Clinical trial NCT03234036
Conditions: Infection, Human Immunodeficiency Virus HIV Infections
Keywords: GSK2838232 safety food effect capsule healthy PK tablet
Sponsor: GlaxoSmithKline
Start date: 2017-08-02; Completion date: 2017-11-10
Enrollment: 26 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study will be conducted in two Parts to confirm the acceptability/selection of a tablet formulation for future clinical development of GSK2838232. Part 1 of the study will assess single ritonavir (RTV)-boosted doses of a new tablet formulation given with food (containing approximately 30% fat) against the reference capsule formulation also given with food and then will assess the impact of fasted conditions on the tablet performance. In Part 2, non-boosted GSK2838232 will be given as once-daily tablet doses for 11 days in a separate group of subjects, assuming the tablet performance is considered acceptable from Part 1. Approximately 16 healthy subjects will be enrolled to provide at least 12 evaluable subjects through the three study periods in Part 1. 10 healthy subjects will be enrolled to provide at least 8 evaluable subjects through the single study period in Part 2. The maximum duration of study participation will be approximately 9 to 10 weeks for Part 1; and 8 to 9 weeks for Part 2.

Detailed description:

Arms: arm 1: A single dose of GSK2838232 200 mg (as 4 x 50 mg) capsule formulation will be administered under fed conditions (treatment A) in period 1 in Part 1A.

A single dose of GSK2838232 200 mg (as 2 x 100 mg) tablet formulation will be administered under fed conditions (treatment B) in period 2 in Part 1A.

Both these treatments in Part 1A will be administered with RTV in fed state with a washout of 10 days.

A single dose of GSK2838232 200 mg (as 2 x 100 mg) tablet formulation (with RTV) will be administered under fasted conditions (treatment C) in period 3 in Part 1B.

There will be a wash out of 15 days between Part 1A and Part 1B. arm 2: A single dose of GSK2838232 200 mg (as 2 x 100 mg) tablet formulation will be administered under fed conditions (treatment B) in period 1 in Part 1A.

A single dose of GSK2838232 200 mg (as 4 x 50 mg) capsule formulation will be administered under fed conditions (treatment A) in period 2 in Part 1A.

A single dose of GSK2838232 200 mg (as 2 x 100 mg) tablet formulation (with RTV) will be administered under fasted conditions (treatment C) in period 3 in Part 1B.

There will be a wash out of 15 days between Part 1A and Part 1B. arm 3: In Part 2, subjects will receive non-RTV boosted GSK2838232 500 mg, given as single daily doses for 11 days. The dose will not exceed 500 mg (as 5 x 100 mg tablets) once daily (QD). arm 4: In Part 2, subjects will receive a Placebo given as single daily doses for 11 days.
Interventions: intervention 1: GSK2838232 100 mg tablet intervention 2: GSK2838232 50 mg capsule intervention 3: Ritonavir 100 mg tablets intervention 4: Placebo for GSK2838232 tablets
Intervention descriptions: intervention 1: It is a white to slightly colored tablet. It will be supplied as prefilled tablets in bulk for dispensing to subjects at the site according to the treatment code. intervention 2: It is a pink unmarked capsule. It will be supplied as prefilled capsules in bulk for dispensing to subjects at the site according to the treatment code. intervention 3: It is a white film-coated ovaloid tablets. intervention 4: It is a white to slightly colored tablet. The placebo tablets supplied will not be identical to GSK2838232 tablets. It will be administered by site staff via an opaque card or paper tube.

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE
Protocol Title: A Two Part Study to Assess i) the Relative Bioavailability and Food 
Effect of a Novel Tablet Formulation of Boosted-GSK2838232 Compared to Capsule and 
ii) the Safety and Pharmacokinetics of Repeated Once-Daily Doses of Non boosted 
GSK2838232
Protocol Number: 205820
Short Title: A two-part study to i) compare a tablet and capsule formulation of 
GSK2838232 with and without food, and ii) assess the safety and pharmacokinetics of 
repeated once-daily doses of GSK2838232 without ritonavir.
Compound Number:
GSK2838232
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 116,094
Approval Date: 18-JUL-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 1
18-JUL-2017
Original Protocol
09-JUN-2017
Amendment 1 18-July-2017
Overall Rationale for the Amendment: The protocol was amended to include an 
assessment of neuropsychiatic adverse events at each AE enquiry as well as a statement 
to inform FDA of any grade 2 or higher alteration in personality-behavior or in mood or 
altered mental status within 7 days, per FDA request.
Minor typographical errors were also amended in the Schedule of Assessments, the 
Exclusion Criteria and the Study Assessment and Procedures. 
Section # and 
Name
Description of Change
Brief Rationale
2. SCHEDULE 
OF 
ASSESSMENTS
A footnote was added to Table 
2 and Table 3 to allow 
assessment of neuropsychiatric 
adverse events.
The “X” in the column for AE 
collection in the screening 
period for Part 2 was deleted.
This change was made per FDA 
request.
Typographical error
6.2. Exclusion 
Criteria
PR Interval range was 
corrected.
Typographical error
9.2.1. Time Period 
and Frequency for 
Collecting Adverse 
Event and Serious 
Adverse Event 
Information
A sentence was added to 
indicate sponsor’s plan to 
inform FDA within 7 days of 
grade 2 or higher alteration in 
personality-behavior or mental 
status.
AEs collection time was 
changed to from the start of 
treatment.
This change was made per FDA 
request.
Typographical error


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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................4
1.
SYNOPSIS...............................................................................................................8
2.
SCHEDULE OF ASSESSMENTS ..........................................................................13
3.
INTRODUCTION....................................................................................................19
3.1.
Study Rationale ..........................................................................................19
3.2.
Background ................................................................................................19
3.2.1.
Pharmacokinetic Summary ..........................................................19
3.3.
Benefit/Risk Assessment ............................................................................21
3.3.1.
Risk Assessment .........................................................................22
3.3.2.
Benefit Assessment.....................................................................27
3.3.3.
Overall Benefit: Risk Conclusion..................................................27
4.
OBJECTIVES AND ENDPOINTS...........................................................................28
5.
STUDY DESIGN ....................................................................................................29
5.1.
Overall Design ............................................................................................29
5.2.
Number of Participants ...............................................................................32
5.3.
Participant and Study Completion...............................................................32
5.4.
Scientific Rationale for Study Design ..........................................................32
5.5.
Dose Justification........................................................................................33
6.
STUDY POPULATION...........................................................................................33
6.1.
Inclusion Criteria.........................................................................................34
6.2.
Exclusion Criteria........................................................................................36
6.3.
Lifestyle Restrictions...................................................................................38
6.3.1.
Meals and Dietary Restrictions ....................................................38
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................39
6.3.3.
Activity .........................................................................................40
6.4.
Screen Failures...........................................................................................40
7.
TREATMENTS.......................................................................................................40
7.1.
Treatments Administered............................................................................40
7.1.1.
Medical Devices...........................................................................42
7.2.
Dose Modification .......................................................................................42
7.3.
Method of Treatment Assignment ...............................................................42
7.4.
Blinding.......................................................................................................42
7.5.
Preparation/Handling/Storage/Accountability..............................................43
7.6.
Treatment Compliance................................................................................44
7.7.
Concomitant Therapy..................................................................................44
7.8.
Treatment after the End of the Study ..........................................................44
8.
DISCONTINUATION CRITERIA.............................................................................45
8.1.
Discontinuation of Study Treatment ............................................................45
8.1.1.
Liver Chemistry Stopping Criteria ................................................45
8.1.2.
QTc Stopping Criteria ..................................................................46
8.1.3.
Temporary Discontinuation ..........................................................46


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8.1.4.
Rechallenge.................................................................................46
8.2.
Withdrawal from the Study..........................................................................46
8.3.
Lost to Follow Up........................................................................................46
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................47
9.1.
Efficacy Assessments.................................................................................48
9.2.
Adverse Events...........................................................................................48
9.2.1.
Time Period and Frequency for Collecting Adverse Event 
and Serious Adverse Event Information.......................................48
9.2.2.
Method of Detecting AEs and SAEs.............................................49
9.2.3.
Follow-up of AEs and SAEs.........................................................49
9.2.4.
Regulatory Reporting Requirements for SAEs .............................49
9.2.5.
Pregnancy ...................................................................................50
9.2.6.
Total Blood Volume .....................................................................50
9.3.
Treatment of Overdose...............................................................................50
9.4.
Safety Assessments ...................................................................................51
9.4.1.
Physical Examinations.................................................................51
9.4.2.
Vital Signs....................................................................................51
9.4.3.
Electrocardiograms......................................................................51
9.4.4.
Holter Monitoring .........................................................................52
9.4.5.
Clinical Safety Laboratory Assessments ......................................52
9.5.
Pharmacokinetics .......................................................................................53
9.5.1.
Blood sample collection ...............................................................53
9.5.2.
Sample analysis...........................................................................53
9.6.
Pharmacodynamics ....................................................................................53
9.7.
Genetics .....................................................................................................53
9.8.
Biomarkers .................................................................................................53
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................53
9.10.
DATA MANAGEMENT................................................................................54
10. STATISTICAL CONSIDERATIONS........................................................................54
10.1.
Sample Size Determination ........................................................................54
10.2.
Populations for Analyses ............................................................................55
10.3.
Definition of Baseline ..................................................................................55
10.4.
Statistical Analyses.....................................................................................55
10.4.1.
Safety Analyses...........................................................................56
10.4.2.
Pharmacokinetic Analyses...........................................................56
10.4.2.1.
Relative Bioavailability................................................58
10.4.2.2.
Food Effect.................................................................58
10.4.2.3.
Steady State Assessments.........................................58
10.4.2.4.
Accumulation..............................................................58
10.4.3.
Efficacy Analyses.........................................................................58
10.4.4.
Other Analyses ............................................................................59
10.4.5.
Interim Analyses ..........................................................................59
11. REFERENCES.......................................................................................................60
12. APPENDICES........................................................................................................61
12.1.
Appendix 1: Abbreviations and Trademarks................................................61
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................63


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12.3.
Appendix 3: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................64
12.4.
Appendix 4: Division of AIDS Table For Grading The Severity of
Adult and Pediatric Adverse Events............................................................67
12.4.1.
Total Bilirubin Table for Term and Preterm Neonates: ...............106
12.5.
Appendix 5: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................108
12.5.1.
Definition of Adverse Events......................................................108
12.5.2.
Definition of Serious Adverse Events.........................................109
12.5.3.
Recording Adverse Events and Serious Adverse Events...........110
12.5.4.
Evaluating Adverse Events and Serious Adverse Events...........111
12.5.5.
Reporting of Serious Adverse Events to GSK............................112
12.6.
Appendix 6: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................113
12.7.
Appendix 7: Study Governance Considerations........................................117


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1.
SYNOPSIS
Protocol Title: A Two Part Study to Assess the Relative Bioavailability and Food Effect 
of a Novel Tablet Formulation of Boosted-GSK2838232 Compared to Capsule as well as 
the Safety and Pharmacokinetics of Repeated Once-Daily Doses of Non-boosted 
GSK2838232
Short Title: A two-part study to i) compare a tablet and capsule formulation of 
GSK2838232 with and without food, and ii) assess the safety and pharmacokinetics of 
repeated once-daily doses of GSK2838232 without ritonavir.
Rationale:
This will be a two-part study design that will confirm the acceptability of a tablet 
formulation in healthy participants for future clinical development of GSK2838232.
Part 1 is a relative bioavailability study that will assess single ritonavir (RTV)-boosted 
doses of a novel tablet formulation given with food (normal, approximately 30% fat) 
against the reference capsule formulation also given with food (Part 1A) and then will 
assess the impact of fasted conditions on the tablet performance (Part 1B).
Part 2 is a study of non-boosted GSK2838232, given as once-daily tablet doses for 
11 days in a separate cohort of participants, assuming the tablet performance is 
considered acceptable from Part 1A.  The dose of GSK2838232 used in Part 2 will be 
confirmed after Part 1A but is likely to be, and will not exceed, 500 mg once daily (QD) 
as tablets.  
Objectives and Endpoints:
Part 1:
Objectives
Endpoints
Primary

To assess the relative 
bioavailability of a novel 
GSK2838232 tablet 
formulations versus the capsule 
formulation (Part 1A)

AUC(0-) and Cmax

To assess the effect of food on 
GSK2838232 exposure of the 
tablet formulation (Part 1A and 
Part 1B)

AUC(0-), Cmax, and tmax


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Objectives
Endpoints
Secondary

To investigate the safety and 
tolerability of GSK2838232 
following single dose 
administration as tablets or 
capsules, with RTV

GSK2838232 safety parameters: 
adverse events; absolute values and 
changes over time of clinical laboratory 
evaluations (hematology, clinical 
chemistry, urinalysis), vital signs, and 
12-lead electrocardiogram (ECG) 
parameters from pre-dose values

To characterize the 
pharmacokinetics of 
GSK2838232 after 
administration of a novel tablet 
formulation and capsule 
formulation with food, and the 
tablet formulation given without 
food

tlag, tmax, t½, tlast, C24, and 
AUC(0-t)
Part 2:
Objectives
Endpoints
Primary

To assess the safety of 
GSK2838232 administered as 
non-boosted once-daily doses of 
a tablet formulation for 11 days

GSK2838232 safety parameters: 
adverse events; absolute values and 
changes over time of clinical laboratory 
evaluations (hematology, clinical 
chemistry, urinalysis), vital signs, and 
ECG parameters from pre-dose values

To assess the pharmacokinetics 
of GSK2838232 administered as 
non-boosted once-daily doses of 
a tablet formulation for 11 days

Day 1 dose: AUC(0-), Cmax, C, 
tmax, tlag

Day 11 dose: AUC(0-), AUC(0-), 
Cmax, C, tmax, t½, tlast
Secondary

To assess time to steady-state of 
GSK2838232 when 
administered as non-boosted 
once-daily doses of a tablet 
formulation for 11 days

Pre-dose concentrations on Days 2 
to 11

To assess accumulation of 
GSK2838232 when 
administered as non-boosted 
once-daily doses of a tablet 
formulation for 11 days

Accumulation ratios: Ro[AUC(0-)], 
R(Cmax), R(C)
AUC(0-) = Area under the curve (Area under the plasma drug concentration-time curve from pre-dose to the end of 
the dosing interval at steady state); AUC(0-inf)= Area under the concentration-time curve from time zero (pre-dose) 
extrapolated to infinite time; Cmax= Maximum observed concentration; t1/2= Apparent terminal phase half-life; tmax= 
Time of occurrence of Cmax; tlag= Lag-time (time delay between drug administration and first observed concentration 
above LOQ in plasma); AUC (0-t) = Area under the concentration-time curve from zero up to a definite time t


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Overall Design
Part 1:
Part 1 is a relative bioavailability study that will further subdivide into two parts (Part 1A 
and Part 1B) (Table 1).  In Part 1A, the safety and pharmacokinetics (PK) of a novel 
tablet formulation of GSK2838232 will be evaluated in open label, randomized, 
cross-over fashion against the capsule formulation as reference.  Each actual treatment 
dose will be separated by a minimum 10-day washout period.  Part 1A will be studied in 
the fed state using a normal fat (i.e., approximately 30%) meal in all participants.  In 
Part 1B, the tablet will be administered in the fasted state to understand the impact of 
food on relative bioavailability.
Table 1
Treatment Groups in Part 1
Sequence
N
Part 1A
Part 1B
Period 1
Period 2
Period 3
1
6
A
B
C
2
6
B
A
1.
All treatments in Part 1A to be administered with RTV in a fed state, following two RTV pre-doses.
2.
There will be a washout of at least 10 days between each Period.
3.
Treatment A = GSK2838232 200 mg/r (as 4 x 50 mg) capsule formulation, fed, normal fat (i.e., 
approximately 30%) meal (reference).
4.
Treatment B = GSK2838232 200 mg/r (as 2 x 100 mg) tablet formulation, fed, normal fat (i.e., 
approximately 30%) meal.
5.
Treatment C = GSK2838232 200 mg/r (as 2 x 100 mg) tablet, confirmed from Part 1A, fasted.
After completion of Part 1A, preliminary PK data will be analyzed, and a decision will be 
made based on safety, tolerability, relative bioavailability PK criteria, as well as 
feasibility considerations, as to whether the tablet formulation will be used to conduct 
Part 1B (fasted) and Part 2.
Part 2:
Part 2 will evaluate non-RTV boosted GSK2838232, given as single daily doses for 
11 days in a separate cohort of participants (N=8; 6A/2P).  The placebo tablet supplied 
will not be identical to GSK2838232 and as such will be administered by site staff via an 
opaque card/paper tube to facilitate the single blind (i.e., the Principal Investigator [PI] 
and the participants themselves will be blinded as to their treatment).  The dose chosen 
for Part 2 will depend upon the preliminary results of the tablet in Part 1A but is likely to 
be, but will not exceed, 500 mg (i.e., 5 x 100 mg tablets) QD.  


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Number of Participants:
It is expected that a sufficient number of participants will be screened in order to enroll 
approximately 16 healthy participants to provide at least 12 evaluable participants 
through the three study periods for Part 1 and 10 healthy participants to provide at least 8 
evaluable participants for the single study period of Part 2.
If participants prematurely discontinue the study, additional participants may be 
randomized and assigned to the same treatment sequence at the discretion of the Sponsor 
in consultation with the Investigator.
Treatment Groups and Duration:
GSK2838232 as tablets or capsules (at a 200 mg dose level) will be administered with 
100 mg RTV, after two pre-doses of 100 mg RTV QD over 48 h.  The use of RTV 
priming is an aspect of GSK2838232 clinical development (specifically relative 
bioavailability studies) so far and allows a more accurate assessment of what will 
ultimately happen in the repeat-dose clinical studies with GSK2838232 when 
administered with RTV.  In Part 2 of the study however, GSK2838232 will be 
administered unboosted and no RTV will be co-administered.
In both Part 1 and Part 2 participants will have a screening visit within 30 days prior to 
first dose, a minimum 10-day washout period between doses (Part 1 only), and a follow-
up visit 7 to 14 days after the last dose.  The maximum duration of study participation 
will be approximately 9 to 10 weeks for Part 1 and 8 to 9 weeks for Part 2.


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Study Schematic
Part 1
Part 2


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2.
SCHEDULE OF ASSESSMENTS
Please see Table 2 and Table 3 below for the Schedule of assessments for study Parts 1 
and 2 respectively.


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Table 2
Schedule of Assessments for Part 1A and Part 1B: Single Dose RBA Food
Procedure
Screening
(within 30 days of 
Day 1 - carried out 
over multiple days –
except as noted in 
footnotes)
Periods 1 through 3
Follow-
up1
Day -3
Day -2
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
7-14 
days
24 h
48 h
72 h
96 h
120 h
Admission to Unit
X2
Outpatient Visit
X
X
Informed Consent
X
Medical/medication/
drug/alcohol history 
(Demographics)
X
Full Physical Examination
X
Brief Physical Examination
X
X
X
Height, Weight, BMI
X
Inclusion/Exclusion
X
Vital signs3
X
X
X
X
X
X
X
X
12 Lead ECG4
X
X
X
X
X
X
X
Echocardiogram5
X
Drug/alcohol/cotinine screen
X
X
HbsAg, HCV, HIV tests
X
Hem/Chem/Urine tests6
X
X
X
X
X
X
Serum FSH (as appropriate)
X
Troponin I7
X
X
X
X
X
24 h Holter Monitoring8
X
Pregnancy test (women)
X
X
X
Run-in Dosing with RTV
X
X
Dosing with GSK2838232+RTV
X
PK Sampling9
X
X
X
X
X
X
Adverse Event Review10
X
X
X
X
X
X
X
X
X
Con Med Review
X
X
X
X
X
X
X
X
X
X
Discharge from Unit11
X
Out Patient Visit
X
X
X
X
X


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BMI = Body Mass Index; ECG = Electrocardiogram; FSH = Follicle Stimulating; HbsAg = Hepatitis B surface Antigen; HCV = Hepatitis C Virus; HIV = Human Immunodeficiency Virus; 
Hem/Chem = Hematology/Clinical Chemistry; RTV = Ritonavir; PK = Pharmacokinetic(s); Con Med = Concomitant medications.
1.
Follow-up Visit to take place after Treatment Period 2.
2.
When participants stay in the unit across treatment periods, drug/alcohol/cotinine screen and pregnancy test (women) are not required on Day -3 for later periods.
3.
On Day 1, Blood pressure (BP) and Heart rate (HR) will be collected at pre-dose (triplicate) and single assessments at 1, 2, 4, 6, 8, 12, 24, 48, and 72 h post-dose.
4.
On Day 1, 12-lead ECG will be collected at pre-dose (triplicate), and single assessments at 1, 2, 4, 6, 8, 12, 24, 48 and 72 h post-dose.
5.
Echocardiograms must be within 100 days of Day 1.
6.
Samples for Chemistry and Hematology:  Blood samples will be obtained after an 8-hour fast.
7.
Collect one troponin sample to be analyzed at local laboratory.  A second sample will be collected, frozen and stored on site for potential high sensitivity troponin analysis.
8.
24-h Holter monitoring to be performed after confirming negative urine drug screen at screening, and must be within 30 days of Day 1.  Holter monitoring on other days only if 
needed.
9.
Plasma PK samples for bioanalysis for GSK2838232 will be collected pre-dose (within 15 minutes prior to dosing) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, and 
120 h post-dose.  Samples will be acidified with an equal volume of 50 mmol citrate acid buffer pH 4.0.
10. An AE enquiry will be made at each visit, participants will be asked if they have experienced any neuropsychiatric adverse events, including psychosis or altered mental status.
(see guidance for grading Altered Mental Status in Appendix 4).
11. Participants may be discharged after all study procedures are completed.  Participants will be in house for PK blood samples on Day 3 (48 h), Day 4 (72 h), Day 5 (96 h) and 
Day 6 (120 h) of both study periods.


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Table 3
Schedule of Assessments for Part 2: Repeated Doses for 11 days:
Measurement
Screening
(within 30 
days of Day 
1 - carried 
out over 
multiple days 
- except as 
noted in 
footnotes)
Follow-
up 
Day
–1
Day
1
Day
2
Day
3
Day
4
Day
5
Day
6
Day
7
Day
8
Day
9
Day
10
Day
11
0 h
Day 
12
24 h
Day 
13
48 h
Day 
14
72 h
Day 
15
96 h
Day
16
120 
h
7-14 
days 
after 
last 
dose
Admission to Unit
X
Informed Consent
X
Medical/medication/
drug/alcohol history 
(Demographics)
X
Full Physical 
Examination
X
X
Brief Physical 
Examination
X
X
Height, Weight, BMI 
X
Inclusion/Exclusion
X
Medical History
X
Vital Signs1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG2
X
X
X
X
X
X
X
X
X
X
Echocardiogram3
X
Drug/alcohol/ /cotinine 
Screen
X
X
HbsAg, HCV, HIV 
Testing
X
Hem/Chem tests4
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
Serum FSH (as 
appropriate)
X
Troponin I5
X
X
X
X
X
X
X
X


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Measurement
Screening
(within 30 
days of Day 
1 - carried 
out over 
multiple days 
- except as 
noted in 
footnotes)
Follow-
up 
Day
–1
Day
1
Day
2
Day
3
Day
4
Day
5
Day
6
Day
7
Day
8
Day
9
Day
10
Day
11
0 h
Day 
12
24 h
Day 
13
48 h
Day 
14
72 h
Day 
15
96 h
Day
16
120 
h
7-14 
days 
after 
last 
dose
24 h Holter Monitoring6
X
Pregnancy Test
(females)
X
X
X
Dosing of GSK2838232
X
X
X
X
X
X
X
X
X
X
X
Plasma PK sampling7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Event 
Assessment8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Discharge from Unit
X9
Out Patient Visit
X
X
X
X
X
BMI = Body Mass Index; ECG = Electrocardiogram; FSH = Follicle Stimulating Hormone; HbsAg = Hepatitis B surface Antigen; HCV = Hepatitis C Virus; 
Hem/Chem = Hematology/Clinical Chemistry; HIV = Human Immunodeficiency Virus; IP = Investigational Product; PK = Pharmacokinetic(s).
1.
A single blood pressure (BP) and Heart rate (HR) assessment will be collected at screening and Day -1.  On Day 1 triplicate BP and HR will be collected at pre-dose and single 
assessments at 1, 4, 24, 48 and 72 h (Day 4) post-dose, Day 5, Day 6, Day 7, Day 8, Day 9, Day 10, Day 11 at pre-dose (triplicate), and single assessment at 1, 4, 24, 48 and 
72 h post-dose, and at follow-up.
2.
A single 12-Lead ECG will be collected at screening and Day -1.  On Day 1 triplicate 12-Lead ECGs will be collected at pre-dose, and then single 12-Lead ECGs at 1, 4 and 12 h 
post-dose.  Single 12-Lead ECGs will be collected on Days 2, 3, 5, 8.  On Day 11 triplicate 12-Lead ECGs will be collected pre-dose, and then single 12-Lead ECGs collected at 1, 
4, 12 and 24 h post-dose and at follow-up.
3.
Echocardiograms must be within 100 days of Day 1.
4.
Samples for Chemistry and Hematology: Blood samples will be obtained after an 8-hour fast.
5.
Collect one troponin sample to be analyzed at local laboratory.  A second sample will be collected and frozen for potential high sensitivity troponin analysis.
6.
24-h Holter monitoring to be performed after confirming negative urine drug screen at screening, and must be within 30 days of Day 1.  Holter monitoring on other days only if 
needed.


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7.
Plasma PK samples for GSK2838232 will be collected as follows:  Day 1; pre-dose (within 15 minutes prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12 and 24 h post-dose 
(prior to Day 2 dose).  Days 3 to 10 pre-dose (within 15 minutes prior to dosing).  Day 11; pre-dose (within 15 minutes prior to dosing) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 
36, 48, 72, 96 and 120 h post-dose.  Samples will be acidified with an equal volume of 50 mmol citrate acid buffer pH 4.0.
8.
An AE enquiry will be made at each visit, participants will be asked if they have experienced any neuropsychiatric adverse events, including psychosis or altered mental status.
(see guidance for grading Altered Mental Status in Appendix 4).
9.
Participants will be discharged after all study procedures are completed on the morning of Day 13 (after the 48 h post-final dose sample time point) with instructions to return 
fasted on the mornings of Day 14 for 72 h PK sample, Day 15 for 96 h PK sample, and Day 16 for 120 h PK sample.


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3.
INTRODUCTION
3.1.
Study Rationale
This will be a two-part study design that will confirm the acceptability/selection of a 
tablet formulation for future clinical development of GSK2838232.
Part 1 is a relative bioavailability study that will assess single RTV-boosted doses of a 
novel tablet formulation given with food (normal, approximately 30% fat) against the 
reference capsule formulation also given with food (Part 1A) and then will assess the 
impact of fasted conditions on the tablet performance (Part 1B).
Part 2 is a study of non-boosted GSK2838232, given as once-daily tablet doses for 
11 days in a separate cohort of participants, assuming the tablet performance is 
considered acceptable from Part 1A.  The dose of GSK2838232 used in Part 2 will be 
confirmed after Part 1A but is likely to be, and will not exceed, 500 mg QD as tablets.  
3.2.
Background
Human immunodeficiency virus (HIV) infection affects approximately 37 million people 
worldwide [UNAIDS Fact Sheet, 2015].  While antiretroviral (ARV) therapy has been 
tremendously successful over the past 20 years in reducing morbidity and mortality, there 
continues to be a medical need given viral resistance to existing drug classes and acute 
and chronic drug toxicities.  New drug classes targeting novel viral replication 
mechanisms would overcome HIV resistance to existing ARV drugs and may improve 
long-term safety by replacing older agents with known safety liabilities.
Maturation inhibitors represent a new class of compound for the treatment of HIV 
infection, distinct from viral entry, protease, reverse transcriptase or integrase inhibitors 
[Qian, 2009].  GSK2838232 is a maturation inhibitor being developed for the treatment 
of human HIV-1.
An extensive preclinical package of work has been completed, including biology/ 
virology, safety assessment (toxicology), and preclinical PK studies.  GSK2838232 has 
also been administered to 124 healthy non-HIV-infected human participants in four 
clinical studies completed so far across a number of single and repeated dose designs, 
utilizing early clinical formulations.  The PK, safety, and tolerability profile obtained so 
far supports continued clinical development of GSK2838232, and there is an ongoing 
study in HIV-infected patients that was initiated in the United States (US) in 1Q2017.  
There is a need to transition to a more suitable tablet formulation, which is one of the 
major objectives of this study.
3.2.1.
Pharmacokinetic Summary
The original formulation used in the first three studies with GSK2838232 (HMI116787, 
200207, and 200912) was Spray Dried Dispersion (SDD).  Data from Study 200912 
demonstrated that a change to the active pharmaceutical ingredient (API) formulation of 


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GSK2838232 was feasible for future clinical studies.  Study 204953 utilized micronized 
API powder in a bottle as well as in a capsule.

GSK2838232 SDD did not overall demonstrate significant escalation in 
exposure from an increase in dose from 100 mg to 200 mg in a cross-study 
comparison.  The API powder in bottle (PiB) formulation showed a 
proportional increase in AUC and Cmax for a 2-fold dose escalation from 
100 mg to 200 mg.

The observed tmax of the API form was significantly increased over the SDD 
formulation (the API formulation also increased tlag relative to SDD).

The bioavailability of the GSK2838232 API formulation was on average 
30 to 50% of the bioavailability of SDD formulation, but there was a large 
observed range of relative intra-subject exposures (11 to 150%).

Both 10 mg SDD and 20 mg API showed a 10-fold or greater increase in AUC 
with steady-state RTV (100 mg QD for 10 days) with a smaller (≤4-fold) 
increase in observed Cmax.  The t½ of GSK2838232 increased from 
15 to 18 hours to 34 to 42 hours in the presence of steady-state RTV, 
regardless of formulation.

After single doses of 50 mg to 250 mg GSK2838232 with RTV, increases in 
maximum observed concentration (Cmax) and area under the concentration-
time curve from time zero (pre-dose) extrapolated to infinite time (AUC[0-]) 
values were broadly proportional to the increase in dose.  On Day 11 after 
repeated daily 20 mg to 200 mg doses of GSK2838232 with RTV, increases in 
Cmax and area under the curve (Area under the plasma drug concentration-
time curve from pre-dose to the end of the dosing interval at steady state) 
(AUC[0-]) values appeared to be proportional to the increase in dose with the 
PiB and capsule formulations.

The relative bioavailability of the micronized API powder blend in capsules 
with RTV was approximately 45% to 60% higher than the bioavailability of 
the micronized API administered as oral suspension from PiB with RTV.

Co-administration of the micronized API powder blend in capsules with RTV 
and a normal fat meal resulted in an approximately 60% increase in geometric 
mean Cmax and AUC(0-) values compared to the fasted state with RTV.
Variability remains fairly constant across formulations and boosted versus unboosted at 
around 30% to 40% (moderate-high).
Full details of non-clinical and clinical data may be found in the current Investigator’s 
Brochure (IB) [GlaxoSmithKline (GSK) Document Number 2012N151889_03].


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3.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of GSK2838232 may be found in the Investigator’s 
Brochure.  The following section outlines the risk assessment and mitigation strategy for 
this protocol:


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3.3.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) GSK2838232
Cardiovascular
Pre-clinical studies have shown the following 
findings: elevated heart rates, an isolated episode of 
non-sustained ventricular tachycardia and minimal to 
mild, sporadic troponin I elevations in dogs.  A 
subsequent investigative cardiovascular study in 
telemetered dogs treated for four weeks did not 
replicate these effects.  Isolated microscopic 
cardiovascular changes were noted (focal extramural 
arteritis and localized epicardial inflammation), 
however these changes were considered of uncertain 
relationship to GSK2838232 because similar findings 
occur at low incidence in normal beagles and there 
were no GSK2838232-related functional changes by 
telemetry and echocardiography, or changes in cTpnI 
and NTproBNP.  In addition, there was no correlation 
between histologic changes and plasma exposure or 
heart tissue concentrations of GSK2838232. 
Toxicology studies in rat and dog (3, 6 and 9 months) 
did not demonstrate any evidence of cardiovascular 
injury or impact on cardiovascular function.
In the four GSK2838232 studies conducted so far, 
there was no pattern of cardiovascular changes of 
clinical significance related to GSK2838232 and no 
Participants will be clinically monitored for 
any signs of myocardial injury (chest pain, 
shortness of breath, pain with inspiration), 
elevated heart rate or arrhythmias.  Samples 
for the assessment of troponin will be taken.  
Baseline ECG and Holter (to use for 
screening and for later comparisons if 
needed)
Exposures of GSK2838232 will be closely 
monitored in the clinical study so as to not 
exceed PK stopping criteria.


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
clinically significant abnormality in electrocardiogram 
(ECG) values other than the two serious adverse 
events (SAEs) documented and discussed.
Review of published bevirimat preclinical and clinical 
safety data indicates no significant toxicities or 
adverse events (AEs) of interest, other than a 30% 
incidence of gastrointestinal symptoms (including 
diarrhea).  There were no significant cardiovascular 
AEs reported in published clinical studies.
Hepatic
In dogs given 70 mg/kg/day for 9 months, there were 
reversible liver changes consisting of pigment 
accumulation (presumed bile) associated in some 
individuals with modest inflammatory cell infiltration 
and isolated serum alanine aminotransferase activity 
(ALT) elevations.  Adverse effects in the liver were 
limited to one species and manifested only after 
prolonged dosing with no apparent effect on the 
clinical health of the animals; the effects were of 
modest severity and reversible, and the potential for 
such effects in human participants can be monitored in 
clinical studies.
In study 200912, a 47-year-old female who received a 
dose of GSK2838232 20 mg and 9 days of RTV 
100 mg, developed abdominal pain, nausea, flatulence 
with grade 4 elevations in ALT/ aspartate 
aminotransferase (AST) and grade 2 elevations in total 
bilirubin.  A liver ultrasound revealed a dilated 
Persons with underlying liver or biliary 
disease or abnormalities in liver function 
tests will be excluded from study 
participation.  Participants will be closely 
monitored for symptoms and signs of liver 
dysfunction, including serial monitoring of 
liver enzymes and chemistries.
Use of concomitant 
medications/supplements and intake of 
alcohol is not allowed during the study.
Exposures of GSK2838232 will be closely 
monitored in the clinical study so as to not 
exceed PK stopping criteria.
The study has pre-defined liver stopping 
criteria.


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
common bile duct and gallstones.  An endoscopic 
retrograde cholangio-pancreatography (ERCP) 
showed a dilated common bile duct with no filling 
defect.  She was diagnosed with a common bile duct 
obstruction due to gallstones that spontaneously 
resolved.  The Investigator considered this liver event 
as unrelated to study drug.
Ritonavir (RTV)
General
The most frequently reported adverse drug reactions 
among patients receiving RTV were gastrointestinal 
(including diarrhea, nausea, vomiting, abdominal pain 
[upper and lower]), neurological disturbances 
(including paresthesia and oral paresthesia), rash, and 
fatigue/asthenia.
Participants will be closely monitored for 
any symptoms potentially associated with 
RTV administration.
Cardiovascular
The RTV label includes the following cardiovascular 
AEs (which occurred in less than 2% of adult patients 
receiving RTV in all phase II/phase III studies and 
considered at least possibly related or of unknown 
relationship to treatment and of at least moderate 
intensity): cardiovascular disorder, cerebral ischemia, 
cerebral venous thrombosis, hypertension, 
hypotension, migraine, myocardial infarct, palpitation, 
peripheral vascular disorder, phlebitis, postural 
hypotension, tachycardia and vasospasm.  During 
post-marketing use of RTV first-degree AV block, 
second-degree AV block, third-degree AV block, right 
Participants will be closely monitored for 
any symptoms potentially associated with 
RTV administration.  Specifically, 
participants will be clinically monitored for 
any signs of myocardial injury (chest pain, 
shortness of breath, pain with inspiration, 
cardiac troponin I [cTnI], ECG changes), 
elevated heart rate or arrhythmias.  Serial 
ECGs will be used at each treatment period 
on-study.


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
bundle branch block have been reported.
Hepatitis
Hepatic transaminase elevations > 5 x the upper limit 
of normal, clinical hepatitis, jaundice, and hepatic 
dysfunction (including fatalities) have occurred in 
patients receiving RTV alone or in combination with 
other antiretroviral drugs.  There may be an increased 
risk for transaminase elevations in patients with 
underlying hepatitis, pre-existing liver diseases, or 
liver enzyme abnormalities, and in patients taking 
multiple concomitant medications and/or with 
advanced acquired immunodeficiency syndrome 
(AIDS).
Enrolment into the study will be limited to 
healthy volunteers who do not have not 
underlying liver disease, hepatitis or liver 
enzyme abnormalities.  Liver enzymes 
(ALT, AST, total and direct bilirubin, 
alkaline phosphatase) will be determined at 
screening and monitored throughout the 
study period.
Pancreatitis
Pancreatitis has been observed in patients receiving 
RTV therapy, and in some cases fatalities have been 
observed.
Participants will be closely monitored for 
any symptoms of pancreatitis, including 
nausea, vomiting, abdominal pain and 
anorexia.  Lipase will be monitored 
throughout the treatment period.


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Adverse Drug Reactions due to 
Drug Interactions
Initiation of RTV, a cytochrome P (CYP) 3A inhibitor, 
in patients receiving medications metabolized by 
CYP3A or initiation of medications metabolized by 
CYP3A in patients already receiving RTV, may 
increase plasma concentrations of medications 
metabolized by CYP3A.  Initiation of medications that 
inhibit or induce CYP3A may increase or decrease 
concentrations of RTV, respectively.  These 
interactions may lead to clinically significant adverse 
reactions, potentially leading to severe, life-
threatening, or fatal events from greater exposures of 
concomitant medications, or clinically significant 
adverse reactions from greater exposures of RTV 
Use of concomitant medications (besides 
GSK2838232), herbals and dietary 
supplements is exclusionary and will be 
prohibited.  Participants will also be 
instructed to avoid ingestion of grapefruit 
juice.


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3.3.2.
Benefit Assessment
This is a study in healthy participants and as such there is no expected benefit to the 
participants that will receive GSK2838232.  Participation in this study may contribute to 
the process of developing new therapies for HIV.  There may be benefit to individual 
participants from the medical evaluations and assessments that could identify conditions 
to which the participant was previously unaware.
3.3.3.
Overall Benefit: Risk Conclusion
GSK2838232, with its novel mechanism of action, can potentially provide benefit to 
HIV-1 infected patients experiencing virologic failure due to multi-drug resistant virus or 
those with intolerance to other antiretroviral therapies.  Given the preclinical profile and 
the clinical profile to date, the overall risk to healthy participants at the proposed 
GSK2838232 doses (with or without RTV) is predicted to be low.
While cardiovascular-related events have been observed, the totality of the pre-clinical 
and clinical data suggest a low likelihood of cardiac toxicity from GSK2838232.  
Nevertheless, there will be close monitoring of cardiovascular (CV) parameters, as 
described below, and CV-related study stopping criteria will be implemented to further 
reduce the potential risk to participants.
In addition, the 9-month dog toxicity study identified adverse liver findings that were 
mild, reversible, can be monitored, and only occurred after prolonged exposure to 
concentrations that are greater than the average exposure expected from the highest dose 
level in this study.  To diminish the potential risk of liver toxicity, persons with 
underlying hepatic or biliary abnormalities will be excluded, liver enzymes will be 
closely monitored, and liver-stopping criteria will be implemented in this study.
Participants will also be at risk for AEs from RTV use (Part 1 only) and will be 
monitored closely for such events.
Projected exposure and Ctrough values for the proposed doses of GSK2838232 indicate a 
high likelihood of attaining concentrations that will afford significant anti-viral benefit to 
HIV-infected patients but will be below the no AE dose level (NOAEL) seen in 
preclinical studies.  Therefore, the risks in this study are considered justified based on 
benefits that may be afforded to participants with HIV infection.


