmacodynamic (and or Biomarker): Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.5.
PD
PK05
Summary Statistics of Log-Transformed Urinary Tetranor and 
Urinary Creatinine Parameters – Part A 
PD parameters: tPGDM, tPGEM 
End points #: 

1)Raw data (mass)  Predose 
aggregated data – 24-12hr, 
12-0hr                                  2) 
Raw data (mass) Post dose 
aggregated data 0-12hrs, 12-
24 hr & 24-48 hr  3)Creatinine 
corrected data predose 
aggregated – 24-12hr, 12-0hr    
4)Creatinine corrected data 
postdose aggregated 0-
12hrs, 12-24 hr & 24-48
PD parameters: Creatinine
End points #: 
1)Raw data (mass) Predose 
aggregated data – 24-12hr, 12-0hr           
2) Raw data (mass) Post dose 
aggregated data 0-12hrs, 12-24 hr & 
24-48 hr  
SAC


CONFIDENTIAL
209275
122
Pharmacodynamic (and or Biomarker): Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.6.
PD
PK05
Summary Statistics of Log-Transformed Urinary Tetranor and 
Urinary Creatinine Parameters – Part B 
PD parameters: tPGDM, tPGEM 
End points #: 

1)Raw data (mass)  Predose 
aggregated data – 24-12hr, 
12-0hr                                  2) 
Raw data (mass) Post dose 
aggregated data 0-12hrs, 12-
24 hr & 24-48 hr  3)Creatinine 
corrected data predose
aggregated – 24-12hr, 12-0hr    
4)Creatinine corrected data 
postdose aggregated 0-
12hrs, 12-24 hr & 24-48
PD parameters: Creatinine
End points #: 

1)Raw data (mass) Predose 
aggregated data – 24-12hr, 
12-0hr                                  2)
Raw data (mass) Post dose 
aggregated data 0-12hrs, 12-
24 hr & 24-48 hr  
SAC
6.7.
PD
PK05
Summary Statistics of Muscle Concentration Data – Part B
SAC
6.8.
PD
PD_T1
Statistical Analysis of Urinary Tetranor and Urinary Creatinine
Parameters: Mixed Effect Model – Part A
tPGDM, tPGEM, Creatinine, 
Creatinine corrected tPGDM and 
Creatinine corrected tPGEM
SAC
6.9.
PD
PD_T1
Statistical Analysis of Urinary Tetranor and Urinary Creatinine
Parameters: Mixed Effect Model – Part B
tPGDM, tPGEM, Creatinine, 
Creatinine corrected tPGDM and 
Creatinine corrected tPGEM
SAC


CONFIDENTIAL
209275
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13.12.10. Pharmacodynamic (and / or Biomarker) Figures
Pharmacodynamic: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Urinary Tetranor
6.1.
PD
LB_PLOT1
Plot of Urinary Tetranor and Urinary Creatinine vs Time by 
Dose– Part A
PD parameters: tPGDM, tPGEM 
End points #: 

1)Creatinine corrected raw data, 
2)Creatinine corrected 
aggregated data 0-12hrs, 
3)Creatinine corrected 
aggregated data 12-24hrs
4)Creatinine corrected 
aggregated data 24-48hrs  

Baseline corrected value, 
Placebo corrected value and 
ratio of tPGDM/tPGEM for first 
3 versions of the data mentioned 
above
PD parameters: Creatinine
End points #: 

1)Raw data, 2)Aggregated data 
0-12hrs 3)Aggregated data 12-
24hrs 4)Aggregated data 24-
48hrs 

Baseline corrected value and 
Placebo corrected value for first 
3 versions of the data mentioned 
above
Note:  X-axis values – actual midpoint of 
collection
SAC


CONFIDENTIAL
209275
124
Pharmacodynamic: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.2.
PD
LB_PLOT1
Plot of Urinary Tetranor and Urinary Creatinine vs Time by 
Dose– Part B
PD parameters: tPGDM, tPGEM for 
Day 1, 7, 9, 10 &17. 
End points #: 

1)Creatinine corrected raw data, 
2)Creatinine corrected 
aggregated data 0-12hrs, 
3)Creatinine corrected 
aggregated data 12-24hrs
4)Creatinine corrected 
aggregated data 24-48hrs 

Baseline corrected value for first 
3 versions of the data mentioned 
above
PD parameters: Creatinine for Day 1, 7, 
9, 10 &17
End points #: 

1)Raw data, 2)Aggregated data 
0-12hrs & 3)Aggregated data 12-
24hrs 4)Aggregated data 24-
48hrs 

Baseline corrected value for first 
3 versions of the data mentioned 
above
Note1:  X-axis values – actual midpoint of 
collection 
Note2: Panel plot each day as panel. Data 
available on day 1 for all cohorts, day 7 & 
10 for cohort 3 only, day 9 &17 for cohort 
1&2.
SAC


CONFIDENTIAL
209275
125
Pharmacodynamic: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.3.
PD
LB_PLOT1
Plot of Urinary Tetranor and Urinary Creatinine vs Time by 
Subject– Part A
PD parameters: tPGDM, tPGEM 
End points #: 

1)Creatinine corrected raw data, 
2)Creatinine corrected 
aggregated data 0-12hrs, 
3)Creatinine corrected 
aggregated data 12-24hrs 
4)Creatinine corrected 
aggregated data 24-48hrs  

Baseline corrected value, 
Placebo corrected value and 
ratio of tPGDM/tPGEM for first 
3 versions of the data mentioned 
above
PD parameters: Creatinine
End points #: 

1)Raw data, 2)Aggregated data 
0-12hrs & 3)Aggregated data 12-
24hrs 4)Aggregated data 24-
48hrs  

Baseline corrected value and 
Placebo corrected value for first 
3 versions of the data mentioned 
above
Note:  X-axis values – actual midpoint of 
collection
SAC


