A Single-centre, Double-blind (Sponsor Open), Placebo Controlled Two Part Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Single and Repeat Doses of GSK2292767 as a Dry Powder in Healthy Participants Who Smoke Cigarettes
Phase: PHASE1
Conditions: Asthma
Sponsor: GlaxoSmithKline

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TITLE PAGE
Protocol Title: A single-centre, double-blind (sponsor open), placebo controlled two part 
study to evaluate the safety, tolerability and pharmacokinetics of single and repeat doses 
of GSK2292767 as a dry powder in healthy participants who smoke cigarettes.
Protocol Number: 202062
Short Title: Double-blind (sponsor open), placebo controlled study to evaluate the
safety, tolerability and pharmacokinetics of single and repeat doses of GSK2292767 in
healthy participants who smoke cigarettes.
Compound Number:
GSK2292767
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 will be provided separately.
Regulatory Agency Identifying Number(s): 2016-003188-21
Approval Date: 05-JAN-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.

P P D
P P D

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 1 
05-JAN-2017
Original Protocol
14-OCT-2016
Amendment 1 05-JAN-2017
Overall Rationale for the Amendment: This protocol amendment was created to 
incorporate the comments received from the Regulatory Authorities in the UK (MHRA). 

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Section # and 
Name
Description of Change
Brief Rationale
9.1.1 Time 
Period and 
Frequency for 
Collecting AE 
and SAE 
Information
Previous Text:
All SAEs will be recorded and 
reported to the sponsor or 
designee within 24 hours, as 
indicated in Appendix 4. The 
investigator will submit any 
updated SAE data to the sponsor 
within 24 hours of it being 
available.
Revised Text:
All SAEs will be recorded and 
reported to the sponsor or 
designee immediately and under 
no circumstances should this 
exceed 24 hours, as indicated in 
Appendix 4. The investigator will 
submit any updated SAE data to 
the sponsor within 24 hours of it 
being available.
To comply with regulation - UK Statutory 
Instrument 2004 No 1031 Part 5 and EC 
Guidance document 2011/C 172/01 (CT-
3)
8.1.4 Safety 
Stopping 
Criteria
Previous Text:
None
Revised Text:
Dose escalation stopping criteria 
include the following:

A serious adverse event 
(SAE) occurring in 1 or 
more participants 
receiving GSK2292767 
that is considered at least 
possibly related to study 
drug;

Two or more severe 
adverse events occurring 
in a group of participants 
receiving GSK2292767 
that are considered at 
least possibly related to 
study drug.
To ensure participant safety for Part A -
single dose escalation.
6.1. Inclusion 
Criteria
Previous Text:
A male participant must agree to 
use contraception as detailed in 
Appendix 5 of this protocol during 
To provide guidance on the duration of 
male contraception use and exclusion of 
sperm donation.

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Section # and 
Name
Description of Change
Brief Rationale
Appendix 5 
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information
the treatment period and for at 
least from the time of first dose of 
study medication until at least five 
half-lives of study medication after 
the last dose of study medication
and refrain from donating sperm 
during this period.
Revised Text: 
A male participant must agree to 
use contraception as detailed in 
Appendix 5 of this protocol during 
the treatment period and for at 
least from the time of first dose of 
study medication until at least 55
(5x11) hours plus an additional 90 
days after the last dose of study 
medication and refrain from 
donating sperm during this period. 
GSK2292767 has a predicted half-
life of approximately 11 hours.
Previous Text:
Refrain from donating sperm for 
duration of study and for 5 half-
lives + 90 days after the last dose 
of drug.
Revised Text:
Refrain from donating sperm for 
duration of study and for at least 
55 hours plus an additional 90 
days after the last dose of drug. 
Appendix 5: 
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information
Previous Text: 
Table 7, Note 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 5 half-lives + 90 days after 
Only WONCB permitted in study, text 
removed for clarity.

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Section # and 
Name
Description of Change
Brief Rationale
the last dose of study treatment
Revised Text:
Note B, removed 
2.2  SOA – Part 
A (Single Dose)
Previous Text:
None
Revised Text: 
Predose PK Urine sample added 
to Part A Schedule of Activities
Predose PK urine sample required for 
complete analysis
7.4 Blinding
Previous Text:
Blinded study with unblinded site 
pharmacist who is dispensing 
drug. 
In order to maintain this blind, an 
unblinded site pharmacist will be 
responsible for the dispensation of 
all study treatment. 
This unblinded site pharmacist will 
instruct the participant to avoid 
discussing the taste, dosing 
frequency, or packaging of the 
study treatment with the 
investigator.
Revised Text:
Blinded study with unblinded site 
pharmacy staff who are labelling 
and ensuring release of the study 
drug
In order to maintain this blind, 
unblinded site pharmacy staff will 
be responsible for labelling and 
ensuring release of the blinded 
study treatment to the investigator 
or designee. 
Process for dispensing drug updated to 
reflect site procedures.