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4.
OBJECTIVES AND ENDPOINTS
Part 1:
Objectives
Endpoints
Primary

To assess the relative 
bioavailability of a novel 
GSK2838232 tablet 
formulations versus the capsule 
formulation (Part 1A)

AUC(0-) and Cmax,

To assess the effect of food on 
GSK2838232 exposure of the 
tablet formulation (Part 1A and 
Part 1B)

AUC(0-), Cmax, and tmax
Secondary

To investigate the safety and 
tolerability of GSK2838232 
following single dose 
administration as tablets or 
capsules, with RTV

GSK2838232 safety parameters: AEs; 
absolute values and changes over time 
of clinical laboratory evaluations 
(hematology, clinical chemistry, 
urinalysis), vital signs, and ECG 
parameters from pre-dose values

To characterize the PK of 
GSK2838232 after 
administration of a novel tablet 
formulation and capsule 
formulation with food, and the 
tablet formulation given without 
food

tlag, tmax, t½, tlast, C24, and 
AUC(0-t)
Part 2:
Objectives
Endpoints
Primary

To assess the safety of 
GSK2838232 administered as 
non-boosted once-daily doses of 
a tablet formulation for 11 days

GSK2838232 safety parameters: AEs; 
absolute values and changes over time 
of clinical laboratory evaluations 
(hematology, clinical chemistry, 
urinalysis), vital signs, and ECG 
parameters from pre-dose values

To assess the PK of 
GSK2838232 administered as 
non-boosted once-daily doses of 
a tablet formulation for 11 days

Day 1 dose: AUC(0-), Cmax, C, 
tmax, tlag

Day 11 dose: AUC(0-), AUC(0-), 
Cmax, C, tmax, t½, tlast


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Objectives
Endpoints
Secondary

To assess time to steady-state of 
GSK2838232 when 
administered as non-boosted 
once-daily doses of a tablet 
formulation for 11 days

Pre-dose concentrations on Days 2 
to 11

To assess accumulation of 
GSK2838232 when 
administered as non-boosted 
once-daily doses of a tablet 
formulation for 11 days

Accumulation ratios: Ro[AUC(0-)], 
R(Cmax), R(C)
t1/2= Apparent terminal phase half-life; tmax= Time of occurrence of Cmax; tlag= Lag-time (time delay between drug 
administration and first observed concentration above LOQ in plasma); AUC (0-t) = Area under the concentration-time 
curve from zero up to a definite time t
5.
STUDY DESIGN
5.1.
Overall Design
This study is divided into two study parts, Part 1 (Figure 1) and Part 2 (Figure 2).
Part 1:
Figure 1
Part 1: Single Dose, Food Effect Study Design Schematic

Part 1 is a relative bioavailability study (Table 4) that will further subdivide into 
two parts (Part 1A and Part 1B).

In Part 1A, the safety and PK of a novel tablet formulation of GSK2838232 will 
be evaluated in open label, randomized, cross-over fashion against the capsule 
formulation as reference.


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
Each actual treatment dose will be separated by a minimum 10-day washout 
period.  Part 1A will be studied in the fed state using a normal fat (i.e., 
approximately 30%) meal in all participants.

The safety and PK will be evaluated, and the tablet will be evaluated for 
suitability, and further clinical assessment in Part 1B, where the tablet will be 
administered in the fasted state to understand the impact of food on relative 
bioavailability.

GSK2838232 as tablets or capsules (at a 200 mg dose level) will be administered 
with 100 mg RTV, after two pre-doses of 100 mg RTV QD over 48 h.  The use of 
RTV priming is an aspect of GSK2838232 clinical development (specifically 
relative bioavailability studies) so far and allows a more accurate assessment of 
what will ultimately happen in the repeat-dose clinical studies with GSK2838232 
when boosted with RTV.  In Part 2 of the study, however, GSK2838232 will be 
administered unboosted and no RTV will be co administered.

Participants will have a screening visit within 30 days prior to first dose, a 
minimum 10-day washout period between doses, and a follow-up visit 7 to 14 
days after the last dose.  The maximum duration of study participation will be 
approximately 9 to 10 weeks.
Table 4
Study Design for Part 1
Sequence
N
Part 1A
Part 1B
Period 1
Period 2
Period 3
1
6
A
B
C
2
6
B
A
1.
All treatments in Part 1A to be administered with RTV in fed state, following two RTV pre-doses.
2.
There will be a washout of at least 10 days between each Period.
3.
Treatment A = GSK2838232 200 mg/r (as 4 x 50 mg) capsule formulation, fed, normal fat (i.e., 
approximately 30%) meal (reference).
4.
Treatment B = GSK2838232 200 mg/r (as 2 x 100 mg) tablet formulation, fed, normal fat (i.e., 
approximately 30%) meal.
5.
Treatment C = GSK2838232 200 mg/r (as 2 x 100 mg) tablet, confirmed from Part 1A, fasted.
After completion of Part 1A, preliminary PK data will be analyzed, and a decision will be 
made based on tolerability, relative bioavailability PK criteria, as well as feasibility 
considerations, as to whether the tablet formulation will be used to conduct Part 1B 
(fasted) and Part 2.


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Part 2:
Figure 2
Single Daily Dose Study Design Schematic

Part 2 will evaluate non-RTV boosted GSK2838232, given as single daily doses 
for 11 days in a separate cohort of participants (N=8; 6A/2P).

The placebo tablet supplied will not be identical to GSK2838232 and as such will 
be administered by site staff via an opaque card/paper tube to facilitate the single 
blind (i.e., the Principal Investigator [PI] and the participants themselves will be 
blinded as to their treatment).

The dose chosen for Part 2 will depend upon the preliminary results of the tablet 
in Part 1A but is likely to be, but will not exceed, 500 mg (i.e., 5 x 100 mg tablets) 
QD.  

Participants will have a screening visit within 30 days prior to first dose, and a 
follow-up visit 7 to 14 days after the last dose.  The maximum duration of study 
participation will be approximately 8 to 9 weeks.
Study Population:
The study population will consist of healthy male or female participants (women of child 
bearing potential [WOCBP] are permitted as long as the criteria for contraception are 
adhered to), as per inclusion/exclusion criteria (Section 6).
Note: Participants in both Part 1 and Part 2 will have a 24-h Holter screen as part of 
baseline evaluation.  Holter monitoring may apply during the study period if needed.
Study Plan:
Because of the requirement to begin RTV pre-dosing 48 hours before each treatment dose 
in Parts 1A and 1B, participants will be admitted to the Clinical Unit three nights before 
each of the treatment periods and remain in the Unit until the last (120 h) PK time-point 
of each treatment period is collected.  There is no such early admission requirement for 
Part 2 (non-boosted GSK2838232).


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If participants prematurely discontinue the study, additional participants may be 
randomized and assigned to the same treatment sequence at the discretion of the Sponsor 
in consultation with the Investigator.
5.2.
Number of Participants
In order to have sufficient evaluable participants for the above mentioned study 
objectives, it is expected that a sufficient number of participants will be screened in order 
to enroll a sufficient number of participants for analysis as given below:
Part 1:
It is expected that approximately 16 healthy participants will be enrolled to provide at 
least 12 evaluable participants through the three study periods (at least 6 participants per 
treatment).  Participants will be evenly assigned to one of the two treatment sequences for 
the crossover design Part 1A.
Part 2:
It is expected that 10 healthy participants will be enrolled to provide at least 8 evaluable 
participants through the single study period.
5.3.
Participant and Study Completion
A completed participant is one who has received the study treatment per the protocol and 
who has completed all phases of the study including the follow-up visit.
The end of the study is defined as the last participant’s last visit.
5.4.
Scientific Rationale for Study Design
Study HMI116787 was the First Time in Human (FTiH) clinical trial of GSK2838232 
and assessed the safety and tolerability of escalating doses (5 mg to 100 mg), food effect 
and the impact of steady-state RTV on GSK2838232 PK.  The study was completed in 
November 2013, and safety and PK data warranted continued investigation of 
GSK2838232.
Subsequent clinical studies 200912 and 200207 were carried out in healthy participants 
and extended the dose range studied as follows:

Study 200207: Repeated doses of GSK2838232 SDD alone (20 mg and then 
50 mg QD for 8 days), and then with RTV as 10 mg SDD GSK2838232 + RTV 
QD for 5 days.

Study 200912: Dosed up to 200 mg GSK2838232 alone as single doses (as either 
SDD or API PiB) or 20 mg GSK2838232 API PiB single dose with steady-state 
RTV.
Study 204953 has completed the clinical phase in 4Q2016 and was a double-blind 
(except for the relative bioavailability cohort, Part 1B), placebo-controlled, single 


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(Part 1A; dose levels of 50 to 250 mg) followed by a repeat dose (Part 2; dose levels of 
20 to 200 mg QD) escalation study to investigate the safety, tolerability and PK of 
GSK2838232 as API, co-dosed with RTV 100 mg QD.  GSK2838232 was administered 
without RTV in the last cohort of repeat dosing to assess achievable plasma 
concentrations with unboosted GSK2838232 (200 mg twice daily [BID]).
This study then completes the assessment of clinical trial formulation (tablets) for 
Phase IIb and III as well as an assessment of higher QD doses of GSK2838232 
unboosted.
5.5.
Dose Justification
The dose for Part 1A and Part 1B of this study will be 200 mg (achieved as either 
4 x 50 mg capsules or 2 x 100 mg tablets) administered with 100 mg RTV.  This dose 
level was tested in Study 204953 and provides a suitable PK profile for assessment of 
formulation performance.
The dose for Part 2 will be confirmed from Part 1A but is likely to be, and will not 
exceed, 500 mg (as 5 x 100 mg tablets).  The dose of 500 mg is justified on the grounds 
that the utility of non-boosted GSK2838232 in a QD regimen may now be an achievable 
goal.  GSK2838232 has been previously assessed in repeated doses of i) 200 mg 
GSK2838232 QD in combination with 100 mg RTV QD for 11 days, and ii) non-boosted 
200 mg GSK2838232 BID for 11 days (Study 204953).  This study will assess the 
highest practical once-daily dose of GSK2838232.
6.
STUDY POPULATION
Specific information regarding warnings, precautions, contraindications, AEs and other 
pertinent information on the GSK IP or other study treatment that may impact participant 
eligibility is provided in the IB.
Deviations from inclusion and exclusion criteria are not allowed because they could 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
participant safety.  Therefore, adherence to the criteria as specified in the protocol is 
essential.


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6.1.
Inclusion Criteria
A participant will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1. Between 18 and 55 years of age inclusive, at the time of signing the informed 
consent.
TYPE OF PARTICIPANT AND DIAGNOSIS INCLUDING DISEASE SEVERITY 
2. Healthy as determined by the Investigator or medically qualified designee based 
on a medical evaluation including medical history, physical examination, 
laboratory tests and cardiac monitoring.
3. A participant with a clinical abnormality or laboratory parameter(s) which is/are 
not specifically listed in the inclusion or exclusion criteria, and outside the 
reference range for the population being studied, may be included only if the 
Investigator in consultation with the Medical Monitor, if required, agree and 
document that the finding is unlikely to introduce additional risk factors and will 
not interfere with the study procedures.
4. A creatinine clearance > 80 mL/min as determined by Cockcroft-Gault equation:
CLcr (mL/min) = (140 – age) * Wt / (72 * Scr) (times 0.85 if female) where age is 
in years, weight (Wt) is in kg, and serum creatinine (Scr) is in units of mg/dL.
WEIGHT
5. Body weight 50.0 kg (110 lbs.) for men and 45.0 kg (99 lbs) for women and 
body mass index (BMI) within the range 18.5 to 31.0 kg/m2 (inclusive).
SEX
6. Males or females
A female participant is eligible to participate if she is not pregnant (as confirmed 
by a negative serum human chorionic gonadotrophin [hCG] test), not lactating, 
and of non-reproductive potential which is defined as:
Reproductive potential:
There is no definitive drug-drug interaction (DDI) information with GSK2838232 
and an interaction with oral contraceptives is possible, so other (barrier, 


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inter-uterine device etc.) methods of contraception will be required.
Females of reproductive potential may only be enrolled if they are using two 
forms of complementary contraception, which must include at least one barrier 
method.  They will be counselled on safer sex practices.
Fertile females, who have an established, long-term lifestyle of sexual abstinence, 
or only same sex partners, require no other means of birth control.
Non-reproductive potential:

Pre-menopausal females with one of the following:

Documented tubal ligation,

Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion,

Hysterectomy,

Documented Bilateral Oophorectomy.

Postmenopausal defined as 12 months of spontaneous amenorrhea in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) and estradiol levels consistent with menopause (refer to 
laboratory reference ranges for confirmatory levels).  Females on hormone 
replacement therapy (HRT) must discontinue HRT to allow confirmation of 
post-menopausal status prior to study enrolment.
Male participants with female partners of child bearing potential must comply 
with the following contraception requirements from the time of first dose of study 
medication until one week after the last dose of study medication.
a.
Vasectomy with documentation of azoospermia.
b.
Male condom plus partner use of one of the contraceptive options below:

Contraceptive subdermal implant that meets the Standard operating 
Procedure (SOP) effectiveness criteria including a <1% rate of failure per 
year, as stated in the product label,

Intrauterine device or intrauterine system that meets the SOP effectiveness 
criteria including a <1% rate of failure per year, as stated in the product 
label,

Oral contraceptive, either combined or progestogen alone or Injectable 
progestogen,

Contraceptive vaginal ring,

Percutaneous contraceptive patches.

These allowed methods of contraception are only effective when used 


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consistently, correctly and in accordance with the product label.  The Investigator
is responsible for ensuring that participants understand how to properly use these 
methods of contraception.
INFORMED CONSENT
7. Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form and in this protocol.
6.2.
Exclusion Criteria
A participant will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1. Alanine transaminase (ALT) >1.5x upper limit of normal (ULN) 
2. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 
3. Current or chronic history of liver disease, or known hepatic or biliary 
abnormalities.
4. Participants who have asthma or a history of asthma.
5. Medical history of cardiac arrhythmias or cardiac disease or a family or personal 
history of long QT syndrome.
CONCOMITANT MEDICATIONS
6. Unable to refrain from the use of prescription or non-prescription drugs, including 
vitamins, herbal and dietary supplements (including St John’s Wort) within 7 days 
(or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is 
longer) prior to the first dose of study medication, unless in the opinion of the 
Investigator and GSK Medical Monitor, the medication will not interfere with the 
study procedures or compromise participant safety.
RELEVANT HABITS
7. History of regular alcohol consumption (within 6 months prior to screening or 
unable to refrain from alcohol use from 5 days prior to admission through the last 
blood sample collected) defined as:

For US sites: an average weekly intake of >14 drinks for males or >7 drinks 


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for females.  One drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) 
of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof 
distilled spirits.
8. Regular use of tobacco- or nicotine- containing products within 6 months prior to 
screening.  Unable to refrain from smoking from the Screening Visit through the 
last blood sample collected.  As confirmed by a urine cotinine test.
CONTRAINDICATIONS
9. History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the Investigator or Medical 
Monitor, contraindicates their participation.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
10. Presence of hepatitis B surface antigen (HBsAg), or positive hepatitis C virus 
(HCV) test result at screening or within 3 months prior to first dose of study 
treatment.
11. Screening or baseline cardiac troponin I greater than the 99% cutoff (>0.045ng/ml 
by the Dimension Vista cTnI assay) for a given assay.
12. A positive pre-study drug/alcohol screen.
13. A positive test for HIV antibody.
14. Where participation in the study would result in donation of blood or blood 
products in excess of 500 mL within 56 days.
15. The participant has participated in a clinical trial and has received an 
investigational product within the following time period prior to the first dosing 
day in the current study: 30 days, 5 half-lives or twice the duration of the 
biological effect of the investigational product (whichever is longer).
16. Exposure to more than four new chemical entities within 12 months prior to the 
first dosing day.
17. Exclusion Criteria for 24-hour Screening Holter:

Any symptomatic arrhythmia (except isolated extra systoles).

Sustained cardiac arrhythmias (such as atrial fibrillation or flutter, 
supraventricular tachycardia (10 consecutive beats), complete heart block).

Non-sustained or sustained ventricular tachycardia (defined as 3 
consecutive ventricular ectopic beats).

Any conduction abnormality (including but not specific to left or right 
incomplete or complete bundle branch block, atrioventricular (AV) block 
[2nd degree or higher], Wolff Parkinson White (WPW) syndrome etc.).


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
Sinus Pauses >3 seconds.

300 or more supraventricular ectopic beats in 24 hours.

250 or more ventricular ectopic beats in 24 hours.
18. Any clinically significant abnormal echocardiogram finding (should be discussed 
with the Medical Monitor prior to enrolment).
19. Exclusion criteria for screening ECG (a single repeat is allowed for eligibility 
determination):
Males
Females
Heart rate
<45 or >100 bpm
<50 or >100 bpm
PR Interval
<120 or > 220 msec
QRS duration
<70 or >120 msec
QTc interval (Fridericia’s)
>450 msec

Note: A heart rate from 100 to 110 bpm can be rechecked by ECG or vitals 
within 30 minutes to verify eligibility.

Evidence of previous myocardial infarction (does not include ST segment 
changes associated with re-polarization).

Any conduction abnormality (including but not specific to left or right 
complete bundle branch block, AV block [2nd degree or higher], WPW 
syndrome).

Sinus Pauses >3 seconds.

Any significant arrhythmia which, in the opinion of the Investigator OR GSK 
Medical monitor, will interfere with the safety for the individual participant.

Non-sustained or sustained ventricular tachycardia (3 consecutive 
ventricular ectopic beats).
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions
Participants should avoid consumption of red wine, Seville oranges, grapefruit or 
grapefruit juice (and/or pomelos, exotic citrus fruits, grapefruit hybrids or fruit juices) 
from 5 days before the first dose of study medication, until follow-up.
Participants should refrain from eating poppy seed-containing food (e.g., poppy cake) at 
least 3 days before admission as this can falsify the urine drug screen.  A positive illicit 
drug result will lead to exclusion from the remainder of the study.

Water is allowed ad libitum throughout the study.


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
While in residence in the clinical research unit (admission through discharge), 
participants will be restricted to food and beverage that is site-provided at specific 
times.  Participants are expected to complete all meals and snacks (100%) within 25 
minutes (Parts 1A and Part 1B).  Non-compliance will be recorded.

Participants will be fed a “normal” standardized diet consisting of an average 
between 3400 to 4000 kcal for each full day in residence (with the exception of Part 
1B dosing days where dosing is conducted under fasted conditions).  A 5% variance 
in calories is allowed.  The macronutrient distributions and caloric criteria are within 
the recommendations in the Dietary Guidelines for Americans, 2010.

Part 1A and Part 2

Standardized meals will be provided to participants in Part 1A starting with Day 1 
through discharge from the clinical research unit.

Standardized meals and snacks should be completed within 25 minutes.  Participants 
will be expected to complete all meals and snacks (100%).  Non-compliance on Day 
1 will be recorded in increments of 25% (e.g., 0%, 1-25%, 26-50%, 51-75% or 76-
100% meal or snack completed).

Participants will undergo at least a 10-hour overnight fast then will be provided a 
meal 30 minutes before dosing and will be expected to complete the meal within 25 
minutes.  Lunch will be provided approximately 4 hours after morning dosing and 
dinner will be provided approximately 9 hours after morning dosing.  On Day 1, all 
participants will receive identical meals at breakfast, lunch, dinner and snack.  On 
non-dosing days, meals will be served per the standard times at the clinical research 
unit.

Part 1B (tablet, fasted):

Participants will undergo at least a 10-hour overnight fast prior to Part 1B 
GSK2838232 tablet dosing.  On the day of dosing, participants will continue fasting 
after dosing (no breakfast).  Lunch will be provided approximately 4 hours after 
morning dosing and dinner will be provided approximately 9 hours after morning 
dosing.  On Day 1, all participants will receive identical meals at lunch, dinner and 
snack.  On non-dosing days, meals will be served per the standard times at the 
clinical research unit.
6.3.2.
Caffeine, Alcohol, and Tobacco

All enrolled participants will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks and chocolate) for 
48 hours before the start of dosing until collection of the final PK sample during 
each session.

All enrolled participants will abstain from red wine for 5 days and other alcohol 
for 24 hours before the start of dosing until collection of the final PK sample 
during each session.


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
Participants who currently use or have used tobacco products within 6 months of 
Screening will not be enrolled.

Participants must refrain from all illicit drugs throughout the study (from 
Screening until discharge from the study).  Drug screening will occur as indicated 
in the Schedule of Assessments (Table 2 and Table 3) for each Part of the study.  
Participants should refrain from eating poppy seed-containing food (e.g., poppy 
cake) at least 3 days before admission as this can falsify the urine drug screen.  A 
positive illicit drug result will lead to exclusion from the remainder of the study.
6.3.3.
Activity

Participants will abstain from strenuous exercise for 1 week before Admission and 
during the course of the study and refrain from increasing their activity above that 
which they normally perform.  Participants may participate in light recreational 
activities during studies (e.g., watch television, read).
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities.  Minimal information includes 
demography, screen failure details, eligibility criteria, and any SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened at the discretion of the PI.  Rescreened participants should be assigned 
the same participant number as for the initial screening.
7.
TREATMENTS
The term ‘study treatment’ is used throughout the protocol to describe GSK2838232, 
RTV or the combination of the products received by the participant as per the protocol 
design.
GSK2838232 will be supplied by GSK as prefilled capsules or tablets in bulk for 
dispensing to participants at the site according to the treatment code.
Ritonavir – commercially available; will be purchased/supplied either by PAREXEL or 
GSK.
7.1.
Treatments Administered
Details of the study treatment are provided in Table 5 below.


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Table 5
Investigational Product and Other Study Treatment
Study Treatment Name:
GSK2838232
NORVIR (ritonavir, 
RTV)
Placebo (Part 2 only)
Dosage formulation:
Tablets or Capsule
Tablets
*Tablet 
(non-matching) for 
the GSK2838232 
tablet formulation)
Unit dose 
strength(s)/Dosage 
level(s):
200 mg:
Capsules: 4 x 50 mg
Tablets: 2 x 100 mg
100 mg
Not applicable
Route of Administration 
Oral
Oral
Oral
Dosing instructions:
Part 1A: To be 
taken with water 
and a meal (fed 
conditions)
Part 1B: To be 
taken with water 
after a fast (fasted 
conditions)
Part 2: To be taken 
with water and a 
meal once daily for 
11 consecutive days
Part 1A: To be taken 
with water and a 
meal (fed conditions)
Part 1B: To be taken 
with water after a fast 
(fasted conditions)
Part 2: To be taken 
with water and a 
meal once daily for 
11 consecutive days
Packaging and Labeling
GSK2838232 will be 
supplied by GSK as 
prefilled capsules or 
tablets in bulk for 
dispensing to 
participants at the 
site according to the 
treatment code.
Placebo for 
GSK2838232 tablets 
will be provided, 
although are 
non-matching as 
tablets
Manufacturer/Source of 
procurement 
GSK
Procured by 
PAREXEL
GSK
Physical Form
Pink unmarked 
capsule
White to slightly 
colored tablet.
White film-coated 
ovaloid tablets
White to slightly 
colored tablet.


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*The placebo (tablet) supplied will not be identical to GSK2838232 and as such will be administered by 
site staff via an opaque card/paper tube to facilitate the single blind (i.e., the participant will be blinded as 
to their treatment).
The unblinded pharmacist or qualified designee will prepare GSK2838232 and placebo 
according to a pre-generated schedule of randomized treatment assignments.
7.1.1.
Medical Devices

Not applicable.
7.2.
Dose Modification
Not applicable.
7.3.
Method of Treatment Assignment
Participants will be assigned to study treatment in accordance with the computer 
generated randomization schedule generated by PAREXEL, using SAS version 9.3 or 
higher.  A separate randomization schedule will be generated for each part of the study.  
At Screening, potential study participants will be assigned a screening number.  
Participants will be randomized before the first dose of Study Drug in Part 1A 
(GSK2838232 tablet or capsule, with RTV) or Part 2 (GSK2838232 tablet or placebo 
tablet, without RTV) after all screening assessments have been completed and after the 
Investigator has verified that they are eligible per study inclusion/exclusion criteria.  No 
participant may begin treatment before randomization and assignment of a unique 
participant identification number.
Each participant scheduled to receive study treatment will receive a participant number 
when randomized.  The randomization number will determine the allocation of treatment 
sequences (ABC or BAC) for Part 1, and of treatment (GSK2838232 without RTV or 
placebo) for Part 2.  Allocation to treatment for Part 1A or Part 1B (with Part 2 being 
fixed) will be according to a predetermined random order.
7.4.
Blinding
Part 1 of the study will be open label and thus not be blinded.
Part 2 of the study will be single blinded because of the unavailability of matching 
placebo tablets.  Certain site personnel preparing the treatment for administration will 
know what the treatment is but will administer the tablet or tablet placebo via an opaque 
tube/envelope to the participants.  The PI and the participants will be completely blinded 
to specific participant treatment assignment.
When possible, GSK/ contract research organization (CRO) personnel will not have 
access to participant-specific treatment assignment so as to not potentially introduce bias 
in discussions with the study center.


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The Investigator or treating physician may unblind a participant’s treatment (Part 2 single 
blind) assignment only in the case of an emergency when knowledge of the study 
treatment is essential for the appropriate clinical management or welfare of the 
participant.  Whenever possible, the Investigator must first discuss options with the GSK 
Medical Monitor or appropriate GSK study personnel before unblinding the participant’s 
treatment assignment.  If this is impractical, the Investigator must notify GSK as soon as 
possible, but without revealing the treatment assignment of the unblinded participant, 
unless that information is important for the safety of participants currently in the study.  
The date and reason for the unblinding must be recorded in the appropriate data 
collection tool.
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 data collection tool.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any participant with an SAE.  If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s treatment assignment, may be sent to Investigators in 
accordance with local regulations and/or GSK policy.
7.5.
Preparation/Handling/Storage/Accountability
A description of the methods and materials required for preparation of GSK2838232, 
RTV or placebo will be detailed in a Technical Agreement. The formulations will be 
extemporaneously prepared as per instructions that will be reviewed and approved by 
GSK before use.
1.
The Investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.
2.
Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment.  All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access 
limited to the Investigator and authorized site staff.
3.
The Investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study treatment 
are provided in the Study Reference Manual.
5.
Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.
6.
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 


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Investigator, where this is required by local laws, or is available upon request from 
GSK.
7.6.
Treatment Compliance

When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff.

When participants are dosed at the site, they will receive study treatment directly 
from the Investigator or designee, under medical supervision.  The date and time of 
each dose administered in the clinic will be recorded in the source documents.  The 
dose of study treatment and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person 
administering the study treatment.  Study site personnel will examine each 
participant’s mouth to ensure that the study treatment was ingested.
7.7.
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) within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study 
treatment until completion of the follow-up visit, unless, in the opinion of the Investigator
and sponsor, the medication will not interfere with the study.
Acetaminophen, at doses of 2 g/day is permitted for use any time during the study.  
Other concomitant medication may be considered on a case by case basis by the 
Investigator in consultation with the Medical Monitor.
7.8.
Treatment after the End of the Study
Participants will not receive any additional treatment from GSK after completion of the 
study because only healthy participants are eligible for study participation.


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8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
8.1.1.
Liver Chemistry Stopping Criteria
Study treatment will be discontinued for a participant if liver chemistry stopping criteria 
are met:
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Section 12.3, Appendix 3.
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology (in alignment with the Food 
and Drug Administration [FDA] premarketing clinical liver safety guidance).  These 
protocol guidelines are in alignment with FDA premarketing clinical liver safety 
guidance:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Discontinuation of study treatment for abnormal liver tests should be considered by the 
Investigator when a participant meets one of the conditions outlined in the algorithm 
above or if the Investigator believes that it is in the best interest of the participant.


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8.1.2.
QTc Stopping Criteria

The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may not 
be changed or substituted once the participant has been enrolled.

For example, if a participant is eligible for the protocol based on QTcF, then 
QTcF must be used for discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, 
the same formula must continue to be used for that participant for all QTc data 
being collected for data analysis.  Safety ECGs and other non-protocol specified 
ECGs are an exception.

A participant that meets the bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from study treatment.

QTc, QTcB, QTcF >500 msec,

Change from baseline: QTcF >60 msec
8.1.3.
Temporary Discontinuation
Not applicable.
8.1.4.
Rechallenge
Not applicable.
8.2.
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.

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 collected and not tested, and the Investigator must document this in the 
site study records.

Refer to the Schedule of Assessments (Table 2 and Table 3) for data to be 
collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed.
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.


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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 with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES
Each participant will have adequate time to provide informed consent of his or her own 
free will and before conducting any study procedures according to the International 
Conference on Harmonization (ICH) and Code of Federal Regulations (CFR) guidelines.  
Each participant will be provided a copy of the signed informed consent document (ICF) 
before the initiation of any study procedures.
After a participant has provided written informed consent and within 30 days of the first 
dose of study treatment, the Investigator or other study personnel will determine if the 
participant is eligible for enrolment in the study.  This will be done by reviewing the 
inclusion and exclusion criteria and completing all of the screening assessments outlined 
in the Schedule of assessments Tables (Table 2 and Table 3).  Screening assessments may 
be carried out over more than 1 day provided that all required assessments are completed 
within 30 days before the first administration of study treatment.
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns.  Therefore, adherence to the study design requirements, including those 
specified in the Schedule of Assessments Tables (Table 2 and Table 3), are essential and 
required for study conduct.
Whenever vital signs, 12-lead ECGs and blood draws are scheduled for the same nominal 
time, the assessments should occur in the following order:
1. 12-lead ECG.
2. Vital signs.
3. Blood draws.
Note: The timing of the assessments should allow the blood draw to occur at the exact 
nominal time.  In the event that the timing for a scheduled assessment conflicts with an 


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assessment that has to be repeated, the scheduled assessment will be performed on 
time/as scheduled and the repeat assessments will be conducted when feasible.
The timing and number of planned study assessments, including: safety and PK 
assessments may be altered during the course of the study based on newly available data 
(e.g., to obtain data closer to the time of peak plasma concentrations) to ensure 
appropriate monitoring.
The Institutional Review Board (IRB) will be informed of any safety issues that require 
alteration of the safety monitoring scheme or amendment of the Informed Consent Form.
The timing of planned study assessments is listed in the Schedule of Assessments Tables 
(Table 2 and Table 3).
9.1.
Efficacy Assessments
Not applicable.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Section 12.5, Appendix 5.
The Investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study treatment or study (see Section 8).  
In addition, all ventricular tachyarrhythmias are considered AEs of interest and should be 
reported to the Sponsor within 24 hours.
9.2.1.
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information

All SAEs will be collected from the signing of the ICF until the follow-up visit
at the time points specified in the Schedule of Assessments Tables (Table 2 and 
Table 3).

All AEs will be collected from the start of treatment until the follow-up visit at 
the time points specified in the Schedule of Assessments Tables (Table 2 and 
Table 3).

The Sponsor will inform FDA within 7 days of any grade 2 or higher “alteration 
in personality-behavior or in mood” or “altered mental status” adverse events 
that occur in participants who have received GSK2838232.

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (CRF) not the AE section.

All SAEs will be recorded and reported to the sponsor or designee within 
24 hours, as indicated in Section 12.5, Appendix 5.  The Investigator will submit 
any updated SAE data to the sponsor within 24 hours of it being available.


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
Investigators are not obligated to actively seek AEs or SAEs in former study 
participants.  However, if the Investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study 
participation, the Investigator must promptly notify the sponsor.

NOTE: The method of recording, evaluating, and assessing causality of AEs and 
SAEs and the procedures for completing and transmitting SAE reports are 
provided in Section 12.5, Appendix 5.
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended 
and nonleading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, 
since your last visit/contact?” 
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts.  All SAEs and nonserious AEs of special interest 
(as defined in Section 3.3.1), will be followed until the event is resolved, stabilized, 
otherwise explained, or the participant is lost to follow-up (as defined in Section 8.3).  
Further information on follow-up procedures is given in Section 12.5, Appendix 5.
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the Investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met.  In addition, all ventricular tachyarrhythmias are considered AEs of interest 
and should be reported to the Sponsor within 24 hours.

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation.  The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
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 


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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.

Please see the SRM for SAE reporting contact details.
9.2.5.
Pregnancy

Details of all pregnancies in female participants and female partners of male 
participants will be collected after the start of study treatment and until the final 
follow-up visit.

If a pregnancy is reported, the Investigator should inform GSK within 24 hours of
learning of the pregnancy and should follow the procedures outlined in 
Section 12.6, Appendix 6.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.2.6.
Total Blood Volume
No more than 500 mL of blood will be collected over the duration of the study, from an 
individual participant, including any extra assessments that may be required.
9.3.
Treatment of Overdose
For this study, any dose of GSK2838232 greater than the planned dose for any given 
participant in each treatment period within a 24-hour time period (1 hour) will be 
considered an overdose.
For this study any dose of RTV greater than the planned dose (100 mg once daily) within 
a 24-hour time period (1 hour) will be considered an overdose.
In the event of an overdose the Investigator or treating physician should:

Contact the GSK Medical Monitor immediately.

Closely monitor the participant for AEs/SAEs and laboratory abnormalities until 
GSK2838232 can no longer be detected systemically (at least 7 days for 
GSK2838232).

Obtain a plasma sample for PK analysis within 5 days from the date of the last 
dose of study treatment if requested by the Medical Monitor (determined on a 
case-by-case basis).

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.


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9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the Schedule of 
Assessments (Table 2 and Table 3).
9.4.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems.  Height 
and weight will also be measured and recorded.

A brief physical examination will include, at a minimum assessments of the lungs, 
cardiovascular system and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
9.4.2.
Vital Signs

Vital signs will be measured in supine position after 10 minutes rest and will 
include systolic and diastolic blood pressure (BP) and heart rate (HR);

BP and HR to be taken in triplicate (taken 5 minutes apart) at pre-dose (Part 1: 
Day 1; Part 2: Day 1 and Day 11) and singular at all other measurement time 
points;

If a blood pressure is outside the normal limits (< 90 mmHg or > 160 mmHg), 
then additional measurements should be taken each minute for 2 more 
occasions.

If a HR is outside the normal limits (< 40 bpm or > 100 bpm) then additional 
measurements should be taken 5 minutes apart for 2 more occasions.

Ensure correct sized cuff is used for arm circumference.

It is acceptable that HR be captured from continuous ECG equipment, 12-lead 
ECG or BP equipment.

The GSK Medical Monitor should be notified for any clinically significant 
changes in vital signs.
9.4.3.
Electrocardiograms

Triplicate 12-lead ECGs will be obtained at least 5 minutes apart in the supine 
position after 10 minutes of rest pre-dose (Part 1: Day 1; Part 2: Day 1 and 
Day 11).  All values will be recorded.

Singular 12-lead ECGs will be recorded at all other timepoints using an ECG 
machine that automatically calculates the HR and measures PR, QRS, QT and 
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
Refer to Section 8.1.2 for QTc withdrawal criteria and additional QTc readings 
that may be necessary.

The Investigator will review the 12-lead ECGs.  The decision to run repeat 
measurements if a result is outside of the normal predicted range (and/or 
considered clinically significant) should be made by the PI based on their 
clinical judgement to ensure participant safety.
9.4.4.
Holter Monitoring
Cardiac monitoring (24 hour) will be performed using Holter monitoring during the 
screening process as shown in the Schedule of Assessments (Table 2 and Table 3).  
Holter monitoring may take place during the study period if needed.
Start date and time, stop date and time, interpretation, and nature of abnormality, if any, 
will be captured in the study database.  Analysis of the Holter monitoring will consider 
the following:

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.

Atrial fibrillation and flutter.
9.4.5.
Clinical Safety Laboratory Assessments

Refer to Section 12.2, Appendix 2 for the list of clinical laboratory tests to be 
performed and to the Schedule of Assessments (Table 2 and Table 3) 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 7 days after the last dose of study 
treatment should be repeated until the values return to normal or baseline or are 
no longer considered significantly abnormal by the Investigator or medical 
monitor.

If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the sponsor 
notified.


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
All protocol-required laboratory assessments, as defined in Section 12.2, 
Appendix 2, must be conducted in accordance with the laboratory manual and 
the Schedule of Assessments (Table 2 and Table 3).

If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the Investigator (e.g., 
SAE or AE or dose modification), then the results must be recorded in the CRF.
9.5.
Pharmacokinetics
9.5.1.
Blood sample collection

Blood samples for PK and metabolism analysis of GSK2838232 will be 
collected at the time points indicated in Schedule of Assessments (Table 2 and 
Table 3).  The actual date and time of each blood sample collection will be 
recorded.  The timing of PK samples may be altered and/or PK samples may be 
obtained at additional time points to ensure thorough PK monitoring.  This will 
not require an amendment to the protocol.
Details of PK blood sample collection (including volume to be collected), processing, 
storage and shipping procedures are provided in the SRM.
9.5.2.
Sample analysis
Concentrations of GSK2838232 will be determined in plasma using the currently 
approved bioanalytical methodology.  Raw data will be archived in the GLP Archives, 
GSK.

Once the plasma has been analyzed for GSK2838232, any remaining sample 
may be analyzed for other compound-related metabolites and the results 
reported under a separate PTS-DMPK, GlaxoSmithKline protocol.
9.6.
Pharmacodynamics
Not applicable.
9.7.
Genetics
Not applicable.
9.8.
Biomarkers
Not applicable.
9.9.
Health Economics OR Medical Resource Utilization and 
Health Economics
Not applicable.


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9.10.
DATA MANAGEMENT

For this study participant data will be entered into ClinBase, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated 
medication dictionary, GSKDrug.