CONFIDENTIAL
209275
126
Pharmacodynamic: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.4.
PD
LB_PLOT1
Plot of Urinary Tetranor and Urinary Creatinine vs Time by 
Subject– Part B
PD parameters: tPGDM, tPGEM for 
Day 1, 7, 9, 10 &17
End points #: 

1)Creatinine corrected raw data, 
2)Creatinine corrected 
aggregated data 0-12hrs, 
3)Creatinine corrected 
aggregated data 12-24hrs 
4)Creatinine corrected 
aggregated data 24-48hrs  

Baseline corrected value for first 
3 versions of the data mentioned 
above
PD parameters: Creatinine for Day 1, 7, 
9, 10 &17
End points #: 

1)Raw data, 2)Aggregated data 
0-12hrs & 3)Aggregated data 12-
24hrs 4)Aggregated data 24-
48hrs  

Baseline corrected value for first 
3 versions of the data mentioned 
above
Note1:  X-axis values – actual midpoint of 
collection
Note2: Each line(profile) for each day. Data 
available on day 1 for all cohorts, 7 & 10 
for cohort 3 only, day 9 &17 for cohort 1&2.
SAC


CONFIDENTIAL
209275
127
Pharmacodynamic: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.5.
PD
LB_PLOT2
Geometric mean and 95% CI Urinary Tetranor and Urinary 
Creatinine vs time – Part A
PD parameters: tPGDM, tPGEM 
End points #: 

1)Creatinine corrected raw data, 
2)Creatinine corrected 
aggregated data 0-12hrs, 
3)Creatinine corrected 
aggregated data 12-24hrs 
4)Creatinine corrected 
aggregated data 24-48hrs  

Baseline corrected value, 
Placebo corrected value and 
ratio of tPGDM/tPGEM for first 
3 versions of the data mentioned 
above
PD parameters: Creatinine
End points #: 

1)Raw data, 2)Aggregated data 
0-12hrs & 3)Aggregated data 12-
24hrs 4)Aggregated data 24-
48hrs  

Baseline corrected value and 
Placebo corrected value for first 
3 versions of the data mentioned 
above
Note:  X-axis values – planned midpoint of 
collection
SAC


CONFIDENTIAL
209275
128
Pharmacodynamic: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.6.
PD
LB_PLOT2
Geometric mean and 95% CI Urinary Tetranor and Urinary 
Creatinine vs time – Part B
PD parameters: tPGDM, tPGEM for 
Day 1, 7, 9, 10 &17
End points #: 

1)Creatinine corrected raw data, 
2)Creatinine corrected 
aggregated data 0-12hrs, 
3)Creatinine corrected 
aggregated data 12-24hrs
4)Creatinine corrected 
aggregated data 24-48hrs  

Baseline corrected value for first
3 versions of the data mentioned 
above
PD parameters: Creatinine for Day 1, 7, 
9, 10 &17
End points #: 

1)Raw data, 2)Aggregated data 
0-12hrs & 3)Aggregated data 12-
24hrs 4)Aggregated data 24-
48hrs  

Baseline corrected value for first 
3 versions of the data mentioned 
above
Note2:  X-axis values – planned midpoint 
of collection
Panel plot with each day as panel. Data 
available on day 1 for all cohorts, day 7 & 
10 for cohort 3 only, day 9 &17 for cohort 
1&2.
SAC


CONFIDENTIAL
209275
129
Pharmacodynamic: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.7.
PD
LIVER14
Plot of Urinary Tetranor and Urinary Creatinine vs PK 
Concentration by Dose– Part A
PD parameters: tPGDM and tPGEM 
End points #: 

Creatinine corrected raw data

Baseline corrected value and 
Placebo corrected value for 
creatinine corrected raw data
PD parameters Creatinine
End points #: 

Raw data  

Baseline corrected value and 
Placebo corrected value for raw 
data
Note: X-Axis- PD concentration &Y- Axis –
PK concertation  
Different colour for each subject
Note: For each PD marker interval, use the 
upper bound as target time; e.g. for 0-2hr 
interval, 2hr is the target time;
Identify PK concentration with nominal time 
at the target time;If there is no PK sample 
taken at target time, use the PK 
concentration data with nominal time 
before but closest to target time;
Use 0 PK concentration for placebo
SAC


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Pharmacodynamic: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.8.
PD
LIVER14
Plot of Urinary Tetranor and Urinary Creatinine vs PK 
Concentration by Dose– Part B
PD parameters: tPGDM and Tpgem for 
Day 1, 10 &17
End points #: 

Creatinine corrected raw data  

Baseline corrected value for 
creatinine corrected raw data
PD parameter: Creatinine for Day 1, 10
&17
End points #: 

Raw data  

Baseline corrected value for raw 
data
Note: : X-Axis- PD concentration &Y- Axis 
– PK concertation . Panel plot with each 
day in separate panel and each subject 
different symbol. Data available on day 1 
for all cohorts, day 10 for cohort 3 only, day 
17 for cohort 1&2.
Note: For each PD marker interval, use the 
upper bound as target time; e.g. for 0-2hr 
interval, 2hr is the target time;
Identify PK concentration with nominal time 
at the target time;If there is no PK sample 
taken at target time, use the PK 
concentration data with nominal time 
before but closest to target time;
Use 0 PK concentration for placebo
SAC


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Pharmacodynamic: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.9.
PD
LIVER14
Plot of Urinary Tetranor and Urinary Creatinine vs PK 
Concentration by Subject – Part A
PD parameters: tPGDM and tPGEM 
End points #: 

Creatinine corrected raw data  

Baseline corrected value and 
Placebo corrected value for 
creatinine corrected raw data
PD parameters Creatinine
End points #: 

