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
Phase: PHASE1
Conditions: Infection, Human Immunodeficiency Virus, HIV Infections
Sponsor: GlaxoSmithKline

2017N322544_01
CONFIDENTIAL
GlaxoSmithKline group of companies
205820
1
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.

PPD
PPD
PPD

PPD
PPD

2017N322544_01
CONFIDENTIAL
205820
4
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

2017N322544_01
CONFIDENTIAL
205820
5
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

2017N322544_01
CONFIDENTIAL
205820
6
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

2017N322544_01
CONFIDENTIAL
205820
7
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

2017N322544_01
CONFIDENTIAL
205820
8
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

2017N322544_01
CONFIDENTIAL
205820
9
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

2017N322544_01
CONFIDENTIAL
205820
10
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.  

2017N322544_01
CONFIDENTIAL
205820
11
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.

2017N322544_01
CONFIDENTIAL
205820
12
Study Schematic
Part 1
Part 2

2017N322544_01
CONFIDENTIAL
205820
13
2.
SCHEDULE OF ASSESSMENTS
Please see Table 2 and Table 3 below for the Schedule of assessments for study Parts 1 
and 2 respectively.

2017N322544_01
CONFIDENTIAL
205820
14
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

2017N322544_01
CONFIDENTIAL
205820
15
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.

2017N322544_01
CONFIDENTIAL
205820
16
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

2017N322544_01
CONFIDENTIAL
205820
17
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.

2017N322544_01
CONFIDENTIAL
205820
18
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.

2017N322544_01
CONFIDENTIAL
205820
19
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 

2017N322544_01
CONFIDENTIAL
205820
20
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].

2017N322544_01
CONFIDENTIAL
205820
21
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:

2017N322544_01
CONFIDENTIAL
205820
22
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.

2017N322544_01
CONFIDENTIAL
205820
23
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.

2017N322544_01
CONFIDENTIAL
205820
24
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.

2017N322544_01
CONFIDENTIAL
205820
25
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.

2017N322544_01
CONFIDENTIAL
205820
26
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.

2017N322544_01
CONFIDENTIAL
205820
27
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.

2017N322544_01
CONFIDENTIAL
205820
28
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

2017N322544_01
CONFIDENTIAL
205820
29
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.

2017N322544_01
CONFIDENTIAL
205820
30

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.

2017N322544_01
CONFIDENTIAL
205820
31
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).

2017N322544_01
CONFIDENTIAL
205820
32
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 

2017N322544_01
CONFIDENTIAL
205820
33
(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.

2017N322544_01
CONFIDENTIAL
205820
34
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, 

2017N322544_01
CONFIDENTIAL
205820
35
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 

2017N322544_01
CONFIDENTIAL
205820
36
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 

2017N322544_01
CONFIDENTIAL
205820
37
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.).

2017N322544_01
CONFIDENTIAL
205820
38

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.

2017N322544_01
CONFIDENTIAL
205820
39

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.

2017N322544_01
CONFIDENTIAL
205820
40

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.

2017N322544_01
CONFIDENTIAL
205820
41
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.

2017N322544_01
CONFIDENTIAL
205820
42
*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.

2017N322544_01
CONFIDENTIAL
205820
43
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 

2017N322544_01
CONFIDENTIAL
205820
44
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.

2017N322544_01
CONFIDENTIAL
205820
45
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.

2017N322544_01
CONFIDENTIAL
205820
46
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.

2017N322544_01
CONFIDENTIAL
205820
47
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 

2017N322544_01
CONFIDENTIAL
205820
48
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.

2017N322544_01
CONFIDENTIAL
205820
49

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 

2017N322544_01
CONFIDENTIAL
205820
50
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.

2017N322544_01
CONFIDENTIAL
205820
51
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 
QTcF intervals.

2017N322544_01
CONFIDENTIAL
205820
52

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.

2017N322544_01
CONFIDENTIAL
205820
53

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.

2017N322544_01
CONFIDENTIAL
205820
54
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 

2017N322544_01
CONFIDENTIAL
205820
55
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 

2017N322544_01
CONFIDENTIAL
205820
56
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

2017N322544_01
CONFIDENTIAL
205820
57

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.