CRFs (including queries and audit trails) will be retained by PAREXEL, and a 
copy of the annotated CRF will be sent to GSK.  Participant initials will not be 
collected or transmitted to GSK according to GSK policy.
10.
STATISTICAL CONSIDERATIONS
All statistical analyses will be performed by PAREXEL International Early Phase 
Biostatistics.  All statistical analyses will be performed using the latest available version 
of SAS (SAS Institute Inc., Cary, North Carolina, United States of America [USA]), 
version 9.3 or higher.  PK parameters will be calculated using Phoenix WinNonlin
(Certara, L.P., 1699 S Hanley Road, St Louis MO 63144 USA), version 6.3 or higher.
Complete details will be documented in the Reporting and Analysis Plan (RAP).
Any deviations from the planned analyses will be described in the clinical study report.
10.1.
Sample Size Determination
Sample sizes are based on prior relative bioavailability studies with GSK2838232 and 
take into account variability and logistical factors while no formal calculation of power or 
sample size for Parts 1 or 2 of the study was performed.  A sample size of approximately 
16 participants for Part 1 and 10 participants for Part 2, considering a drop-out rate of 
25%, of the study should be sufficient to provide useful estimates of inter-participant 
variability for GSK2838232 PK parameters and safety assessments.
Additional participants will be randomized and enrolled to ensure a minimum of 
12 evaluable participants for Part 1 (crossover of tablet and capsule) and 8 evaluable 
participants for Part 2 (6 active: 2 placebo).
Sample size assumptions
For Part 1 of the study: The between-subject variability (%CVb) for AUC(0-), and 
Cmax parameters from previous studies at different doses were 21% to 47% and 41% to 
44%, respectively.  Assuming within-subject variability (%CVw) for AUC(0-) and 
Cmax is 80% of highest between-subject variability (which will be 38% and 35%, 
respectively), and with the sample size of 12, it is estimated that the precision (i.e., half 


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width of the 90% confidence interval on the log scale) for the relative bioavailability 
assessment will be within 31.7% of the point estimate for AUC(0-), and within 29.0% 
of the point estimate for Cmax. If the point estimate of the ratio of geometric mean for 
Cmax is 1, then 90% confidence interval will be approximately (0.78, 1.29).
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
All Participants Screened Population
The All Participants Screened Population will include all participants who consent to 
participate in the clinical study. Participants in this population will be used for 
disposition summary.
Safety Population
The Safety Population will include all participants who received at least 1 dose of the 
study treatment (including placebo) with at least 1 post-baseline safety assessment.  
Participants in this population will be used for all demographic and safety summaries or 
listings.  The population will be defined separately for Part 1A, Part 1B and Part 2 of the 
study.
Pharmacokinetic Population
The PK Population will include all participants in the Safety population for whom at least 
one evaluable PK sample is obtained and analyzed.  Pharmacokinetic samples that may 
be affected by protocol deviations will be reviewed by the study team to determine 
whether or not the sample will be excluded.  All PK analyses will be based on this 
analysis population.  The population will be defined separately for Part 1A, Part 1B, and 
Part 2 of the study.
10.3.
Definition of Baseline
Unless specified, baseline will be the last value before the first dose of study treatment. 
10.4.
Statistical Analyses
All safety analyses will be performed on the Safety Population.
All PK analyses will be performed on the PK Population.
For assessment of relative bioavailability of tablet versus capsule (AUC(0-) and Cmax) 
and effect of food (AUC(0-), Cmax, and tmax), loge-transformed selected PK
parameters (except tmax) will be analyzed using a mixed effects model.  The point 
estimates and their associated 90% confidence interval (CI) will be provided for the 


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ratios, test/reference (for bioavailability) and fed/fasted (food effect) in PK parameter 
values on the original scale.
For the parameter tmax, the corresponding non-parametric analysis will be performed on 
the original scale using CIs for the estimation of the treatment difference.
Steady-state GSK2838232 concentrations will be assessed by estimating the slope of pre-
dose concentrations following repeated daily administration.  Accumulation of plasma 
GSK2838232 will be assessed as the ratios of Day 11/Day 1 AUC(0-), Cmax, and C
values.
10.4.1.
Safety Analyses
Clinical safety observations will include AEs, vital sign measurements, ECGs and 
clinical laboratory measurements (hematology, clinical chemistry and urinalysis).  Safety 
data will be tabulated and, where appropriate, analyzed by the use of descriptive 
statistics.
The number (%) of participants withdrawing from the study treatment, study and reason 
for withdrawal will be summarized for each treatment with placebo participants 
combined within each study part.
Reported AEs will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA).  The number (%) of participants with treatment-emergent AEs (TEAEs) and 
treatment-related AEs will be tabulated by system organ class (SOC), preferred term and 
by treatment group within each study part.  Severity of the TEAEs and treatment-related 
AEs will also be summarized by SOC, preferred term and by treatment group within each 
study part.  Deaths, SAEs and AEs leading to withdrawal will be listed.
Descriptive statistics for observed and change from baseline in laboratory parameters (if 
applicable), vital signs measurements and ECGs will be presented by treatment group 
within each study part.  Clinical laboratory toxicities will be graded based on the Division 
of AIDS (DAIDS) grading system, as specified in Section 12.4, Appendix 4.  Summaries 
of laboratory toxicity grade will be provided.
10.4.2.
Pharmacokinetic Analyses
The following plasma PK parameters will be determined using standard 
non-compartmental methods as data permit and in compliance with the GlaxoSmithKline 
SOP:
Part 1:

AUC(0-t)

AUC(0-)

Cmax

C24


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
tlag

tmax

t½

tlast
Part 2:
Day 1 dose:

AUC(0-)

Cmax

C

tmax

tlag
Day 11 dose:

AUC(0-)

AUC(0-)

Cmax

C

tmax

t½

tlast
Accumulation:

R(AUC(0-))

R(Cmax)

R(C)
Any additional PK parameters that are calculated will be provided in the RAP.  Actual 
elapsed times from dosing will be used in the PK analysis.  The AUC will be determined 
using the linear-up/log-down trapezoidal rule.  Individual PK parameter values will be 
listed, and a descriptive summary by treatment will be provided.
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively.  Plasma GSK2838232 concentration-time data will be listed 
by participant, treatment group and time and summarized by treatment group and time for 
each part of the study.  Individual participant profiles for GSK2838232 
concentration-time data will be presented on both a linear and semi-log scale.  Linear and 
semi-log figures for mean and median GSK2838232 plasma concentrations versus time 
will also be generated.


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10.4.2.1.
Relative Bioavailability
In Part 1A, the following plasma PK parameters will be assessed to determine the relative 
bioavailability as data permit:

AUC(0-)

Cmax
The dependent variable will be the log-transformed PK parameters of interest (AUC(0-) 
and Cmax) and the independent variables will include a fixed effect for treatment (table 
or capsule), sequence and period, and participant as a random effect. The estimated 
difference and CI obtained on the log scale will be exponentiated to provide an estimate 
of the table to capsule ratio and its associated 90% CI.
10.4.2.2.
Food Effect
Food effect will be assessed in Part 1 using Analysis of Variance (ANOVA).  The 
dependent variable will be the log-transformed PK parameters of interest (AUC(0-∞) and 
Cmax) and the independent variables will include a fixed effect for treatment (with or 
without food) and subject as a random effect.  The estimated difference and confidence 
interval (CI) obtained on the log scale will be exponentiated to provide an estimate of the 
fed to fasted ratio and its associated 90% CI.
10.4.2.3.
Steady State Assessments
For Part 2, mean plasma GSK2838232 pre-dose values between Days 2 through 11 and 
Cof Day 11 will be plotted against time.  Achievement of plasma GSK2838232 steady-
state will be assessed by calculating the 90% CI of the slope of the linear regression of 
log (C) versus time.  The dependent variable in the linear regression model will be 
log (C) and the model will include a random intercept effect for participant and a fixed 
slope effect for study day.  Steady state will be reached if the 90% CI for the slope 
estimate includes zero.
10.4.2.4.
Accumulation
For Part 2, the extent of accumulation of GSK2838232 will be evaluated by comparing 
AUC(0-), Cmax and Cτ between Day 11 and Day 1.  For each of these comparisons an 
analysis of variance will be conducted on the log scale.  The difference between Day 11 
and Day 1 least square (LS) means and a 90% CI will be computed by fitting a mixed 
effects model with the log-transformed PK parameter as the dependent variable, day as a 
fixed effect and participant as a random effect.  The estimated difference and confidence 
interval obtained on the log-scale will be exponentiated to provide an estimate of the 
Day 11 to Day 1 ratio and its associated 90% CI.  If the model fails to converge, 
participants will be fit as a fixed effect.
10.4.3.
Efficacy Analyses
Not applicable.


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10.4.4.
Other Analyses
Not applicable.
10.4.5.
Interim Analyses
The dose and formulation to be administered in Part 1B and Part 2 will be decided, based 
on the outcome and results of an informal analysis of data from Part 1A of the study.
The Reporting and Analysis Plan will describe the planned interim analyses in greater 
detail.


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11.
REFERENCES
GlaxoSmithKline Document Number 2012N151889_03 Compound GSK2838232. 
Investigator's Brochure, Version 03. 11 Nov 2016.
James L.P. Pharmacokinetics of Acetaminophen - Protein Adducts Liver Failure. Drug 
Metab Disp, 37:1779-1784. 2009
NORVIR (ritonavir) Product Information. January, 2013.
Qian K, Morris-Natschke SL and Lee KH. HIV entry inhibitors and their potential in HIV 
therapy. Medicinal Research Reviews, 2009;29:369-93.
U.S. Department of Agriculture and U.S. Department of Health and Human Services. 
Dietary Guidelines for Americans, 2010. 7th Edition, Washington, DC: U.S. Government 
Printing Office, December 2010.
United Nations program on HIV/AIDS (UNAIDS), Fact Sheet 2015. Available from 
www.UNAIDS.org


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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
AIDS
Acquired Immunodeficiency Syndrome
ALT
Alanine Aminotransferase
ANOVA
Analysis of Variance
API
Active Pharmaceutical Ingredient
ARV
Antiretroviral
AST
Aspartate Aminotransferase
AUC (0-t)
Area under the concentration-time curve from zero up to a definite 
time t
AUC(0-)
Area under the curve (Area under the plasma drug concentration-
time curve from pre-dose to the end of the dosing interval at 
steady state)
AUC(0-inf)
Area under the concentration-time curve from time zero (pre-dose) 
extrapolated to infinite time
AV
Atrioventricular
BID
Twice Daily
BMI
Body Mass Index
BP
Blood Pressure
CFR
Code of Federal Regulations
CI
Confidence Interval
Cmax
Maximum observed concentration
Con Med
Concomitant medication
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form
CRO
Contract Research Organization
CV
Cardiovascular
CYP
Cytochrome P subfamily of enzymes
DAIDS
Division of AIDS
DDI
Drug-drug Interaction
ECG
Electrocardiogram
ERCP
Endoscopic retrograde cholangio-pancreatography
FDA
Food and Drug Administration
FSH
Follicle Stimulating
FTiH
First Time in Human
GCSP
Global Clinical Safety and Pharmacovigilance
GSK
GlaxoSmithKline
HbsAg
Hepatitis B surface Antigen
hCG
Human Chorionic Gonadotrophin
HCV
Hepatitis C Virus
Hem/Chem
Hematology and Clinical Chemistry
HIV
Human Immunodeficiency Virus


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HR
Heart Rate
HRT
Hormone Replacement Therapy
IB
Investigator’s Brochure
IEC
Independent Ethics Committees
IRB
Institutional Review Board
MedDRA
Medical Dictionary for Regulatory Activities
MSDS
Material Safety Data Sheet
NOAEL
No Adverse Event Dose Level
PI
Principal Investigator
PiB
Powder in Bottle
PK
Pharmacokinetic(s)
QD
Once daily
RAP
Reporting and Analysis Plan
RTV
Ritonavir
SAE
Serious Adverse Event
SOC
System Organ Class
SOP
Standard Operating Procedure
SRM
Study Reference Manual
SSD
Spray Dried Dispersion
SUSAR
Suspected Unexpected Serious Adverse Reactions
t1/2
Apparent terminal phase half-life
TEAE
Treatment-Emergent Adverse Event
tlag
Lag-time (time delay between drug administration and first 
observed
tmax
Time of occurrence of Cmax
ULN
Upper Limit of Norma
US
United States (of America)
WOCBP
Women of child bearing potential
WPW
Wolf Parkinson White syndrome
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Norvir
Phoenix
SAS
WinNonlin


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12.2.
Appendix 2: Clinical Laboratory Tests
Hematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed below:
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC 
Indices:
WBC count with 
Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical Chemistry 1
BUN
Potassium
Aspartate 
Aminotransferase 
(AST) / Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase 
(ALT) / Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose
Calcium
Alkaline 
phosphatase
Albumin
Triglycerides
Cholesterol (total cholesterol, HDL, LDL, VLDLc 
(calculated) and Non-HDLc [calculated])
Lipase
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Other Screening Tests
HIV
Hepatitis B (HBsAg)
Hepatitis C (Hep C antibody)
Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)
FSH and estradiol (as appropriate)
Serum hCG Pregnancy test (as appropriate)2
NOTES:
1Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up Assessments 
after liver stopping or monitoring event are given in Section 8.1.1 and Section 12.2, Appendix 2.
2Serum testing will be performed at Screening testing.


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12.3.
Appendix 3: Liver Safety: Required Actions and Follow-up 
Assessments
Phase 1 Liver chemistry stopping criteria have been designed to assure participant safety 
and to evaluate liver event etiology (in alignment with the FDA premarketing clinical 
liver safety guidance).
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT ≥3 x ULN
If ALT ≥ 3 x ULN AND bilirubin1,2 2 x ULN (> 35% direct 
bilirubin) or  INR > 1.5, Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Report the event to GSK within 
24 hours

Complete the liver event CRF, and 
complete an SAE data collection tool if 
the event also meets the criteria for an 
SAE2

Perform liver event follow up 
assessments 

Monitor the participant until liver 
chemistries resolve, stabilise, or return 
to within baseline (see MONITORING
below)
MONITORING:
If ALT ≥ 3 x ULN AND bilirubin 
2 x ULN or INR > 1.5

Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin) 
and perform liver event follow up 

Viral hepatitis serology3

Obtain INR and recheck with each 
liver chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for 
pharmacokinetic (PK) analysis.

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin 
2 x ULN

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


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Liver Chemistry Stopping Criteria 
assessments within 24 hours

Monitor participants twice weekly until 
liver chemistries resolve, stabilise or 
return to within baseline

A specialist or hepatology consultation 
is recommended
If ALT ≥3 x ULN AND bilirubin 
< 2 x ULN and INR ≤1.5:

Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin) 
and perform liver event follow up 
assessments within 24 to 72 hours

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

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 ≥ 3 x ULN AND bilirubin 
2 x ULN or INR > 1.5:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG) or gamma globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver 
injury in participants with definite or 
likely acetaminophen use in the 
preceding week [James, 2009].

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1. Serum bilirubin fractionation should be performed if testing is available.  If serum 
bilirubin fractionation is not immediately available, discontinue study treatment for 
that participant if ALT 3 x ULN and bilirubin 2 x ULN.  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 3 x ULN and bilirubin 2 x ULN (> 35% direct bilirubin) or 
ALT 3 x ULN and INR > 1.5, if INR measured, which may indicate severe liver 
injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of 
hepatic impairment or cirrhosis); INR measurement is not required and the threshold 
value stated will not apply to participants receiving anticoagulants.


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3. Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core 
Antibody (IgM); Hepatitis C RNA; Cytomegalovirus IgM antibody; Epstein-Barr 
viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or 
monospot testing); Hepatitis E IgM antibody.


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12.4.
Appendix 4: Division of AIDS Table For Grading The 
Severity of Adult and Pediatric Adverse Events
The DAIDS Table [Division if AIDS (DAIDS) Table (NIH), 2014] will be used to grade 
the severity of an AE that is not specifically identified in the grading table.  In addition, 
all deaths related to an AE are to be classified as grade 5.
Parameter
Grade 1
Mild
Grade 2 
Moderate
Grade 3 
Severe
Grade 4 
Potentially Life 
Threatening
Clinical 
adverse event 
NOT
identified 
elsewhere in 
the grading 
table
Mild symptoms 
causing no or 
minimal 
interference 
with usual 
social & 
functional 
activities with 
intervention not 
indicated
Moderate 
symptoms 
causing greater 
than minimal 
interference with 
usual social & 
functional 
activities with 
intervention 
indicated
Severe symptoms 
causing inability to 
perform usual 
social & functional 
activities with 
intervention or 
hospitalization 
indicated
Potentially life-
threatening 
symptoms causing 
inability to perform 
basic self-care 
functions with 
intervention 
indicated to prevent 
permanent 
impairment, 
persistent disability, 
or death


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Major Clinical Conditions Grading Table
Cardiovascular:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Arrhythmia
(by ECG or physical
examination)
Specify type, if 
applicable
No symptoms AND
No intervention 
indicated
No symptoms AND Non-
urgent intervention 
indicated
Non-life-threatening 
symptoms AND Non-
urgent
intervention indicated
Life-threatening arrhythmia OR
Urgent intervention indicated
Blood Pressure
Abnormalities 1
Hypertension (with the 
lowest reading taken 
after repeat testing 
during a visit)
≥ 18 years of age
140 to < 160 mmHg 
systolic
OR
90 to < 100 mmHg 
160 to < 180 mmHg 
systolic OR
100 to < 110
mmHg diastolic
180 mmHg systolic
OR
≥110 mmHg diastolic
Life-threatening consequences in a 
participant not previously diagnosed 
with hypertension (e.g., malignant 
hypertension) OR Hospitalization 
<18 years of age
> 120/80 mmHg
95th to < 99th percentile 
+5 mmHg adjusted for 
age, height, and gender 
(systolic and/or diastolic)
9th percentile
+5 mmHg adjusted for 
age, height, and gender 
(systolic and/or diastolic)
Life-threatening consequences in a 
participant not previously diagnosed 
with hypertension (e.g., malignant 
hypertension) OR Hospitalization 
indicated
Hypotension
No symptoms
Symptoms corrected with 
oral fluid replacement
Symptoms AND IV
fluids indicated
Shock requiring use of vasopressors 
or mechanical assistance to maintain 
blood pressure


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Cardiac Ischemia or
Infarction
Report only one
Not applicable
Not applicable
New symptoms with 
ischemia (stable angina) 
OR New testing consistent 
with ischemia
Unstable angina OR Acute 
myocardial infarction
Heart Failure
No symptoms AND
Laboratory or
cardiac imaging 
abnormalities
Symptoms with mild to 
moderate activity or 
exertion
Symptoms at rest or with 
minimal activity or 
exertion (e.g., hypoxemia) 
OR Intervention indicated 
(e.g., oxygen)
Life-threatening consequences OR
Urgent intervention indicated (e.g., 
vasoactive medications, ventricular 
assist device, heart transplant)
Haemorrhage
(with significant acute
blood loss)
Not applicable
Symptoms AND No 
transfusion indicated
Symptoms AND
Transfusion of 2 units 
packed RBCs indicated
Life-threatening hypotension OR
Transfusion of > 2 units packed 
RBCs (for children, packed RBCs
> 10 cc/kg) indicated
Prolonged PR Interval 
or AV Block
Report only one
>16 years of age
PR interval 0.21 to 
< 0.25 seconds
PR interval ≥0.25
seconds OR Type I
2nd degree AV block
Type II 2nd degree AV 
block OR Ventricular 
pause 3.0 seconds
Complete AV block
≤ 16 years of age
1st degree AV block
(PR interval 
> normal for age and 
rate)
Type I 2nd degree AV
block
Type II 2nd degree AV 
block OR Ventricular 
pause ≥ 3.0 seconds
Complete AV block
Prolonged QTc
Interval 2
0.45 to 0.47 seconds > 0.47 to 0.50 seconds
> 0.50 seconds OR
06 seconds above 
baseline
Life-threatening consequences (e.g., 
Torsade de pointes, other associated 
serious ventricular dysrhythmia)


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Thrombosis or
Embolism
Report only one
Not applicable
Symptoms AND No 
intervention indicated
Symptoms AND
Intervention indicated
Life-threatening embolic event (e.g., 
pulmonary embolism, thrombus)
1. Blood pressure norms for children < 18 years of age can be found in: Expert Panel on Integrated Guidelines for Cardiovascular Health 
and Risk Reduction in Children and Adolescents.  Pediatrics 2011;128;S213; originally published online November 14, 2011; DOI: 
10.1542/peds.2009-2107C
2. As per Bazett’s formula


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Dermatologic:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Alopecia (scalp only)
Detectable by study 
participant, caregiver, or 
physician AND Causing no 
or minimal interference 
with usual social & 
functional activities
Obvious on visual 
inspection AND
Causing greater than 
minimal interference 
with usual social & 
functional activities
Not applicable
Not applicable
Bruising
Localized to one area
Localized to more than 
one area
Generalized
Not applicable
Cellulitis
Not applicable
Non-parenteral 
treatment indicated 
(e.g., oral antibiotics, 
IV treatment indicated (e.g., 
IV antibiotics, antifungals, 
antivirals)
Life-threatening 
consequences (e.g., sepsis, 
tissue necrosis)
Hyperpigmentation
Slight or localized causing 
no or minimal interference 
with usual social & 
functional activities
Marked or generalized 
causing greater than 
minimal interference 
with usual social & 
functional activities
Not applicable
Not applicable
Hypopigmentation
Slight or localized causing 
no or minimal interference 
with usual social & 
functional activities
Marked or generalized 
causing greater than 
minimal interference 
with usual social & 
functional activities
Not applicable
Not applicable
Petechiae
Localized to one area
Localized to more than 
one area
Generalized
Not applicable


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Pruritus1
(without skin lesions)
Itching causing no or 
minimal interference with 
usual social & functional 
activities
Itching causing greater 
than minimal 
interference with usual 
social & functional 
i i i
Itching causing inability to 
perform usual social & 
functional activities
Not applicable
Rash
Specify type, if applicable
Localized rash
Diffuse rash OR Target 
lesions
Diffuse rash AND Vesicles 
or limited number of bullae 
or superficial ulcerations of 
mucous membrane limited 
to one site
Extensive or generalized 
bullous lesions OR
Ulceration of mucous 
membrane involving two or 
more distinct mucosal sites 
OR Stevens- Johnson 
syndrome OR Toxic 
1. For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions section


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Endocrine and Metabolic:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Diabetes Mellitus
Controlled without 
medication
Controlled with 
medication OR
Modification of current 
medication regimen
Uncontrolled despite 
treatment modification 
OR Hospitalization for 
immediate glucose control 
indicated
Life-threatening 
consequences (e.g., 
ketoacidosis, hyperosmolar 
non- ketotic coma, end organ 
failure)
Gynaecomastia
Detectable by study 
participant, caregiver, or 
physician AND Causing 
no or minimal 
interference with usual 
social & functional 
activities
Obvious on visual 
inspection AND Causing 
pain with greater than 
minimal interference with 
usual social & functional 
activities
Disfiguring changes AND
Symptoms requiring 
intervention or causing 
inability to perform usual 
social & functional 
activities
Not applicable
Hyperthyroidism
No symptoms AND
Abnormal laboratory 
value
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Thyroid 
suppression therapy 
indicated
Symptoms causing 
inability to perform usual 
social & functional 
activities OR
Uncontrolled despite 
treatment modification
Life-threatening 
consequences (e.g., thyroid 
storm)


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Hypothyroidism
No symptoms AND
Abnormal laboratory 
value
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Thyroid 
replacement therapy 
indicated
Symptoms causing 
inability to perform usual 
social & functional 
activities OR
Uncontrolled despite 
treatment modification
Life-threatening 
consequences (e.g., 
myxedema coma)
Lipoatrophy 1
Detectable by study 
participant, caregiver, or 
physician AND Causing 
no or minimal 
interference with usual 
social & functional 
activities
Obvious on visual 
inspection AND Causing 
greater than minimal 
interference with usual 
social & functional 
activities
Disfiguring changes
Not applicable
Lipohypertrophy 2
Detectable by study 
participant, caregiver, or 
physician AND Causing 
no or minimal 
interference with usual 
social & functional 
activities
Obvious on visual 
inspection AND Causing 
greater than minimal 
interference with usual 
social & functional 
activities
Disfiguring changes
Not applicable
1. Definition: A disorder characterized by fat loss in the face, extremities, and buttocks.
2. Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and abdomen.


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Gastrointestinal:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Anorexia
Loss of appetite without 
decreased oral intake
Loss of appetite 
associated with 
decreased oral intake 
without significant 
weight loss
Loss of appetite 
associated with 
significant weight loss
Life-threatening 
consequences OR
Aggressive intervention 
indicated (e.g., tube feeding, 
total parenteral nutrition)
Ascites
No symptoms
Symptoms AND
Intervention indicated 
(e.g., diuretics, 
therapeutic paracentesis)
Symptoms recur or 
persist despite 
intervention
Life-threatening 
consequences
Bloating or Distension
Report only one
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
Symptoms causing 
inability to perform usual 
social & functional 
activities
Not applicable
Cholecystitis
Not applicable
Symptoms AND Medical 
intervention indicated
Radiologic, endoscopic, 
or operative intervention 
indicated
Life-threatening 
consequences (e.g., sepsis, 
perforation)
Constipation
Not applicable
Persistent constipation 
requiring regular use of 
dietary modifications, 
laxatives, or enemas
Obstipation with manual 
evacuation indicated
Life-threatening 
consequences (e.g., 
obstruction)


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Diarrhoea
≥ 1 year of age
Transient or intermittent 
episodes of unformed 
stools OR Increase of 3 
stools over baseline per 
24-hour period
Persistent episodes of 
unformed to watery 
stools OR Increase of 
4 to 6 stools over 
baseline per 24-hour 
period
Increase of 7 stools per 
24-hour period OR IV 
fluid replacement 
indicated
Life-threatening 
consequences (e.g., 
hypotensive shock)
<1 year of age
Liquid stools (more 
unformed than usual) but 
usual number of stools
Liquid stools with 
increased number of 
stools OR Mild 
dehydration
Liquid stools with 
moderate dehydration
Life-threatening 
consequences (e.g., liquid 
stools resulting in severe 
dehydration, hypotensive 
shock)
Dysphagia or Odynophagia
Report only one and specify 
location
Symptoms but able to eat 
usual diet
Symptoms causing 
altered dietary intake 
with no intervention 
indicated
Symptoms causing 
severely altered dietary 
intake with intervention 
indicated
Life-threatening reduction in 
oral intake
Gastrointestinal
Bleeding
Not requiring intervention 
other than iron supplement
Endoscopic intervention 
indicated
Transfusion indicated
Life-threatening 
consequences (e.g., 
hypotensive shock)
Mucositis or Stomatitis
Report only one and specify 
location
Mucosal erythema
Patchy 
pseudomembranes or 
ulcerations
Confluent 
pseudomembranes or 
ulcerations OR Mucosal 
bleeding with minor 
trauma
Life-threatening 
consequences (e.g., 
aspiration, choking) OR 
Tissue necrosis OR Diffuse 
spontaneous mucosal 
bleeding


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Nausea
Transient (< 24 hours) or 
intermittent AND No or 
minimal interference with 
oral intake
Persistent nausea 
resulting in decreased 
oral intake for 24 to 
48 hours
Persistent nausea 
resulting in minimal oral 
intake for > 48 hours OR 
Rehydration indicated 
(e.g., IV fluids)
Life-threatening 
consequences (e.g., 
hypotensive shock)
Pancreatitis
Not applicable
Symptoms with 
hospitalization not 
indicated
Symptoms with 
hospitalization indicated
Life-threatening 
consequences (e.g., 
circulatory failure, 
haemorrhage, sepsis)
Perforation (colon or 
rectum)
Not applicable
Not applicable
Intervention indicated
Life-threatening 
consequences
Proctitis
Rectal discomfort with no 
intervention indicated
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Medical 
intervention indicated
Symptoms causing 
inability to perform usual 
social & functional 
activities OR Operative 
intervention indicated
Life-threatening 
consequences (e.g., 
perforation)
Rectal Discharge
Visible discharge
Discharge requiring the 
use of pads
Not applicable
Not applicable
Vomiting
Transient or intermittent 
AND No or minimal 
interference with oral 
intake
Frequent episodes with 
no or mild dehydration
Persistent vomiting 
resulting in orthostatic 
hypotension OR 
Aggressive rehydration 
indicated (e.g., IV fluids)
Life-threatening 
consequences (e.g., 
hypotensive shock)


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Musculoskeletal:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Arthralgia
Joint pain causing no or 
minimal interference with 
usual social & functional 
activities
Joint pain causing 
greater than minimal 
interference with usual 
social & functional 
i i i
Joint pain causing inability 
to perform usual social & 
functional activities
Disabling joint pain causing 
inability to perform basic 
self-care functions
Arthritis
Stiffness or joint swelling 
causing no or minimal 
interference with usual 
social & functional 
activities
Stiffness or joint 
swelling causing greater 
than minimal 
interference with usual 
social & functional 
Stiffness or joint swelling 
causing inability to perform 
usual social & functional 
activities
Disabling joint stiffness or 
swelling causing inability to 
perform basic self-care 
functions
Myalgia (generalized)
Muscle pain causing no or 
minimal interference with 
usual social & functional 
activities
Muscle pain causing 
greater than minimal 
interference with usual 
social & functional 
ti iti
Muscle pain causing 
inability to perform usual 
social & functional 
activities
Disabling muscle pain 
causing inability to perform 
basic self-care functions
Osteonecrosis
Not applicable
No symptoms but with 
radiographic findings 
AND No operative 
intervention indicated
Bone pain with 
radiographic findings OR
Operative intervention 
indicated
Disabling bone pain with 
radiographic findings 
causing inability to perform 
basic self-care functions
Osteopenia 1
≥ 30 years of age
BMD t-score
-2.5 to -1
Not applicable
Not applicable
Not applicable
<30 years of age
BMD z-score
-2 to -1
Not applicable
Not applicable
Not applicable


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Osteoporosis 1
≥ 30 years of age
Not applicable
BMD t-score <-2.5
Pathologic fracture (e.g., 
compression fracture 
causing loss of vertebral 
Pathologic fracture causing 
life-threatening 
consequences
<30 years of age
Not applicable
BMD z-score <-2
Pathologic fracture (e.g., 
compression fracture 
causing loss of vertebral 
height)
Pathologic fracture causing 
life-threatening 
consequences
1.
Bone mineral density (BMD) t and z scores can be found in: Kanis JA on behalf of the World Health Organization Scientific Group 
(2007).  Assessment of osteoporosis at the primary health-care level.  Technical Report.  World Health Organization Collaborating 
Center for Metabolic Bone Diseases, University of Sheffield, UK. 2007: Printed by the University of Sheffield.


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Neurologic:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Acute CNS Ischemia
Not applicable
Not applicable
Transient ischemic attack Cerebral vascular accident 
(e.g., stroke with 
neurological deficit)
Altered Mental Status (for 
Dementia, see Cognitive, 
Behavioral, or Attentional 
Disturbance below)
Changes causing no or 
minimal interference with 
usual social & functional 
activities
Mild lethargy or 
somnolence causing
greater than minimal 
interference with usual 
social & functional 
activities
Confusion, memory 
impairment, lethargy, or 
somnolence causing 
inability to perform usual 
social & functional 
activities
Delirium OR Obtundation 
OR Coma
Ataxia
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities OR No symptoms 
with ataxia detected on 
examination
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities
Symptoms causing 
inability to perform usual 
social & functional 
activities
Disabling symptoms 
causing inability to perform 
basic self-care functions
Cognitive, Behavioural, or 
Attentional Disturbance 
(includes dementia and 
attention deficit disorder)
Specify type, if applicable
Disability causing no or 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources not indicated
Disability causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Specialized 
resources on part- time 
basis indicated
Disability causing 
inability to perform usual 
social & functional 
activities OR Specialized 
resources on a full- time 
basis indicated
Disability causing inability 
to perform
basic self-care functions OR
Institutionalization 
indicated


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Developmental Delay
<18 years of age
Specify type, if applicable
Mild developmental delay, 
either motor or cognitive, 
as determined by 
comparison with a 
developmental screening 
tool appropriate for the 
setting
Moderate developmental 
delay, either motor or 
cognitive, as determined 
by comparison with a 
developmental screening 
tool appropriate for the 
setting
Severe developmental 
delay, either motor or 
cognitive, as determined 
by comparison with a 
developmental screening 
tool appropriate for the 
setting
Developmental regression,
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate 
for the setting
Headache
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities
Symptoms causing 
inability to perform usual 
social & functional 
activities
Symptoms causing inability 
to perform basic self-care 
functions OR
Hospitalization indicated 
OR Headache with 
significant impairment of 
alertness or other neurologic 
function
Neuromuscular Weakness 
(includes myopathy and 
neuropathy)
Specify type, if applicable
Minimal muscle weakness 
causing no or minimal 
interference with usual 
social & functional 
activities OR No symptoms 
with decreased strength on 
examination
Muscle weakness 
causing greater than 
minimal interference 
with usual social & 
functional activities
Muscle weakness causing 
inability to perform usual 
social & functional 
activities
Disabling muscle weakness 
causing inability to perform
basic self-care functions OR 
Respiratory muscle 
weakness impairing 
ventilation


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Neurosensory Alteration 
(includes paresthesia and 
painful neuropathy)
Specify type, if applicable
Minimal paresthesia 
causing no or minimal 
interference with usual 
social & functional 
activities OR No symptoms 
with sensory alteration on 
examination
Sensory alteration or 
paresthesia causing 
greater than minimal 
interference with usual 
social & functional 
activities
Sensory alteration or 
paresthesia causing 
inability to perform usual 
social & functional 
activities
Disabling sensory alteration 
or paresthesia causing 
inability to perform basic 
self-care functions
Seizures
New Onset Seizure
≥ 18 years of age
Not applicable
Not applicable
1 to 3 seizures
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult to 
control (e.g.,
refractory epilepsy)
<18 years of age
(includes new or pre-existing 
febrile seizures)
Seizure lasting < 5 minutes 
with < 24 hours postictal 
state
Seizure lasting 5 to < 20 
minutes with 
< 24 hours postictal state
Seizure lasting 20 
minutes OR > 24 hours 
postictal state
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult to 
control (e.g., refractory 
epilepsy)


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Pre-existing Seizure
Not applicable
Increased frequency 
from previous level of 
control without change in 
seizure character
Change in seizure 
character either in 
duration or quality (e.g., 
severity or focality)
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult to 
control (e.g., refractory 
epilepsy)
Syncope
Near syncope without loss 
of consciousness (e.g., pre-
syncope)
Loss of consciousness 
with no intervention 
indicated
Loss of consciousness 
AND Hospitalization or 
intervention required
Not applicable


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Pregnancy, Puerperium and Perinatal:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Foetal Death or Stillbirth 
(report using mother’s 
participant ID)
Not applicable
Not applicable
Foetal loss occurring at 
20 weeks gestation
Not applicable
Preterm Delivery 1 (report 
using mother’s participant 
ID)
Delivery at 34 to 
< 37 weeks gestational age
Delivery at 28 to 
< 34 weeks gestational 
age
Delivery at 24 to 
< 28 weeks gestational 
age
Delivery at < 24 weeks 
gestational age
Spontaneous Abortion or 
Miscarriag2 (report using 
mother’s participant ID)
Report only one
Chemical pregnancy
Uncomplicated 
spontaneous abortion or 
miscarriage
Complicated spontaneous 
abortion or miscarriage
Not applicable
1. Definition: A delivery of a live-born neonate occurring at ≥20 to < 37 weeks gestational age.
2. Definition: A clinically recognized pregnancy occurring at < 20 weeks gestational age.


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Psychiatric: 
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Insomnia
Mild difficulty falling 
asleep, staying asleep, or 
waking up early
Moderate difficulty 
falling asleep, staying 
asleep, or waking up 
early
Severe difficulty falling 
asleep, staying asleep, or 
waking up early
Not applicable
Psychiatric Disorders 
(includes anxiety, depression, 
mania, and psychosis)
Specify disorder
Symptoms with 
intervention not 
indicated OR Behavior 
causing no or minimal 
interference with usual 
social & functional 
activities
Symptoms with 
intervention indicated OR
Behavior causing greater 
than minimal interference 
with usual social & 
functional activities
Symptoms with 
hospitalization indicated 
OR Behavior causing 
inability to perform usual 
social & functional 
activities
Threatens harm to self or 
others OR Acute psychosis 
OR Behavior causing 
inability to perform basic 
self-care functions
Suicidal Ideation or
Attempt
Report only one
Preoccupied with 
thoughts of death AND
No wish to kill oneself
Preoccupied with 
thoughts of death AND
Wish to kill oneself with 
no specific plan or intent
Thoughts of killing 
oneself with partial or 
complete plans but no 
attempt to do so OR
Hospitalization indicated
Suicide attempted


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Respiratory:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Acute Bronchospasm
Forced expiratory 
volume in 1 second or 
peak flow reduced to 
70 to < 80% OR Mild 
symptoms with 
intervention not 
indicated
Forced expiratory volume 
in 1 second or peak flow 
50 to < 70% OR
Symptoms with 
intervention indicated OR
Symptoms causing greater 
than minimal interference 
with usual social & 
functional activities
Forced expiratory volume 
in 1 second or peak flow 
25 to < 50% OR
Symptoms causing 
inability to perform usual 
social & functional 
activities
Forced expiratory volume in 
1 second or peak flow < 25% 
OR Life-threatening 
respiratory or hemodynamic 
compromise OR Intubation
Dyspnoea or Respiratory
Distress
Report only one
Dyspnoea on exertion 
with no or minimal 
interference with usual 
social & functional 
activities OR Wheezing 
OR Minimal increase in 
respiratory rate for age
Dyspnoea on exertion 
causing greater than 
minimal interference with 
usual social & functional 
activities OR Nasal flaring 
OR Intercostal retractions 
OR Pulse oximetry 90 to 
< 95%
Dyspnoea at rest causing 
inability to perform usual 
social & functional 
activities OR Pulse 
oximetry < 90%
Respiratory failure with 
ventilator support indicated 
(e.g., CPAP, BPAP, 
intubation)


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Sensory:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Hearing Loss
≥12 years of age
Not applicable
Hearing aid or 
intervention not 
indicated
Hearing aid or 
intervention indicated
Profound bilateral hearing 
loss (> 80 dB at 2 kHz and 
above) OR Non-serviceable 
hearing (i.e., > 50 dB 
audiogram and < 50% 
speech discrimination)
< 12 years of age (based on 
a 1, 2, 3, 4, 6 and 8 kHz 
audiogram)
> 20 dB hearing loss at 
4 kHz
> 20 dB hearing loss at 
> 4 kHz
> 20 dB hearing loss at 
≥3 kHz in one ear with 
additional speech 
language related services 
indicated (where 
available) OR Hearing 
loss sufficient to indicate 
therapeutic intervention, 
including hearing aids
Audiologic indication for 
cochlear implant and 
additional speech- language 
related services indicated 
(where available)
Tinnitus
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities with intervention 
not indicated
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities with 
intervention indicated
Symptoms causing 
inability to perform usual 
social & functional 
activities
Not applicable


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Uveitis
No symptoms AND
Detectable on examination
Anterior uveitis with 
symptoms OR
Medicamylasal 
intervention indicated
Posterior or pan- uveitis 
OR Operative 
intervention indicated
Disabling visual loss in 
affected eye(s)
Vertigo
Vertigo causing no or 
minimal interference with 
usual social & functional 
activities
Vertigo causing greater 
than minimal 
interference with usual 
social & functional 
activities
Vertigo causing inability 
to perform usual social & 
functional activities
Disabling vertigo causing 
inability to perform basic 
self-care functions
Visual Changes
(assessed from baseline)
Visual changes causing no 
or minimal interference 
with usual social & 
functional activities
Visual changes causing 
greater than minimal 
interference with usual 
social & functional 
activities
Visual changes causing 
inability to perform usual 
social & functional 
activities
Disabling visual loss in 
affected eye(s)


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Systemic:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Acute Allergic
Reaction
Localized urticaria 
(wheals) with no medical 
intervention indicated
Localized urticaria with 
intervention indicated 
OR Mild angioedema 
with no intervention 
indicated
Generalized urticaria OR
Angioedema with 
intervention indicated OR
Symptoms of mild 
bronchospasm
Acute anaphylaxis OR Life-
threatening bronchospasm OR
Laryngeal oedema
Chills
Symptoms causing no or 
minimal
interference with usual 
social & functional 
activities
Symptoms causing 
greater than minimal 
interference with usual 
social &
functional activities
Symptoms causing 
inability to perform usual 
social & functional 
activities
Not applicable
Cytokine Release
Syndrome 1
Mild signs and symptoms 
AND Therapy (i.e., 
antibody infusion) 
interruption not indicated
Therapy (i.e., antibody 
infusion) interruption 
indicated AND
Responds promptly to 
symptomatic treatment 
OR Prophylactic 
medications indicated 
for ≤ 24 hours
Prolonged severe signs and 
symptoms OR Recurrence 
of symptoms following 
initial improvement
Life-threatening consequences 
(e.g., requiring pressor or 
ventilator support)
Fatigue or Malaise
Report only one
Symptoms causing no or 
minimal
interference with usual 
social & functional
activities
Symptoms causing 
greater than minimal 
interference with usual 
social &
functional activities
Symptoms causing 
inability to perform usual 
social & functional 
activities
Incapacitating symptoms of 
fatigue or malaise causing 
inability to perform basic self-
care functions


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Fever (non-axillary 
temperatures only)
38.0 to < 38.6°C or
100.4 to < 101.5°F
3 8.6 to < 39.3°C
or 101.5 to
< 102.7°F
39.3 to < 40.0°C or
102.7 to < 104.0°F
40.0°C or 104.0°F
Pain 2 (not associated with 
study agent injections and 
not specified elsewhere)
Specify location
Pain causing no or 
minimal interference with 
usual social & functional 
activities
Pain causing greater 
than minimal 
interference with usual 
social & functional 
activities
Pain causing inability to 
perform usual social
& functional activities
Disabling pain causing 
inability to perform basic self-
care functions OR
Hospitalization indicated
Serum Sickness 3
Mild signs and symptoms Moderate signs and 
symptoms AND
Intervention indicated 
(e.g., antihistamines)
Severe signs and 
symptoms AND Higher 
level intervention 
indicated (e.g., steroids or 
IV fluids)
Life-threatening consequences 
(e.g., requiring pressor or 
ventilator support)
Underweight 4
> 5 to 19 years of age
Not applicable
WHO BMI z-score
< -2 to ≤-3
WHO BMI z-score
< -3
WHO BMI z-score
< -3 with life-threatening 
consequences
2 to 5 years of age
Not applicable
WHO Weight-for-
height z-score
< -2 to ≤-3
WHO Weight-for- height 
z-score < 3
WHO Weight-for-height z-
score < -3 with life-
threatening consequences
< 2 years of age
Not applicable
WHO Weight-for-
length z-score
< -2 to -3
WHO Weight-for- length 
z-score < -3
WHO Weight-for-length z-
score < -3 with life-
threatening consequences


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Weight Loss (excludes 
postpartum weight
loss)
Not applicable
5 to < 9% loss in body 
weight from baseline
≥9 to < 20% loss in body 
weight from baseline
≥20% loss in body weight 
from baseline OR Aggressive 
intervention indicated (e.g., 
tube feeding, total parenteral 
nutrition)
1.
Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of breath.
2.
For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section.
3.
Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked discomfort, and/or 
dyspnoea
4.
WHO reference tables may be accessed by clicking the desired age range or by accessing the following URLs: 
http://www.who.int/growthref/who2007_bmi_for_age/en/ for participants >5 to 19 years of age and 
http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤ 5 years of age


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Urinary:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Urinary Tract
Obstruction
Not applicable
Signs or symptoms of 
urinary tract obstruction 
without hydronephrosis 
or renal dysfunction
Signs or symptoms of 
urinary tract obstruction 
with hydronephrosis or 
renal dysfunction
Obstruction causing life-
threatening
consequences


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Site Reactions to Injections and Infusions:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Injection Site Pain or
Tenderness
Report only one
Pain or tenderness 
causing no or minimal 
limitation of use of limb
Pain or tenderness 
causing greater than 
minimal limitation of use 
of limb
Pain or tenderness causing 
inability to perform usual 
social & functional 
activities
Pain or tenderness causing 
inability to perform basic 
self-care function OR
Hospitalization indicated
Injection Site Erythema or 
Redness 1
Report only one
> 15 years of age
2.5 to < 5 cm in 
diameter OR 6.25 to 
< 25 cm2 surface area 
AND Symptoms causing 
no or minimal 
interference with usual 
social & functional 
activities
5 to < 10 cm in 
diameter OR 25 to 
< 100 cm2 surface area
OR Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities
10 cm in diameter OR
100 cm2 surface area 
OR Ulceration OR
Secondary infection OR
Phlebitis OR Sterile 
abscess OR Drainage OR
Symptoms causing 
inability to perform usual 
social & functional 
activities
Potentially life- threatening 
consequences (e.g., abscess, 
exfoliative dermatitis, 
necrosis involving dermis or 
deeper tissue)
≤15 years of age
≤2.5 cm in diameter
> 2.5 cm in diameter with 
< 50% surface area of the 
extremity segment 
involved (e.g., upper arm 
or thigh)
50% surface area of the 
extremity segment 
involved (e.g., upper arm 
or thigh) OR Ulceration 
OR Secondary infection 
OR Phlebitis OR Sterile 
abscess OR Drainage
Potentially life- threatening 
consequences (e.g., abscess, 
exfoliative dermatitis, 
necrosis involving dermis or 
deeper tissue)


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Injection Site
Induration or Swelling
Report only one
> 15 years of age
Same as for Injection 
Site Erythema or 
Redness, > 15 years of 
age
Same as for Injection 
Site Erythema or 
Redness, > 15 years of 
age
Same as for Injection 
Site Erythema or 
Redness, > 15 years of 
age
Same as for Injection Site 
Erythema or Redness, 
> 15 years of age
≤15 years of age
Same as for Injection 
Site Erythema or 
Redness, ≤15 years of 
Same as for Injection 
Site Erythema or 
Redness, ≤15 years of 
Same as for Injection 
Site Erythema or 
Redness, ≤15 years of 
Same as for Injection Site 
Erythema or Redness, 
≤15 years of age
Injection Site Pruritus
Itching localized to the 
injection site that is 
relieved spontaneously 
or in < 48 hours of 
treatment
Itching beyond the 
injection site that is not 
generalized OR Itching 
localized to the injection 
site requiring 48 hours 
treatment
Generalized itching 
causing inability to 
perform usual social & 
functional activities
Not applicable
1. Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or measured surface area.