Raw data  

Baseline corrected value and 
Placebo corrected value for raw 
data
Note: X-Axis- PD concentration &Y- Axis –
PK concertation 
For each PD marker interval, use the 
upper bound as target time; e.g. for 0-2hr 
interval, 2hr is the target time;
Identify PK concentration with nominal time 
at the target time;If there is no PK sample 
taken at target time, use the PK 
concentration data with nominal time 
before but closest to target time;
Use 0 PK concentration for placebo
SAC


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Pharmacodynamic: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.10.
PD
LIVER14
Plot of Urinary Tetranor and Urinary Creatinine vs PK 
Concentration by Subject – Part B
PD parameters: tPGDM and Tpgem for 
Day 1, 10 &17
End points #: 

Creatinine corrected raw data  

Baseline corrected value for 
creatinine corrected raw data
PD parameter: Creatinine for Day 1, 10
&17
End points #: 

Raw data  

Baseline corrected value for raw 
data
Note:  X-Axis- PD concentration &Y- Axis –
PK concertation. Different symbol for each 
day. (Data available on day 1 for all 
cohorts, day 10 for cohort 3 only, day 17 
for cohort 1&2.
Note: For each PD marker interval, use the 
upper bound as target time; e.g. for 0-2hr 
interval, 2hr is the target time;
Identify PK concentration with nominal time 
at the target time;If there is no PK sample 
taken at target time, use the PK 
concentration data with nominal time 
before but closest to target time;
Use 0 PK concentration for placebo
SAC


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Pharmacodynamic: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.11.
PD
LB_PLOT1
Plot of Ratio of Urinary Tetranor Parameters vs Time by Dose –
Part A
Ratios of PD parameters to consider: 
tPGDM/tPGEM 
End points #: 

1)Creatinine corrected data, 
2)Creatinine corrected 
aggregated data 0-12hrs, 
3)Creatinine corrected 
aggregated data 12-24hrs 
4)Creatinine corrected 
aggregated data 24-48hrs  

Time matched ratio for above 
mentioned 4 versions of data
Note:  X-axis values – actual midpoint of 
collection
SAC


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Pharmacodynamic: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.12.
PD
LB_PLOT1
Plot of Ratio of Urinary Tetranor Parameters vs Time by Dose–
Part B
Ratios of PD parameters to consider: 
tPGDM/tPGEM for Day 1, 7, 9, 10 & 17
End points #: 

1)Creatinine corrected raw data, 
2)Creatinine corrected 
aggregated data 0-12hrs, 
3)Creatinine corrected 
aggregated data 12-24hrs 
4)Creatinine corrected 
aggregated data 24-48hrs   

Time matched ratio for above 
mentioned 4 versions of data
Note: Panel plot with each panel for each 
day. Data available on day 1 for all cohorts, 
7 & 10 for cohort 3 only, 9 &17 for cohort 
1&2.
SAC


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Pharmacodynamic: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.13.
PD
LB_PLOT1
Plot of Ratio of Urinary Tetranor Parameters vs Time by 
Subject– Part A
Ratios of PD parameters to consider:
tPGDM/tPGEM 
End points #: 

1)Creatinine corrected raw data, 
2)Creatinine corrected 
aggregated data 0-12hrs, 
3)Creatinine corrected 
aggregated data 12-24hrs 
4)Creatinine corrected 
aggregated data 24-48hrs   

Time matched ratio for above 
mentioned 4 versions of data
Note:  X-axis values – actual midpoint of 
collection
SAC


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Pharmacodynamic: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.14.
PD
LB_PLOT1
Plot of Ratio of Urinary Tetranor Parameters vs Time by 
Subject– Part B
Ratios of PD parameters to consider: 
tPGDM/tPGEM for Day 1, 7, 9, 10 & 17
End points #: 

1)Creatinine corrected raw data, 
2)Creatinine corrected 
aggregated data 0-12hrs, 
3)Creatinine corrected 
aggregated data 12-24hrs 
4)Creatinine corrected 
aggregated data 24-48hrs  

Time matched ratio for above 
mentioned 4 versions of data
Note: Each line(profile) for each day. Data 
available on day 1 for all cohorts, day 7 & 
10 for cohort 3 only, day 9 &17 for cohort 
1&2.
SAC


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Pharmacodynamic: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.15.
PD
LB_PLOT2
Geometric mean and 95% CI Ratio of Urinary Tetranor 
Parameters vs time – Part A
Ratios of PD parameters to consider:
tPGDM/tPGEM 
End points #: 

1)Creatinine corrected raw data, 
2)Creatinine corrected 
aggregated data 0-12hrs, 
3)Creatinine corrected 
aggregated data 12-24hrs 
4)Creatinine corrected 
aggregated data 24-48hrs   

Time matched ratio for above 
mentioned 4 versions of data
Note:  X-axis values – actual midpoint of 
collection
SAC


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Pharmacodynamic: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.16.
PD
LB_PLOT2
Geometric mean and 95% CI Ratio of Urinary Tetranor 
Parameters vs time – Part B
Ratios of PD parameters to consider: 
tPGDM/tPGEM for Day 1, 7, 9, 10 & 17
End points #: 

1)Creatinine corrected raw data, 
2)Creatinine corrected 
aggregated data 0-12hrs, 
3)Creatinine corrected 
aggregated data 12-24hrs 
4)Creatinine corrected 
aggregated data 24-48hrs   

Time matched ratio for above 
mentioned 4 versions of data
Note: Panel plot with each panel for each 
day. Data available on day 1 for all cohorts, 
day 7 & 10 for cohort 3 only, day 9 &17 for 
cohort 1&2.
SAC
#Refer to Section 10.1.1 for derivation of PD endpoints


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13.12.11. ICH Listings

The requirements for each display (i.e. IDSL, ICH etc) specified in the programming notes may be retained, all other reference notes can be 
deleted.