2017N322544_01
CONFIDENTIAL
205820
58
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.

2017N322544_01
CONFIDENTIAL
205820
59
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.

2017N322544_01
CONFIDENTIAL
205820
60
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

2017N322544_01
CONFIDENTIAL
205820
61
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

2017N322544_01
CONFIDENTIAL
205820
62
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

2017N322544_01
CONFIDENTIAL
205820
63
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.

2017N322544_01
CONFIDENTIAL
205820
64
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

2017N322544_01
CONFIDENTIAL
205820
65
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.

2017N322544_01
CONFIDENTIAL
205820
66
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.

2017N322544_01
CONFIDENTIAL
205820
67
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

2017N322544_01
CONFIDENTIAL
205820
68
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

2017N322544_01
CONFIDENTIAL
205820
69
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)

2017N322544_01
CONFIDENTIAL
205820
70
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

2017N322544_01
CONFIDENTIAL
205820
71
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

2017N322544_01
CONFIDENTIAL
205820
72
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

2017N322544_01
CONFIDENTIAL
205820
73
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)

2017N322544_01
CONFIDENTIAL
205820
74
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.

2017N322544_01
CONFIDENTIAL
205820
75
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)

2017N322544_01
CONFIDENTIAL
205820
76
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

2017N322544_01
CONFIDENTIAL
205820
77
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)

2017N322544_01
CONFIDENTIAL
205820
78
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

2017N322544_01
CONFIDENTIAL
205820
79
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.

2017N322544_01
CONFIDENTIAL
205820
80
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

2017N322544_01
CONFIDENTIAL
205820
81
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

2017N322544_01
CONFIDENTIAL
205820
82
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)

2017N322544_01
CONFIDENTIAL
205820
83
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

2017N322544_01
CONFIDENTIAL
205820
84
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.

2017N322544_01
CONFIDENTIAL
205820
85
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

2017N322544_01
CONFIDENTIAL
205820
86
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)

2017N322544_01
CONFIDENTIAL
205820
87
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

2017N322544_01
CONFIDENTIAL
205820
88
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)

2017N322544_01
CONFIDENTIAL
205820
89
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

2017N322544_01
CONFIDENTIAL
205820
90
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

2017N322544_01
CONFIDENTIAL
205820
91
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

2017N322544_01
CONFIDENTIAL
205820
92
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

2017N322544_01
CONFIDENTIAL
205820
93
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)

2017N322544_01
CONFIDENTIAL
205820
94
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.

2017N322544_01
CONFIDENTIAL
205820
95
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

2017N322544_01
CONFIDENTIAL
205820
96
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

2017N322544_01
CONFIDENTIAL
205820
97
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

2017N322544_01
CONFIDENTIAL
205820
98
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

2017N322544_01
CONFIDENTIAL
205820
99
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

2017N322544_01
CONFIDENTIAL
205820
100
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

2017N322544_01
CONFIDENTIAL
205820
101
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

2017N322544_01
CONFIDENTIAL
205820
102
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

2017N322544_01
CONFIDENTIAL
205820
103
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

2017N322544_01
CONFIDENTIAL
205820
104
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.

2017N322544_01
CONFIDENTIAL
205820
105
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

2017N322544_01
CONFIDENTIAL
205820
106
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

2017N322544_01
CONFIDENTIAL
205820
107
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.

2017N322544_01
CONFIDENTIAL
205820
108
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 

2017N322544_01
CONFIDENTIAL
205820
109
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

2017N322544_01
CONFIDENTIAL
205820
110
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.

2017N322544_01
CONFIDENTIAL
205820
111
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.

2017N322544_01
CONFIDENTIAL
205820
112
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.

2017N322544_01
CONFIDENTIAL
205820
113
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.

2017N322544_01
CONFIDENTIAL
205820
114

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).

2017N322544_01
CONFIDENTIAL
205820
115
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.

2017N322544_01
CONFIDENTIAL
205820
116

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.

2017N322544_01
CONFIDENTIAL
205820
117
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 

2017N322544_01
CONFIDENTIAL
205820
118
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., 

2017N322544_01
CONFIDENTIAL
205820
119
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:

2017N322544_01
CONFIDENTIAL
205820
120

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.