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Laboratory Values – Chemistries
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Acidosis
Not applicable
pH 7.3 to < LLN
pH < 7.3 without life-
threatening consequences
pH < 7.3 with life-
threatening consequences
Albumin, Low
(g/dL; g/L)
3.0 to < LLN
30 to < LLN
2.0 to < 3.0
20 to < 30
< 2.0
< 20
Not applicable
Alkaline Phosphatase, High
1.25 to < 2.5 x ULN
2.5 to < 5.0 x ULN
5.0 to < 10.0 x ULN
10.0 x ULN
Alkalosis
Not applicable
pH > ULN to ≤7.5
pH > 7.5 without life-
threatening consequences
pH > 7.5 with life-
threatening consequences
ALT or SGPT, High
Report only one
1.25 to < 2.5 x ULN
2.5 to < 5.0 x ULN
5.0 to < 10.0 x ULN
≥10.0 x ULN
Amylase (Pancreatic) or 
Amylase (Total), High Report
only one
1.1 to < 1.5 x ULN
1.5 to < 3.0 x ULN
3.0 to < 5.0 x ULN
5.0 x ULN
AST or SGOT, High
Report only one
1.25 to < 2.5 x ULN
2.5 to < 5.0 x ULN
5.0 to < 10.0 x ULN
10.0 x ULN
Bicarbonate, Low
(mEq/L; mmol/L)
16.0 to < LLN
16.0 to < LLN
11.0 to < 16.0
11.0 to < 16.0
8.0 to < 11.0
8.0 to < 11.0
< 8.0
< 8.0


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Bilirubin
Direct Bilirubin 1, High
>28 days of age
Not applicable
Not applicable
>ULN
>ULN with life- threatening 
consequences (e.g., signs 
and symptoms of liver 
failure)
≤ 28 days of age
ULN to1 mg/dL
>1 to 1.5 mg/dL
>1.5 to 2 mg/dL
>2 mg/dL
Total Bilirubin, High
>28 days of age
1.1 to < 1.6 x ULN
1.6 to < 2.6 x ULN
2.6 to < 5.0 x ULN
5.0 x ULN
≤ 28 days of age
See Section 12.4.1.  Total 
Bilirubin for Term and 
Preterm Neonates
See Section 12.4.1.  
Total Bilirubin for Term 
and Preterm Neonates
See Section 12.4.1.  
Total Bilirubin for Term 
and Preterm Neonates
See Section 12.4.1.  Total 
Bilirubin for Term and 
Preterm Neonates
Calcium, High
(mg/dL; mmol/L)
≥ 7 days of age
10.6 to < 11.5
2.65 to < 2.88
11.5 to < 12.5
2.88 to < 3.13
12.5 to < 13.5
3.13 to < 3.38
13.5
3.38
<7 days of age
11.5 to < 12.4
2.88 to < 3.10
12.4 to < 12.9
3.10 to < 3.23
12.9 to < 13.5
3.23 to < 3.38
13.5
3.38
Calcium (Ionized), High
(mg/dL; mmol/L)
>ULN to < 6.0
>ULN to < 1.5
6.0 to <6.4
1.5 to < 1.6
6.4 to < 7.2
1.6 to < 1.8
7.2
8


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Calcium, Low
(mg/dL; mmol/L)
≥ 7 days of age
7.8 to < 8.4
1.95 to < 2.10
7.0 to < 7.8
1.75 to < 1.95
6.1 to < 7.0
1.53 to < 1.75
< 6.1
< 1.53
<7 days of age
6.5 to < 7.5
1.63 to < 1.88
6.0 to < 6.5
1.50 to < 1.63
5.50 to < 6.0
1.38 to < 1.50
< 5.50
< 1.38
Calcium (Ionized), Low
(mg/dL; mmol/L)
< LLN to 4.0
< LLN to 1.0
3.6 to < 4.0
0.9 to < 1.0
3.2 to < 3.6
0.8 to < 0.9
< 3.2
< 0.8
Cardiac Troponin I, High
Not applicable
Not applicable
Not applicable
Levels consistent with 
myocardial infarction or 
unstable angina as defined 
by the local laboratory
Creatine Kinase, High
3 to < 6 x ULN
6 to < 10 x ULN
10 to < 20 x ULN
20 x ULN
Creatinine, High
1.1 to 1.3 x ULN
> 1.3 to 1.8 x ULN OR 
Increase of > 0.3 mg/dL 
above baseline
> 1.8 to < 3.5 x ULN OR 
Increase of 1.5 to < 2.0 x 
above baseline
3.5 x ULN OR Increase of 
2.0 x above baseline


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Creatinine Clearance 2
or eGFR, Low
Report only one
Not applicable
< 90 to 60 mL/min or 
mL/min/1.73 m2
OR
10 to < 30% decrease 
from baseline
< 60 to 30 mL/min or 
mL/min/1.73 m2
OR
30 to <50% decrease 
from baseline
< 30 ml/min or 
mL/min/1.73 m2
OR
50% decrease from 
baseline or dialysis needed
Glucose
(mg/dL; mmol/L)
Fasting, High
110 to 125
6.11 to < 6.95
> 125 to 250
6.95 to < 13.89
> 250 to 500
13.89 to < 27.75
> 500
27.75
Nonfasting, High
116 to 160
6.44 to < 8.89
> 160 to 250
8.89 to < 13.89
> 250 to 500
13.89 to < 27.75
> 500
27.75
Glucose, Low
(mg/dL; mmol/L)
≥ 1 month of age
55 to 64
3.05 to 3.55
40 to < 55
2.22 to < 3.05
30 to < 40
1.67 to < 2.22
< 30
< 1.67
<1 month of age
50 to 54
2.78 to 3.00
40 to < 50
2.22 to < 2.78
30 to < 40
1.67 to < 2.22
< 30
< 1.67
Lactate, High
ULN to < 2.0 x ULN 
without acidosis
≥2.0 x ULN without 
acidosis
Increased lactate with 
pH< 7.3 without life-
threatening consequences
Increased lactate with 
pH< 7.3 with life-
threatening consequences
Lipase, High
1.1 to < 1.5 x ULN
1.5 to < 3.0 x ULN
3.0 to < 5.0 x ULN
5.0 x ULN


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Lipid Disorders
(mg/dL; mmol/L)
Cholesterol, Fasting, High
≥ 18 years of age
200 to < 240
5.18 to < 6.19
240 to < 300
6.19 to < 7.77
300
7.77
Not applicable
< 18 years of age
170 to < 200
4.40 to < 5.15
200 to < 300
5.15 to < 7.77
300
7.77
Not applicable
LDL, Fasting, High
≥18 years of age
130 to < 160
3.37 to < 4.12
160 to < 190
4.12 to < 4.90
190
4.90
Not applicable
> 2 to < 18 years of age
110 to < 130
2.85 to < 3.34
130 to < 190
3.34 to < 4.90
190
4.90
Not applicable
Triglycerides, Fasting, High 150 to 300
1.71 to 3.42
> 300 to 500
> 3.42 to 5.7
> 500 to < 1,000
> 5.7 to 11.4
> 1,000
> 11.4
Magnesium 3, Low
(mEq/L; mmol/L)
1.2 to < 1.4
0.60 to < 0.70
0.9 to < 1.2
0.45 to < 0.60
0.6 to < 0.9
0.30 to < 0.45
< 0.6
< 0.30
Phosphate, Low
(mg/dL; mmol/L)
>14 years of age
2.0 to < LLN
0.81 to < LLN
1.4 to < 2.0
0.65 to < 0.81
1.0 to < 1.4
0.32 to <0.65
< 1.0
< 0.32
1 to 14 years of age
3.0 to < 3.5
0.97 to < 1.13
2.5 to < 3.0
0.81 to < 0.97
1.5 to < 2.5
0.48 to < 0.81
< 1.5
< 0.48


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
<1 year of age
3.5 to < 4.5
1.13 to < 1.45
2.5 to < 3.5
0.81 to < 1.13
1.5 to < 2.5
0.48 to < 0.81
< 1.5
< 0.48
Potassium, High
(mEq/L; mmol/L)
5.6 to < 6.0
5.6 to < 6.0
6.0 to < 6.5
6.0 to < 6.5
6.5 to < 7.0
6.5 to < 7.0
7.0
7.0
Potassium, Low
(mEq/L; mmol/L)
3.0 to < 3.4
3.0 to < 3.4
2.5 to < 3.0
2.5 to < 3.0
2.0 to < 2.5
2.0 to < 2.5
< 2.0
< 2.0
Sodium, High
(mEq/L; mmol/L)
146 to < 150
146 to < 150
150 to < 154
150 to < 154
154 to < 160
154 to < 160
160
160
Sodium, Low
(mEq/L; mmol/L)
130 to < 135
130 to < 135
125 to < 130
125 to < 135
121 to < 125
121 to < 125
120
120
Uric Acid, High
(mg/dL; mmol/L)
7.5 to < 10.0
0.45 to < 0.59
10.0 to < 12.0
0.59 to < 0.71
12.0 to < 15.0
0.71 to < 0.89
15.0
0.89
1. Direct bilirubin > 1.5 mg/dL in a participant < 28 days of age should be graded as grade 2, if < 10% of the total bilirubin
2. Use the applicable formula (i.e., Cockroft-Gault in mL/min or Schwatrz in mL/min/1.73m2) 
3. To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114


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Hematology:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Absolute CD4+ Count, Low
(cell/mm3; cells/L)
> 5 years of age
(not HIV infected)
300 to < 400
300 to < 400
200 to < 300
200 to < 300
100 to < 200
100 to < 200
< 100
<100
Absolute Lymphocyte
Count, Low
(cell/mm3; cells/L)
>5 years of age
(not HIV infected)
600 to < 650
0.600 x 109 to
< 0.650 x 109
500 to < 600
0.500 x 109 to
< 0.600 x 109
350 to < 500
0.350 x 109 to <0.500x109< 350
< 0.350x109
Absolute Neutrophil
Count (ANC), Low
(cells/mm3; cells/L)
> 7 days of age
800 to 1,000
0.800 x 109 to 
1.000 x 109
600 to 799
0.600 x 109 to 0.799 x 109 400 to 599
0.400 x 109 to 0.599 x 109 < 400
< 0.400 x 109
2 to 7 days of age
1,250 to 1,500
1.250 x 109 to 
1.500 x 109
1,000 to 1,249
1.000 x 109 to 1.249 x 109750 to 999
0.750 x 109 to 0.999 x 109 < 750
< 0.750 x 109
≤1 day of age
4,000 to 5,000
4.000 x 109to 5.000 x 
109
3,000 to 3,999
3.000 x 109 to 3.999 x 109 1,500 to 2,999
1.500 x 109 to 2.999 x 109< 1,500
< 1.500 x 109


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Fibrinogen, Decreased
(mg/dL; g/L)
100 to < 200
1.00 to < 2.00
OR
0.75 to < 1.00 x LLN
75 to < 100
0.75 to < 1.00
OR
≥ 0.50 to < 0.75 x LLN
50 to < 75
0.50 to < 0.75
OR
0.25 to < 0.50 x LLN
< 50
< 0.50
OR
< 0.25 x LLN
OR Associated with gross 
bleeding
Haemoglobin 1, Low
(g/dL; mmol/L) 2
≥13 years of age
(male only)
10.0 to 10.9
6.19 to 6.76
9.0 to < 10.0
5.57 to < 6.19
7.0 to < 9.0
4.34 to < 5.57
< 7.0
< 4.34
≥ 13 years of age
(female only)
9.5 to 10.4
5.88 to 6.48
8.5 to < 9.5
5.25 to < 5.88
6.5 to < 8.5
4.03 to < 5.25
< 6.5
< 4.03
57 days of age to <13 years of 
age
(male and female)
9.5 to 10.4
5.88 to 6.48
8.5 to < 9.5
5.25 to < 5.88
6.5 to < 8.5
4.03 to < 5.25
< 6.5
< 4.03
36 to 56 days of age
(male and female)
8.5 to 9.6
5.26 to 5.99
7.0 to < 8.5
4.32 to < 5.26
6.0 to < 7.0
3.72 to < 4.32
< 6.0
< 3.72
22 to 35 days of age
(male and female)
9.5 to 11.0
5.88 to 6.86
8.0 to < 9.5
4.94 to < 5.88
6.7 to < 8.0
4.15 to < 4.94
< 6.7
< 4.15
8 to ≤ 21 days of age
(male and female)
11.0 to 13.0
6.81 to 8.10
9.0 to < 11.0
5.57 to < 6.81
8.0 to < 9.0
4.96 to < 5.57
< 8.0
< 4.96
≤ 7 days of age
(male and female)
13.0 to 14.0
8.05 to 8.72
10.0 to < 13.0
6.19 to < 8.05
9.0 to < 10.0
5.59 to < 6.19
< 9.0
< 5.59


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
INR, High
(not on anticoagulation
therapy)
1.1 to < 1.5 x ULN
1.5 to < 2.0 x ULN
2.0 to < 3.0 x ULN
≥3.0 x ULN
Methaemoglobin
(% haemoglobin)
5.0 to < 10.0%
10.0 to < 15.0%
15.0 to < 20.0%
≥ 20.0%
PTT, High
(not on anticoagulation
therapy)
1.1 to < 1.66 x ULN
1.66 to < 2.33 x ULN
2.33 to < 3.00 x ULN
≥ 3.00 x ULN
Platelets, Decreased
(cells/mm3; cells/L)
100,000 to
< 124,999
100.000 x 109 to
< 124.999 x 109
50,000 to
< 100,000
50.000 x 109 to
< 100.000 x 109
25,000 to
< 50,000
25.000 x 109 to
< 50.000 x 109
< 25,000
< 25.000 x 109
PT, High
(not on anticoagulation
therapy
1.1 to < 1.25 x ULN
1.25 to < 1.50 x ULN
1.50 to < 3.00 x ULN
≥3.00 x ULN
WBC, Decreased
(cells/mm3; cells/L)
> 7 days of age
2,000 to 2,499
2.000 x 109 to 
2.499 x 109
1,500 to 1,999
1.500 x 109 to 1.999 x 109 1,000 to 1,499
1.000 x 109 to 1.499 x 109 < 1,000
< 1.000 x 109
≤ 7 days of age
5,500 to 6,999
5.500 x 109 to 
6.999 x 109
4,000 to 5,499
4.000 x 109 to 5.499 x 109 2,500 to 3,999
2.500 x 109 to 3.999 x 109 < 2,500
< 2.500 x 109


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1. Male and female sex is defined as sex at birth.
2. The conversion factor used to convert g/dL to mmol/L is 0.6206 and is the most commonly used conversion factor.  For grading 
haemoglobin results obtained by an analytic method with a conversion factor other than 0.6206, the result must be converted to g/dL 
using the appropriate conversion factor for the particular laboratory.


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Urinalysis:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Glycosuria (random collection 
tested by dipstick)
Trace to 1+ or 250 mg 2+ or ˃ 250 to 500 mg
> 2+ or > 500 mg
Not applicable
Haematuria (not to be reported 
based on dipstick findings or 
on blood believed to be of
menstrual origin)
6 to < 10 RBCs per high 
power field
≥10 RBCs per high
power field
Gross, with or without 
clots OR With RBC casts 
OR Intervention indicated
Life-threatening 
consequences
Proteinuria (random collection 
tested by dipstick)
1+
2+
3+ or higher
Not applicable


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12.4.1.
Total Bilirubin Table for Term and Preterm Neonates:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Total Bilirubin 1, High
(mg/dL; µmol/L) 2
Term Neonate 3
<24 hours of age
4 to < 7
68.4 to < 119.7
7 to < 10
119.7 to <171
10 to < 17
171 to <290.7
17
≥ 290.7
24 to <48 hours of age
5 to < 8
85.5 to < 136.8
8 to < 12
136.8 to < 205.2
12 to < 19
205.2 to < 324.9
19
324.9
48 to <72 hours of age
8.5 to < 13
145.35 to  <222.3
13 to < 15
222.3 to < 256.5
15 to < 22
256.5 to < 376.2
22
376.2
72 hours to <7 days of age
11 to < 16
188.1 to < 273.6
16 to < 18
273.6 to < 307.8
18 to < 24
307.8 to < 410.4
24
410.4
7 to 28 days of age
(breast feeding)
5 to < 10
85.5 to < 171
10 to < 20
171 to < 342
20 to < 25
342 to < 427.5
25
427.5
7 to 28 days of age
(not breast feeding)
1.1 to < 1.6 x ULN
1.6 to < 2.6 x ULN
2.6 to < 5.0 x ULN
5.0 x ULN
Preterm Neonate20
35 to < 37 weeks gestational 
age
Same as for Total 
Bilirubin, High, Term 
Neonate (based on days of 
age).
Same as for Total 
Bilirubin, High, Term 
Neonate (based on days of 
age).
Same as for Total
Bilirubin, High,
Term Neonate (based on 
days of age).
Same as for Total 
Bilirubin, High, Term 
Neonate (based on days of 
age).
32 to < 35 weeks gestational 
age and < 7 days of age
Not applicable
Not applicable
10 to < 14
171 to < 239.4
14
239.4


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
28 to < 32 weeks gestational 
age and < 7 days of age
Not applicable
Not applicable
6 to < 10
102.6 to < 171
10
171
< 28 weeks gestational age 
and < 7 days of age
Not applicable
Not applicable
5 to < 8
85.5 to < 136.8
8
136.8
7 to 28 days of age (breast 
feeding)
5 to < 10
85.5 to < 171
10 to < 20
171 to < 342
20 to < 25
342 to < 427.5
25
427.5
7 to 28 days of age (not 
breast feeding)
1.1 to < 1.6 x ULN
1.6 to < 2.6 x ULN
2.6 to < 5.0 x ULN
5.0 x ULN
1. Severity grading for total bilirubin in neonates is complex because of rapidly changing total bilirubin normal ranges in the first week of 
life followed by the benign phenomenon of breast milk jaundice after the first week of life.  Severity grading in this appendix 
corresponds approximately to cut-offs for indications for phototherapy at grade 3 and for exchange transfusion at grade 4.
2. A laboratory value of 1 mg/dL is equivalent to 17.1 mol/L.
3. Definitions: Term is defined as 37 weeks gestational age; near-term, as 35 weeks gestational age; preterm, as < 35weeks 
gestational age; and neonate, as 0 to 28 days of age.


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12.5.
Appendix 5: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
12.5.1.
Definition of Adverse Events
Adverse Event Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the Adverse Event Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the Investigator (i.e., not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication.  Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent.  Such overdoses should be reported regardless of sequelae.
Events NOT Meeting the Adverse Event Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 


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convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
12.5.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A Serious Adverse Event is defined as any untoward medical occurrence that, at any dose:
c.
Results in death
d.
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.
e.
Requires inpatient hospitalization or prolongation of existing hospitalization
NOTE:

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.
f.
Results in persistent disability/incapacity

NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
g.
Is a congenital anomaly/birth defect


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h.
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.
i.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.

* Serum bilirubin fractionation should be performed if testing is available; if 
unavailable, measure urinary bilirubin via dipstick.  If fractionation is unavailable 
and ALT 3xULN and total bilirubin 2xULN, then the event is still to be reported 
as an SAE.

** INR testing not required per protocol and the threshold value does not apply to 
participants receiving anticoagulants.  If INR measurement is obtained, the value is 
to be recorded on the SAE form.

Refer to Section 12.2, Appendix 2 for the required liver chemistry follow-up 
instructions
12.5.3.
Recording Adverse Events and Serious Adverse Events
Adverse Events and Serious Adverse Events Recording

When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
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.


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12.5.4.
Evaluating Adverse Events and Serious Adverse Events
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 sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities.  An AE that is assessed as 
severe should not be confused with an SAE.  Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.

An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The Investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out.

The Investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.

The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the Investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the Investigator has 
minimal information to include in the initial report to GSK.  However, it is very 
important that the Investigator always make an assessment of causality for every 
event before the initial transmission of the SAE data to GSK.

The Investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.


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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.

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.
12.5.5.
Reporting of Serious Adverse Events 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 for more than 24 hours, then the site will use 
the paper SAE data collection tool (see next section).

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The Investigator or medically-qualified sub-Investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see next 
section) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in the SRM.


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12.6.
Appendix 6: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
Women in the following categories are not considered WOCBP
7. Premenarchal
8. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
9. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study.  Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Male participants

Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following (during the protocol-defined 
time frame in Section 6.1):

Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent.

Agree to use a male condom plus an additional method of contraception 
with a failure rate of < 1% per year when having penile-vaginal intercourse 
with a woman of childbearing potential as described in Table 6.


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
Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration (during the protocol-defined time frame).

Refrain from donating sperm for duration of study and for 3 months after study 
completion or from last dose.
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 6.
Table 6
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly.
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulationb

oral

intravaginal

transdermal
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.) 
Sexual abstinence 
(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 drug.  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).


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NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly.  Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies. 
b.
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method.  In this case two highly effective methods of contraception should be utilized during the 
treatment period and for at least 30 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer)  after the last dose of study treatment 
Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine or serum pregnancy test 

Additional pregnancy testing may be performed at the discretion of the Investigator
during the treatment period or after the last dose of study treatment and as required 
locally.

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.

Pregnancy testing will be performed using the test kit provided by the central 
laboratory.
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 participants who receive study treatment.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the Investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy.

Partner will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded to GSK.

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date.  Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy.  The 
Investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.


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
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the Investigator, will be reported to 
GSK. While the Investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous 
reporting.
Any female participant who becomes pregnant while participating will be withdrawn 
from the study.


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12.7.
Appendix 7: Study Governance Considerations
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.
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.
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 


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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.
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.
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.
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., 


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laboratory data).  The Investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF.

The Investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.

The Investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.

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. 
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.
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:


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
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP 
guidelines.

Inadequate recruitment of participants by the Investigator.

Discontinuation of further study treatment development.

SAP_001.pdf: 
 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
205820 
 
1 
 
DIVISION 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
 
Title 
: Reporting and Analysis Plan for: A Two Part Study to Assess 
i) the Relative Bioavailability and Food Effect of a Novel 
Tablet Formulation of Boosted-GSK2838232 Compared to 
Capsule and ii) the Safety and Pharmacokinetics of Repeated 
Once-Daily Doses of Non boosted GSK2838232 
Compound Number  
: GSK2838232 
Effective Date  
: 07-DEC-2017 (Final 1.0) 
 
Description : 
• 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 205820. 
• 
This RAP is intended to describe the statistical analyses for safety and 
pharmacokinetic analyses required for the study. 
• 
This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable. 
 
RAP Authors: 
Approver 
Date 
Approval Method 
  
06-DEC-2017 
e-mail approval 
Principal Biostatistician (PCPS, GSK) 
 
12-DEC-2017 
e-mail approval 
Principal Biostatistician (PAREXEL EP Berlin) 
 
12-DEC-2017 
e-mail approval 
QCD Senior Scientific (PAREXEL Quantitative  
Clinical Development) 
 
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
 
PPD
PPD
PPD


 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
205820 
 
2 
 
RAP Team Approvals: 
 
Approver 
Date 
Approval Method 
 
12-DEC-2017 
e-mail approval 
Director, Clinical Pharmacology (CPMS, GSK) 
 
12-DEC-2017 
e-mail approval 
Principal Clinical Research Scientist (CPSSO, 
GSK) 
 
06-DEC-2017 
e-mail approval 
Sm Executive Medical Director (GSK) 
 
12-DEC-2017 
e-mail approval 
Principal Programmer (PCPS, GSK) 
 
07-DEC-2017 
e-mail approval 
Principal Data Manager (CPSSO, GSK) 
Clinical Statistics and Clinical Programming Line Approvals: 
Approver 
Date 
Approval Method 
  
07-DEC-2017 
e-mail approval 
Director, Biostatistics (PCPS, GSK) 
  
12-DEC-2017 
e-mail approval 
Manager, Programming (PCPS, GSK) 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
CONFIDENTIAL 
 
 
 
205820 
 
3 
 
TABLE OF CONTENTS 
Page 
DIVISION ........................................................................................................................ 1 
1. 
INTRODUCTION ...................................................................................................... 6 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 6 
2.1 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 6 
2.2 
Study Objectives and Endpoints ................................................................... 6 
2.3 
Study Design ................................................................................................ 8 
2.4 
Statistical Hypotheses/Statistical Analysis .................................................. 11 
3. 
PLANNED ANALYSES .......................................................................................... 12 
3.1 
Interim Analyses ......................................................................................... 12 
3.2 
Final Analyses ............................................................................................ 12 
4. 
ANALYSIS POPULATIONS ................................................................................... 12 
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 
Multicentre Studies ..................................................................................... 15 
5.4 
Examination of Covariates, Other Strata and Subgroups ............................ 15 
5.5 
Multiple Comparisons and Multiplicity ......................................................... 15 
5.6 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 15 
6. 
STUDY POPULATION ANALYSES ....................................................................... 17 
6.1 
Overview of Planned Analyses ................................................................... 17 
6.2 
Disposition of Participants ........................................................................... 17 
6.3 
Demographic and Baseline Characteristics ................................................. 17 
6.4 
Concomitant Medications ............................................................................ 17 
6.5 
Treatment Compliance and Protocol Deviations ......................................... 18 
6.6 
Extent of Exposure ..................................................................................... 18 
7. 
EFFICACY ANALYSES .......................................................................................... 18 
8. 
SAFETY ANALYSES ............................................................................................. 19 
8.1 
Adverse Events Analyses ........................................................................... 19 
8.2 
Adverse Events of Special Interest Analyses .............................................. 19 
8.3 
Clinical Laboratory Analyses ....................................................................... 19 
8.4 
Other Safety Analyses ................................................................................ 19 
9. 
PHARMACOKINETIC ANALYSES ......................................................................... 20 
9.1 
Primary Pharmacokinetic Analyses ............................................................. 20 
9.1.1 
Endpoint / Variables ..................................................................... 20 
9.1.1.1 
Drug Concentration Measures .................................... 20 
9.1.1.2 
Derived Pharmacokinetic Parameters......................... 20 
9.1.2 
Summary Measure ...................................................................... 21 
9.1.3 
Population of Interest ................................................................... 21 


 
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9.1.4 
Strategy for Intercurrent (Post-Randomization) Events ................ 21 
9.1.5 
Statistical Analyses / Methods ..................................................... 21 
Statistical Methodology Specification ........................................... 22 
9.2 
Secondary Pharmacokinetic Analyses ........................................................ 24 
9.2.1 
Endpoint / Variables ..................................................................... 24 
9.2.1.1 
Drug Concentration Measures .................................... 24 
9.2.1.2 
Derived Pharmacokinetic Parameters......................... 24 
9.2.2 
Summary Measure ...................................................................... 25 
9.2.3 
Population of Interest ................................................................... 26 
9.2.4 
Strategy for Intercurrent (Post-Randomization) Events ................ 26 
9.2.5 
Statistical Analyses / Methods ..................................................... 26 
Statistical Methodology Specification ........................................... 26 
9.3 
Exploratory Pharmacokinetic Analyses ....................................................... 28 
10. POPULATION PHARMACOKINETIC (POPPK) ANALYSES .................................. 28 
11. PHARMACODYNAMIC ANALYSES....................................................................... 28 
12. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES ................................. 28 
13. REFERENCES ....................................................................................................... 28 
14. APPENDICES ........................................................................................................ 28 
14.1 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 28 
14.2.1 Exclusions from Per Protocol Population .................................................... 28 
14.2 
Appendix 2: Schedule of Activities .............................................................. 29 
14.2.1 Protocol Defined Schedule of Events .......................................................... 29 
Schedule of Assessments for Part 1A and Part 1B: Single 
Dose RBA ± Food....................................................... 29 
Schedule of Assessments for Part 2: Repeated Doses for 
11 days: ...................................................................... 31 
14.3 
Appendix 3: Assessment Windows ............................................................. 34 
14.3.1 Definitions of Assessment Windows for Analyses ....................................... 34 
14.4 
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 35 
14.4.1 Study Phases ............................................................................................. 35 
14.4.4.1 
Study Phases for Concomitant Medication ................. 35 
14.4.2 Treatment Emergent Flag for Adverse Events ............................................ 35 
14.4.3 Adverse Events Assignment to Treatment Period for Part 1 ....................... 35 
14.4.4 Concomitant Medication Assignment to Treatment Period for Part 1 .......... 36 
14.5 
Appendix 5: Data Display Standards & Handling Conventions .................... 37 
14.5.1 Reporting Process ...................................................................................... 37 
14.5.2 Reporting Standards ................................................................................... 37 
14.5.3 Reporting Standards for Pharmacokinetic Data .......................................... 38 
14.6 
Appendix 6: Derived and Transformed Data ............................................... 40 
14.6.1 General ....................................................................................................... 40 
14.6.2 Study Population ......................................................................................... 40 
14.6.3 Efficacy ....................................................................................................... 41 
14.6.4 Safety ......................................................................................................... 41 
14.6.5 Pharmacokinetic ......................................................................................... 42 
14.6.6 Population Pharmacokinetic (PopPK) ......................................................... 42 


 
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14.6.7 Pharmacodynamic ...................................................................................... 42 
14.7 
Appendix 7: Reporting Standards for Missing Data ..................................... 43 
14.7.1 Premature Withdrawals ............................................................................... 43 
14.7.2 Handling of Missing Data ............................................................................ 43 
14.7.3 Handling of Missing and Partial Dates ........................................................ 43 
14.8 
Appendix 8: Values of Potential Clinical Importance ................................... 45 
14.8.1 Laboratory Values ....................................................................................... 45 
14.8.2 ECG ............................................................................................................ 46 
14.8.3 Vital Signs ................................................................................................... 46 
14.9 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses ...................... 47 
14.9.1 Population Pharmacokinetic (PopPK) Dataset Specification ....................... 47 
14.9.2 Population Pharmacokinetic (PopPK) Methodology .................................... 47 
14.10 Appendix 10: Pharmacokinetic / Pharmacodynamic Analyses .................... 48 
14.10.1 
Pharmacokinetic / Pharmacodynamic Dataset 
Specification ............................................................................................... 48 
14.10.2 
Pharmacokinetic / Pharmacodynamic Methodology ..................... 48 
14.11 Appendix 11: Abbreviations & Trade Marks ................................................ 49 
14.11.1 
Abbreviations ............................................................................... 49 
14.11.2 
Trademarks ................................................................................. 51 
14.12 Appendix 12: List of Data Displays.............................................................. 52 
14.12.1 
Data Display Numbering .............................................................. 52 
14.12.2 
Mock Example Shell Referencing ................................................ 52 
14.12.3 
Deliverable [Priority] ..................................................................... 52 
14.12.4 
Study Population Tables .............................................................. 53 
14.12.5 
Efficacy Tables ............................................................................ 56 
14.12.6 
Efficacy Figures ........................................................................... 56 
14.12.7 
Safety Tables ............................................................................... 57 
14.12.8 
Safety Figures ............................................................................. 62 
14.12.9 
Pharmacokinetic Tables ............................................................... 63 
14.12.10 
Pharmacokinetic Figures ............................................................. 65 
14.12.11 
Pharmacokinetic Population (PopPK) Tables ............................... 67 
14.12.12 
Pharmacokinetic Population (PopPK) Figures ............................. 67 
14.12.13 
Pharmacodynamic Tables ........................................................... 67 
14.12.14 
Pharmacodynamic Figures .......................................................... 67 
14.12.15 
Pharmacokinetic / Pharmacodynamic Tables .............................. 67 
14.12.16 
Pharmacokinetic / Pharmacodynamic figures .............................. 67 
14.12.17 
ICH Listings ................................................................................. 68 
14.12.18 
Non-ICH Listings .......................................................................... 74 
14.13 Appendix 13: Example Mock Shells for Data Displays ................................ 75 
 
 


 
CONFIDENTIAL 
 
 
 
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6 
 
1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol: 
Revision Chronology: 
2017N322544_00 
09-JUN-2017 
Original  
2017N322544_01 
17-JUL-2017 
Amendment No.: 1.  
The protocol was amended to include an assessment of 
neuropsychiatric adverse events at each AE enquiry as well 
as a statement to inform FDA of any grade 2 or higher 
alteration in personality-behavior or in mood or altered mental 
status within 7 days, per FDA request. 
Minor typographical errors were also amended in the 
Schedule of Assessments, the Exclusion Criteria and the 
Study Assessment and Procedures. 
 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1 
Changes to the Protocol Defined Statistical Analysis Plan 
There were no changes or deviations to the originally planned statistical analysis 
specified in the amended protocol (dated: 17-JUL-2017). 
2.2 
Study Objectives and Endpoints 
Part 1. 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
• To assess the relative bioavailability of a 
novel GSK2838232 tablet formulations 
versus the capsule formulation (Part 1A) 
• AUC(0-∞) and Cmax 
• To assess the effect of food on 
GSK2838232 exposure of the tablet 
formulation (Part 1A and Part 1B) 
• AUC(0-∞), Cmax, and tmax 
Secondary Objectives 
Secondary Endpoints 
• To investigate the safety and tolerability of 
GSK2838232 following single dose 
administration as tablets or capsules, with 
Ritonavir (RTV) 
• GSK2838232 safety parameters: adverse events 
(AEs); absolute values and changes over time of 
clinical laboratory evaluations (hematology, clinical 
chemistry, urinalysis), vital signs, and 12-lead 
electrocardiogram (ECG) parameters from pre-dose 
values 
• To characterize the pharmacokinetics (PK) 
of GSK2838232 after administration of a 
novel tablet formulation and capsule 
formulation with food, and the tablet 
formulation given without food 
• 
tlag, tmax, t½, tlast, C24, and AUC(0-t) 


 
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Part 2. 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
• To assess the safety of GSK2838232 
administered as non-boosted once-daily 
doses of a tablet formulation for 11 days 
• 
GSK2838232 safety parameters: AEs; absolute values 
and changes over time of clinical laboratory 
evaluations (hematology, clinical chemistry, urinalysis), 
vital signs, and ECG parameters from pre-dose values 
• To assess the PK of GSK2838232 
administered as non-boosted once-daily 
doses of a tablet formulation for 11 days 
• 
Day 1 dose: AUC(0-τ), Cmax, Cτ, tmax, tlag 
• 
Day 11 dose: AUC(0-τ), AUC(0-∞), Cmax, Cτ, tmax, 
t½, tlast 
Secondary Objectives 
Secondary Endpoints 
• To assess time to steady-state of 
GSK2838232 when administered as non-
boosted once-daily doses of a tablet 
formulation for 11 days 
• 
Pre-dose concentrations on Days 2 to 11 
• To assess accumulation of GSK2838232 
when administered as non-boosted once-
daily doses of a tablet formulation for 11 
days 
• 
Accumulation ratios: Ro[AUC(0-τ)], R(Cmax), R(Cτ) 
AUC(0-τ) = Area under the curve (Area under the plasma drug concentration-time curve from pre-dose to the end of 
the dosing interval); AUC(0-∞) = Area under the concentration-time curve from time zero (pre-dose) extrapolated to 
infinite time; Cmax = Maximum observed concentration; Cτ=Observed concentration at the end of the dosing interval;  
t½ = Apparent terminal phase half-life; tmax = Time of occurrence of Cmax; tlag = Lag time (time delay between drug 
administration and first observed concentration above LOQ in plasma); AUC(0-t) = Area under the concentration-time 
curve from zero up to last quantifiable concentration; tlast = Time of last quantifiable concentration 
 
 
 


 
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2.3 
Study Design 
Overview of Study Design and Key Features 
This study is divided into two study parts, Part 1 (Table 1 and Figure 1) and Part 2 (Figure 2). 
Table 1 
Study Design for Part 1 
Sequence 
N 
Part 1A 
Part 1B 
Period 1 
Period 2 
Period 3 
1 
6 
A 
B 
C 
2 
6 
B 
A 
1. All treatments in Part 1A to be administered with RTV in fed state, following two RTV pre-doses. 
2. There will be a washout of at least 10 days between each Period. 
3. Treatment A = GSK2838232 200 mg/r (as 4 x 50 mg) capsule formulation, fed, normal fat (i.e., approximately 
30%) meal (reference). 
4. Treatment B = GSK2838232 200 mg/r (as 2 x 100 mg) tablet formulation, fed, normal fat (i.e., approximately 30%) 
meal. 
5. Treatment C = GSK2838232 200 mg/r (as 2 x 100 mg) tablet, confirmed from Part 1A, fasted. 
 