Select appropriate standard based on study design (i.e. parallel vs cross-over), when applicable. 

The ADaM datasets for the Core Study Population/Safety displays can be found in the IDSL Library under Reference Statistical Displays 
ADaM Datasets for Core RAP Displays.
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
Screened
ES7
Listing of Reasons for Screen Failure – Part A
Journal Guidelines
SAC
2.
Screened
ES7
Listing of Reasons for Screen Failure – Part B
Journal Guidelines
SAC
3.
Screened
ES7
Listing of Reasons for Screen Failure – Part C
Journal Guidelines
SAC
4.
Safety
CP_ES10x
Listing of Reasons for Study Withdrawal – Part A
ICH E3
SAC
5.
Safety
ES2 
Listing of Reasons for Study Withdrawal – Part B
ICH E3
SAC
6.
Safety
CP_ES10x
Listing of Reasons for Study Withdrawal – Part C
ICH E3
SAC
7.
Safety
SD2
Listing of Reasons for Study Treatment Discontinuation – Part B
ICH E3
Required for all 
studies except single 
dose studies.
SAC
8.
Safety
BL2
Listing of Participants for Whom the Treatment Blind was Broken – Part A
ICH E3
Blinded studies only.
SAC


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ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
9.
Safety
BL1
Listing of Participants for Whom the Treatment Blind was Broken – Part B
ICH E3
Blinded studies only.
SAC
10.
Safety
BL2
Listing of Participants for Whom the Treatment Blind was Broken – Part C
ICH E3
Blinded studies only.
SAC
11.
Safety
TA2
Listing of Planned and Actual Treatments – Part A
SAC
12.
Safety
TA1
Listing of Planned and Actual Treatments – Part B
SAC
13.
Safety
TA2
Listing of Planned and Actual Treatments – Part C
SAC
Protocol Deviations
14.
Safety
DV2A
Listing of Important Protocol Deviations – Part A
ICH E3
Listing also includes 
analysis population 
exclusions.
SAC
15.
Safety
DV2
Listing of Important Protocol Deviations – Part B
ICH E3
Listing also includes 
analysis population 
exclusions.
SAC
16.
Safety
DV2A
Listing of Important Protocol Deviations – Part C
ICH E3
Listing also includes 
analysis population 
exclusions.
SAC
17.
Safety
IE4
Listing of Participants with Inclusion/Exclusion Criteria Deviations – Part A
ICH E3
SAC


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ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
18.
Safety
IE3
Listing of Participants with Inclusion/Exclusion Criteria Deviations – Part B
ICH E3
SAC
19.
Safety
IE4
Listing of Participants with Inclusion/Exclusion Criteria Deviations – Part C
ICH E3
SAC
Populations Analysed
20.
Randomized
SP3a
Listing of Participants Excluded from Any Population – Part A
ICH E3
e.g., participants 
screened but not 
randomized, 
participants 
randomized but not 
treated, participants 
with deviations 
leading to exclusion 
from per protocol 
population (can be 
separate listing per 
population).
SAC


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ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
21.
Randomized
SP3
Listing of Participants Excluded from Any Population – Part B
ICH E3
e.g., participants 
screened but not 
randomized, 
participants 
randomized but not 
treated, participants 
with deviations 
leading to exclusion 
from per protocol 
population (can be 
separate listing per 
population).
SAC
22.
Randomized
SP3a
Listing of Participants Excluded from Any Population – Part C
ICH E3
e.g., participants 
screened but not 
randomized, 
participants 
randomized but not 
treated, participants 
with deviations 
leading to exclusion 
from per protocol 
population (can be 
separate listing per 
population).
SAC
Demographic and Baseline Characteristics


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ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
23.
Safety
DM4
Listing of Demographic Characteristics – Part A
ICH E3
SAC
24.
Safety
DM2
Listing of Demographic Characteristics – Part B
ICH E3
SAC
25.
Safety
DM4
Listing of Demographic Characteristics – Part C
ICH E3
SAC
26.
Safety
SU2
Listing of Substance Use – Part A
SAC
27.
Safety
SU2
Listing of Substance Use – Part B
SAC
28.
Safety
SU2
Listing of Substance Use – Part C
SAC
Prior and Concomitant Medications
29.
Safety
CP_CM4
Listing of Concomitant Medications Using Generic Term – Part A
SAC
30.
Safety
CP_CM3
Listing of Concomitant Medications Using Generic Term – Part B
SAC
31.
Safety
CP_CM4
Listing of Concomitant Medications Using Generic Term – Part C
SAC
32.
Safety
MH3
Listing of Medical Conditions – Part A
SAC
33.
Safety
MH2
Listing of Medical Conditions – Part B
SAC
34.
Safety
MH3
Listing of Medical Conditions – Part C
SAC
35.
Safety
FH5
Listing of Family History Conditions – Part A
SAC
36.
Safety
FH5
Listing of Family History Conditions – Part B
SAC
37.
Safety
FH5
Listing of Family History Conditions – Part C
SAC
Exposure and Treatment Compliance
38.
Safety
EX4
Listing of Exposure Data – Part A
ICH E3
SAC
39.
Safety
EX3 
Listing of Exposure Data – Part B
ICH E3
SAC
40.
Safety
EX4
Listing of Exposure Data – Part C               
ICH E3
SAC
Adverse Events


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ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
41.
Safety
CP_AE9 
Listing of All Adverse Events – Part A
ICH E3
SAC
42.
Safety
CP_AE8 
Listing of All Adverse Events – Part B
ICH E3
SAC
43.
Safety
CP_AE9 
Listing of All Adverse Events – Part C
ICH E3
SAC
44.
Safety
CP_AE9
Listing of Drug Related Adverse Events – Part A
ICH E3
Fatal and Non-Fatal 
SAEs are combined 
into a single listing for 
ClinPharm studies 
(i.e., “Listing of 
Serious Adverse 
Events”).
SAC
45.
Safety
CP_AE8
Listing of Drug Related Adverse Events – Part B
ICH E3
Fatal and Non-Fatal 
SAEs are combined 
into a single listing for 
ClinPharm studies 
(i.e., “Listing of 
Serious Adverse 
Events”).
SAC