Figure 1   Part 1: Single Dose, Food Effect Study Design Schematic 
 
 
 
 
 
 


 
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9 
 
Overview of Study Design and Key Features 
 
Figure 2   Part 2: Single Daily Dose Study Design Schematic 
 
 
Design Features 
Part 1: 
• 
Part 1 is a relative bioavailability study (Table 1) that will further subdivide into 
two parts (Part 1A and Part 1B). 
• 
In Part 1A, the safety and PK of a novel tablet formulation of GSK2838232 will be 
evaluated in open label, randomized, cross over fashion against the capsule 
formulation as reference. 
• 
Each actual treatment dose will be separated by a minimum 10 day washout 
period.  Part 1A will be studied in the fed state using a normal fat (i.e., 
approximately 30%) meal in all participants. 
• 
The safety and PK will be evaluated, and the tablet will be evaluated for 
suitability, and further clinical assessment in Part 1B, where the tablet will be 
administered in the fasted state to understand the impact of food on relative 
bioavailability. 
• 
GSK2838232 as tablets or capsules (at a 200 mg dose level) will be 
administered with 100 mg RTV, after two pre-doses of 100 mg RTV once daily 
(QD) over 48 h.  The use of RTV priming is an aspect of GSK2838232 clinical 
development (specifically relative bioavailability studies) so far and allows a more 
accurate assessment of what will ultimately happen in the repeat-dose clinical 
studies with GSK2838232 when boosted with RTV.  In Part 2 of the study, 
however, GSK2838232 will be administered unboosted and no RTV will be co 
administered. 
• 
Participants will have a screening visit within 30 days prior to first dose, a 
minimum 10-day washout period between doses, and a follow-up visit 7 to 14 
days after the last dose.  The maximum duration of study participation will be 
approximately 9 to 10 weeks. 
After completion of Part 1A, preliminary PK data will be analyzed, and a decision will 
be made based on tolerability, relative bioavailability PK criteria, as well as feasibility 
considerations, as to whether the tablet formulation will be used to conduct Part 1B 
(fasted) and Part 2. 
 
Part 2: 
• 
Part 2 will evaluate non-RTV boosted GSK2838232, given as single daily doses 


 
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Overview of Study Design and Key Features 
for 11 days in a separate cohort of participants (N=8; 6A/2P). 
• 
The placebo tablet supplied will not be identical to GSK2838232 and as such will 
be administered by site staff via an opaque card/paper tube to facilitate the single 
blind (i.e., the Principal Investigator [PI] and the participants themselves will be 
blinded as to their treatment). 
• 
The dose chosen for Part 2 will depend upon the preliminary results of the tablet 
in Part 1A but is likely to be, but will not exceed, 500 mg (i.e., 5 x 100 mg tablets) 
QD.   
• 
Participants will have a screening visit within 30 days prior to first dose, and a 
follow-up visit 7 to 14 days after the last dose.  The maximum duration of study 
participation will be approximately 8 to 9 weeks. 
Details of the assessments and procedures participants will undergo are listed in 
Section 9 of the Clinical Study Protocol (CSP). The time points and visits are 
provided in the schedule of assessments, (Table 2 and Table 3 of the CSP for the 
Schedule of assessments for study Parts 1 and 2 respectively). 
Dosing 
• 
The dose for Part 1A and Part 1B of this study will be 200 mg (achieved as either 
4 x 50 mg capsules or 2 x 100 mg tablets) administered with 100 mg RTV.   
• 
The dose for Part 2 will be confirmed from Part 1A but is likely to be, and will not 
exceed, 500 mg (as 5 x 100 mg tablets). 
Treatment 
Assignment 
• The randomization number will determine the allocation of treatment sequences 
(ABC or BAC) for Part 1, and of treatment (GSK2838232 without RTV or placebo) 
for Part 2.   
• Part 1 treatments: 
o Treatment A = GSK2838232 200 mg/r (as 4 x 50 mg) capsule formulation, 
fed, normal fat (i.e., approximately 30%) meal (reference). 
o Treatment B = GSK2838232 200 mg/r (as 2 x 100 mg) tablet formulation, 
fed, normal fat (i.e., approximately 30%) meal. 
o Treatment C = GSK2838232 200 mg/r (as 2 x 100 mg) tablet, formulation 
confirmed from Part 1A, fasted. 
• 
Part 2 treatments: 
o Treatment D = GSK2838232 500 mg/r (as 5 x 100 mg) tablet formulation, 
fed, normal fat (i.e., approximately 30%) meal (reference). 
o Treatment E = Placebo 
The dose chosen for Part 2 will depend upon the preliminary results of the tablet 
in Part 1A but is likely to be, but will not exceed, 500 mg (i.e., 5 x 100 mg tablets) 
QD.   
Interim Analysis 
• 
No formal interim analyses are planned for this study; an informal analysis of data 
from Part 1A of the study will decide the dose and formulation to be administered 
in Part 1B and Part 2. 
 
 


 
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2.4 
Statistical Hypotheses/Statistical Analysis 
No formal statistical hypotheses will be tested. Analysis will be descriptive and 
exploratory. An estimation approach providing point estimates and corresponding 
confidence intervals will be used, where appropriate. 
Part 1A Relative Bioavailability 
Part 1A of this study is designed to estimate the bioavailability of a novel GSK2838232 
tablet formulations versus the capsule formulation at 200 mg/r.  No formal hypothesis 
will be tested. The dependent variable will be the log-transformed PK parameters of 
interest (AUC(0-∞) and Cmax) and the independent variables will include fixed effects 
for treatment (table or capsule), sequence and period, and participant (sequence) as a 
random effect. For each primary pharmacokinetic endpoint, point estimates and 
corresponding 90% confidence intervals will be constructed for the ratio of the geometric 
mean of the test treatment (GSK2838232 200 mg/r tablet) to the geometric mean of the 
reference treatment (GSK2838232 200 mg/r capsule), µ(test)/µ(reference). 
Part 1A and 1B Food Effect 
Part 1A and 1B of this study are designed to evaluate the effect of food on GSK2838232 
exposure of the tablet formulation.  No formal hypothesis will be tested. The dependent 
variable will be the log-transformed PK parameters of interest (AUC(0-∞) and Cmax) 
and the independent variables will include a fixed effect for treatment (with or without 
food) and participant as a random effect. The estimated difference and confidence 
interval (CI) obtained on the log scale will be exponentiated to provide an estimate of the 
fed to fasted ratio and its associated 90% CI.  
For the parameter tmax the corresponding non-parametric analysis will be performed on 
the original scale using CIs for the estimation of the treatment difference based on the 
Hodges-Lehman estimator. 
Part 2 Steady State Assessments 
Part 2 of this study is designed to assess time to steady-state of GSK2838232 when 
administered as non-boosted once-daily doses of a tablet formulation for 11 days. No 
formal hypothesis will be tested. Mean plasma GSK2838232 pre-dose values between 
Days 2 through 11 and Cτ of Day 11 will be plotted against time. Achievement of plasma 
GSK2838232 steady-state will be assessed by calculating the 90% CI of the slope of the 
linear regression of log (Cτ) versus time. The dependent variable in the linear regression 
model will be log (Cτ) and the model will include a random intercept effect for 
participant and a fixed slope effect for study day. Steady state will be reached if the 90% 
CI for the slope estimate includes zero. 
Part 2 Accumulation 
Part 2 of this study is designed to assess accumulation of GSK2838232 when 
administered as non-boosted once-daily doses of a tablet formulation for 11 days. No 
formal hypothesis will be tested. The extent of accumulation of GSK2838232 will be 


 
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evaluated by comparing AUC(0-τ), Cmax and Cτ between Day 11 and Day 1. For each of 
these comparisons an analysis of variance will be conducted on the log scale. The 
difference between Day 11 and Day 1 least square (LS) means and a 90% CI will be 
computed by fitting a mixed effects model with the log-transformed PK parameter as the 
dependent variable, day as a fixed effect and participant as a random effect. The 
estimated difference and confidence interval obtained on the log-scale will be 
exponentiated to provide an estimate of the Day 11 to Day 1 ratio and its associated 90% 
CI. If the model fails to converge, participants will be fit as a fixed effect. 
3. 
PLANNED ANALYSES 
3.1 
Interim Analyses 
No formal interim analyses are planned for this study. The dose and formulation to be 
administered in Part 1B and Part 2 will be decided, based on the outcome and results of 
an informal analysis of preliminary safety and PK data from Part 1A of the study. In 
addition, and descriptive analysis of preliminary safety and PK data from Part 1 and 2 of 
the study will be performed. 
3.2 
Final Analyses 
The final planned primary analyses will be performed after the completion of the 
following sequential steps: 
o All participants have completed the study as defined in the protocol. 
o All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management. 
o All criteria for unblinding the randomisation codes have been met.  
o Randomisation codes have been distributed according to PAREXEL procedures. 
4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened 
• 
All participants who were screened for eligibility 
• 
Study Population 
Safety 
• 
The Safety Population will include all participants 
who received at least 1 dose of the study 
treatment (including placebo) with at least 1 post-
baseline safety assessment.   
• 
This population will be based on the treatment 
the participant received. 
• 
The population will be defined separately for Part 
1 and Part 2 of the study. 
• 
Safety and 
Demography 


 
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Population 
Definition / Criteria 
Analyses Evaluated 
PK 
• 
All participants in the Safety population who had 
at least 1 non-missing PK assessment (Non-
quantifiable [NQ] values will be considered as 
non-missing values). Pharmacokinetic samples 
that may be affected by protocol deviations will 
be reviewed by the study team to determine 
whether the sample will be excluded. 
• 
This population will be based on the treatment 
the participant received. 
• 
The population will be defined separately for Part 
1A, Part 1B and Part 2 of the study. 
• 
PK 
NOTES :  
• 
Please refer to Appendix 8: List of Data Displays which details the population to be used for each 
displays being generated. 
 
4.1 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, participant management or participant 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 (PDMP) version final 1.0 
dated 22 Aug 2017. 
• 
Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised on the protocol deviations dataset.  
• 
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 Electronic Case Record Form (eCRF). 
 
 


 
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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1 
Study Treatment & Sub-group Display Descriptors 
 
Treatment Group Descriptions – Part 1 
RandAll NG  
Data Displays for Reporting  
Code 
Description 
Description 
Order in 
TFL 
C1 
GSK2838232 200 mg/r (as 4 x 50 mg) 
capsule formulation, fed, normal fat (i.e., 
approximately 30%) meal (reference) 
GSK 200 mg/r capsule fed 
1 
T1 
GSK2838232 200 mg/r (as 2 x 100 mg) 
tablet formulation, fed, normal fat (i.e., 
approximately 30%) meal 
GSK 200 mg/r tablet fed 
2 
T2 
GSK2838232 200 mg/r (as 2 x 100 mg) 
tablet, confirmed from Part 1A, fasted 
GSK 200 mg/r tablet fasted 
3 
 
Treatment comparisons will be displayed as follows using the descriptors as specified: 
1. 
GSK 200 mg/r tablet fed vs GSK 200 mg/r capsule fed 
2. 
GSK 200 mg/r tablet fed vs GSK 200 mg/r tablet fasted 
 
Treatment Group Descriptions – Part 2 
RandAll NG  
Data Displays for Reporting  
Code 
Description 
Description 
Order in 
TFL 
T3 
GSK2838232 500 mg/r (as 5 x 100 mg) 
tablet formulation, fed, normal fat (i.e., 
approximately 30%) meal (reference).  
GSK 500 mg/r tablet fed 
2 
P 
Placebo 
Placebo 
1 
Treatment comparisons will be displayed as follows using the descriptors as specified: 
1. GSK 500 mg/r tablet fed vs Placebo 
 
 
 
 
 


 
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5.2 
Baseline Definitions  
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment, including those from unscheduled visits. If time is not 
collected, Day 1 assessments are assumed to be taken prior to first dose and used as 
baseline. In part 1, baseline definitions are applicable to each period. 
Parameter 
Study Assessments Considered As Baseline 
Baseline Used in 
Data Display 
Screening 
Day -2 
Day -1 
Day 1 (Pre-Dose) 
Safety Data 
Vital Signs 
X 
X* 
X 
X  
Mean of replicate 
assessments on Day 
1 
ECG 
X 
X* 
X 
X  
Mean of replicate 
assessments on Day 
1 
Laboratory tests 
X 
X* 
X 
 
Day -1 
* Vital Sign, ECG and laboratory tests are not collected at day -2 for Part 2. 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
5.3 
Multicentre Studies 
Not applicable. 
5.4 
Examination of Covariates, Other Strata and Subgroups 
Not applicable. 
5.5 
Multiple Comparisons and Multiplicity 
Not applicable. 
5.6 
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 
14.3 
Appendix 3: Assessment Windows 
14.4 
Appendix 4: Study Phases and Treatment Emergent Adverse Events 
14.5 
Appendix 5: Data Display Standards & Handling Conventions 
14.6 
Appendix 6: Derived and Transformed Data 
14.7 
Appendix 7: Reporting Standards for Missing Data 


 
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Section 
Component 
14.8 
Appendix 8: Values of Potential Clinical Importance 
 
 
 


 
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6. 
STUDY POPULATION ANALYSES 
6.1 
Overview of Planned Analyses 
The study population analyses will be based on the Safety Population, unless otherwise 
specified. 
Study population analyses including analyses of participant’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. 
6.2 
Disposition of Participants 
A summary of the number of participants in each of the analysis populations described in 
Section 4 will be provided and this table will be displayed by treatment/sequence and 
overall of each part. A listing of participants excluded from analysis populations will also 
be provided. 
A summary of participant status and reason for study withdrawal will be provided. This 
display will show the number and percentage of participants who withdrew from the 
study, including primary reasons for study withdrawal.  
A summary of study treatment status will be provided. This display will show the number 
and percentage of participants who have completed the study or have discontinued study 
treatment and a summary of the primary reasons for discontinuation of study treatment. A 
listing of study treatment discontinuation will be generated. The listing will include last 
dose date, and reasons for study treatment discontinuation as well as study part and 
period, when applicable, of discontinuation.  
6.3 
Demographic and Baseline Characteristics 
The demographic characteristics (e.g., age, ethnicity, sex, height, and body weight) will 
be summarized and listed by participant. Race will be summarized and listed separately 
from the other demographic characteristics. Age, height, body mass index (BMI) and 
weight will be summarized using the mean, standard deviation, minimum, median, and 
maximum. The count and percentage will be computed for sex, race and ethnicity. The 
summary table will be displayed by treatment/treatment sequence and overall of each 
part. 
Medical conditions present at screening will be summarized by treatment/treatment 
sequence and overall of each part, and listed by participant. 
Substance use will be listed. 
6.4 
Concomitant Medications 
Concomitant medications will be coded using GSK Drug coding dictionary, summarized 
by treatment and study part, and listed by participant. The summary of concomitant 


 
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medications will show the number and percentage of participants taking concomitant 
medications by ingredient. Multi-ingredient products will be summarized by their 
separate ingredients rather than as a combination of ingredients. Anatomical Therapeutic 
Chemical (ATC) classification Level 1 (Body System) information will be included in the 
dataset created, however, will not appear on the listing or summary. 
In the summary of concomitant medications, each participant is counted once within each 
unique ingredient. For example, if a participant takes amoxicillin on two separate 
occasions, the participant is counted only once under the ingredient “amoxicillin”.  
In the summary of concomitant medications, the ingredients will be summarized by the 
base only, using CMBASECD and CMBASE. 
6.5 
Treatment Compliance and Protocol Deviations 
Information of each participant not received the correct treatment during each treatment 
period, the reason for not receiving the correct treatment, and any other protocol 
deviations will be summarized by treatment /sequence and overall of each part, and listed 
by participant and period (treatment). In addition, a listing will be provided including 
dose administered along with dosing dates and time for the investigational product. 
Participants who did not satisfy all inclusion and exclusion criteria and corresponding 
criteria that were violated will be summarized and listed. 
For the food effect of Part 1, a by-participant listing of the meal data will also be 
generated including start and stop date and time of meal, dosing time, type of meal and 
whether the totality of the meal was ingested. 
6.6 
Extent of Exposure 
A by-participant summary of treatments administered in each part will be generated, with 
dose, and dosing start date, dosing end date and number of dose. A by-participant listing 
of data on participant exposure will be generated including dose date and time, unit, 
formulation, route and frequency. 
7. 
EFFICACY ANALYSES 
Not applicable. 
 
 


 
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8. 
SAFETY ANALYSES 
The safety analyses will be based on the “Safety Population”, unless otherwise specified.  
8.1 
Adverse Events Analyses 
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs) 
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 12: List of Data Displays. 
8.2 
Adverse Events of Special Interest Analyses 
Not applicable. 
8.3 
Clinical Laboratory Analyses 
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are in Appendix 12: List of Data Displays. 
8.4 
Other Safety Analyses 
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 12: List of Data Displays. 
 
 
 


 
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9. 
PHARMACOKINETIC ANALYSES 
9.1 
Primary Pharmacokinetic Analyses 
9.1.1 
Endpoint / Variables 
9.1.1.1 
Drug Concentration Measures 
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively. Plasma GSK2838232 concentration-time data will be listed by 
participant, treatment group and time and summarized by treatment group and time for 
each part of the study. Individual participant profiles for GSK2838232 concentration-
time data will be presented on both a linear and semi-log scale. Linear and semi-log 
figures for mean and median GSK2838232 plasma concentrations versus time will also 
be generated. 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 14.5.3 
Reporting Standards for Pharmacokinetic). 
9.1.1.2 
Derived Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin. 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. 
Part 1: 
Parameter 
Parameter Description 
AUC(0-∞) 
Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite 
time will be calculated as:  
AUC = AUC(0-last) + C(last) / lambda_z 
Cmax 
Maximum observed concentration, determined directly from the concentration-time data 
tmax 
Time of occurrence of Cmax, determined directly from the concentration-time data 
 
Part 2 
Parameter 
Parameter Description 
AUC(0-τ) 
Area under the plasma drug concentration-time curve from pre-dose to the end of the dosing 
interval (where τ = 24 h) (Day 1 and Day 11) 
AUC(0-∞) 
Area under the concentration-time curve extrapolated to infinity will be calculated as:  
AUC = AUC(0-last) + C(last) / lambda_z 
Cmax 
Maximum observed concentration, determined directly from the concentration-time data. (Day 
1 and Day 11) 
tmax 
Time of occurrence of Cmax, determined directly from the concentration-time data (Day 1 and 
Day 11) 
tlag 
Lag-time (time delay between drug administration and first observed concentration), 


 
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Parameter 
Parameter Description 
determined directly from the concentration-time data (Day 1) 
tlast 
Time of last quantifiable concentration, determined directly from the concentration-time data 
(Day 11) 
t½ 
Apparent terminal phase half-life, calculated as; t½ = ln2 / lambda_z (Day 11) 
Cτ 
Observed concentration at the end of the dosing interval, determined directly from the 
concentration-time data (where τ = 24 h) (Day 1 and Day 11) 
Ctrough 
Observed pre-dose concentrations on Days 2 to 11, determined directly from the 
concentration-time data 
NOTES: 
• 
C24, Cτ and Ctrough will be extracted from the concentration data by Clinical Statistics group and merged with 
other calculated PK parameters provided by CPMS. 
 
All the derived parameters described above will be listed.  For each of these parameters, 
except tmax and tlag, the following summary statistics will be calculated for each 
treatment group:  n, arithmetic mean, standard deviation (SD), median, minimum, 
maximum, geometric mean with associated 90% CI, standard deviation of logarithmically 
transformed data, and the between-participant CV (%CVb) based on the geometric mean 
for the loge-transformed PK parameters. For tmax and tlag, median, maximum, 
minimum, arithmetic mean and standard deviation will be calculated. 
9.1.2 
Summary Measure 
The measures used for the treatment comparisons are the following: 
• For part 1; AUC(0-∞), Cmax, and, for food effect, tmax. 
• For part 2; Not applicable. 
9.1.3 
Population of Interest  
The primary pharmacokinetic analyses will be based on the Pharmacokinetic population, 
unless otherwise specified. 
9.1.4 
Strategy for Intercurrent (Post-Randomization) Events 
Not applicable. 
9.1.5 
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 9.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 


 
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Statistical Methodology Specification 
The following pharmacokinetic statistical analyses will only be performed if sufficient 
data is available (i.e. if participants have well defined plasma profiles). 
Part 1A Relative Bioavailability 
Endpoint / Variables 
• AUC(0-∞) and Cmax 
Model Specification 
• AUC(0-∞) and Cmax will be separately analysed using a mixed effects model. The dependent 
variable will be the log-transformed PK parameters of interest (AUC(0-∞) and Cmax) and the 
independent variables will include fixed effects for treatment (GSK2838232 200 mg/r tablet or 
GSK2838232 200 mg/r capsule), sequence and period, and participant (sequence) as a 
random effect. 
Model Checking & Diagnostics 
• Model assumptions will be applied, but appropriate adjustments may be made based on the 
data. 
• The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used. 
• Normality 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 models will be 
explored using appropriate transformed data. 
Model Results Presentation 
• Geometric least-squares means for each treatment (tablet or capsule), point estimates and 
associated 90% confidence intervals for the ratios for each parameter will be produced in 
tabular format.  Estimates of within-subject variability (%CVw) will also be provided.  %CVw 
represents a pooled measure of within-subject variability across all treatments. 
• Comparative plots of individual PK parameters will be generated by treatment on linear and 
semi-logarithmic scales. 
• Plots of adjusted geometric mean ratio of test to reference treatment together with 90% 
confidence intervals will be produced. 
• Listing of individual PK parameter ratios will be generated. 
• Supportive SAS output from statistical analysis will be generated. 
Subgroup Analyses 
• Not applicable 
Sensitivity and Supportive Analyses 
• Not applicable 
 
 


 
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Part 1 A and 1B Food Effect 
Endpoint / Variables 
• AUC(0-∞) and Cmax 
Model Specification 
• AUC(0-∞) and Cmax will be separately analysed using a mixed effects model. The dependent 
variable will be the log-transformed PK parameters of interest (AUC(0-∞) and Cmax) and the 
independent variables will include a fixed effect for treatment (with or without food) and 
participant as a random effect.  
• To assess the effect of food on GSK2838232 exposure of the tablet formulation (Part 1A and 
Part 1B) 
Model Checking & Diagnostics 
• Model assumptions will be applied, but appropriate adjustments may be made based on the 
data. 
• The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used. 
• Normality 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 models will be explored using 
appropriate transformed data. 
Model Results Presentation 
• The estimated difference and CI obtained on the log scale will be exponentiated to provide an 
estimate of the fed to fasted ratio and its associated 90% CI. Estimates of within-subject 
variability (%CVw) will also be provided.  %CVw represents a pooled measure of within-subject 
variability across all treatments. 
• Comparative plots of individual PK parameters will be generated by treatment on linear and 
semi-logarithmic scales. 
• Plots of adjusted geometric mean ratio of test to reference treatment together with 90% 
confidence intervals will be produced. 
• Listing of individual PK parameter ratios will be generated. 
• Supportive SAS output from statistical analysis will be generated. 
Subgroup Analyses 
• Not applicable 
Sensitivity and Supportive Analyses 
• Not applicable 
 
 
 


 
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Endpoint / Variables 
• tmax 
Model Specification 
• Non-parametric analysis, using PROC NPAR1WAY will be performed on the original scale PK 
parameters of interest (tmax). The dependent variable will be the original scale PK parameter 
of interest (tmax) and the independent variables will be treatment (with or without food). 
• SAS code; 
PROC NPAR1WAY data= data hl ALPHA=0.1; 
CLASS treatment; 
VAR pk; 
EXACT hl; 
/* where PK parameter pk = tmax*/ 
ods select HodgesLehmann; 
RUN; 
 
Model Checking & Diagnostics 
• Model assumptions will be applied, but appropriate adjustments may be made based on the 
data. 
Model Results Presentation 
• 90% CIs for the estimation of the treatment difference based on the Hodges-Lehman estimator 
will be produced 
Subgroup Analyses 
• Not applicable 
Sensitivity and Supportive Analyses 
• Not applicable 
 
9.2 
Secondary Pharmacokinetic Analyses 
9.2.1 
Endpoint / Variables 
9.2.1.1 
Drug Concentration Measures  
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 14.5.3 
Reporting Standards for Pharmacokinetic) 
9.2.1.2 
Derived Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin. 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. 


 
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Part 1: 
Parameter 
Parameter Description 
AUC(0-t) 
Area under the concentration-time curve from zero up to the last quantifiable concentration  
will be calculated using the linear trapezoidal rule for each incremental trapezoid and the log 
trapezoidal rule for each decremental trapezoid 
tmax 
Time to reach Cmax, determined directly from the concentration-time data. 
tlag 
Lag-time (time delay between drug administration and first observed concentration) 
t½ 
Apparent terminal half-life will be calculated as: t½ = ln2 / lambda_z 
tlast 
Time of last quantifiable concentration, determined directly from the concentration-time data. 
C24 
Observed concentration 24 hours post-dose, determined directly from the concentration-time 
data. 
NOTES: 
• 
Additional parameters may be included as required. 
• 
Lambda_z is the terminal phase rate constant. 
 
Part 2 
Parameter 
Parameter Description 
Ctrough 
Observed pre-dose concentrations on Days 2 to 11, determined directly from the 
concentration-time data 
Ro[AUC(0-τ)] 
Accumulation ratio based on AUC(0-τ), determined by; Day 11 AUC(0-τ) / Day 1 AUC(0-τ)  
R(Cmax) 
Accumulation ratio based on Cmax, determined by; Day 11 Cmax / Day 1 Cmax 
R(Cτ) 
Accumulation ratio based on Cτ, determined by; Day 11 Cτ / Day 1 Cτ 
NOTES: 
• 
Additional parameters may be included as required. 
• 
Cτ, and Ctrough will be extracted from the concentration data by Clinical Statistics group and merged with other 
calculated PK parameters provided by CPMS. 
 
All the derived parameters described above will be listed.  For each of these parameters, 
except tmax and tlag, the following summary statistics will be calculated for each 
treatment group:  n, arithmetic mean, standard deviation (SD), median, minimum, 
maximum, geometric mean with associated 90% CI, standard deviation of logarithmically 
transformed data, and the between-participant CV (%CVb) based on the geometric mean 
for the loge-transformed PK parameters. For tmax and tlag, median, maximum, 
minimum, arithmetic mean and standard deviation will be calculated. 
9.2.2 
Summary Measure 
The measures used for the treatment comparisons are the followings: 
• For part 1; Not applicable. 
• For part 2; Accumulation ratios: Ro[AUC(0-τ)], R(Cmax), R(Cτ). 


 
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9.2.3 
Population of Interest  
The secondary pharmacokinetic analyses will be based on the Pharmacokinetic 
population, unless otherwise specified. 
9.2.4 
Strategy for Intercurrent (Post-Randomization) Events 
Not applicable. 
9.2.5 
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 9.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
Statistical Methodology Specification 
Part 2 Steady State Assessments 
Endpoint / Variables 
• GSK2838232 pre-dose values between Days 2 through 11  
Model Specification 
• Achievement of plasma GSK2838232 steady-state will be assessed by calculating the 90% CI 
of the slope of the linear regression of loge(Cτ) versus time. The dependent variable in the 
mixed effect model will be loge(Cτ) and the model will include a random intercept effect for 
participant and a fixed slope effect for study day. Day will be treated as a continuous variable 
in the model. 
Model Checking & Diagnostics 
• Model assumptions will be applied, but appropriate adjustments may be made based on the 
data. 
• The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used. 
• An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ on 
the REPEATED line. 
• In the event that this model fails to converge, alternative correlation structures may be 
considered such as CSH or CS. 
• Akaike's Information Criteria (AIC) will be used to assist with the selection of covariance 
structure. 
• Normality 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 models will be 
explored using appropriate transformed data. 


 
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Model Results Presentation 
• Steady state will be reached if the pre-dose concentration slope estimate is close to zero or the 
90% CI for the slope estimate includes zero. 
• Mean plasma GSK2838232 pre-dose values between Days 2 through 11 and Cτ of Day 11 will 
be plotted against time on linear and semi-logarithmic scale.. 
Subgroup Analyses 
• Not applicable 
Sensitivity and Supportive Analyses 
• Not applicable 
 
Part 2 Accumulation 
Endpoint / Variables 
• 
AUC(0-τ), Cmax and Cτ between Day 11 and Day 1 
Model Specification 
• The extent of accumulation of GSK2838232 will be evaluated by comparing AUC(0-τ), Cmax 
and Cτ between Day 11 and Day 1. For each of these comparisons an analysis of variance will 
be conducted on the log scale. The difference between Day 11 and Day 1 least square (LS) 
means and a 90% CI will be computed by fitting a mixed effects model with the log-
transformed PK parameter as the dependent variable, day as a fixed effect and participant as a 
random effect. 
Model Checking & Diagnostics 
• Model assumptions will be applied, but appropriate adjustments may be made based on the 
data. 
• The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used. 
• Normality 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 models will be 
explored using appropriate transformed data. 
Model Results Presentation 
• Geometric least-squares means for each treatment, point estimates and associated 90% 
confidence intervals for the ratios for each parameter will be produced in tabular format.  
Estimates of within-subject variability (%CVw) will also be provided.  %CVw represents a 
pooled measure of within-subject variability across all treatments. 
• Comparative plots of individual Accumulation Ratio will be generated by dose group on linear 
and semi-logarithmic scales.   
• The accumulation ratio will be listed and summarized along with other PK parameters. 
• Supportive SAS output from statistical analysis will be generated. 


 
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Subgroup Analyses 
• Not applicable 
Sensitivity and Supportive Analyses 
• Not applicable 
 
9.3 
Exploratory Pharmacokinetic Analyses 
Not applicable. 
10. 
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES 
Not applicable. 
11. 
PHARMACODYNAMIC ANALYSES 
Not applicable. 
12. 
PHARMACOKINETIC / PHARMACODYNAMIC 
ANALYSES 
Not applicable. 
13. 
REFERENCES 
GlaxoSmithKline documents:  
GUI_51487: Non-compartmental Analysis of Pharmacokinetic Data, CPMS Global 
Reporting and Analysis Plan (RAP) Template [Phases I to IV] Version 2.0 [Dated: 08-
AUG-2017] 
14. 
APPENDICES 
14.1 
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
14.2.1 
Exclusions from Per Protocol Population 
Not applicable. 
 
 
 


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14.2 
Appendix 2: Schedule of Activities 
14.2.1 
Protocol Defined Schedule of Events 
Schedule of Assessments for Part 1A and Part 1B: Single Dose RBA ± Food 
Procedure 
Screening 
(within 30 days of 
Day 1 - carried out 
over multiple days – 
except as noted in 
footnotes) 
Periods 1 through 3 
Follow-
up1 
Day -3 
Day -2 
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
7-14 
days 
 
 
 
 
24 h 
48 h 
72 h 
96 h 
120 h 
 
 
Admission to Unit 
 
X2 
 
 
 
 
 
 
 
 
 
 
Outpatient Visit 
X 
 
 
 
 
 
 
 
 
 
 
X 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/medication/ 
drug/alcohol history 
(Demographics) 
X 
 
 
 
 
 
 
 
 
 
 
 
Full Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
Brief Physical Examination 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Height, Weight, BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signs3 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
12 Lead ECG4 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
Echocardiogram5 
X 
 
 
 
 
 
 
 
 
 
 
 
Drug/alcohol/cotinine screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
HbsAg, HCV, HIV tests 
X 
 
 
 
 
 
 
 
 
 
 
 
Hem/Chem/Urine tests6 
X 
 
X 
X 
 
X 
 
X 
 
 
 
X 
Serum FSH (as appropriate) 
X 
 
 
 
 
 
 
 
 
 
 
 
Troponin I7 
X 
 
 
X 
X 
X 
 
X 
 
 
 
 
24 h Holter Monitoring8 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (women) 
X 
X 
 
 
 
 
 
 
 
 
 
X 
Run-in Dosing with RTV 
 
 
X 
X 
 
 
 
 
 
 
 
 
Dosing with GSK2838232+RTV 
 
 
 
 
X 
 
 
 
 
 
 
 


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Procedure 
Screening 
(within 30 days of 
Day 1 - carried out 
over multiple days – 
except as noted in 
footnotes) 
Periods 1 through 3 
Follow-
up1 
Day -3 
Day -2 
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
7-14 
days 
 
 
 
 
24 h 
48 h 
72 h 
96 h 
120 h 
 
 
PK Sampling9 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
Adverse Event Review10 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Con Med Review 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Discharge from Unit11 
 
 
 
 
 
X 
 
 
 
 
 
 
Out Patient Visit 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
BMI = Body Mass Index; ECG = Electrocardiogram; FSH = Follicle Stimulating; HbsAg = Hepatitis B surface Antigen; HCV = Hepatitis C Virus; HIV = Human Immunodeficiency Virus; 
Hem/Chem = Hematology/Clinical Chemistry; RTV = Ritonavir; PK = Pharmacokinetic(s); Con Med = Concomitant medications. 
1. Follow-up Visit to take place after Treatment Period 2. 
2. When participants stay in the unit across treatment periods, drug/alcohol/cotinine screen and pregnancy test (women) are not required on Day -3 for later periods. 
3. On Day 1, Blood pressure (BP) and Heart rate (HR) will be collected at pre-dose (triplicate) and single assessments at 1, 2, 4, 6, 8, 12, 24, 48, and 72 h post-dose. 
4. On Day 1, 12-lead ECG will be collected at pre-dose (triplicate), and single assessments at 1, 2, 4, 6, 8, 12, 24, 48 and 72 h post-dose. 
5. Echocardiograms must be within 100 days of Day 1. 
6. Samples for Chemistry and Hematology:  Blood samples will be obtained after an 8-hour fast. 
7. Collect one troponin sample to be analyzed at local laboratory.  A second sample will be collected, frozen and stored on site for potential high sensitivity troponin analysis. 
8. 24-h Holter monitoring to be performed after confirming negative urine drug screen at screening, and must be within 30 days of Day 1.  Holter monitoring on other days only if 
needed. 
9. Plasma PK samples for bioanalysis for GSK2838232 will be collected pre-dose (within 15 minutes prior to dosing) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, and 
120 h post-dose.  Samples will be acidified with an equal volume of 50 mmol citrate acid buffer pH 4.0. 
10. An AE enquiry will be made at each visit, participants will be asked if they have experienced any neuropsychiatric adverse events, including psychosis or altered mental status. 
(see guidance for grading Altered Mental Status in Appendix 4). 
11. Participants may be discharged after all study procedures are completed.  Participants will be in house for PK blood samples on Day 3 (48 h), Day 4 (72 h), Day 5 (96 h) and 
Day 6 (120 h) of both study periods. 
 
 


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Schedule of Assessments for Part 2: Repeated Doses for 11 days: 
Measurement 
Screening 
(within 30 
days of Day 
1 - carried 
out over 
multiple days 
- except as 
noted in 
footnotes) 
 
Follow-
up  
 
Day 
–1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 
Day 
8 
Day 
9 
Day 
10 
Day 
11 
0 h 
Day 
12 
24 h 
Day 
13 
48 h 
Day 
14 
72 h 
Day 
15 
96 h 
Day 
16 
120 
h 
7-14 
days 
after 
last 
dose 
Admission to Unit 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/medication/ 
drug/alcohol history 
(Demographics) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full Physical 
Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Brief Physical 
Examination 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Height, Weight, BMI  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
12-lead ECG2 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
X 
 
 
 
 
X 
Echocardiogram3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug/alcohol/ /cotinine 
Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbsAg, HCV, HIV 
Testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hem/Chem tests4 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Urinalysis 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Serum FSH (as 
appropriate) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Troponin I5 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 


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Measurement 
Screening 
(within 30 
days of Day 
1 - carried 
out over 
multiple days 
- except as 
noted in 
footnotes) 
 
Follow-
up  
 
Day 
–1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 
Day 
8 
Day 
9 
Day 
10 
Day 
11 
0 h 
Day 
12 
24 h 
Day 
13 
48 h 
Day 
14 
72 h 
Day 
15 
96 h 
Day 
16 
120 
h 
7-14 
days 
after 
last 
dose 
24 h Holter Monitoring6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
(females) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Dosing of GSK2838232 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Plasma PK sampling7 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Event 
Assessment8 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Discharge from Unit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X9 
 
 
 
 
Out Patient Visit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
BMI = Body Mass Index; ECG = Electrocardiogram; FSH = Follicle Stimulating Hormone; HbsAg = Hepatitis B surface Antigen; HCV = Hepatitis C Virus; 
Hem/Chem = Hematology/Clinical Chemistry; HIV = Human Immunodeficiency Virus; IP = Investigational Product; PK = Pharmacokinetic(s). 
1. A single blood pressure (BP) and Heart rate (HR) assessment will be collected at screening and Day -1.  On Day 1 triplicate BP and HR will be collected at pre-dose and single 
assessments at 1, 4, 24, 48 and 72 h (Day 4) post-dose, Day 5, Day 6, Day 7, Day 8, Day 9, Day 10, Day 11 at pre-dose (triplicate), and single assessment at 1, 4, 24, 48 and 
72 h post-dose, and at follow-up. 
2. A single 12-Lead ECG will be collected at screening and Day -1.  On Day 1 triplicate 12-Lead ECGs will be collected at pre-dose, and then single 12-Lead ECGs at 1, 4 and 12 h 
post-dose.  Single 12-Lead ECGs will be collected on Days 2, 3, 5, 8.  On Day 11 triplicate 12-Lead ECGs will be collected pre-dose, and then single 12-Lead ECGs collected at 1, 
4, 12 and 24 h post-dose and at follow-up. 
3. Echocardiograms must be within 100 days of Day 1. 
4. Samples for Chemistry and Hematology: Blood samples will be obtained after an 8-hour fast. 
5. Collect one troponin sample to be analyzed at local laboratory.  A second sample will be collected and frozen for potential high sensitivity troponin analysis. 
6. 24-h Holter monitoring to be performed after confirming negative urine drug screen at screening, and must be within 30 days of Day 1.  Holter monitoring on other days only if 
needed. 


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7. Plasma PK samples for GSK2838232 will be collected as follows:  Day 1; pre-dose (within 15 minutes prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12 and 24 h post-dose 
(prior to Day 2 dose).  Days 3 to 10 pre-dose (within 15 minutes prior to dosing).  Day 11; pre-dose (within 15 minutes prior to dosing) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 
36, 48, 72, 96 and 120 h post-dose.  Samples will be acidified with an equal volume of 50 mmol citrate acid buffer pH 4.0. 
8. An AE enquiry will be made at each visit, participants will be asked if they have experienced any neuropsychiatric adverse events, including psychosis or altered mental status. 
(see guidance for grading Altered Mental Status in Appendix 4). 
9. Participants will be discharged after all study procedures are completed on the morning of Day 13 (after the 48 h post-final dose sample time point) with instructions to return 
fasted on the mornings of Day 14 for 72 h PK sample, Day 15 for 96 h PK sample, and Day 16 for 120 h PK sample 
 


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14.3 
Appendix 3: Assessment Windows 
14.3.1 
Definitions of Assessment Windows for Analyses 
Not applicable. 
 
 


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14.4 
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events 
14.4.1 
Study Phases 
Assessments and events will be classified according to the time of occurrence relative to 
study treatment. 
Treatment Phase 
Definition 
Pre-Treatment  
Date/Time < Study Treatment Start Date/Time 
On- Treatment 
Study Treatment Start Date/Time ≤  Date/Time ≤ Study Treatment Stop Date/Time 
Post- Treatment 
Date/Time > Study Treatment Stop Date/Time  
 
14.4.4.1 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. 
 
 
14.4.2 
Treatment Emergent Flag for Adverse Events 
Flag 
Definition 
Treatment 
Emergent 
• 
If AE onset date is on or after treatment start date & on or before treatment stop 
date. (plus washout or protocol-specified time limit (e.g. half-life of drug, certain 
number of days, etc.). 
• 
Study Treatment Start Date/Time ≤ AE Start Date/Time. 
• 
For studies with greater than one treatment period (e.g., crossover study), if AE 
onset is during one period and worsens during a later period it would be counted 
in both periods. For the initial period the logic would be as above. For the later 
period the logic would use the treatment dates associated with the later period: 
• 
Treatment Period Start Date ≤ AE Worsening Date. 
NOTES:  
• 
If the study treatment stop date is missing, then the AE will be considered to be On-Treatment. 
• 
Time of study treatment dosing and start/stop time of AEs should be considered, if collected. 
 
14.4.3 
Adverse Events Assignment to Treatment Period for Part 1  
Adverse events (AEs) will be assigned to a treatment period and corresponding treatment 
received in that treatment period after the imputations defined in RAP section 14.7.3 have 
been performed. 


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• Treatment Period 1: all AEs with start date/time at the time of or after IMP 
administration in Treatment Period 1 and before IMP administration in Treatment 
Period 2  
• Treatment Period 2: all AEs with start date/time at the time of or after IMP 
administration in Treatment Period 2 and before IMP administration in Treatment 
Period 3  
• Treatment Period 3: all AEs with start date/time at the time of or after IMP 
administration in Treatment Period 3  
Thus, AEs occurring during the 1st washout will be assigned to the treatment received in 
Treatment Period 1, AEs occurring during the 2th washout will be assigned to the 
treatment received in Treatment Period 2 and AEs occurring during follow-up will be 
assigned to the treatment received in Treatment Period 3. 
14.4.4 
Concomitant Medication Assignment to Treatment Period 
for Part 1 
Concomitant medications (CMs) will be assigned to a treatment period and 
corresponding treatment received in that treatment period after the imputations defined in 
RAP section 14.7.3 have been performed. 
• Treatment Period 1: all CMs with start date/time at the time of or after IMP 
administration in Treatment Period 1 and before IMP administration in Treatment 
Period 2  
• Treatment Period 2: all CMs with start date/time at the time of or after IMP 
administration in Treatment Period 2 and before IMP administration in Treatment 
Period 3  
• Treatment Period 3: all CMs with start date/time at the time of or after IMP 
administration in Treatment Period 3  
Thus, CMs occurring during the 1st washout will be assigned to the treatment received in 
Treatment Period 1, CMs occurring during the 2th washout will be assigned to the 
treatment received in Treatment Period 2  and CMs occurring during follow-up will be 
assigned to the treatment received in Treatment Period 3. 
 
 


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14.5 
Appendix 5: Data Display Standards & Handling 
Conventions 
14.5.1 
Reporting Process 
Software 
• The currently supported versions of SAS and WinNonlin software will be used. 
Analysis Datasets  
• Analysis datasets will be created according to AdaM IG Version 1.1. 
• For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented for conversion from SI to SDTM. 
• Define XML Version 2.0 
Generation of RTF Files 
• RTF files will be generated for Tables, Listings, and Figures, one RTF file per item. 
 
14.5.2 
Reporting Standards 
General 
• The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated: 
o 4.03 to 4.23: General Principles 
o 5.01 to 5.08: Principles Related to Data Listings 
o 6.01 to 6.11: Principles Related to Summary Tables 
o 7.01 to 7.13: Principles Related to Graphics  
• Do not include participant level listings in the main body of the GSK Clinical Study Report. All 
participant 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. 
• Numeric data will be reported at the precision collected on the eCRF. 
• The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of decimal places (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 participant’s listings.  
Unscheduled Visits 


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• 
Unscheduled visits will not be included in summary tables and/or figures. 
• 
All unscheduled visits will be included in listings. 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
• Refer to IDSL Statistical Principals 7.01 to 7.13 
• The same symbol and line type will be used across figures to represent a given treatment 
group. The placebo group will be displayed using symbol type=empty circle and line type= solid 
line and color=black. 
• When line plots are presented with treatment groups overlaid, the x-values will be offset 
(jittered) so the data are not plotted on top of each other. 
• X-axis variables of time and dose will be plotted as continuous numeric variables.. 
 
14.5.3 
Reporting Standards for Pharmacokinetic Data 
Pharmacokinetic Concentration Data 
PC Windows Non-
Linear (WNL) File 
PC WNL file (CSV format) for the non compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created according to 
Standards for the Transfer and Reporting of PK Data using HARP.  
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: C24, Cτ, Ctrough. 
Ro[AUC(0-τ)], R(Cmax), R(Cτ) 
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. 
 
 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Reporting of Pharmacokinetic Concentration Data 
Descriptive Summary 
Statistics 
Refer to IDSL Statistical Principle 6.06.1 
Assign zero to NQ values (Refer to GUI_51487 for further details) 


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Reporting of Pharmacokinetic Parameters 
Descriptive Summary 
Statistics (Loge 
Transformed) 
N, n, geometric mean, 95% CI of geometric mean, standard deviation 
(SD) of logged data and between and or within geometric coefficient of 
variation (CVb/w (%)) will be reported. 
[1] Geometric mean = exp(mean loge-transformed values) 
[2] CVb (%) = √ (exp(SD2) - 1) * 100 
(SD = SD of log transformed data)  
[3] CVw (%) = √ (exp(MSE) - 1) * 100  
(MSE = mean square error from mixed effect model of loge-transformed data). 
All Parameters  
N, n, mean, SD, median, minimum, maximum 
Summary Tables 
The following PK parameters will not be summarised: %AUCex 
Listings 
Additionally, include the first point, last point and number of points used 
in the determination of lambda_z for listings. 
Graphical Displays 
• Refer to IDSL Statistical Principals 7.01 to 7.13. 
• The same symbol and line type will be used across figures to represent a given treatment 
group. The placebo group will be displayed using symbol type=empty circle and line type= solid 
line and color=black. 
• When line plots are presented with treatment groups overlaid, the x-values will be offset 
(jittered) so the data are not plotted on top of each other. 
• X-axis variables of time and dose will be plotted as continuous numeric variables. 
 
 
 
 


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14.6 
Appendix 6: Derived and Transformed Data 
14.6.1 
General 
Multiple Measurements at One Time Point 
• 
Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented. 
• 
If there are two values within a time window (as per Section 14.3.1) 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 visits for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables. 
Study Day 
• 
Calculated as the number of days from First Dose Date: 
• 
Ref Date = Missing              → Study Day = Missing  
• 
Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date 
• 
Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1     
 
14.6.2 
Study Population 
Demographics 
Age 
• GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows: 
o Any participant with a missing day will have this imputed as day ‘15’. 
o Any participant with a missing date and month will have this imputed as ‘30th June’. 
o The age will be calculated by Data Management and mapped from ClinBase to SDTM 
dataset DM 
• Birth date will be presented in listings as ‘YYYY’. 
Body Mass Index (BMI) 
• Calculated as Weight (kg) / [Height (m)]2 
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. 
• Planned Treatment Duration is defined as 1 day for study part 1, and as 11 day for study part 2. 
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 


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Demographics 
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. 
14.6.3 
Efficacy 
Not applicable. 
14.6.4 
Safety 
ECG Parameters 
RR Interval 
• IF RR interval (msec) is not provided directly, then RR can be derived as : 
[1] If QTcB is machine read & QTcF is not provided, then : 
𝑅𝑅𝑅𝑅= ቈ൬𝑄𝑄𝑄𝑄
𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄൰
2
቉ ∗1000 
[2] If QTcF is machine read and QTcB is not provided, then:  
𝑅𝑅𝑅𝑅= ቈ൬𝑄𝑄𝑄𝑄
𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄൰
3
቉ ∗1000 
• 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 eCRF, corrected QT intervals by Bazett’s (QTcB) and 
Fredericia’s (QTcF) formulas will be calculated, in msec, depending on the availability of other 
measurements. 
• IF RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as :  
 
𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄= 
𝑄𝑄𝑄𝑄
ට𝑅𝑅𝑅𝑅
1000
 
 
𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄= 
𝑄𝑄𝑄𝑄
3ට𝑅𝑅𝑅𝑅
1000
 
• Also QTc interval will be categorized as follows: 
ECG Parameter 
Potential Clinical Importance Range (PCI)  
Units 
Absolute QTc Interval 
>450 to ≤480 
msec 
Absolute QTc Interval 
>480 to ≤500 
msec 
Absolute QTc Interval 
>500 
msec 
Increase from Baseline QTc 
≤30 
msec 
Increase from Baseline QTc 
>30 to ≤60 
msec 
Increase from Baseline QTc 
>60 
msec 


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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, will be imputed with the value of the number without the sign for the 
descriptive statistics and the calculation of changes from baseline, e.g., a value of <2.2 will be 
imputed as 2.2 for the calculations. There will be no imputation in the data listings; all values will 
be displayed as recorded in the database. 
 
14.6.5 
Pharmacokinetic 
Calculation of Pharmacokinetic Parameter Values Not Described in Section 9 (refer to GUI_51487 for 
pharmacokinetic analysis information) 
lambda_z  (terminal phase rate constant) 
• 
Slope of the line determined by linear regression of logarithmically transformed concentration v. time 
data 
%AUCex  (percentage of AUC(0-∞) obtained by extrapolation) 
• 
Calculated as 100 x [AUC(0-∞) – AUC(0-t)] / AUC(0-∞) 
 
14.6.6 
Population Pharmacokinetic (PopPK) 
Not applicable. 
14.6.7 
Pharmacodynamic 
Not applicable. 
 
 


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14.7 
Appendix 7: Reporting Standards for Missing Data 
14.7.1 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• Participant study completion (i.e. as specified in the protocol) was defined as 
participants who has received the study treatment per the protocol and who has 
completed all phases of the study including the follow-up visit. 
• The end of the study is defined as the last participant’s last visit. 
• Withdrawn participants will not 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. 
• Withdrawal visits will be summarised as withdrawal visits. 
 
14.7.2 
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 participant 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. 
 
14.7.3 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
Partial dates will be displayed as captured in participant listing displays. 
Adverse 
Events 
• The eCRF 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 : 
Treatment States and 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 (i.e. no year specified) will remain 


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Element 
Reporting Detail 
missing, with no imputation applied. Consequently, time to onset and duration of 
such events will be missing. 
Element 
Reporting Detail 
Concomitant 
Medications/ 
Medical 
History 
• Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention: 
o If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month 
o If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month. 
• The recorded partial date will be displayed in listings. 
 
 


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14.8 
Appendix 8: Values of Potential Clinical Importance 
14.8.1 
Laboratory Values 
Division of AIDS (DAIDS, Version 2.0, November 2014) AE grades 2, 3, and 4 of lab 
abnormalities will be listed by subject, period/treatment, visit, and actual date and time. 
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 
 
Hemoglobin  
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 
𝜇𝜇mol/L 
∆ from BL 
 
↑ 44.2 
Glucose 
mmol/L 
 
3 
9 
Magnesium 
mmol/L 
 
0.5 
1.23 
Phosphorus 
mmol/L 
 
0.8 
1.6 
Potassium 
mmol/L 
 
3 
5.5 
Sodium 
mmol/L 
 
130 
150 
Total CO2 
mmol/L 
 
18 
32 
 
Liver Function 
Test Analyte 
Units 
Category 
Potential Clinical Importance 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 
≥ 1.5xULN 
T. Bilirubin + ALT 
µmol/L 
High 
1.5xULN T. Bilirubin 
 
+ 
U/L 
≥ 2x ULN ALT 


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14.8.2 
ECG 
ECG Parameter 
Units 
Potential Clinical Importance 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 
 
14.8.3 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Potential Clinical Importance Range 
Lower (<x) 
Upper (>x) 
Systolic Blood Pressure 
mmHg 
< 85 
> 160 
Diastolic Blood Pressure 
mmHg 
< 45 
> 100 
Heart Rate 
bpm 
< 40 
> 110 
 
 
 
 


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14.9 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses 
14.9.1 
Population Pharmacokinetic (PopPK) Dataset Specification 
Not applicable. 
14.9.2 
Population Pharmacokinetic (PopPK) Methodology 
Not applicable. 
 
 


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14.10 
Appendix 10: Pharmacokinetic / Pharmacodynamic 
Analyses 
14.10.1 
Pharmacokinetic / Pharmacodynamic Dataset Specification 
Not applicable. 
14.10.2 
Pharmacokinetic / Pharmacodynamic Methodology 
Not applicable. 
 
 


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14.11 
Appendix 11: Abbreviations & Trade Marks 
14.11.1 
Abbreviations 
Abbreviation 
Description 
A&R 
Analysis and Reporting  
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AlkPhos 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANOVA 
Analysis of Variance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical, Therapeutical, Chemical 
AUC 
Area-under-the-curve 
AUC(0-∞) 
Area under the concentration-time curve extrapolated to infinity  
AUC(0-last) 
Area under the concentration-time curve from time zero to the time of the last 
quantifiable concentration  
AUC(0-t) 
Partial area under the concentration-time curve to time  
BMI 
Body Mass Index 
BP 
Blood Pressure 
C24 
Observed concentration 24 hours post-dose, determined directly from the 
concentration-time data. 
CDISC 
Clinical Data Interchange Standards Consortium 
Chem 
Chemistry 
CI 
Confidence Interval 
CL 
Clearance 
CM 
Concomitant Medication 
Cmax 
Maximum observed concentration, determined directly from the concentration-
time data. 
CPMS 
Clinical Pharmacology Modelling & Simulation 
CS 
Clinical Statistics 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
Cτ 
Observed concentration at time τ 
DLT 
Dose-limiting Toxicity 
DP 
Decimal Places 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Record Form 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GSK 
GlaxoSmithKline 
GUI 
Guidance 
HBsAG 
Hepatitis-B-Virus Surface Antigen 
HCV 
Hepatitis C virus 
Hem 
Hematology 
HIV 
Human Immunodeficiency Virus 


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Abbreviation 
Description 
IA 
Interim Analysis 
ICH 
International Conference on Harmonisation 
IDSL 
Integrated Data Standards Library 
IP 
Investigational Product 
Lambda_z 
Terminal Phase Rate Constant 
LOQ 
Limit of Quantification 
LS 
Least Squares 
MedDRA 
Medical dictionary for Regulatory Activities 
PCI 
Potential Clinical Importance  
PD 
Pharmacodynamic 
PDMP 
Protocol Deviation Management Plan 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PopPK 
Population Pharmacokinetic 
PP 
Per Protocol 
PT 
Preferred Term 
QCD 
Quantitative Clinical Development 
QD 
Once daily 
QTcB 
Bazett’s QT Interval Corrected for Heart Rate 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
RAP 
Reporting & Analysis Plan 
Ro 
Accumulation ratio 
RTV 
Ritonavir 
SAC 
Statistical Analysis Complete 
SAE 
Serious Adverse Event 
SD 
Standard deviation 
SDTM 
Study Data Tabulation Model 
SGOT 
Serum GlutamicOxaloacetic Transaminas 
SGPT 
Serum Glutamic-Pyruvic Transaminase 
SOC 
System Organ Class 
SOP 
Standard Operation Procedure 
SRT 
Safety Review Team 
t½ 
Apparent terminal half-life  
TA 
Therapeutic Area 
TFL 
Tables, Figures & Listings  
tlag 
Lag-time (time delay between drug administration and first observed) 
tlast 
Time of last quantifiable concentration, determined directly from the 
concentration-time data. 
tmax 
Time to reach Cmax, determined directly from the concentration-time data. 
 


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14.11.2 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
Not applicable 
 
WinNonlin 
 
 
SAS 
 
 
Phoenix 
 
 
 


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14.12 
Appendix 12: List of Data Displays 
14.12.1 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.24 
Not applicable 
Efficacy 
Not applicable 
Not applicable 
Safety 
3.1 to 3.46 
3.1 to 3.6 
Pharmacokinetic 
5.1 to 5.18 
5.1 to 5.23 
Section 
Listings 
ICH Listings 
1 to 67 
Other Listings 
68 to 74 
 
14.12.2 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated and if required an example mock-up 
displays provided in Appendix 13: Example Mock Shells for Data Displays. 
Section 
Figure 
Table 
Listing 
Study Population 
POP_Fn 
POP_Tn 
POP_Ln 
Efficacy 
EFF_Fn 
EFF_Tn 
EFF_Ln 
Safety 
SAFE_Fn 
SAFE_Tn 
SAFE_Ln 
Pharmacokinetic 
PK_Fn 
PK_Tn 
PK_Ln 
NOTES:  
• 
Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’ 
 
14.12.3 
Deliverable [Priority] 
Delivery [Priority] [1] 
Description 
SAC [1] 
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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14.12.4 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Participant Disposition 
1.1. 
Safety 
ES8 
Summary of Participant Status and Reason for Study 
Withdrawal – Part 1 
ICH E3, FDAAA, EudraCT 
Summarize by treatment /sequence 
and overall of each part 
SAC [1] 
1.2. 
Safety 
ES8 
Summary of Participant Status and Reason for Study 
Withdrawal – Part 2 
ICH E3, FDAAA, EudraCT 
Summarize by treatment /sequence 
and overall of each part 
SAC [1] 
1.3. 
Safety 
SD1 
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment – Part 1 
ICH E3 
Summarize by treatment /sequence 
and overall of each part 
SAC [1] 
1.4. 
Safety 
SD1 
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment – Part 2 
ICH E3 
Summarize by treatment /sequence 
and overall of each part 
SAC [1] 
1.5. 
Safety 
ES4 
Summary of Participant Disposition at Each Study Epoch – Part 
1 
ICH E3 
SAC [1] 
1.6. 
Safety 
ES4 
Summary of Participant Disposition at Each Study Epoch – Part 
2 
ICH E3 
SAC [1] 
1.7. 
Screened  
ES6 
Summary of Screening Status and Reasons for Screen Failure – 
Part 1 
Journal Requirements 
SAC [1] 
1.8. 
Screened 
ES6 
Summary of Screening Status and Reasons for Screen Failure – 
Part 2 
Journal Requirements 
 
 
SAC [1] 


 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Protocol Deviation 
1.9. 
Safety 
DV1 
Summary of Protocol Deviations – Part 1 
ICH E3 
 
SAC [1] 
1.10. 
Safety 
DV1 
Summary of Protocol Deviations – Part 2 
ICH E3 
 
SAC [1] 
Population Analysed 
1.11. 
Screened 
SP1 
Summary of Study Populations – Part 1 
By treatment and combined overall 
SAC [1] 
1.12. 
Screened 
SP1 
Summary of Study Populations – Part 2 
By treatment and combined overall 
SAC [1] 
Demographic and Baseline Characteristics 
1.13. 
Safety 
DM3 
Summary of Demographic Characteristics – Part 1 
ICH E3, FDAAA, EudraCT 
 
SAC [1] 
1.14. 
Safety 
DM1 
Summary of Demographic Characteristics – Part 2 
ICH E3, FDAAA, EudraCT 
 
SAC [1] 
1.15. 
Safety 
DM11 
Summary of Age Ranges – Part 1 
EudraCT 
 
SAC [1] 
1.16. 
Safety 
DM11 
Summary of Age Ranges – Part 2 
EudraCT 
 
SAC [1] 
1.17. 
Safety 
DM5 
Summary of Race and Racial Combinations – Part 1 
ICH E3, FDA, FDAAA, EudraCT 
 
SAC [1] 
1.18. 
Safety 
DM5 
Summary of Race and Racial Combinations – Part 2 
ICH E3, FDA, FDAAA, EudraCT 
 
SAC [1] 
Prior and Concomitant Medications 


 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
1.19. 
Safety 
MH4 
Summary of Medical Conditions – Part 1 
ICH E3.  
 
SAC [1] 
1.20. 
Safety 
MH4 
Summary of Medical Conditions – Part 2 
ICH E3 
 
SAC [1] 
1.21. 
Safety 
CM1 
Summary of Concomitant Medications – Part 1 
ICH E3.  
 
SAC [1] 
1.22. 
Safety 
CM1 
Summary of Concomitant Medications – Part 2 
ICH E3 
 
SAC [1] 
Exposure and Treatment Compliance 
1.23. 
Safety 
EX1 
Summary of Exposure to Study Treatment – Part 1 
ICH E3 
SAC [1] 
1.24. 
Safety 
EX1 
Summary of Exposure to Study Treatment – Part 2 
ICH E3 
SAC [1] 
 
 


 
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14.12.5 
Efficacy Tables 
Not applicable. 
 
14.12.6 
Efficacy Figures 
Not applicable. 
 
 
 
 


 
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14.12.7 
Safety Tables 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events (AEs) 
3.1.  
Safety 
AE5A 
Summary of All Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term – Part 1 
ICH E3 
Use AE5A/B (with a Total column 
across all grades/severities.) 
SAC [1] 
3.2.  
Safety 
AE5A 
Summary of All Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term – Part 2 
ICH E3 
Use AE5A/B (with a Total column 
across all grades/severities.) 
SAC [1] 
3.3.  
Safety 
AE3 
Summary of Common (>=5%) Adverse Events by Overall 
Frequency – Part 1 
ICH E3 
SAC [1] 
3.4.  
Safety 
AE3 
Summary of Common (>=5%) Adverse Events by Overall 
Frequency – Part 2 
ICH E3 
SAC [1] 
3.5.  
Safety 
AE5A 
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term and Maximum Intensity – Part 1 
ICH E3 
 
SAC [1] 
3.6.  
Safety 
AE5A 
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term and Maximum Intensity – Part 2 
ICH E3 
 
SAC [1] 
3.7.  
Safety 
AE15 
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Participant 
and Occurrences) – Part 1 
FDAAA, EudraCT 
SAC [1] 
3.8.  
Safety 
AE15 
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Participant 
and Occurrences) – Part 2 
FDAAA, EudraCT 
SAC [1] 


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.9.  
Safety 
AE3 
Summary of Common (>=5%) Grade 2-4 Adverse Events by 
Overall Frequency – Part 1 
ICH E3 
SAC [1] 
3.10. 
Safety 
AE3 
Summary of Common (>=5%) Grade 2-4 Adverse Events by 
Overall Frequency – Part 2 
ICH E3 
SAC [1] 
3.11. 
Safety 
AE3 
Summary of Common (>=5%) Drug-Related Grade 2-4 Adverse 
Events by Overall Frequency – Part 1 
ICH E3 
SAC [1] 
3.12. 
Safety 
AE3 
Summary of Common (>=5%) Drug-Related Grade 2-4 Adverse 
Events by Overall Frequency – Part 2 
ICH E3 
SAC [1] 
Serious and Other Significant Adverse Events 
3.13. 
Safety 
AE16 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences) – 
Part 1 
FDAAA, EudraCT 
 
SAC [1] 
3.14. 
Safety 
AE16 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences) – 
Part 2 
FDAAA, EudraCT 
SAC [1] 
3.15. 
Safety 
AE1 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term /by Overall Frequency 
– Part 1 
IDSL 
 
SAC [1] 
3.16. 
Safety 
AE1 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term /by Overall Frequency 
– Part 2 
IDSL 
SAC [1] 
Laboratory: Chemistry  


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.17. 
Safety 
LB17 
Summary of Worst Case Chemistry Results to Potential Clinical 
Importance (PCI) Criteria Post-Baseline Relative to Baseline – 
Part 1 
ICH E3 
SAC [1] 
3.18. 
Safety 
LB17 
Summary of Worst Case Chemistry Results to Potential Clinical 
Importance (PCI) Criteria Post-Baseline Relative to Baseline – 
Part 2 
ICH E3 
SAC [1] 
3.19. 
Safety 
LB1 
Summary of Chemistry Changes from Baseline – Part 1 
ICH E3 
Includes Baseline values.. 
SAC [1] 
3.20. 
Safety 
LB1 
Summary of Chemistry Changes from Baseline – Part 2 
ICH E3 
Includes Baseline values 
SAC [1] 
Laboratory: Hematology 
3.21. 
 Safety 
LB17 
Summary of Worst Case Hematology Results to Potential 
Clinical Importance (PCI) Criteria Post-Baseline Relative to 
Baseline – Part 1 
ICH E3 
SAC [1] 
3.22. 
 Safety 
LB17 
Summary of Worst Case Hematology Results to Potential 
Clinical Importance (PCI) Criteria Post-Baseline Relative to 
Baseline – Part 2 
ICH E3 
SAC [1] 
3.23. 
 Safety 
LB1 
Summary of Hematology Changes from Baseline – Part 1 
ICH E3 
Includes Baseline values. 
SAC [1] 
3.24. 
 Safety 
LB1 
Summary of Hematology Changes from Baseline – Part 2 
ICH E3 
Includes Baseline values. 
SAC [1] 
Laboratory: Urinalysis 
3.25. 
 Safety 
LB15 
Summary of Worst Case Urine Data Results Relative to Normal 
Range Criteria Post-Baseline Relative to Baseline – Part 1 
ICH E3 
SAC [1] 


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.26. 
 Safety 
LB15 
Summary of Worst Case Urine Data Results Relative to Normal 
Range Criteria Post-Baseline Relative to Baseline – Part 2 
ICH E3 
SAC [1] 
3.27. 
 Safety 
LB1 
Summary of Urine Changes from Baseline – Part 1 
ICH E3 
Includes Baseline values. 
SAC [1] 
3.28. 
 Safety 
LB1 
Summary of Urine Changes from Baseline– Part 2 
ICH E3 
Includes Baseline values. 
SAC [1] 
Laboratory: Abnormalities 
3.29. 
 Safety 
LB1 
Summary of Grade 1 or Higher Lab Abnormalities– Part 1 
Summary of Treatment Emergent 
Lab toxicity only. 
SAC [1] 
3.30. 
 Safety 
LB1 
Summary of Grade 1 or Higher Lab Abnormalities – Part 2 
Summary of Treatment Emergent 
Lab toxicity only. 
SAC [1] 
Laboratory: Hepatobiliary (Liver) 
3.31. 
 Safety 
LIVER1 
Summary of Liver Monitoring/Stopping Event Reporting – Part 1 
IDSL 
SAC [1] 
3.32. 
 Safety 
LIVER1 
Summary of Liver Monitoring/Stopping Event Reporting – Part 1 
IDSL 
SAC [1] 
3.33. 
 Safety 
LIVER10 
Summary of Subjects Meeting Emergent Hepatobiliary 
Laboratory Abnormalities Event Reporting – Part 1 
IDSL 
SAC [1] 
3.34. 
 Safety 
LIVER10 
Summary of Subjects Meeting Emergent Hepatobiliary 
Laboratory Abnormalities Event Reporting – Part 2 
IDSL 
SAC [1] 
ECG 
3.35. 
 Safety 
EG1 
Summary of ECG Findings –Part 1  
IDSL 
Use ECG findings categories (and 
change from baseline categories, if 
applicable). 
SAC [1] 


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.36. 
 Safety 
EG1 
Summary of ECG Findings –Part 2 
IDSL 
Use ECG findings categories (and 
change from baseline categories, if 
applicable). 
SAC [1] 
3.37. 
Safety 
EG2 
Summary of Change from Baseline in ECG Values–Part 1 
IDSL 
Includes Baseline values. 
SAC [1] 
3.38. 
Safety 
EG2 
Summary of Change from Baseline in ECG Values–Part 2 
IDSL 
Includes Baseline values. 
SAC [1] 
3.39. 
Safety 
EG1 
Summary of Category of QTc Data–Part 1 
IDSL 
SAC [1] 
3.40. 
Safety 
EG1 
Summary of Category of QTc Data–Part 2 
IDSL 
SAC [1] 
3.41. 
Safety 
EG1 
Summary of Category of QTc Change from Baseline–Part 1 
IDSL 
Includes Baseline values. 
SAC [1] 
3.42. 
Safety 
EG1 
Summary of Category of QTc Change from Baseline –Part 2 
IDSL 
Includes Baseline values. 
SAC [1] 
Vital Signs 
3.43. 
Safety 
VS1 
Summary of Vital Signs – Part 1 
ICH E3 
SAC [1] 
3.44. 
Safety 
VS1 
Summary of Vital Signs – Part 2 
ICH E3 
SAC [1] 
3.45. 
Safety 
VS1 
Summary of Change from Baseline in Vital Signs – Part 1 
ICH E3 
Includes Baseline values. 
SAC [1] 
3.46. 
Safety 
VS1 
Summary of Change from Baseline in Vital Signs – Part 2 
ICH E3 
Includes Baseline values. 
SAC [1] 
 


 
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14.12.8 
Safety Figures 
Safety : Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Laboratory Values 
3.1.  
Safety 
As EG9 
Plot of Selected Clinical Lab Tests Mean Change from Baseline 
by Treatment and Time – Part 1 
Only include scheduled visits and 
for selected lab test (BNP, Tnp1, 
ALT, AST, Bili)  
Plots will be presented with 
treatment groups overlaid 
SAC [1] 
3.2.  
Safety 
As EG9 
Plot of Selected Clinical Lab Tests Mean Change from Baseline 
by Treatment and Time – Part 2 
Only include scheduled visits and 
for selected lab test (BNP, Tnp1, 
ALT, AST, Bili)  
Plots will be presented with 
treatment groups overlaid 
SAC [1] 
ECG 
3.3.  
Safety 
EG9 
Plot of Mean Change from Baseline QTcB and QTcF Data by 
Treatment and Time – Part 1 
Plots will be presented with 
treatment groups overlaid 
SAC [1] 
3.4.  
Safety 
EG9 
Plot of Mean Change from Baseline QTcB and QTcF Data by 
Treatment and Time – Part 2 
Plots will be presented with 
treatment groups overlaid 
SAC [1] 
Vital Signs 
3.5.  
Safety 
As EG8 
 
Box Plot of Change from Baseline for Vital Signs by Treatment 
and Time – Part 1 
Plots will be presented with 
treatment groups overlaid 
SAC [1] 
3.6.  
Safety 
As EG8 
 
Box Plot of Change from Baseline for Vital Signs by Treatment 
and Time – Part 2 
Plots will be presented with 
treatment groups overlaid 
SAC [1] 
 


 
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14.12.9 
Pharmacokinetic Tables 
Pharmacokinetic: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Pharmacokinetic 
5.1.  
PK  
PK14 
Listing of Derived Plasma GSK2838232 PK Parameters – Part 
1A 
Sort by participant and treatment 
SAC [1] 
5.2.  
PK  
PK14 
Listing of Derived Plasma GSK2838232 PK Parameters – Part 
1B 
Sort by participant and treatment 
SAC [1] 
5.3.  
PK  
PK13 
Listing of Derived Plasma GSK2838232 PK Parameters – Part 2 
Sort by participant and treatment 
SAC [1] 
Bioavailability 
5.4.  
PK  
PK01 
Summary Statistics of Plasma GSK2838232 PK Concentration-
Time Data, Bioavailability 
 
SAC [1] 
5.5.  
PK  
PK04 
Summary Statistics of Derived Plasma GSK2838232  PK 
Parameters by Treatment, Bioavailability 
 
SAC [1] 
5.6.  
PK  
PK05 
Summary Statistics of Loge-transformed Derived Plasma 
GSK2838232  PK Parameters, Bioavailability 
 
SAC [1] 
5.7.  
PK  
Non-Standard1 
Summary of Result of Plasma GSK2838232  PK Parameter 
Treatment Comparisons for Relative Bioavailability 
 
SAC [1] 
5.8.  
PK  
PK15 
Listing of Individual Derived Plasma GSK2838232 PK 
Parameters Treatment Ratios 
PK Parameter: AUC(0-inf), and Cmax 
Ratio: Tablet/Capsule 
SAC [1] 
Food Effect 
5.9.  
PK  
PK01 
Summary Statistics of Plasma GSK2838232 PK Concentration-
Time Data, Food Effect 
 
SAC [1] 
5.10. 
PK  
PK04 
Summary Statistics of Derived Plasma GSK2838232  PK 
Parameters by Treatment, Food Effect 
 
SAC [1] 


 
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Pharmacokinetic: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
5.11. 
PK  
PK05 
Summary Statistics of Loge-transformed Derived Plasma 
GSK2838232  PK Parameters, Food Effect 
 
SAC [1] 
5.12. 
PK  
Non-Standard2 
Summary of Result of Plasma GSK2838232  PK Parameter 
Treatment Comparisons for Food Effect 
 
SAC [1] 
5.13. 
PK  
PK15 
Listing of Individual Derived Plasma GSK2838232 PK 
Parameters Treatment Ratios 
PK Parameter: AUC(0-inf), Cmax, and 
tmax 
Ratio: Fed/Fasted 
SAC [1] 
Steady State Assessments and Accumulation 
5.14. 
PK 
PK04 
Summary Statistics of Plasma GSK2838232 PK Parameters by 
Treatment and by Day – Part 2 
Day 1 & Day 11 
SAC [1] 
5.15. 
PK  
PK04 
Summary Statistics of Derived Plasma GSK2838232  PK 
Parameters by Treatment and by Day – Part 2 
Day 1 & Day 11 
SAC [1] 
5.16. 
PK 
PK05 
Summary of Loge-transformed Derived Plasma GSK2838232 PK 
Parameters by Treatment and by Day – Part 2 
Day 1 & Day 11 
SAC [1] 
5.17. 
PK  
Non-Standard3 
Summary of Results of GSK2838232 PK Parameter Treatment 
Comparisons -Accumulation Assessments- Part 2 
One for each treatment 
SAC [1] 
5.18. 
PK  
Non-Standard4 
Summary Results of Steady State GSK2838232 Concentrations 
Assessments- Part 2 
One for each treatment 
SAC [1] 
 
 
 


 
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14.12.10 
Pharmacokinetic Figures 
Pharmacokinetic : Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Biovailability 
5.1.  
PK  
PK16B 
Individual Plasma GSK2838232 PK Concentration-Time Plots 
for Relative Bioavailability  
Linear and Semi-Log Scale  
By participant, overlay all 
treatments for each participant 
SAC [1] 
5.2.  
PK  
PK17 
Mean Plasma GSK2838232 PK Concentration for Relative 
Bioavailability 
Linear and Semi-Log Scale  
Overlay all treatments 
SAC [1] 
5.3.  
PK  
PK18 
Median Plasma GSK2838232 PK Concentration for Relative 
Bioavailability 
Linear and Semi-Log Scale  
Overlay all treatments 
SAC [1] 
5.4.  
PK 
PK28 
Geometric Mean Treatment Ratio and 90% Confidence Interval 
of GSK2838232 PK Parameter for the Relative Bioavailability  
 
SAC [1] 
5.5.  
PK  
PK25 
Comparative Plot of Individual Plasma GSK2838232 PK 
Parameters for Relative Bioavailability by treatment 
 
SAC [1] 
Food Effect 
5.6.  
PK  
PK16A 
Individual Plasma GSK2838232 PK Concentration-Time Plots 
for Food Effect 
Linear and Semi-Log Scale  
By participant, overlay all 
treatments for each participant 
SAC [1] 
5.7.  
PK  
PK17 
Mean Plasma GSK2838232 PK Concentration for Food Effect 
Linear and Semi-Log Scale  
Overlay all treatments 
SAC [1] 
5.8.  
PK  
PK18 
Median Plasma GSK2838232 PK Concentration for Food Effect 
Linear and Semi-Log Scale  
Overlay all treatments 
SAC [1] 
5.9.  
PK 
PK28 
Geometric Mean Treatment Ratio and 90% Confidence Interval 
of GSK2838232 PK Parameter for Food Effect  
 
SAC [1] 


 
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Pharmacokinetic : Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
5.10. 
PK  
PK25 
Comparative Plot of Individual Plasma GSK2838232 PK 
Parameters for Food Effect by treatment 
 
SAC [1] 
Steady State Assessments  and Accumulation 
5.11. 
PK  
PK16a 
Individual Plasma GSK2838232 PK Concentration-Time Plots by 
Day – Part 2 
Linear and Semi-Log Scale  
By participant, overlay days for 
each participant 
SAC [1] 
5.12. 
PK  
PK17 
Mean Plasma GSK2838232 PK Concentration by Day – Part 2 
Linear and Semi-Log Scale  
SAC [1] 
5.13. 
PK  
PK18 
Median Plasma GSK2838232 PK Concentration by Day – Part 2 
Linear and Semi-Log Scale  
SAC [1] 
5.19. 
PK  
PK16a 
Individual Plasma GSK2838232  Predose Concentration-Time 
Plots for Steady State Assessment – Part 2 
Linear and Semi-Log Scale  
Overlay all individual profile with all 
days profiles 
SAC [1] 
5.20. 
PK  
PK17 
Mean Plasma GSK2838232  Concentration-Time Plots for 
Steady State Assessment – Part 2 
Linear and Semi-Log Scale  
SAC [1] 
5.21. 
PK  
PK18 
Median Plasma GSK2838232  Concentration-Time Plots for 
Steady State Assessment – Part 2 
Linear and Semi-Log Scale  
SAC [1] 
5.22. 
PK  
PK16a 
Individual and Box Plot of Plasma GSK2838232  PK Parameters 
by Day – Part 2 
Include all the PK parameters.  
SAC [1] 
5.23. 
PK  
PK25 
Comparative Plot of Plasma GSK2838232 PK Parameters for 
Accumulation 
Linear and Log Scale 
 
SAC [1] 
 
 
 


 
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14.12.11 
Pharmacokinetic Population (PopPK) Tables 
Not applicable. 
 