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ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
46.
Safety
CP_AE9
Listing of Drug Related Adverse Events – Part C
ICH E3
Fatal and Non-Fatal 
SAEs are combined 
into a single listing for 
ClinPharm studies 
(i.e., “Listing of 
Serious Adverse 
Events”).
SAC
47.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events – Part A
ICH E3
SAC
48.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events – Part B
ICH E3
SAC
49.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events – Part C
ICH E3
SAC
50.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ Classes, Preferred 
Terms, and Verbatim Text – Part A
IDSL
SAC
51.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ Classes, Preferred 
Terms, and Verbatim Text – Part B
IDSL
SAC
52.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ Classes, Preferred 
Terms, and Verbatim Text – Part C
IDSL
SAC
Serious and Other Significant Adverse Events


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ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
53.
Safety
CP_AE9a 
Listing of Serious Adverse Events (Fatal & Non-Fatal) – Part A
ICH E3
Fatal and Non-Fatal 
SAEs are combined 
into a single listing for 
ClinPharm studies 
(i.e., “Listing of 
Serious Adverse 
Events”).
SAC
54.
Safety
CP_AE8a 
Listing of Serious Adverse Events (Fatal & Non-Fatal) – Part B
ICH E3
Fatal and Non-Fatal 
SAEs are combined 
into a single listing for 
ClinPharm studies 
(i.e., “Listing of 
Serious Adverse 
Events”).
SAC
55.
Safety
CP_AE9a 
Listing of Serious Adverse Events (Fatal & Non-Fatal) – Part C
ICH E3
Fatal and Non-Fatal 
SAEs are combined 
into a single listing for 
ClinPharm studies 
(i.e., “Listing of 
Serious Adverse 
Events”).
SAC
56.
Safety
CP_AE9
Listing of Adverse Events Leading to Withdrawal from Study – Part A
ICH E3
SAC
57.
Safety
CP_AE8
Listing of Adverse Events Leading to Withdrawal from Study – Part B
ICH E3
SAC


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ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
58.
Safety
CP_AE9
Listing of Adverse Events Leading to Withdrawal from Study – Part C
ICH E3
SAC
Liver events
59.
Safety
LIVER5
Listing of Liver Monitoring/Stopping Event Reporting – Part A
IDSL
SAC
60.
Safety
LIVER5
Listing of Liver Monitoring/Stopping Event Reporting – Part B
IDSL
SAC
61.
Safety
LIVER5
Listing of Liver Monitoring/Stopping Event Reporting – Part C
IDSL
SAC
62.
Safety
LIVER7
Listing of Liver Biopsy Details – Part A
SAC
63.
Safety
LIVER7
Listing of Liver Biopsy Details – Part B
SAC
64.
Safety
LIVER7
Listing of Liver Biopsy Details – Part C
SAC
65.
Safety
LIVER8
Listing of Liver Imaging Details – Part A
SAC
66.
Safety
LIVER8
Listing of Liver Imaging Details – Part B
SAC
67.
Safety
LIVER8
Listing of Liver Imaging Details – Part C
SAC
All Laboratory
68.
Safety
LB14
Listing of Clinical Chemistry Laboratory Data with Character Results – Part A
ICH E3
SAC
69.
Safety
LB14
Listing of Clinical Chemistry Laboratory Data with Character Results – Part B
ICH E3
SAC
70.
Safety
LB14
Listing of Clinical Chemistry Laboratory Data with Character Results – Part C
ICH E3
SAC
71.
Safety
CP_LB6
Listing of All Clinical Chemistry Laboratory Data for Subjects with PCI Abnormalities 
– Part A
Add ’Lab test’ column 
before ‘Treatment/Period’ 
column’
SAC
72.
Safety
CP_LB5
Listing of All Clinical Chemistry Laboratory Data for Subjects with PCI Abnormalities 
– Part B
Add ’Lab test’ column 
before ‘Treatment/Period’ 
column’
SAC


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ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
73.
Safety
CP_LB6
Listing of All Clinical Chemistry Laboratory Data for Subjects with PCI Abnormalities 
– Part C
Add ’Lab test’ column 
before ‘Treatment/Period’ 
column’
SAC
74.
Safety
CP_LB6
Listing of Clinical Chemistry Abnormalities of Potential Clinical Importance – Part A
Add ’Lab test’ column 
before ‘Treatment/Period’ 
column’
SAC
75.
Safety
CP_LB5
Listing of Clinical Chemistry Abnormalities of Potential Clinical Importance – Part B
Add ’Lab test’ column 
before ‘Treatment/Period’ 
column’
SAC
76.
Safety
CP_LB6
Listing of Clinical Chemistry Abnormalities of Potential Clinical Importance – Part C
Add ’Lab test’ column 
before ‘Treatment/Period’ 
column’
SAC
77.
Safety
LB14
Listing of Haematology Laboratory Data with Character Results – Part A
ICH E3
‘Treatment/Period’ will be 
included as column and 
will be added after ‘Lab 
Test’ 
SAC
78.
Safety
LB14
Listing of Haematology Laboratory Data with Character Results – Part B
ICH E3
SAC
79.
Safety
LB14
Listing of Haematology Laboratory Data with Character Results – Part C
ICH E3
SAC
80.
Safety
CP_LB6
Listing of All Haematology Laboratory Data for Subjects with PCI Abnormalities –
Part A
Add ’Lab test’ column 
before ‘Treatment/Period’ 
column’
SAC
81.
Safety
CP_LB5
Listing of All Haematology Laboratory Data for Subjects with PCI Abnormalities –
Part B
Add ’Lab test’ column 
before ‘Treatment/Period’ 
column’
SAC