14.12.12 
Pharmacokinetic Population (PopPK) Figures 
Not applicable. 
 
14.12.13 
Pharmacodynamic Tables 
Not applicable. 
 
14.12.14 
Pharmacodynamic Figures 
Not applicable. 
 
14.12.15 
Pharmacokinetic / Pharmacodynamic Tables 
Not applicable. 
 
14.12.16 
Pharmacokinetic / Pharmacodynamic figures 
Not applicable. 
 
 
 


 
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14.12.17 
ICH Listings 
ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Participant Disposition 
1.  
Screened 
ES7 
Listing of Reasons for Screen Failure – Part 1 
Journal Guidelines 
SAC [1] 
2.  
Screened 
ES7 
Listing of Reasons for Screen Failure – Part 2 
Journal Guidelines 
SAC [1] 
3.  
Safety 
ES3 
Listing of Reasons for Study Withdrawal – Part 1 
ICH E3 
SAC [1] 
4.  
Safety 
ES2 
Listing of Reasons for Study Withdrawal – Part 2 
ICH E3 
SAC [1] 
5.  
Safety 
SD3 
Listing of Reasons for Study Treatment Discontinuation – Part 1 
ICH E3 
SAC [1] 
6.  
Safety 
SD2 
Listing of Reasons for Study Treatment Discontinuation – Part 2 
ICH E3 
SAC [1] 
7.  
Safety 
BL1 
Listing of Participants for Whom the Treatment Blind was Broken 
– Part 2 
ICH E3 
SAC [1] 
8.  
Safety 
CP_RA1x 
Listing of Planned and Actual Treatments – Part 1 
IDSL 
SAC [1] 
9.  
Safety 
CP_RA1p 
Listing of Planned and Actual Treatments – Part 2 
IDSL 
SAC [1] 
Protocol Deviations 
10.  
Safety 
DV2A 
Listing of Important Protocol Deviations – Part 1 
ICH E3 
Listing also includes analysis 
population exclusions. 
SAC [1] 
11.  
Safety 
DV2 
Listing of Important Protocol Deviations – Part 2 
ICH E3 
Listing also includes analysis 
population exclusions. 
SAC [1] 
12.  
Safety 
IE4 
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations – Part 1 
ICH E3 
SAC [1] 
13.  
Safety 
IE3 
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations – Part 2 
ICH E3 
SAC [1] 


 
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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Populations Analysed 
14.  
Safety 
SP3A 
Listing of Participants Excluded from Any Population – Part 1 
ICH E3 
SAC [1] 
15.  
Safety 
SP3 
Listing of Participants Excluded from Any Population – Part 2 
ICH E3 
SAC [1] 
Demographic and Baseline Characteristics 
16.  
Safety 
DM4 
Listing of Demographic Characteristics – Part 1 
ICH E3 
SAC [1] 
17.  
Safety 
DM2 
Listing of Demographic Characteristics – Part 2 
ICH E3 
SAC [1] 
18.  
Safety 
DM10 
Listing of Race – Part 1 
ICH E3 
SAC [1] 
19.  
Safety 
DM9 
Listing of Race – Part 2 
ICH E3 
SAC [1] 
Prior and Concomitant Medications 
20.  
Safety 
CP_CM4 
Listing of Concomitant Medications – Part 1 
IDSL 
SAC [1] 
21.  
Safety 
CP_CM3 
Listing of Concomitant Medications – Part 2 
IDSL 
SAC [1] 
Exposure and Treatment Compliance 
22.  
Safety 
EX4 
Listing of Exposure Data – Part 1 
ICH E3 
SAC [1] 
23.  
Safety 
EX3 
Listing of Exposure Data – Part 2 
ICH E3 
SAC [1] 
Adverse Events 
24.  
Safety 
CP_AE9 
Listing of All Adverse Events – Part 1 
ICH E3 
SAC [1] 
25.  
Safety 
CP_AE8 
Listing of All Adverse Events – Part 2 
ICH E3 
SAC [1] 
26.  
Safety 
AE7 
Listing of Participant Numbers for Individual Adverse Events – 
Part 1 
ICH E3 
SAC [1] 
27.  
Safety 
AE7 
Listing of Participant Numbers for Individual Adverse Events – 
Part 2 
ICH E3 
SAC [1] 
28.  
Safety 
AE2 
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text – Part 1 
IDSL 
SAC [1] 


 
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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
29.  
Safety 
AE2 
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text – Part 2 
IDSL 
SAC [1] 
Serious and Other Significant Adverse Events 
30.  
Safety 
CP_AE9a 
Listing of Fatal Serious Adverse Events – Part 1 
ICH E3 
SAC [1] 
31.  
Safety 
CP_AE8a 
Listing of Fatal Serious Adverse Events – Part 2 
ICH E3 
SAC [1] 
32.  
Safety 
CP_AE9a 
Listing of Non-Fatal Serious Adverse Events – Part 1 
ICH E3 
SAC [1] 
33.  
Safety 
CP_AE8a 
Listing of Non-Fatal Serious Adverse Events – Part 2 
ICH E3 
SAC [1] 
34.  
Safety 
AE14 
Listing of Reasons for Considering as a Serious Adverse Event 
ICH E3 
SAC [1] 
35.  
Safety 
CP_AE9a 
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment – Part 1 
ICH E3 
SAC [1] 
36.  
Safety 
CP_AE8a 
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment – Part 2 
ICH E3 
SAC [1] 
37.  
Safety 
CP_AE9a 
Listing of Grade 3 or 4 Adverse Events – Part 1 
Division of AIDS Table For Grading 
SAC [1] 
38.  
Safety 
CP_AE8a 
Listing of Grade 3 or 4 Adverse Events – Part 2 
Division of AIDS Table For Grading 
SAC [1] 
Hepatobiliary (Liver) 
39.  
Safety 
MH2 
Listing of Medical Conditions for Participants with Liver Stopping 
Events – Part 1 
IDSL 
SAC [1] 
40.  
Safety 
MH2 
Listing of Medical Conditions for Participants with Liver Stopping 
Events – Part 2 
IDSL 
SAC [1] 
41.  
Safety 
SU2 
Listing of Substance Use for Participants with Liver Stopping 
Events – Part 1 
IDSL 
SAC [1] 
42.  
Safety 
SU2 
Listing of Substance Use for Participants with Liver Stopping 
Events – Part 2 
IDSL 
SAC [1] 
All Laboratory 


 
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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
43.  
Safety 
LB13 
Listing of Reference Ranges for Clinical Laboratory Tests 
 
SAC [1] 
44.  
Safety 
LB6 
Listing of Hematology Data– Part 1 
If any laboratory test results are outside 
of the reference range, they will be 
flagged with high/low and/or toxicity 
grade in the listing 
SAC [1] 
45.  
Safety 
LB5 
Listing of Hematology Data– Part 2 
If any laboratory test results are outside 
of the reference range, they will be 
flagged with high/low and/or toxicity 
grade in the listing 
SAC [1] 
46.  
Safety 
LB6 
Listing of Clinical Chemistry Data– Part 1 
If any laboratory test results are outside 
of the reference range, they will be 
flagged with high/low and/or toxicity 
grade in the listing 
SAC [1] 
47.  
Safety 
LB5 
Listing of Clinical Chemistry Data– Part 2 
If any laboratory test results are outside 
of the reference range, they will be 
flagged with high/low and/or toxicity 
grade in the listing 
SAC [1] 
48.  
Safety 
LB6 
Listing of Urinalysis Data– Part 1 
If any laboratory test results are outside 
of the reference range, they will be 
flagged with high/low and/or toxicity 
grade in the listing 
SAC [1] 
49.  
Safety 
LB5 
Listing of Urinalysis Data– Part 2 
If any laboratory test results are outside 
of the reference range, they will be 
flagged with high/low and/or toxicity 
grade in the listing 
SAC [1] 


 
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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
50.  
Safety 
LB6 
Listing of All Laboratory Data for Participants with Any Value of 
Potential Clinical Importance– Part 1 
ICH E3 
May be split into separate listings by 
chemistry, hematology, etc. Display 
ALL labs for a participant who 
experienced a value of potential clinical 
importance. 
SAC [1] 
51.  
Safety 
LB5 
Listing of All Laboratory Data for Participants with Any Value of 
Potential Clinical Importance– Part 2 
ICH E3 
May be split into separate listings by 
chemistry, hematology, etc. Display 
ALL labs for a participant who 
experienced a value of potential clinical 
importance. 
SAC [1] 
52.  
Safety 
LB6 
Listing of Lab Results Identified as Adverse Events– Part 1 
Lab results identified as AEs. Only 
needed if there are a sufficient number 
of labs identified as AEs. 
SAC [1] 
53.  
Safety 
LB5 
Listing of Lab Results Identified as Adverse Events – Part 2 
Lab results identified as AEs. Only 
needed if there are a sufficient number 
of labs identified as AEs. 
SAC [1] 
54.  
Safety 
LB6 
Listing of Grade 2 or Higher Lab Abnormalities – Part 1 
 
SAC [1] 
55.  
Safety 
LB5 
Listing of Grade 2 or Higher Lab Abnormalities – Part 2 
 
SAC [1] 
56.  
Safety 
LB14 
Listing of Laboratory Data with Character Results – Part 1 
ICH E3 
SAC [1] 
57.  
Safety 
LB14 
Listing of Laboratory Data with Character Results – Part 2 
ICH E3 
SAC [1] 
58.  
Safety 
UR2B 
Listing of Urinalysis Data for Participants with Any Value of 
Potential Clinical Importance – Part 1 
ICH E3 
Display ALL data for a participant who 
experienced a value of potential clinical 
importance. 
SAC [1] 


 
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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
59.  
Safety 
UR2A 
Listing of Urinalysis Data for Participants with Any Value of 
Potential Clinical Importance – Part 2 
ICH E3 
Display ALL data for a participant who 
experienced a value of potential clinical 
importance. 
SAC [1] 
ECG and Holter 
60.  
Safety 
EG4 
Listing of All ECG Values for Participants with Any Value of 
Potential Clinical Importance – Part 1 
IDSL 
SAC [1] 
61.  
Safety 
EG3 
Listing of All ECG Values for Participants with Any Value of 
Potential Clinical Importance – Part 2 
IDSL 
SAC [1] 
62.  
Safety 
EG6 
Listing of All ECG Findings for Participants with an Abnormal 
ECG Finding – Part 1 
IDSL 
SAC [1] 
63.  
Safety 
EG5 
Listing of All ECG Findings for Participants with an Abnormal 
ECG Finding – Part 2 
IDSL 
SAC [1] 
64.  
Safety 
HM8 
Listing of Holter Monitoring – Part 1 
IDSL 
 
SAC [1] 
65.  
Safety 
HM8 
Listing of Holter Monitoring – Part 2 
IDSL 
 
SAC [1] 
Vital Signs 
66.  
Safety 
VS5 
Listing of All Vital Signs Data for Participants with Any Value of 
Potential Clinical Importance – Part 1 
IDSL 
SAC [1] 
67.  
Safety 
VS4 
Listing of All Vital Signs Data for Participants with Any Value of 
Potential Clinical Importance – Part 2 
IDSL 
SAC [1] 
 
 


 
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14.12.18 
Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Pharmacokinetic 
68.  
PK  
PK08 
Listing of Plasma GSK2838232 PK Concentration-Time Data  –
Part 1A 
Sort by participant, treatment, day, 
and time 
SAC [1] 
69.  
PK  
PK08 
Listing of Plasma GSK2838232 PK Concentration-Time Data  –
Part 1B 
Sort by participant, treatment, day, 
and time 
SAC [1] 
70.  
PK  
PK07 
Listing of Plasma GSK2838232 PK Concentration-Time Data  –
Part 2 
Sort by participant, treatment, day, 
and time 
SAC [1] 
PK Statistical Analysis 
71.  
PK 
SAS output of 
Table5.6 
SAS Output of Summary Results of GSK2838232 PK Parameter 
Treatment Comparisons for the Relative Bioavailability – Part 1A 
 
SAC [1] 
72.  
PK 
SAS output of 
Table 5.10 
SAS Output of Summary Results of GSK2838232 PK Parameter 
Treatment Comparisons for the Food Effect – Part 1B 
 
SAC [1] 
73.  
PK 
SAS output of 
Table 5.16 
SAS Output of Summary Results of Steady-State GSK2838232 
Concentrations Assessment – Part 2 
 
SAC [1] 
74.  
PK 
SAS output of 
Table 5.17 
SAS Output of Summary Results of GSK2838232 PK Parameter 
Treatment Comparisons – Accumulation Ratio – Part 2  
 
SAC [1] 
 
 
 


 
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14.13 
Appendix 13: Example Mock Shells for Data Displays 


 
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Example:    Non-Standard1 
 
 
 
 
 
 
 
 
 
 
                 Page 1 of n 
 
 


 
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Example:    Non-Standard2 
 
 
 
 
 
 
 
 
 
 
                 Page 1 of n 
 
 


 
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Example:    Non-Standard3 
 
 
 
 
 
 
 
 
 
                 Page 1 of n 
 
 
 


 
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Example:    Non-Standard4 
 
 
 
 
 
 
 
 
 
                 Page 1 of n 
 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 1 of 47 
STATISTICAL ANALYSIS PLAN ADDENDUM 
 
 
 
 
205820 
 
Reporting and Analysis Plan for: A Two Part Study to Assess i) the Relative Bioavailability and Food 
Effect of a Novel Tablet Formulation of Boosted-GSK2838232 Compared to Capsule and ii) the Safety 
and Pharmacokinetics of Repeated Once-Daily Doses of Non boosted GSK2838232 
 
 
 
 
 
Version:  Final 1.0 
Date: 16/Apr/2018 
 
 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 2 of 47 
REVISION HISTORY 
Version 
Version Date 
Author 
Summary of Changes Made 
Final 1.0 
See Footer 
 
New Document 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 3 of 47 
SIGNATURE PAGE - GLAXOSMITHKLINE RESEARCH & DEVELOPMENT 
LIMITED 
Declaration 
The undersigned has/have reviewed and agree to the statistical analyses and procedures of this clinical study as 
presented in this document. 
 
 
 
 
 
 
Date (DD Mmm YY) 
Principal Biostatistician (PCPS, GSK) 
 
 
 
 
 
 
 
 
Date (DD Mmm YY) 
Director, Clinical Pharmacology (CPMS, GSK) 
 
 
 
 
 
 
 
 
Date (DD Mmm YY) 
Principal Clinical Research Scientist (CPSSO, GSK) 
 
 
 
 
 
 
 
 
Date (DD Mmm YY) 
Sm Executive Medical Director (GSK) 
 
 
 
PPD
PPD
PPD
PPD


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 4 of 47 
 
 
 
 
 
 
 
Date (DD Mmm YY) 
Principal Programmer (PCPS, GSK) 
 
 
 
 
 
 
 
 
Date (DD Mmm YY) 
Principal Data Manager (CPSSO, GSK) 
 
 
 
 
 
 
 
 
Date (DD Mmm YY) 
Senior Director, Biostatistics (PCPS, GSK) 
 
 
 
 
 
 
 
 
Date (DD Mmm YY) 
Manager, Programming (PCPS, GSK) 
 
 
 
 
PPD
PPD
PPD
PPD


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 5 of 47 
SIGNATURE PAGE - PAREXEL 
Declaration 
The undersigned agree to the statistical analyses and procedures of this clinical study. 
If this document has been signed electronically, signature(s) and date(s) are present at the end of the document: 
Document prepared and approved by: 
 
 
 
 
 
 
 
 
Date (DD Mmm YY) 
Sr. Biostatistician 
 
 
 
 
 
 
 
Document prepared and approved by: 
 
 
 
 
 
 
   
 
Date (DD Mmm YY) 
QCD Senior Scientific  
 
 
PPD
PPD


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 6 of 47 
TABLE OF CONTENTS 
REVISION HISTORY .................................................................................................................... 2 
SIGNATURE PAGE - GLAXOSMITHKLINE RESEARCH & DEVELOPMENT LIMITED ... 3 
SIGNATURE PAGE - PAREXEL ................................................................................................. 5 
TABLE OF CONTENTS ................................................................................................................ 6 
LIST OF TABLES .......................................................................................................................... 7 
ABBREVIATION AND ACRONYM LIST .................................................................................. 8 
1. 
STATISTICAL ANALYSIS PLAN ADDENDUM.......................................................... 9 
2. 
OVERVIEW OF CHANGES REQUIRED ..................................................................... 10 
2.1 
Summary of Changes.......................................................................................... 10 
2.2 
Study objective and secondary end point ........................................................... 11 
2.3 
Study Design....................................................................................................... 11 
2.4 
Statistical Hypothesis/Statistical Analysis.......................................................... 11 
2.5 
Study Treatment and Sub-group Display Descriptors ........................................ 11 
2.6 
Concomitant Medications ................................................................................... 13 
2.7 
Treatment Compliance and Protocol Deviations ................................................ 13 
2.8 
Derived Pharmacokinetic Parameters ................................................................. 13 
2.9 
Statistical Analysis/Method ................................................................................ 15 
3. 
TABLES/LISTINGS/FIGURES ...................................................................................... 16 
3.1 
Final Tables, Listings and Figures ...................................................................... 16 
4. 
SHELLS ........................................................................................................................... 45 
5. 
REFERENCES ................................................................................................................ 47 
 
 
 
 
 
 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 7 of 47 
LIST OF TABLES 
Table 1 
Study Population Tables........................................................................................... 17 
Table 2 
Safety Tables ............................................................................................................ 19 
Table 3 
Safety Figures ........................................................................................................... 24 
Table 4 
Pharmacokinetic Tables ........................................................................................... 25 
Table 5 
Pharmacokinetic Figures .......................................................................................... 27 
Table 6  
ICH Listings ............................................................................................................. 30 
Table 7 
Non-ICH Lisitngs ..................................................................................................... 36 
Table 8 
Study Population Tables (Changes from RAP)........................................................ 37 
Table 9 
Safety Figures (Changes from RAP) ........................................................................ 38 
Table 10 
Pharmacokinetic Tables (Changes from RAP) ........................................................ 39 
Table 11 
Pharmacokinetic Figures (Changes from RAP) ....................................................... 40 
Table 12 
ICH Listing (Changes from RAP) ............................................................................ 43 
Table 13 
Non-ICH Listings (Change from RAP) ................................................................... 44 
 
 
 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 8 of 47 
ABBREVIATION AND ACRONYM LIST  
Abbreviation / Acronym 
Definition / Expansion 
AUC 
Area under the concentration-time curve 
AUC(0-inf)  
AUC from time zero extrapolated to infinity 
AUC(0-t)  
AUC from time zero to the last quantifiable concentration 
AUC(0-τ),ss 
AUC over the dosing interval at steady state 
BLQ 
Below the lower limit of quantification 
CI 
Confidence interval 
Clast 
Last quantifiable concentration at tlast 
CLR 
Renal clearance 
CL/F 
Apparent clearance following oral administration 
CL/F,ss 
Apparent clearance following oral administration at steady state 
CSP 
Clinical Study Protocol 
Cmax 
Maximum observed concentration 
Cmin 
Minimum observed concentration in the dosing interval 
Ctrough 
Concentration immediately prior to dosing 
CV 
Coefficient of variation 
PK 
Pharmacokinetic 
Rac 
Accumulation ratio 
RAP 
Report And Analysis Plan 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation  
SE 
Standard error of the mean 
t½ 
Apparent terminal elimination half-life  
t½,ss 
Apparent terminal elimination half-life at steady state 
tlast 
Time of last quantifiable concentration 
tmax 
Time corresponding to occurrence of Cmax 
λz 
Terminal elimination rate constant 
λz,ss 
Terminal elimination rate constant at steady state 
%AUCex 
Percentage of AUC(0-inf) obtained by extrapolation 
 
 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 9 of 47 
1. 
STATISTICAL ANALYSIS PLAN ADDENDUM 
The Statistical Analysis Plan (SAP) Addendum details the changes and/or additional analyses required that are 
not currently described in the final RAP Version 1.0 dated 07/Dec/2017.The SAP Addendum describes any 
deviations from the planned analyses, additional analyses and if applicable, new Tables, Listings and Figures 
(TLFs) that are to be produced.  
As Sponsor (GlaxoSmithKline Research & Development Limited) does not have any template available for RAP 
Addendum, PAREXEL Template of SAP Addendum is used to document the changes after database lock and finalization of 
the RAP. 
 
 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 10 of 47 
2. 
OVERVIEW OF CHANGES REQUIRED  
2.1 
Summary of Changes  
• 
Secondary end point is considered as pre-dose concentration on days 3 to 11 rather than pre-dose 
concentration on day 2 to 11. This is applicable to final RAP Sections 2.2, 2.4  and  9.2.5 
• 
PK parameter Ctrough is calculated for days 3 to 11 rather than for days 2 to 11.  This is 
applicable to final RAP Sections 9.1.1.2, and  9.2.1.2 
However Ctrough should not be considered as PK Parameter of the study and this should not be 
included in ADPP dataset and those values can only be used from ADPC dataset directly and use 
for Steady State Assessment only. No summary statistics will be provided for this PK parameter. 
• 
Part 2 treatments is changed as Treatment R = GSK2838232 500 mg tablet fed rather than 
D=GSK2838232 500 mg/r tablet fed and Treatment P=Placebo than Treatment E=Placebo. This 
is applicable to final RAP Section 2.3 
• 
Listing and summary of the protocol deviation should be presented for all Important Protocol 
Deviation rather than all Protocol Deviation. This is applicable to final RAP section 6.5. 
• 
For each of the PK parameters given in section of RAP, for the summary statistics calculation, 
geometric mean associated with 95% CI should be calculated for each treatment group; however 
in RAP geometric mean associated with 90% CI should be calculated for each treatment group 
for the summary statistics. This is applicable to RAP sections 9.1.1.2 and  9.2.1.2 
• 
In the statistical methodology, analysis for the steady state assessment should only be mentioned 
as predose concentrations from days 3 to 11, and no Ctrough or Ctau terminology will be 
considered for this analysis. 
There will be no changes to the structure/format of the tables, figures and listings based on this change. The 
details of these changes are provided from sections 2.2 to 2.9 below. Details of the changes in the Tables, 
Listings and Figures are mainly due to clarity purpose (added more clarity in title, and programming notes) as 
well as some Tables and Listings are clubbed for better presentation, and hence due to that number of the tables, 
listings and figures are changed.  


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 11 of 47 
2.2 
Study objective and secondary end point 
In the final SAP Section 2.2 in the secondary objective section of part 2 is stated that secondary endpoint is pre-
dose concentration on days 2 to 11. However, for the final analyses secondary endpoint is considered as pre-dose 
concentration on day 3 to 11.  
2.3 
Study Design  
In the final SAP Section 2.3  in treatment assignment section it is stated that Part 2 treatment section states as 
below:  
“Part 2 treatments: 
Treatment D = GSK2838232 500 mg (as 5 x 100 mg) tablet formulation, fed, normal fat (i.e., approximately 
30%) meal (reference). 
Treatment E = Placebo 
However this should be like this: 
“Part 2 treatments: 
Treatment R = GSK2838232 500 mg (as 5 x 100 mg) tablet formulation, fed, normal fat (i.e., approximately 
30%) meal. 
Treatment P = Placebo 
2.4 
Statistical Hypothesis/Statistical Analysis 
For Part 2 study state assessment in the RAP section 2.4 it is stated as below: 
Mean plasma GSK2838232 pre-dose values between Days 2 through 11 and Cτ of Day 11 will be plotted against 
time.  
However it should be as below: 
Mean plasma GSK2838232 pre-dose values between Days 3 through 11 and Cτ of Day 11 will be plotted against 
time.  
2.5 
Study Treatment and Sub-group Display Descriptors 
In the RAP Section 5.1 Part 2 treatment group descriptors are given as below: 
 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 12 of 47 
Treatment Group Descriptions – Part 2 
RandAll NG  
Data Displays for Reporting  
Code 
Description 
Description 
Order in 
TFL 
T3 
GSK2838232 500 mg (as 5 x 100 mg) 
tablet formulation, fed, normal fat (i.e., 
approximately 30%) meal (reference).  
GSK 500 mg/r tablet fed 
2 
P 
Placebo 
Placebo 
1 
However it should be as follows: 
 
 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 13 of 47 
 
Treatment Group Descriptions – Part 2 
RandAll NG  
Data Displays for Reporting  
Code 
Description 
Description 
Order in 
TFL 
T3 
GSK2838232 500 mg (as 5 x 100 mg) 
tablet formulation, fed, normal fat (i.e., 
approximately 30%) meal (reference).  
GSK 500 mg tablet fed 
2 
P 
Placebo 
Placebo 
1 
 
2.6 
Concomitant Medications 
As per RAP Section 6.4 it is stated that “in the summary of concomitant medications, the ingredients will be 
summarized by the base only, using CMBASECD and CMBASE”. However this is not followed. 
2.7 
Treatment Compliance and Protocol Deviations 
In RAP Section 6.5 it is stated below: 
“Information of each participant not received the correct treatment during each treatment period, the reason for 
not receiving the correct treatment, and any other protocol deviations will be summarized by treatment 
sequence/group and overall of each part, and listed by participant and period (treatment). In addition, a listing 
will be provided including dose administered along with dosing dates and time for the investigational product.  
However it should be as below: 
Information of each participant not received the correct treatment during each treatment period, the reason for 
not receiving the correct treatment, and any other important protocol deviations will be summarized by treatment 
and overall of each part if enough important protocol deviations occur, and listed by participant and period 
(treatment). In addition, a listing will be provided including dose administered along with dosing dates and time 
for the investigational product. 
2.8 
Derived Pharmacokinetic Parameters 
In final RAP section 9.1.1.2, details of derived pharmacokinetic parameter are given as follows: 
Parameter 
Parameter Description 
AUC(0-τ) 
Area under the plasma drug concentration-time curve from pre-dose to the end of the dosing 
interval (where τ = 24 h) (Day 1 and Day 11) 
AUC(0-∞) 
Area under the concentration-time curve extrapolated to infinity will be calculated as:  
AUC = AUC(0-last) + C(last) / lambda_z 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 14 of 47 
Parameter 
Parameter Description 
Cmax 
Maximum observed concentration, determined directly from the concentration-time data. 
(Day 1 and Day 11) 
Tmax 
Time of occurrence of Cmax, determined directly from the concentration-time data (Day 1 
and Day 11) 
Tlag 
Lag-time (time delay between drug administration and first observed concentration), 
determined directly from the concentration-time data (Day 1) 
Tlast 
Time of last quantifiable concentration, determined directly from the concentration-time data 
(Day 11) 
t½ 
Apparent terminal phase half-life, calculated as; t½ = ln2 / lambda_z (Day 11) 
Cτ 
Observed concentration at the end of the dosing interval, determined directly from the 
concentration-time data (where τ = 24 h) (Day 1 and Day 11) 
Ctrough 
Observed pre-dose concentrations on Days 3 to 11, determined directly from the 
concentration-time data 
NOTES: C24, Cτ and Ctrough will be extracted from the concentration data by Clinical Statistics group and merged with other calculated PK parameters 
provided by CPMS. 
 
All the derived parameters described above will be listed.  For each of these parameters, except tmax and tlag, 
the following summary statistics will be calculated for each treatment group:  n, arithmetic mean, standard 
deviation (SD), median, minimum, maximum, geometric mean with associated 90% CI, standard deviation of 
logarithmically transformed data, and the between-participant CV (%CVb) based on the geometric mean for the 
loge-transformed PK parameters. For tmax and tlag, N, n, median, maximum, minimum, arithmetic mean and 
standard deviation will be calculated. 
However this should be as below: 
Parameter 
Parameter Description 
AUC(0-τ) 
Area under the plasma drug concentration-time curve from pre-dose to the end of the dosing 
interval (where τ = 24 h) (Day 1 and Day 11) 
AUC(0-∞) 
Area under the concentration-time curve extrapolated to infinity will be calculated as:  
AUC = AUC(0-last) + C(last) / lambda_z 
Cmax 
Maximum observed concentration, determined directly from the concentration-time data. 
(Day 1 and Day 11) 
Tmax 
Time of occurrence of Cmax, determined directly from the concentration-time data (Day 1 
and Day 11) 
Tlag 
Lag-time (time delay between drug administration and first observed concentration), 
determined directly from the concentration-time data (Day 1) 
Tlast 
Time of last quantifiable concentration, determined directly from the concentration-time data 
(Day 11) 
t½ 
Apparent terminal phase half-life, calculated as; t½ = ln2 / lambda_z (Day 11) 
Cτ 
Observed concentration at the end of the dosing interval, determined directly from the 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 15 of 47 
Parameter 
Parameter Description 
concentration-time data (where τ = 24 h) (Day 1 and Day 11) 
NOTES: C24, and Cτ will be extracted from the concentration data by Clinical Statistics group and merged with other calculated PK parameters provided 
by CPMS. 
 
All the derived parameters described above will be listed.  For each of these parameters, except tmax and tlag, 
the following summary statistics will be calculated for each treatment group: N, n, arithmetic mean, standard 
deviation (SD), median, minimum, maximum, geometric mean with associated 95% CI, standard deviation of 
logarithmically transformed data, and the between-participant CV (%CVb) based on the geometric mean for the 
loge-transformed PK parameters. For tmax and tlag, N, n, median, maximum, minimum, arithmetic mean and 
standard deviation will be calculated. 
2.9 
Statistical Analysis/Method 
Part 2 
Parameter 
Parameter Description 
Ctrough 
Observed pre-dose concentrations on Days 3 to 11, determined directly from the 
concentration-time data 
Ro[AUC(0-
τ)] 
Accumulation ratio based on AUC(0-τ), determined by; Day 11 AUC(0-τ) / Day 1 AUC(0-
τ)  
R(Cmax) 
Accumulation ratio based on Cmax, determined by; Day 11 Cmax / Day 1 Cmax 
R(Cτ) 
Accumulation ratio based on Cτ, determined by; Day 11 Cτ / Day 1 Cτ 
NOTES: 
• 
Additional parameters may be included as required. 
• 
Cτ, and Ctrough will be extracted from the concentration data by Clinical Statistics group and merged with other calculated PK parameters provided 
by CPMS. 
 
All the derived parameters described above will be listed.  For each of these parameters, except tmax and tlag, 
the following summary statistics will be calculated for each treatment group:   n, arithmetic mean, standard 
deviation (SD), median, minimum, maximum, geometric mean with associated 90% CI, standard deviation of 
logarithmically transformed data, and the between-participant CV (%CVb) based on the geometric mean for the 
loge-transformed PK parameters. For tmax and tlag, N, n,median, maximum, minimum, arithmetic mean and 
standard deviation will be calculated. 
However is should be as follows: 
Part 2 
Parameter 
Parameter Description 
Ro[AUC(0-τ)] 
Accumulation ratio based on AUC(0-τ), determined by; Day 11 AUC(0-τ) / Day 1 AUC(0-τ)  


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 16 of 47 
Parameter 
Parameter Description 
R(Cmax) 
Accumulation ratio based on Cmax, determined by; Day 11 Cmax / Day 1 Cmax 
R(Cτ) 
Accumulation ratio based on Cτ, determined by; Day 11 Cτ / Day 1 Cτ 
NOTES: 
• 
Additional parameters may be included as required. 
• 
Cτ will be extracted from the concentration data by Clinical Statistics group and merged with other calculated PK parameters 
provided by CPMS. 
 
All the derived parameters described above will be listed.  For each of these parameters, except tmax and tlag, 
the following summary statistics will be calculated for each treatment group:  N, n, arithmetic mean, standard 
deviation (SD), median, minimum, maximum, geometric mean with associated 95% CI, standard deviation of 
logarithmically transformed data, and the between-participant CV (%CVb) based on the geometric mean for the 
loge-transformed PK parameters. For tmax and tlag, N, n,median, maximum, minimum, arithmetic mean and 
standard deviation will be calculated. 
As per final RAP Section 9.2.5, statistical methodology section of Part 2 Steady State Assessment, end point or 
variable is given as GSK2838232 pre-dose values between Days 2 through 11, however it should be 
GSK2838232 pre-dose values between Days 3 through 11. 
3. 
TABLES/LISTINGS/FIGURES 
3.1  Final Tables, Listings and Figures 
 
Final Table, Listings and Figures that are used for the Final SAC deliverables are shown in tables 1 to 7 for  
Study Population Tables, Safety Tables, Safety Figures, Pharmacokinetic Tables, Pharmacokinetic Figures, ICH 
Listings and Non-ICH Listings respectively. The last column “Any Change from the RAP” specifies whether 
there is any change from RAP for respective Table, Listing or Figure. 
Overview of changes from the RAP in final Tables, Listings and Figures are given in tables 8 to 14 for Study 
Population Tables, Safety Figures, Pharmacokinetic Tables, Pharmacokinetic Figures, ICH Listings and Non-
ICH Listings respectively. 
Tables 8 to 14 contain only the Tables, Listings and Figures which has any changes from the RAP. Column apart 
from “Changes from RAP” contains the details from the final RAP. 
 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 17 of 47 
 
Table 1  
Study Population Tables 
 
No 
Population  IDSL 
Shell/TST 
ID 
/Example 
shell 
Title 
Programming Note  
Any 
Changes  
in 
existing 
RAP 
1.1 
Safety 
ES8A 
Summary of Participant 
Status and Reason for Study 
Withdrawal – Part 1 
ICH E3, FDAAA, 
EudraCT 
Summarize by treatment 
/sequence and overall of 
each part 
No 
1.2 
Safety 
ES8 
Summary of Participant 
Status and Reason for Study 
Withdrawal – Part 2 
ICH E3, FDAAA, 
EudraCT 
Summarize by treatment 
/sequence and overall of 
each part 
No 
1.3 
Safety 
SD1 
Summary of Treatment 
Status and Reasons for 
Discontinuation of Study 
Treatment – Part 1 
ICH E3 
Summarize by treatment 
/sequence and overall of 
each part 
No 
1.4 
Safety 
SD1 
Summary of Treatment 
Status and Reasons for 
Discontinuation of Study 
Treatment – Part 2 
ICH E3 
Summarize by treatment 
/sequence and overall of 
each part 
No 
1.5 
Safety 
ES4 
Summary of Participant 
Disposition at Each Study 
Epoch – Part 1 
ICH E3 
No 
1.6 
Safety 
ES4 
Summary of Participant 
Disposition at Each Study 
Epoch – Part 2 
ICH E3 
No 
1.7 
Screened  
ES6 
Summary of Screening 
Status and Reasons for 
Screen Failure – Part 1 
Journal Requirements 
No 
1.8 
Screened 
ES6 
Summary of Screening 
Status and Reasons for 
Screen Failure – Part 2 
Journal Requirements 
 
 
No 
1.9 
Safety 
DV1 
Summary of Important 
Protocol Deviations – Part 1 
ICH E3.  
If important protocol 
deviation events are less 
than 15, please produce 
the summary with 
wording”not enough 
Yes 


PAREXEL International 
Statistical Analysis Plan Addendum 
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Development Limited 
 
Final 1.0 
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16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
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Page 18 of 47 
important protocol 
deviation to warren a 
summary”. 
1.10 
Safety 
DV1 
Summary of  Important 
Protocol Deviations – Part 2 
ICH E3. If important 
protocol deviation 
events are less than 15, 
please produce the 
summary with 
wording”not enough 
important protocol 
deviation to warren a 
summary”. 
Yes 
1.11 
Screened 
SP1 
Summary of Study 
Populations – Part 1 
By treatment and 
combined overall 
No 
1.12 
Screened 
SP1 
Summary of Study 
Populations – Part 2 
By treatment and 
combined overall 
No 
1.13 
Safety 
DM3 
Summary of Demographic 
Characteristics – Part 1 
ICH E3, FDAAA, 
EudraCT 
 
No 
1.14 
Safety 
DM1 
Summary of Demographic 
Characteristics – Part 2 
ICH E3, FDAAA, 
EudraCT 
 
No 
1.15 
Safety 
DM11 
Summary of Age Ranges – 
Part 1 
EudraCT 
 
No 
1.16 
Safety 
DM11 
Summary of Age Ranges – 
Part 2 
EudraCT 
 
No 
1.17 
Safety 
DM5 
Summary of Race and 
Racial Combinations – Part 
1 
ICH E3, FDA, FDAAA, 
EudraCT 
 
No 
1.18 
Safety 
DM5 
Summary of Race and 
Racial Combinations – Part 
2 
ICH E3, FDA, FDAAA, 
EudraCT 
 
No 
1.19 
Safety 
MH4 
Summary of Medical 
Conditions – Part 1 
ICH E3  
 
No 
1.20 
Safety 
MH4 
Summary of Medical 
Conditions – Part 2 
ICH E3 
 
No 
1.21 
Safety 
CM8 
Summary of Concomitant 
Medications – Part 1 
ICH E3  
 
No 
1.22 
Safety 
CM8 
Summary of Concomitant 
Medications – Part 2 
ICH E3 
 
No 
1.23 
Safety 
EX1 
Summary of Exposure to 
Study Treatment – Part 1 
ICH E3 
No 
1.24 
Safety 
EX1 
Summary of Exposure to 
Study Treatment – Part 2 
ICH E3 
No 


PAREXEL International 
Statistical Analysis Plan Addendum 
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205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 19 of 47 
 
 
Table 2  
Safety Tables 
 
No 
Population  IDSL 
Shell/TST 
ID 
/Example 
shell 
Title 
Programming Note  
Any 
Changes in 
existing RAP 
3.1 
Safety 
AE5A 
Summary of All Adverse 
Events by Maximum 
Intensity by System Organ 
Class and Preferred Term – 
Part 1 
ICH E3 
Use AE5A/B (with a 
Total column across all 
grades/severities.) 
No 
3.2 
Safety 
AE5A 
Summary of All Adverse 
Events by Maximum 
Intensity by System Organ 
Class and Preferred Term – 
Part 2 
ICH E3 
Use AE5A/B (with a 
Total column across all 
grades/severities.) 
No 
3.3 
Safety 
AE3 
Summary of Common 
(>=5%) Adverse Events by 
Overall Frequency – Part 1 
ICH E3 
No 
3.4 
Safety 
AE3 
Summary of Common 
(>=5%) Adverse Events by 
Overall Frequency – Part 2 
ICH E3 
No 
3.5 
Safety 
AE5A 
Summary of All Drug-
Related Adverse Events by 
System Organ Class and 
Preferred Term and 
Maximum Intensity – Part 1 
ICH E3 
 
No 
3.6 
Safety 
AE5A 
Summary of All Drug-
Related Adverse Events by 
System Organ Class and 
Preferred Term and 
Maximum Intensity – Part 2 
ICH E3 
 
No 
3.7 
Safety 
AE15 
Summary of Common 
(>=5%) Non-serious 
Adverse Events by System 
Organ Class and Preferred 
Term (Number of 
Participant and 
Occurrences) – Part 1 
FDAAA, EudraCT 
No 
3.8 
Safety 
AE15 
Summary of Common 
(>=5%) Non-serious 
Adverse Events by System 
Organ Class and Preferred 
Term (Number of 
Participant and 
FDAAA, EudraCT 
No 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 20 of 47 
Occurrences) – Part 2 
3.9 
Safety 
AE3 
Summary of Common 
(>=5%) Grade 2-4 Adverse 
Events by Overall 
Frequency – Part 1 
ICH E3 
No 
3.10 
Safety 
AE3 
Summary of Common 
(>=5%) Grade 2-4 Adverse 
Events by Overall 
Frequency – Part 2 
ICH E3 
No 
3.11 
Safety 
AE3 
Summary of Common 
(>=5%) Drug-Related Grade 
2-4 Adverse Events by 
Overall Frequency – Part 1 
ICH E3 
No 
3.12 
Safety 
AE3 
Summary of Common 
(>=5%) Drug-Related Grade 
2-4 Adverse Events by 
Overall Frequency – Part 2 
ICH E3 
No 
3.13 
Safety 
AE16 
Summary of Serious 
Adverse Events by System 
Organ Class and Preferred 
Term (Number of 
Participants and 
Occurrences) – Part 1 
FDAAA, EudraCT 
 
No 
3.14 
Safety 
AE16 
Summary of Serious 
Adverse Events by System 
Organ Class and Preferred 
Term (Number of 
Participants and 
Occurrences) – Part 2 
FDAAA, EudraCT 
No 
3.15 
Safety 
AE1 
Summary of Adverse 
Events Leading to 
Permanent Discontinuation 
of Study Treatment or 
Withdrawal from Study by 
System Organ Class and 
Preferred Term /by Overall 
Frequency – Part 1 
IDSL 
 
No 
3.16 
Safety 
AE1 
Summary of Adverse 
Events Leading to 
Permanent Discontinuation 
of Study Treatment or 
Withdrawal from Study by 
System Organ Class and 
Preferred Term /by Overall 
Frequency – Part 2 
IDSL 
No 
3.17 
Safety 
LB17 
Summary of Worst Case 
Chemistry Results to 
Potential Clinical 
ICH E3 
No 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 21 of 47 
Importance (PCI) Criteria 
Post-Baseline Relative to 
Baseline – Part 1 
3.18 
Safety 
LB17 
Summary of Worst Case 
Chemistry Results to 
Potential Clinical 
Importance (PCI) Criteria 
Post-Baseline Relative to 
Baseline – Part 2 
ICH E3 
No 
3.19 
Safety 
LB1 
Summary of Chemistry 
Changes from Baseline – 
Part 1 
ICH E3 
Includes Baseline 
values. 
No 
3.20 
Safety 
LB1 
Summary of Chemistry 
Changes from Baseline – 
Part 2 
ICH E3 
Includes Baseline 
values. 
No 
3.21 
 Safety 
LB17 
Summary of Worst Case 
Hematology Results to 
Potential Clinical 
Importance (PCI) Criteria 
Post-Baseline Relative to 
Baseline – Part 1 
ICH E3 
No 
3.22 
 Safety 
LB17 
Summary of Worst Case 
Hematology Results to 
Potential Clinical 
Importance (PCI) Criteria 
Post-Baseline Relative to 
Baseline – Part 2 
ICH E3 
No 
3.23 
 Safety 
LB1 
Summary of Hematology 
Changes from Baseline – 
Part 1 
ICH E3 
Includes Baseline 
values. 
No 
3.24 
 Safety 
LB1 
Summary of Hematology 
Changes from Baseline – 
Part 2 
ICH E3 
Includes Baseline 
values. 
No 
3.25 
 Safety 
LB15 
Summary of Worst Case 
Urine Data Results Relative 
to Normal Range Criteria 
Post-Baseline Relative to 
Baseline – Part 1 
ICH E3 
No 
3.26 
 Safety 
LB15 
Summary of Worst Case 
Urine Data Results Relative 
to Normal Range Criteria 
Post-Baseline Relative to 
Baseline – Part 2 
ICH E3 
No 
3.27 
 Safety 
LB1 
Summary of Urine Changes 
from Baseline – Part 1 
ICH E3 
Includes Baseline 
values. 
No 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 22 of 47 
3.28 
 Safety 
LB1 
Summary of Urine Changes 
from Baseline– Part 2 
ICH E3 
Includes Baseline 
values. 
No 
3.29 
 Safety 
LB1 
Summary of Grade 1 or 
Higher Lab Abnormalities– 
Part 1 
Summary of Treatment 
Emergent Lab toxicity 
only. 
No 
3.30 
 Safety 
LB1 
Summary of Grade 1 or 
Higher Lab Abnormalities – 
Part 2 
Summary of Treatment 
Emergent Lab toxicity 
only. 
No 
3.31 
 Safety 
LIVER1 
Summary of Liver 
Monitoring/Stopping Event 
Reporting – Part 1 
IDSL 
No 
3.32 
 Safety 
LIVER1 
Summary of Liver 
Monitoring/Stopping Event 
Reporting – Part 1 
IDSL 
No 
3.33 
 Safety 
LIVER10 
Summary of Subjects 
Meeting Emergent 
Hepatobiliary Laboratory 
Abnormalities Event 
Reporting – Part 1 
IDSL 
No 
3.34 
 Safety 
LIVER10 
Summary of Subjects 
Meeting Emergent 
Hepatobiliary Laboratory 
Abnormalities Event 
Reporting – Part 2 
IDSL 
No 
3.35 
 Safety 
EG1 
Summary of ECG Findings 
–Part 1  
IDSL 
Use ECG findings 
categories (and change 
from baseline 
categories, if 
applicable). 
No 
3.36 
 Safety 
EG1 
Summary of ECG Findings 
–Part 2 
IDSL 
Use ECG findings 
categories (and change 
from baseline 
categories, if 
applicable). 
No 
3.37 
Safety 
EG2 
Summary of Change from 
Baseline in ECG Values–
Part 1 
IDSL 
Includes Baseline 
values. 
No 
3.38 
Safety 
EG2 
Summary of Change from 
Baseline in ECG Values–
Part 2 
IDSL 
Includes Baseline 
values. 
No 
3.39 
Safety 
EG1 
Summary of Category of 
QTc Data–Part 1 
IDSL 
No 
3.40 
Safety 
EG1 
Summary of Category of 
IDSL 
No 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 23 of 47 
QTc Data–Part 2 
3.41 
Safety 
EG1 
Summary of Category of 
QTc Change from Baseline–
Part 1 
IDSL 
Includes Baseline 
values. 
No 
3.42 
Safety 
EG1 
Summary of Category of 
QTc Change from Baseline 
–Part 2 
IDSL 
Includes Baseline 
values. 
No 
3.43 
Safety 
VS1 
Summary of Vital Signs – 
Part 1 
ICH E3 
No 
3.44 
Safety 
VS1 
Summary of Vital Signs – 
Part 2 
ICH E3 
No 
3.45 
Safety 
VS1 
Summary of Change from 
Baseline in Vital Signs – 
Part 1 
ICH E3 
Includes Baseline 
values. 
No 
3.46 
Safety 
VS1 
Summary of Change from 
Baseline in Vital Signs – 
Part 2 
ICH E3 
Includes Baseline 
values. 
No 
 
 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 24 of 47 
Table 3  
 Safety Figures 
 
No 
Population  IDSL 
Shell/TST 
ID 
/Example 
shell 
Title 
Programming Note  
Any 
Changes 
in 
existing 
RAP 
3.1 
Safety 
As EG9 
Plot of Selected Clinical 
Lab Tests Mean (95% CI) 
Change from Baseline by 
Treatment and Time – Part 
1 
Only include scheduled visits 
and for selected lab test 
(BNP, Tnp1, ALT, AST, 
Bili)  
Plots will be presented with 
treatment groups overlaid 
Yes 
3.2 
Safety 
As EG9 
Plot of Selected Clinical 
Lab Tests Mean (95% CI) 
Change from Baseline by 
Treatment and Time – Part 
2 
Only include scheduled visits 
and for selected lab test 
(BNP, Tnp1, ALT, AST, 
Bili)  
Plots will be presented with 
treatment groups overlaid 
Yes 
3.3 
Safety 
EG9 
Plot of Mean (95% CI) 
Change from Baseline 
QTcB and QTcF Data by 
Treatment and Time – Part 
1 
Plots will be presented with 
treatment groups overlaid 
Yes 
3.4 
Safety 
EG9 
Plot of Mean (95% CI) 
Change from Baseline 
QTcB and QTcF Data by 
Treatment and Time – Part 
2 
Plots will be presented with 
treatment groups overlaid 
Yes 
3.5 
Safety 
As EG8 
 
Box Plot of Change from 
Baseline for Vital Signs by 
Treatment and Time – Part 
1 
Plots will be presented with 
treatment groups overlaid 
No 
3.6 
Safety 
As EG8 
 
Box Plot of Change from 
Baseline for Vital Signs by 
Treatment and Time – Part 
2 
Plots will be presented with 
treatment groups overlaid 
No 
 
 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 25 of 47 
Table 4  
Pharmacokinetic Tables 
 
No 
Population  IDSL 
Shell/TST ID 
/Example 
shell 
Title 
Programming Note  
Any 
Changes in 
existing 
RAP 
5.1 
PK  
PK14 
Listing of Derived Plasma 
GSK2838232 PK 
Parameters – Part 1 
Sort by participant 
and treatment 
Yes 
5.2 
PK  
PK13 
Listing of Derived Plasma 
GSK2838232 PK 
Parameters – Part 2 
Sort by participant 
and treatment 
No 
5.3 
PK  
PK01 
Summary Statistics of 
Plasma GSK2838232 PK 
Concentration-Time Data, 
Bioavailability 
 
No 
5.4 
PK  
PK04 
Summary Statistics of 
Derived Plasma 
GSK2838232  PK 
Parameters by Treatment, 
Bioavailability 
 
No 
5.5 
PK  
PK05 
Summary Statistics of 
Loge-transformed Derived 
Plasma GSK2838232  PK 
Parameters, Bioavailability 
 
No 
5.6 
PK  
Non-Standard1 
Summary of Result of 
Plasma GSK2838232  PK 
Parameter Treatment 
Comparisons for Relative 
Bioavailability 
PK Parameter: 
AUC(0-inf), and 
Cmax 
Ratio: Tablet/Capsule 
No 
5.7 
PK  
PK15 
Listing of Individual 
Derived Plasma 
GSK2838232 PK 
Parameters Treatment 
Ratios 
 
No 
5.8 
PK  
PK01 
Summary Statistics of 
Plasma GSK2838232 PK 
Concentration-Time Data, 
Food Effect 
 
No 
5.9 
PK  
PK04 
Summary Statistics of 
Derived Plasma 
GSK2838232  PK 
Parameters by Treatment, 
Food Effect 
 
No 
5.10 
PK  
PK05 
Summary Statistics of 
Loge-transformed Derived 
Plasma GSK2838232  PK 
 
No 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 26 of 47 
Parameters, Food Effect 
5.11 
PK  
Non-Standard2 
Summary of Result of 
Plasma GSK2838232  PK 
Parameter Treatment 
Comparisons for Food 
Effect 
 
No 
5.12 
PK  
Non-Standard 
6 
Summary of Result of 
Plasma GSK2838232  PK 
Parameter Treatment 
Comparisons for Food 
Effect (Non-parametric) 
PK Parameter Tmax 
Yes 
5.13 
PK  
PK15 
Listing of Individual 
Derived Plasma 
GSK2838232 PK 
Parameters Treatment 
Ratios 
PK Parameter: 
AUC(0-inf), Cmax, 
and tmax 
Ratio: Fed/Fasted 
No 
5.14 
PK 
PK01 
Summary Statistics of 
Plasma GSK2838232 PK 
Concentration-Time Data –
Part 2 
Day 1 & Day 11 
No 
5.15 
PK  
PK04 
Summary Statistics of 
Derived Plasma 
GSK2838232  PK 
Parameters by Treatment 
and by Day – Part 2 
Day 1 & Day 11 
No 
5.16 
PK 
PK05 
Summary of Loge-
transformed Derived 
Plasma GSK2838232 PK 
Parameters by Treatment 
and by Day – Part 2 
Day 1 & Day 11 
No 
5.17 
PK  
Non-Standard3 
Summary of Results of 
GSK2838232 PK 
Parameter Treatment 
Comparisons -
Accumulation 
Assessments- Part 2 
One for each 
treatment 
No 
5.18 
PK  
Non-Standard4 
Summary Results of 
Steady State GSK2838232 
Concentrations 
Assessments- Part 2 
One for each 
treatment 
No 
 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 27 of 47 
Table 5 
Pharmacokinetic Figures 
 
No 
Population  IDSL 
Shell/TST ID 
/Example 
shell 
Title 
Programming Note  
Any 
Changes 
in 
existing 
RAP 
5.1 
PK  
PK16B 
Individual Plasma 
GSK2838232 PK 
Concentration-Time Plots 
for Relative Bioavailability  
Linear and Semi-Log 
Scale  
By participant, overlay 
all treatments for each 
participant 
Include LOQ line in plot 
Yes 
5.2 
PK  
PK17 
Mean Plasma GSK2838232 
PK Concentration for 
Relative Bioavailability 
Linear and Semi-Log 
Scale  
Overlay all treatments 
Include LOQ line in plot 
Yes 
5.3 
PK  
PK18 
Median Plasma 
GSK2838232 PK 
Concentration for Relative 
Bioavailability 
Linear and Semi-Log 
Scale  
Overlay all treatments 
Include LOQ line in plot 
Yes 
5.4 
PK 
PK28 
Geometric Mean Treatment 
Ratio and 90% Confidence 
Interval of GSK2838232 PK 
Parameter for the Relative 
Bioavailability  
 
No 
5.5 
PK  
PK25 
Comparative Plot of 
Individual Plasma 
GSK2838232 PK 
Parameters for Relative 
Bioavailability by treatment 
 
No 
5.6 
PK  
PK16A 
Individual Plasma 
GSK2838232 PK 
Concentration-Time Plots 
for Food Effect 
Linear and Semi-Log 
Scale  
By participant, overlay 
all treatments for each 
participant 
Include LOQ line in plot 
Yes 
5.7 
PK  
PK17 
Mean Plasma GSK2838232 
PK Concentration for Food 
Effect 
Linear and Semi-Log 
Scale  
Overlay all treatments 
Include LLQ line in plot 
Yes 
5.8 
PK  
PK18 
Median Plasma 
GSK2838232 PK 
Concentration for Food 
Linear and Semi-Log 
Scale  
Overlay all treatments 
Yes 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 28 of 47 
Effect 
Include LOQ line on 
plot 
5.9 
PK 
PK28 
Geometric Mean Treatment 
Ratio and 90% Confidence 
Interval of GSK2838232 PK 
Parameter for Food Effect  
 
No 
5.10 
PK  
PK25 
Comparative Plot of 
Individual Plasma 
GSK2838232 PK 
Parameters for Food Effect 
by treatment 
 
No 
5.11 
PK  
PK16a 
Individual Plasma 
GSK2838232 PK 
Concentration-Time Plots by 
Day – Part 2 
Linear and Semi-Log 
Scale  
By participant, overlay 
days for each participant 
Include LLQ line on plot 
Yes 
5.12 
PK  
PK17 
Mean Plasma GSK2838232 
PK Concentration by Day – 
Part 2 
Linear and Semi-Log 
Scale  
Include LLQ line on plot 
Plot Day 1 and Day 11 
on Separate page 
Yes 
5.13 
PK  
PK18 
Median Plasma 
GSK2838232 PK 
Concentration by Day – Part 
2 
Linear and Semi-Log 
Scale  
Include LLQ line on plot 
Plot Day 1 and Day 11 
on Separate page 
Yes 
5.14 
PK  
PK16a 
Individual Plasma 
GSK2838232  Predose 
Concentration-Time Plots 
for Steady State Assessment 
– Part 2 
Linear and Semi-Log 
Scale  
Overlay all individual 
profile with all days 
profiles 
Day on x-axis, predose 
concentration on y-axis, 
join day to day for each 
subject. 
Yes 
5.15 
PK  
PK17 
Mean Plasma GSK2838232  
Concentration-Time Plots 
for Steady State Assessment 
– Part 2 
Linear and Semi-Log 
Scale  
Days on same plot with 
x-axis as Days, mean 
concentration plotted 
across and joined 
Yes 
5.16 
PK  
PK18 
Median Plasma 
GSK2838232  
Concentration-Time Plots 
for Steady State Assessment 
– Part 2 
Linear and Semi-Log 
Scale  
Days on same plot with 
x-axis as Days, median 
concentration plotted 
across and joined 
Yes 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 29 of 47 
5.17 
PK  
PK16a 
Individual and Box Plot of 
Plasma GSK2838232  PK 
Parameters by Day – Part 2 
Include all the PK 
parameters.  
Yes 
5.18 
PK  
PK25 
Comparative Plot of Plasma 
GSK2838232 PK 
Parameters for 
Accumulation 
Linear and Log Scale 
 
Yes 
 
 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 30 of 47 
Table 6  
ICH Listings 
 
No 
Population  IDSL 
Shell/TST 
ID 
/Example 
shell 
Title 
Programming Note  
Any 
Changes 
in 
existing 
RAP 
1 
Screened 
ES7 
Listing of Reasons for Screen 
Failure – Part 1 
 
No 
2 
Screened 
ES7 
Listing of Reasons for Screen 
Failure – Part 2 
 
No 
3 
Safety 
ES3 
Listing of Reasons for Study 
Withdrawal – Part 1 
 
No 
4 
Safety 
ES2 
Listing of Reasons for Study 
Withdrawal – Part 2 
 
No 
5 
Safety 
SD3 
Listing of Reasons for Study 
Treatment Discontinuation – 
Part 1 
 
No 
6 
Safety 
SD2 
Listing of Reasons for Study 
Treatment Discontinuation – 
Part 2 
 
No 
7 
Safety 
BL1 
Listing of Participants for 
Whom the Treatment Blind was 
Broken – Part 2 
 
No 
8 
Safety 
CP_RA1x 
Listing of Planned and Actual 
Treatments – Part 1 
 
No 
9 
Safety 
CP_RA1p 
Listing of Planned and Actual 
Treatments – Part 2 
 
No 
10 
Safety 
DV2A 
Listing of Important Protocol 
Deviations – Part 1 
ICH E3 
Listing also includes 
analysis population 
exclusions. 
No 
11 
Safety 
DV2 
Listing of Important Protocol 
Deviations – Part 2 
ICH E3 
Listing also includes 
analysis population 
exclusions. 
No 
12 
Safety 
IE4 
Listing of Participants with 
Inclusion/Exclusion Criteria 
Deviations – Part 1 
ICH E3 
No 
13 
Safety 
IE3 
Listing of Participants with 
Inclusion/Exclusion Criteria 
Deviations – Part 2 
ICH E3 
No 
14 
Safety 
SP3A 
Listing of Participants 
Excluded from Any Population 
– Part 1 
ICH E3 
No 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 31 of 47 
15 
Safety 
SP3 
Listing of Participants 
Excluded from Any Population 
– Part 2 
ICH E3 
No 
16 
Safety 
DM4 
Listing of Demographic 
Characteristics – Part 1 
ICH E3 
No 
17 
Safety 
DM2 
Listing of Demographic 
Characteristics – Part 2 
ICH E3 
No 
18 
Safety 
DM10 
Listing of Race – Part 1 
ICH E3 
No 
19 
Safety 
DM9 
Listing of Race – Part 2 
ICH E3 
No 
20 
Safety 
CP_CM4 
Listing of Concomitant 
Medications – Part 1 
IDSL 
No 
21 
Safety 
CP_CM3 
Listing of Concomitant 
Medications – Part 2 
IDSL 
No 
22 
Safety 
EX4 
Listing of Exposure Data – Part 
1 
ICH E3 
No 
23 
Safety 
EX3 
Listing of Exposure Data – Part 
2 
ICH E3 
No 
24 
Safety 
CP_AE9 
Listing of All Adverse Events – 
Part 1 
ICH E3 
No 
25 
Safety 
CP_AE8 
Listing of All Adverse Events – 
Part 2 
ICH E3 
No 
26 
Safety 
AE7 
Listing of Participant Numbers 
for Individual Adverse Events – 
Part 1 
ICH E3 
No 
27 
Safety 
AE7 
Listing of Participant Numbers 
for Individual Adverse Events – 
Part 2 
ICH E3 
No 
28 
Safety 
AE2 
Listing of Relationship 
Between Adverse Event System 
Organ Classes, Preferred 
Terms, and Verbatim Text – 
Part 1 
IDSL 
No 
29 
Safety 
AE2 
Listing of Relationship 
Between Adverse Event System 
Organ Classes, Preferred 
Terms, and Verbatim Text – 
Part 2 
IDSL 
No 
30 
Safety 
CP_AE9a 
Listing of Fatal Serious 
Adverse Events – Part 1 
ICH E3 
No 
31 
Safety 
CP_AE8a 
Listing of Fatal Serious 
Adverse Events – Part 2 
ICH E3 
No 
32 
Safety 
CP_AE9a 
Listing of Non-Fatal Serious 
Adverse Events – Part 1 
ICH E3 
No 
33 
Safety 
CP_AE8a 
Listing of Non-Fatal Serious 
ICH E3 
No 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 32 of 47 
Adverse Events – Part 2 
34 
Safety 
AE14 
Listing of Reasons for 
Considering as a Serious 
Adverse Event 
ICH E3 
No 
35 
Safety 
CP_AE9a 
Listing of Adverse Events 
Leading to Withdrawal from 
Study / Permanent 
Discontinuation of Study 
Treatment – Part 1 
ICH E3 
No 
36 
Safety 
CP_AE8a 
Listing of Adverse Events 
Leading to Withdrawal from 
Study / Permanent 
Discontinuation of Study 
Treatment – Part 2 
ICH E3 
No 
37 
Safety 
CP_AE9a 
Listing of Grade 3 or 4 Adverse 
Events – Part 1 
Division of AIDS 
Table For Grading 
No 
38 
Safety 
CP_AE8a 
Listing of Grade 3 or 4 Adverse 
Events – Part 2 
Division of AIDS 
Table For Grading 
No 
39 
Safety 
MH2 
Listing of Medical Conditions 
for Participants with Liver 
Stopping Events – Part 1 
IDSL 
No 
40 
Safety 
MH2 
Listing of Medical Conditions 
for Participants with Liver 
Stopping Events – Part 2 
IDSL 
No 
41 
Safety 
SU2 
Listing of Substance Use for 
Participants with Liver 
Stopping Events – Part 1 
IDSL 
No 
42 
Safety 
SU2 
Listing of Substance Use for 
Participants with Liver 
Stopping Events – Part 2 
IDSL 
No 
43 
Safety 
LB13 
Listing of Reference Ranges for 
Clinical Laboratory Tests 
 
No 
44 
Safety 
LB6 
Listing of Hematology Data– 
Part 1 
If any laboratory test 
results are outside of 
the reference range, 
they will be flagged 
with high/low and/or 
toxicity grade in the 
listing 
No 
45 
Safety 
LB5 
Listing of Hematology Data– 
Part 2 
If any laboratory test 
results are outside of 
the reference range, 
they will be flagged 
with high/low and/or 
toxicity grade in the 
listing 
No 
46 
Safety 
LB6 
Listing of Clinical Chemistry 
If any laboratory test 
No 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
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Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 33 of 47 
Data– Part 1 
results are outside of 
the reference range, 
they will be flagged 
with high/low and/or 
toxicity grade in the 
listing 
47 
Safety 
LB5 
Listing of Clinical Chemistry 
Data– Part 2 
If any laboratory test 
results are outside of 
the reference range, 
they will be flagged 
with high/low and/or 
toxicity grade in the 
listing 
No 
48 
Safety 
LB6 
Listing of Urinalysis Data– Part 
1 
If any laboratory test 
results are outside of 
the reference range, 
they will be flagged 
with high/low and/or 
toxicity grade in the 
listing 
No 
49 
Safety 
LB5 
Listing of Urinalysis Data– Part 
2 
If any laboratory test 
results are outside of 
the reference range, 
they will be flagged 
with high/low and/or 
toxicity grade in the 
listing 
No 
50 
Safety 
LB6 
Listing of All Laboratory Data 
for Participants with Any Value 
of Potential Clinical 
Importance– Part 1 
ICH E3 
May be split into 
separate listings by 
chemistry, 
hematology, etc. 
Display ALL labs for 
a participant who 
experienced a value 
of potential clinical 
importance. 
No 
51 
Safety 
LB5 
Listing of All Laboratory Data 
for Participants with Any Value 
of Potential Clinical 
Importance– Part 2 
ICH E3 
May be split into 
separate listings by 
chemistry, 
hematology, etc. 
Display ALL labs for 
a participant who 
experienced a value 
of potential clinical 
importance. 
No 
52 
Safety 
LB6 
Listing of Lab Results 
Identified as Adverse Events– 
Lab results identified 
as AEs. Only needed 
No 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
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TP-EP.BS-WW-008-04 
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Page 34 of 47 
Part 1 
if there are a 
sufficient number of 
labs identified as 
AEs. 
53 
Safety 
LB5 
Listing of Lab Results 
Identified as Adverse Events – 
Part 2 
Lab results identified 
as AEs. Only needed 
if there are a 
sufficient number of 
labs identified as 
AEs. 
No 
54 
Safety 
LB6 
Listing of Grade 2 or Higher 
Lab Abnormalities – Part 1 
 
No 
55 
Safety 
LB5 
Listing of Grade 2 or Higher 
Lab Abnormalities – Part 2 
 
No 
56 
Safety 
LB14 
Listing of Laboratory Data with 
Character Results – Part 1 
ICH E3 
No 
57 
Safety 
LB14 
Listing of Laboratory Data with 
Character Results – Part 2 
ICH E3 
No 
58 
Safety 
UR2B 
Listing of Urinalysis Data for 
Participants with Any Value of 
Potential Clinical Importance – 
Part 1 
ICH E3 
Display ALL data for 
a participant who 
experienced a value 
of potential clinical 
importance. 
No 
59 
Safety 
UR2A 
Listing of Urinalysis Data for 
Participants with Any Value of 
Potential Clinical Importance – 
Part 2 
ICH E3 
Display ALL data for 
a participant who 
experienced a value 
of potential clinical 
importance. 
No 
60 
Safety 
EG4 
Listing of All ECG Values for 
Participants with Any Value of 
Potential Clinical Importance – 
Part 1 
IDSL 
No 
61 
Safety 
EG3 
Listing of All ECG Values for 
Participants with Any Value of 
Potential Clinical Importance – 
Part 2 
IDSL 
No 
62 
Safety 
EG6 
Listing of All ECG Findings for 
Participants with an Abnormal 
ECG Finding – Part 1 
IDSL 
No 
63 
Safety 
EG5 
Listing of All ECG Findings for 
Participants with an Abnormal 
ECG Finding – Part 2 
IDSL 
No 
64 
Safety 
HM8 
Listing of Holter Monitoring – 
Part 1 
IDSL 
 
No 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 35 of 47 
65 
Safety 
HM8 
Listing of Holter Monitoring – 
Part 2 
IDSL 
 
No 
66 
Safety 
VS5 
Listing of All Vital Signs Data 
for Participants with Any Value 
of Potential Clinical Importance 
– Part 1 
IDSL 
No 
67 
Safety 
VS4 
Listing of All Vital Signs Data 
for Participants with Any Value 
of Potential Clinical Importance 
– Part 2 
IDSL 
No 
68 
Safety  
Non-
Standard 5 
Listing of Meal- Part 1 
 
Yes 
 
 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 36 of 47 
Table 7  
Non-ICH Lisitngs 
 
No 
Population  IDSL 
Shell/TST ID 
/Example shell 
Title 
Programming Note  
Any 
Changes in 
existing 
RAP 
69 
PK  
PK08 
Listing of Plasma 
GSK2838232 PK 
Concentration-Time Data  
–Part 1 
Sort by participant, 
treatment, day, and 
time 
Yes 
70 
PK  
PK07 
Listing of Plasma 
GSK2838232 PK 
Concentration-Time Data  
–Part 2 
Sort by participant, 
treatment, day, and 
time 
Yes 
71 
PK 
SAS output of 
Table 5.6 
SAS Output of Summary 
Results of GSK2838232 
PK Parameter Treatment 
Comparisons for the 
Relative Bioavailability – 
Part 1A 
 
Yes 
72 
PK 
SAS output of 
Table 5.10 
SAS Output of Summary 
Results of GSK2838232 
PK Parameter Treatment 
Comparisons for the Food 
Effect – Part 1B 
 
Yes 
73 
PK  
SAS output of 
Table 5.12 
SAS Output of Summary 
Results of GSK2838232 
PK Parameter Treatment 
Comparisons for the Food 
Effect (Non-parametric) – 
Part 1B 
 
Yes 
74 
PK 
SAS output of 
Table 5.16 
SAS Output of Summary 
Results of Steady-State 
GSK2838232 
Concentrations Assessment 
– Part 2 
 
Yes 
75 
PK 
SAS output of 
Table 5.17 
SAS Output of Summary 
Results of GSK2838232 
PK Parameter Treatment 
Comparisons – 
Accumulation Ratio – Part 
2  
 
Yes 
 
 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 37 of 47 
Table 8  
Study Population Tables (Changes from RAP) 
 
No  
Populatio
n  
IDSL 
Shell/TST 
ID 
/Example 
shell 
Title 
Programming 
Note  
Changes done from the RAP 
1.9 
Safety 
DV1 
Summary of 
Protocol 
Deviations – Part 1 
ICH E3 
. 
1. Title has been changed from 
“Summary of Protocol 
Deviations – Part 1” to 
“Summary of Important 
Protocol Deviations – Part 1” 
2. Programming note has been 
appended with following texts: 
“If important protocol deviation 
events are less than 15, please 
produce the summary with 
wordings”not enough important 
protocol deviation to warren a 
summary”. 
1.10 
Safety 
DV1 
Summary of  
Protocol 
Deviations – Part 2 
ICH E3 
 
1. Title has been changed from 
“Summary of Protocol 
Deviations – Part 2” to 
“Summary of Important 
Protocol Deviations – Part 2” 
2. Programming note has been 
appended with following texts: 
“If important protocol deviation 
events are less than 15, please 
produce the summary with 
wordings 
”not enough important protocol 
deviation to warren a summary”. 
 
 
 
 
 
 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 38 of 47 
 
Table 9  
Safety Figures (Changes from RAP) 
 
No 
Population  
IDSL 
Shell/TST ID 
/Example 
shell 
Title 
Programming 
Note  
Changes from  RAP 
3.1 
Safety 
As EG9 
Plot of Selected Clinical 
Lab Tests Mean Change 
from Baseline by 
Treatment and Time – 
Part 1 
Only include 
scheduled visits 
and for selected 
lab test (BNP, 
Tnp1, ALT, 
AST, Bili)  
Plots will be 
presented with 
treatment 
groups overlaid 
Title has been changed 
to “Plot of Selected 
Clinical Lab Tests 
Mean (95% CI) 
Change from Baseline 
by Treatment and 
Time – Part 1” 
3.2 
Safety 
As EG9 
Plot of Selected Clinical 
Lab Tests Mean Change 
from Baseline by 
Treatment and Time – 
Part 2 
Only include 
scheduled visits 
and for selected 
lab test (BNP, 
Tnp1, ALT, 
AST, Bili)  
Plots will be 
presented with 
treatment 
groups overlaid 
Title has been changed 
to “Plot of Selected 
Clinical Lab Tests 
Mean (95% CI) 
Change from Baseline 
by Treatment and 
Time – Part 2” 
3.3 
Safety 
EG9 
Plot of Mean Change 
from Baseline QTcB and 
QTcF Data by Treatment 
and Time – Part 1 
Plots will be 
presented with 
treatment 
groups overlaid 
Title has been changed 
to “Plot of Mean (95% 
CI) Change from 
Baseline QTcB and 
QTcF Data by 
Treatment and Time – 
Part 1” 
3.4 
Safety 
EG9 
Plot of Mean Change 
from Baseline QTcB and 
QTcF Data by Treatment 
and Time – Part 2 
Plots will be 
presented with 
treatment 
groups overlaid 
Title has been changed 
to “Plot of Mean (95% 
CI) Change from 
Baseline QTcB and 
QTcF Data by 
Treatment and Time – 
Part 2” 
 
 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 39 of 47 
Table 10 
Pharmacokinetic Tables (Changes from RAP) 
 
No 
Population  IDSL 
Shell/TST ID 
/Example 
shell 
Title 
Programming 
Note  
Changes from  RAP 
5.1 
PK  
PK14 
Listing of Derived Plasma 
GSK2838232 PK 
Parameters – Part 
1A 
Sort by 
participant and 
treatment 
This table is clubbed 
with table 5.2 
Title has been 
changed to “Listing 
of Derived Plasma 
GSK2838232 PK 
Parameters – Part 
1” 
5.2 
PK  
PK14 
Listing of Derived Plasma 
GSK2838232 PK 
Parameters – Part 
1B 
Sort by 
participant and 
treatment 
This table has been 
removed. 
5.3 
PK 
PK13 
Listing of Derived Plasma 
GSK2838232 PK 
Parameters – Part 2 
Sort by 
participant and 
treatment 
Table no is changed 
to 5.2 
x.xx 
PK  
Non-Standard 
6 
Summary of Result of 
Plasma GSK2838232  PK 
Parameter Treatment 
Comparisons for Food 
Effect (Non-parametric) 
PK Parameter 
Tmax 
Newly added, with 
Table no 5.12 
5.14 
PK 
PK04 
Summary Statistics of 
Plasma GSK2838232 PK 
Parameters by Treatment 
and by Day – Part 2 
Day 1 & Day 
11 
Title has been 
changed to 
“Summary Statistics 
of Plasma 
GSK2838232 PK 
Concentration time 
data by Treatment 
and by Day – Part 2 
 
 
 
 
 
 
 
 
 
 
 
 
 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 40 of 47 
 
Table 11 
Pharmacokinetic Figures (Changes from RAP) 
 
No 
Population  IDSL 
Shell/TST 
ID 
/Example 
shell 
Title 
Programming 
Note  
Changes  from RAP 
5.1 
PK  
PK16B 
Individual Plasma 
GSK2838232 PK 
Concentration-Time Plots 
for Relative Bioavailability  
Linear and Semi-
Log Scale  
By participant, 
overlay all 
treatments for 
each participant 
Include LOQ 
line in plot 
In programming note 
“Include LOQ line in 
plot” is added 
5.2 
PK  
PK17 
Mean Plasma GSK2838232 
PK Concentration for 
Relative Bioavailability 
Linear and Semi-
Log Scale  
Overlay all 
treatments 
Include LOQ 
line in plot 
In programming note 
“Include LOQ line in 
plot” is added 
5.3 
PK  
PK18 
Median Plasma 
GSK2838232 PK 
Concentration for Relative 
Bioavailability 
Linear and Semi-
Log Scale  
Overlay all 
treatments 
Include LOQ 
line in plot 
In programming note 
“Include LOQ line in 
plot” is added 
5.6 
PK  
PK16A 
Individual Plasma 
GSK2838232 PK 
Concentration-Time Plots 
for Food Effect 
Linear and Semi-
Log Scale  
By participant, 
overlay all 
treatments for 
each participant 
Include LOQ 
line in plot 
In programming note 
“Include LOQ line in 
plot” is added 
5.7 
PK  
PK17 
Mean Plasma GSK2838232 
PK Concentration for Food 
Effect 
Linear and Semi-
Log Scale  
Overlay all 
treatments 
Include LLQ line 
in plot 
In programming note 
“Include LOQ line in 
plot” is added 
5.8 
PK  
PK18 
Median Plasma 
GSK2838232 PK 
Concentration for Food 
Effect 
Linear and Semi-
Log Scale  
Overlay all 
treatments 
Include LOQ 
In programming note 
“Include LOQ line in 
plot” is added 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
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TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 41 of 47 
line on plot 
5.11 
PK  
PK16a 
Individual Plasma 
GSK2838232 PK 
Concentration-Time Plots 
by Day – Part 2 
Linear and Semi-
Log Scale  
By participant, 
overlay days for 
each participant 
Include LLQ line 
on plot 
In programming note 
“Include LOQ line in 
plot” is added 
5.12 
PK  
PK17 
Mean Plasma GSK2838232 
PK Concentration by Day – 
Part 2 
Linear and Semi-
Log Scale  
Include LLQ line 
on plot 
Plot Day 1 and 
Day 11 on 
Separate page 
In programming note  
Include LLQ line on 
plot 
Plot Day 1 and Day 11 
on Separate page 
are added. 
5.13 
PK  
PK18 
Median Plasma 
GSK2838232 PK 
Concentration by Day – Part 
2 
Linear and Semi-
Log Scale  
Include LLQ line 
on plot 
Plot Day 1 and 
Day 11 on 
Separate page 
In programming note  
Include LLQ line on 
plot 
Plot Day 1 and Day 11 
on Separate page 
are added. 
5.19 
PK  
PK16a 
Individual Plasma 
GSK2838232  Predose 
Concentration-Time Plots 
for Steady State Assessment 
– Part 2 
Linear and Semi-
Log Scale  
Overlay all 
individual profile 
with all days 
profiles 
Day on x-axis, 
predose 
concentration on 
y-axis, join day 
to day for each 
subject. 
In programming note 
Day on x-axis, predose 
concentration on y-
axis, and join day to 
day for each subject is 
added. 
Figure no change to 
5.14 
5.20 
PK  
PK17 
Mean Plasma GSK2838232  
Concentration-Time Plots 
for Steady State Assessment 
– Part 2 
Linear and Semi-
Log Scale  
Days on same 
plot with x-axis 
as Days, mean 
concentration 
plotted across 
and joined 
In programming note 
Days on same plot 
with x-axis as Days, 
mean concentration 
plotted across and 
joined, is added. 
Figure no change 5.15 
5.21 
PK  
PK18 
Median Plasma 
GSK2838232  
Concentration-Time Plots 
for Steady State Assessment 
– Part 2 
Linear and Semi-
Log Scale  
Days on same 
plot with x-axis 
as Days, median 
concentration 
In programming note  
Days on same plot 
with x-axis as Days, 
median concentration 
plotted across and 
joined, is added. 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
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TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 42 of 47 
plotted across 
and joined 
Figure no changed to 
5.16 
5.22 
PK  
PK16a 
Individual and Box Plot of 
Plasma GSK2838232  PK 
Parameters by Day – Part 2 
Include all the 
PK parameters.  
Figure no change to 
5.17 
5.23 
PK  
PK25 
Comparative Plot of Plasma 
GSK2838232 PK 
Parameters for 
Accumulation 
Linear and Log 
Scale 
 
Figure no change to 
5.18 
 
 


PAREXEL International 
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GlaxoSmithKline Research & 
Development Limited 
 
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Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 43 of 47 
Table 12 
ICH Listing (Changes from RAP) 
 
No 
Population  IDSL 
Shell/TST ID 
/Example 
shell 
Title 
Programming 
Note  
Changes from  
RAP 
xx 
Safety  
Non-Standard 
5 
Listing of Meal Data  -  Part 
1 
Part 1 only 
Newly Added with 
listing no 68 
 
 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
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TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 44 of 47 
Table 13 
Non-ICH Listings (Change from RAP) 
 
No 
Population  
IDSL 
Shell/TST 
ID 
/Example 
shell 
Title 
Programming 
Note  
Changes from RAP 
68 
PK  
PK08 
Listing of Plasma 
GSK2838232 PK 
Concentration-
Time Data  –Part 
1A 
Sort by participant, 
treatment, day, and 
time 
This listing has been 
combined with listing 
number 69. 
Title of this listing is 
changed to “Listing of 
Plasma GSK2838232 
PK Concentration-Time 
Data  –Part 1” 
This listing number has 
been changed to 69. 
69 
PK  
PK08 
Listing of Plasma 
GSK2838232 PK 
Concentration-
Time Data  –Part 
1B 
Sort by participant, 
treatment, day, and 
time 
This listing has been 
removed 
xx 
PK  
SAS 
output of 
Table 5.12 
SAS Output of 
Summary Results 
of GSK2838232 
PK Parameter 
Treatment 
Comparisons for 
the Food Effect 
(Non-parametric) – 
Part 1B 
 
This is newly added 
73 
PK 
SAS 
output of 
Table 5.16 
SAS Output of 
Summary Results 
of Steady-State 
GSK2838232 
Concentrations 
Assessment – Part 
2 
 
This listing number is 
changed to 74 
74 
PK 
SAS 
output of 
Table 5.17 
SAS Output of 
Summary Results 
of GSK2838232 
PK Parameter 
Treatment 
Comparisons – 
Accumulation 
Ratio – Part 2  
 
This listing no is 
changed to 75 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
16/Apr/2018 
TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 45 of 47 
 
4. 
SHELLS 
Example: Non-Standard 5 
 
Protocol: AAA111111  
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of xx 
Population: Safety 
 
 
Listing x 
Listing of Meal Data (Safety Population) 
 
 
 
{Inv./} 
Subj. 
 
{Age(y)/ 
Sex/ 
Race} 
 
Trt. 
 
Visit/Pl.
Time 
 
Start 
Date/Star
t Time of 
Meal  
 
Stop 
Date/Sto
p Time 
of Meal  
Start 
Date/Star
t Time of 
Dosing 
 
Meal  
Type 
 
Totality 
of the 
Meal 
been 
Ingested
? 
 
Proporti
onal of 
the Meal 
Consumed
? 
 
 
 
 
 
 
 
 
 
36/ 
M/ 
Mixed Race 
A 
PART1 
P1D1/PRED
OSE 
/09:00 
 
9/09:10  
 
/09:30 
 High Fat 
Meal 
  No 
76-
100% 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD
PPD


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
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Final 1.0 
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TP-EP.BS-WW-008-04 
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 46 of 47 
 
 
 
 
 
 
 
 
 
 
 
 
Example: Non-Standard 6 
 
Protocol: AAA111111  
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of xx 
Population: Pharmacokinetic  
 
Table x 
Summary of Result of Plasma GSK2838232 PK Parameter Treatment Comparisons for Food Effect (Non-Parametric) 
 
 
 
 
Median 
_________________________________ 
 
PK Parameter 
Comparison 
Test/Ref. 
GSK 200 mg/r 
tablet fasted 
(N=xx) 
GSK 200 mg/r 
tablet fed 
(N=xx) 
Diffe
rence 
90% Confidence 
Interval 
p-value  
Tmax(h) 
GSK 200 mg/r tablet fed 
vs GSK 200 mg/r tablet 
fasted 
xx.xx 
xx.xx 
(xx.xx,xx.xx) 
x.xxxx 
 
 
 
 
 
 
 
 
 
 
 
 


PAREXEL International 
Statistical Analysis Plan Addendum 
GlaxoSmithKline Research & 
Development Limited 
 
Final 1.0 
205820 
 
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TP-EP.BS-WW-008-04 
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Related to:  SOP-EP.BS-WW-002 
 
Page 47 of 47 
5. 
REFERENCES 
1. SAS® Version 9.3 of the SAS System for Personal Computers. Copyright © 2002-2003. SAS Institute Inc. 
SAS and all other SAS Institute Inc. product or service names are registered trademarks or trademarks of 
SAS Institute Inc., Cary, NC, USA. 
2. WinNonlin Professional Software Version 5.2. http://www.pharsight.com