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ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
82.
Safety
CP_LB6
Listing of All Haematology Laboratory Data for Subjects with PCI Abnormalities –
Part C
Add ’Lab test’ column 
before ‘Treatment/Period’ 
column’
SAC
83.
Safety
CP_LB6
Listing of Haematology Abnormalities of Potential Clinical Importance – Part A
Add ’Lab test’ column 
before ‘Treatment/Period’ 
column’
SAC
84.
Safety
CP_LB5
Listing of Haematology Abnormalities of Potential Clinical Importance – Part B
Add ’Lab test’ column 
before ‘Treatment/Period’ 
column’
SAC
85.
Safety
CP_LB6
Listing of Haematology Abnormalities of Potential Clinical Importance – Part C
Add ’Lab test’ column 
before ‘Treatment/Period’ 
column’
SAC
86.
Safety
LB14
Listing of Hormone Assessment Data with Character Results – Part B
ICH E3
SAC
87.
Safety
LB14
Listing of Urinalysis Data with Character Results – Part A
ICH E3
SAC
88.
Safety
LB14
Listing of Urinalysis Laboratory Data with Character Results – Part B
ICH E3
SAC
89.
Safety
LB14
Listing of Urinalysis Laboratory Data with Character Results – Part C
ICH E3
SAC
90.
Safety
UR2B
Listing of Urinalysis Data for Participants with Any Value of Potential Clinical 
Importance – Part A
ICH E3
Display ALL data for a 
subject who 
experienced a value 
of potential clinical 
importance.
SAC


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ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
91.
Safety
UR2A
Listing of Urinalysis Data for Participants with Any Value of Potential Clinical 
Importance – Part B
ICH E3
Display ALL data for a 
subject who 
experienced a value 
of potential clinical 
importance.
SAC
92.
Safety
UR2B
Listing of Urinalysis Data for Participants with Any Value of Potential Clinical 
Importance – Part C
ICH E3
Display ALL data for a
subject who 
experienced a value 
of potential clinical 
importance.
SAC
ECG
93.
Safety
CP_EG4
Listing of All ECG Values for Subjects with any Value of Potential Clinical 
Importance – Part A
IDSL
Required for 
ClinPharm studies 
only. Display ALL 
ECGs for a subject 
who experienced a 
value of potential 
clinical importance.
SAC


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ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
94.
Safety
CP_EG3
Listing of All ECG Values for Subjects with any Value of Potential Clinical 
Importance – Part B
IDSL
Required for 
ClinPharm studies 
only. Display ALL 
ECGs for a subject 
who experienced a 
value of potential 
clinical importance.
SAC
95.
Safety
CP_EG4
Listing of All ECG Values for Subjects with any Value of Potential Clinical 
Importance – Part C
IDSL
Required for 
ClinPharm studies 
only. Display ALL 
ECGs for a subject 
who experienced a 
value of potential 
clinical importance.
SAC
96.
Safety
CP_EG4
Listing of ECG Values of Potential Clinical Importance – Part A
IDSL
Required for 
ClinPharm studies 
only.
SAC
97.
Safety
CP_EG3
Listing of ECG Values of Potential Clinical Importance – Part B
IDSL
Required for 
ClinPharm studies 
only.
SAC


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ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
98.
Safety
CP_EG4
Listing of ECG Values of Potential Clinical Importance – Part C
IDSL
Required for 
ClinPharm studies 
only.
SAC
99.
Safety
CP_EG6
Listing of All ECG Findings for Subjects with an Abnormal Finding – Part A
SAC
100.
Safety
CP_EG5
Listing of All ECG Findings for Subjects with an Abnormal Finding – Part B
SAC
101.
Safety
CP_EG6
Listing of All ECG Findings for Subjects with an Abnormal Finding – Part C
SAC
102.
Safety
CP_EG6
Listing of Abnormal ECG Findings – Part A
IDSL
Required for 
ClinPharm studies 
only.
SAC
103.
Safety
CP_EG5
Listing of Abnormal ECG Findings – Part B
IDSL
Required for 
ClinPharm studies 
only.
SAC
104.
Safety
CP_EG6
Listing of Abnormal ECG Findings – Part C
IDSL
Required for 
ClinPharm studies 
only.
SAC
Vital Signs


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ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
105.
Safety
CP_VS5
Listing of All Vital Signs for Subjects with any Value of Potential Clinical Importance 
– Part A
IDSL
Required for 
ClinPharm studies 
only. Display ALL Vital 
Signs for a subject 
who experienced a 
value of potential 
clinical importance.
SAC
106.
Safety
CP_VS4
Listing of All Vital Signs for Subjects with any Value of Potential Clinical Importance 
– Part B
IDSL
Required for 
ClinPharm studies 
only. Display ALL Vital 
Signs for a subject 
who experienced a 
value of potential 
clinical importance.
SAC
107.
Safety
CP_VS5
Listing of All Vital Signs for Subjects with any Value of Potential Clinical Importance 
– Part C
IDSL
Required for 
ClinPharm studies 
only. Display ALL Vital 
Signs for a subject 
who experienced a 
value of potential 
clinical importance.
SAC


CONFIDENTIAL
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ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
108.
Safety
CP_VS5
Listing of Vital Signs of Potential Clinical Importance – Part A
IDSL
Required for 
ClinPharm studies 
only.
SAC
109.
Safety
CP_VS4
Listing of Vital Signs of Potential Clinical Importance – Part B
IDSL
Required for 
ClinPharm studies
only.
SAC
110.
Safety
CP_VS5
Listing of Vital Signs of Potential Clinical Importance – Part C
IDSL
Required for 
ClinPharm studies 
only.
SAC


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13.12.12. Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetics
111.
PK
PK08
Listing of Plasma GSK3439171 Pharmacokinetic Concentration
(ng/mL) - Time Data – Part A
SAC
112.
PK
PK07
Listing of Plasma GSK3439171 Pharmacokinetic Concentration
(ng/mL) - Time Data – Part B
SAC
113.
PK
PK08
Listing of Plasma GSK3439171 Pharmacokinetic Concentration
(ng/mL) - Time Data – Part C
SAC
114.
PK
PK09
Listing of Urine Sample Collections – Part B
SAC
115.
PK
PK11
Listing of Urine Excretion Rate Data – Part B
SAC
116.
PK
PK14
Listing of Derived Plasma GSK3439171 Pharmacokinetic 
Parameters – Part A
SAC
117.
PK
PK13
Listing of Derived Plasma GSK3439171 Pharmacokinetic 
Parameters – Part B
SAC
118.
PK
PK14
Listing of Derived Plasma GSK3439171 Pharmacokinetic 
Parameters – Part C
SAC
119.
PK
NA
Raw SAS Output from Statistical Analysis plasma GSK3439171 
Pharmacokinetic Parameters: Analysis of Variance (ANOVA) –
Part A
SAC
120.
PK
NA
Raw SAS Output from Statistical Analysis plasma GSK3439171 
Pharmacokinetic Parameters: Analysis of Variance (ANOVA) –
Part B
SAC


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Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
121.
PK
NA
Raw SAS Output from Statistical Analysis plasma GSK3439171 
Pharmacokinetic Parameters: Analysis of Variance (ANOVA) –
Part C
SAC
122.
PK
NA
Raw SAS Output from Statistical Analysis of Log Transformed 
plasma GSK3439171 Pharmacokinetic Parameters: Analysis of 
Variance (ANOVA) – Part A
SAC
123.
PK
NA
Raw SAS Output from Statistical Analysis of Log Transformed 
plasma GSK3439171 Pharmacokinetic Parameters: Analysis of 
Variance (ANOVA) – Part B
SAC
124.
PK
NA
Raw SAS Output from Statistical Analysis of Log Transformed 
plasma GSK3439171 Pharmacokinetic Parameters: Analysis of 
Variance (ANOVA) – Part C
SAC
125.
PK
NA
Raw SAS Output from Statistical Analysis of Log-Transformed 
Plasma GSK3439171 Pharmacokinetic Parameters Assessing 
Accumulation Ratio – Part B
SAC
PK
NA
Raw SAS Output from Statistical Analysis of Log-Transformed 
Plasma GSK3439171 Pharmacokinetic Parameters Assessing 
Time Invariance – Part B
SAC
126.
PK
NA
Raw SAS Output from Statistical Analysis of Log-Transformed 
Plasma GSK3439171 Pharmacokinetic Parameters Assessing 
Achievement of Steady State – Part B
SAC
127.
PK
NA
Raw SAS Output from Statistical Analysis of log transformed 
plasma GSK3439171 Pharmacokinetic Parameters Assessing 
Dose Proportionality (Power Model) – Part A
SAC


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Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
128.
PK
NA
Raw SAS Output from Statistical Analysis of log transformed 
plasma GSK3439171 Pharmacokinetic Parameters Assessing 
Dose Proportionality (Power Model) – Part B
SAC
129.
PK
Listing of Entero-Test – Part B
SAC
Pharmacodynamics/Biomarkers
130.
PD
PD_L1
Listing of All Pharmacodynamic Parameters – Part A
SAC
131.
PD
PD_L1
Listing of Urine Pharmacodynamic Parameters – Part B
SAC
132.
PD
PD_L1
Listing of Muscle Pharmacodynamic Parameters – Part B
SAC
133.
PD
NA
Raw SAS Output from Statistical Analysis of Log Transformed 
Pharmacodynamic Parameters: Analysis of Variance (ANOVA) –
Part A
SAC
134.
PD
NA
Raw SAS Output from Statistical Analysis of Log Transformed 
Pharmacodynamic Parameters: Analysis of Variance (ANOVA) –
Part B
SAC
13.12.13. Other Listings
Other Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Study Population Tables
135.
Screened
OT_L1
Listing of Rescreened Subjects
SAC


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13.13.
Example Mock Shells for Data Displays
Please note that the mock shells provided below are not study specific but example mock shells.


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Example LB_PLOT1
Protocol: XYZ100001                                                                             Page 1 of 1
Population: Safety/Other study specific
Figure 8.xx
                                                                Individual Plot of Clinical Chemistry Parameters Over Time by Dose – Part A
Please add lower and upper normal ranges in the plot.
PPD
PPD
PPD
PPD


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Example LB_PLOT2
Protocol: XYZ100001                                                                             Page 1 of 1
Population: Safety/Other study specific
Figure 8.xx
Mean ±SD Plot of Change from Baseline for Clinical Chemistry Parameters 
Over time – Part A


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Example : PK_T1                                                                                                                                                                               Page 1 of n
Protocol : GSKxxx
Population : Pharmacokinetic
Table PK_T1
Statistical Analysis of plasma GSKxxx Pharmacokinetic Parameters: ANOVA – Part A
Parameter
Treatment
N
n
LS Mean
95% CI
(Lower,Upper)
{%CVw}
AUC(0-t) (units) 50mg
24
24
xxxx.xx
(xxxx.xx,xxxx.xx)
xx.xx
100mg
24
24
xxxx.xx
(xxxx.xx,xxxx.xx)
xx.xx
200mg
24
24
xxxx.xx
(xxxx.xx,xxxx.xx)
xx.xx
Cmax (units)
50mg
24
24
xxxx.xx
(xxxx.xx,xxxx.xx)
xx.xx
100mg
24
24
xxxx.xx
(xxxx.xx,xxxx.xx)
xx.xx
200mg
24
24
xxxx.xx
(xxxx.xx,xxxx.xx)
xx.xx


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Example : PK_T2                                                                                                                                                                               Page 1 of n
Protocol : GSKxxx
Population : Pharmacokinetic
Table PK_T2
Statistical Analysis of log transformed plasma GSKxxx Pharmacokinetic Parameters: ANOVA – Part A
Parameter
Treatment
N
n
LS Geom.
Mean
95% CI
(Lower,Upper)
{%CVw}
AUC(0-t) (units) 50mg
24
24
xxxx.xx
(xxxx.xx,xxxx.xx)
xx.xx
100mg
24
24
xxxx.xx
(xxxx.xx,xxxx.xx)
xx.xx
200mg
24
24
xxxx.xx
(xxxx.xx,xxxx.xx)
xx.xx
Cmax (units)
50mg
24
24
xxxx.xx
(xxxx.xx,xxxx.xx)
xx.xx
100mg
24
24
xxxx.xx
(xxxx.xx,xxxx.xx)
xx.xx
200mg
24
24
xxxx.xx
(xxxx.xx,xxxx.xx)
xx.xx


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Example : PK_T3                                                                                                                                                                               Page 1 of n
Protocol : GSKxxx
Population : Pharmacokinetic
Table PK_T3
Statistical Analysis of log transformed plasma GSKxxx 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.xxx, x.xxx)
AUC(0-∞) (μg.h/mL)
x.xx 
(x.xxx, x.xxx)
AUC(0-τ) (μg.h/mL)
x.xx 
(x.xxx, x.xxx)


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Example : PK_T4                                                                                                                                                                               Page 1 of n
Protocol : GSKxxx
Population : Pharmacokinetic
Table PK_T4
Statistical Analysis of log transformed plasma GSKxxx Pharmacokinetic Parameters Assessing Dose Proportionality 
(Power Model) – Part B
Visit
Parameter (units)
Slope 
Log Parameter vs Log Dose
90% CI of the Slope
Day 1
AUC(0-t) (μg.h/mL)
  x.xx 
(x.xxx, x.xxx)
AUC(0-∞) (μg.h/mL)
x.xx 
(x.xxx, x.xxx)
AUC(0-τ) (μg.h/mL)
x.xx 
(x.xxx, x.xxx)


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Example : PK_T5                                                                                                                                                                               Page 1 of n
Protocol : GSKxxx
Population : Pharmacokinetic
Table PK_T5
Statistical Analysis of log transformed plasma GSKxxx Pharmacokinetic Parameters Assessing Accumulation Ratio and Time Invariance
– Part B


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Example : PK_T6                                                                                                                                                                               Page 1 of n
Protocol : GSKxxx
Population : Pharmacokinetic
Table PK_T6
Statistical Analysis of log transformed plasma GSKxxx Pharmacokinetic Parameters Assessing Achievement of Steady State– Part B
                  .
                  .
                  .    
                  .


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Example : PD_T1                                                                                                                                                                               Page 1 of n
Protocol : GSKxxx
Population : Pharmacodynamic
                                                 Table 
Statistical Analysis of Urinary Tetranor and Urinary Creatinine Parameters:
Mixed Effect Model – Part A
                                                       
  Parameter: tPGEM   
  --------------------------------------------------------------------------------------------------------                      
  Visit                                            Placebo           Dose1    ………………………….     Dose6
                                                  (N=xxx)          
(N=xxx)                   (N=xxx)
  --------------------------------------------------------------------------------------------------------
  Day -1, 24-12hr   n
                          
xxx                  xxx                       xxx
                   Adjusted Geometric Mean         x.xxx               x.xxx                      x.xxx 
                   90% C.I.                    (x.xxx, x.xxx)      (x.xxx, x.xxx)             (x.xxx, x.xxx)
  
           
Day -1, 12-0hr   n
                            xxx                  xxx                        xxx
                   Adjusted Geometric Mean         x.xxx                x.xxx                      x.xxx 
                   90% C.I.                    (x.xxx, x.xxx)      (x.xxx, x.xxx)             (x.xxx, x.xxx)
Day 1, 0-12hr       n
                            xxx                  xxx                        xxx
                   Adjusted Geometric Mean         x.xxx                x.xxx                      x.xxx 
                   90% C.I.                    (x.xxx, x.xxx)      (x.xxx, x.xxx)             (x.xxx, x.xxx)
           Change from Baseline            x.xxx                x.xxx
    x.xxx
                   90% C.I.                  (x.xxx, x.xxx)        (x.xxx, x.xxx)
(x.xxx, x.xxx)
Day 1, 12-24hr       n
                            xxx                  xxx                        xxx
                   Adjusted Geometric Mean         x.xxx                x.xxx                      x.xxx 
                   90% C.I.                    (x.xxx, x.xxx)      (x.xxx, x.xxx)             (x.xxx, x.xxx)


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           Change from Baseline            x.xxx                x.xxx
    x.xxx
                   90% C.I.                   (x.xxx, x.xxx)        (x.xxx, x.xxx)
(x.xxx, x.xxx)  
Day 1, 24-48hr      n
                            xxx                  xxx                        xxx
                   Adjusted Geometric Mean         x.xxx                x.xxx                      x.xxx 
                   90% C.I.                    (x.xxx, x.xxx)      (x.xxx, x.xxx)             (x.xxx, x.xxx)
Example OT_L1 
Protocol : GSKxxx
Population : Screened
                                  Part A        XXXXXX.XXXXXX       XXXXXX            XXXXXX
                                                            XXXXXX.XXXXXX       XXXXXX            XXXXXX
                                                
                                                            XXXXXX.XXXXXX       XXXXXX            XXXXXX