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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS.............................................................................................................10
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................14
2.1.
SOA -Screening..........................................................................................15
2.2.
SOA – Part A (Single Dose)........................................................................16
2.3.
SOA – Part B (Repeat Dose) ......................................................................18
2.4.
SOA – Follow-up.........................................................................................21
3.
INTRODUCTION....................................................................................................22
3.1.
Asthma .......................................................................................................22
3.2.
COPD.........................................................................................................23
3.3.
Study Rationale ..........................................................................................23
3.4.
Background ................................................................................................23
3.5.
Benefit/Risk Assessment ............................................................................24
3.5.1.
Risk Assessment .........................................................................25
3.5.2.
Overall Benefit Risk Conclusion...................................................27
4.
OBJECTIVES AND ENDPOINTS...........................................................................28
5.
STUDY DESIGN ....................................................................................................29
5.1.
Overall Design ............................................................................................29
5.2.
Number of Participants ...............................................................................31
5.3.
Participant and Study Completion...............................................................31
5.4.
Scientific Rationale for Study Design ..........................................................31
5.5.
Dose Justification........................................................................................32
5.5.1.
Starting dose and maximum dose justification .............................34
6.
STUDY POPULATION...........................................................................................36
6.1.
Inclusion Criteria.........................................................................................36
6.2.
Exclusion Criteria........................................................................................37
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 .........................................................................................39
6.4.
Screen Failures...........................................................................................39
7.
TREATMENTS.......................................................................................................39
7.1.
Treatments Administered............................................................................40
7.2.
Dose Modification .......................................................................................40
7.3.
Method of Treatment Assignment ...............................................................41
7.3.1.
Part A ..........................................................................................41
7.3.2.
Part B ..........................................................................................42
7.4.
Blinding.......................................................................................................43
7.5.
Preparation/Handling/Storage/Accountability..............................................44
7.6.
Treatment Compliance................................................................................44
7.7.
Concomitant Therapy..................................................................................45
7.8.
Treatment after the End of the Study ..........................................................45

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8.
DISCONTINUATION CRITERIA.............................................................................45
8.1.
Discontinuation of Study Treatment ............................................................45
8.1.1.
Pharmacokinetic Stopping Criteria...............................................45
8.1.2.
Liver Chemistry Stopping Criteria ................................................45
8.1.3.
QTc Stopping Criteria ..................................................................46
8.1.4.
Safety Stopping Criteria...............................................................47
8.1.5.
Temporary Discontinuation ..........................................................47
8.1.6.
Rechallenge.................................................................................47
8.1.6.1.
Study Treatment Restart or Rechallenge....................47
8.2.
Withdrawal from the Study..........................................................................47
8.3.
Lost to Follow Up........................................................................................47
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................49
9.1.
Adverse Events...........................................................................................50
9.1.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................50
9.1.2.
Method of Detecting AEs and SAEs.............................................51
9.1.3.
Follow-up of AEs and SAEs.........................................................51
9.1.4.
Regulatory Reporting Requirements for SAEs .............................51
9.1.5.
Pregnancy ...................................................................................51
9.2.
Treatment of Overdose...............................................................................51
9.3.
Safety Assessments ...................................................................................52
9.3.1.
Physical Examinations.................................................................52
9.3.2.
Vital Signs....................................................................................52
9.3.3.
Electrocardiograms......................................................................53
9.3.4.
Spirometry ...................................................................................53
9.3.5.
Cardiac Telemetry .......................................................................53
9.3.6.
Holter Monitoring .........................................................................53
9.3.7.
Bronchoscopy..............................................................................53
9.3.8.
Clinical Safety Laboratory Assessments ......................................54
9.4.
Pharmacokinetics .......................................................................................54
9.5.
Pharmacodynamics ....................................................................................55
9.6.
Genetics .....................................................................................................55
9.7.
Biomarkers .................................................................................................55
9.7.1.
Induced Sputum...........................................................................55
9.8.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................55
10. STATISTICAL CONSIDERATIONS........................................................................56
10.1.
Sample Size Determination ........................................................................56
10.2.
Populations for Analyses ............................................................................56
10.3.
Statistical Analyses.....................................................................................57
10.3.1.
Safety Analyses...........................................................................57
10.3.2.
Pharmacokinetic Analyses...........................................................57
10.3.2.1.
Dose Proportionality, for Part A ..................................58
10.3.2.2.
Dose Accumulation, for Part B....................................58
10.3.2.3.
Steady State, for Part B..............................................58
10.3.2.4.
Peak to Trough Ratio..................................................58
10.3.3.
Other Analyses ............................................................................58
10.3.4.
Interim Analyses ..........................................................................58
11. REFERENCES.......................................................................................................59

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12. APPENDICES........................................................................................................61
12.1.
Appendix 1: Abbreviations and Trademarks................................................61
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................64
12.3.
Appendix 3: Study Governance Considerations..........................................66
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................70
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................75
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments Guidelines.............................................................................78
12.7.
Appendix 7: Protocol Amendment History...................................................80

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1.
SYNOPSIS
Protocol Title: A single-centre, double-blind (sponsor open), placebo controlled two part 
study to evaluate the safety, tolerability and pharmacokinetics of single and repeat doses 
of GSK2292767 as a dry powder in healthy participants who smoke cigarettes.
Short Title: Double-blind (sponsor open), placebo controlled study to evaluate the 
safety, tolerability and pharmacokinetics of single and repeat doses of GSK2292767 in 
healthy participants who smoke cigarettes.
Rationale: This study is the first administration of GSK2292767 to humans. The study 
will evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) 
of single and repeat inhaled doses of GSK2292767 in healthy smokers. This study is 
intended to provide sufficient confidence in the safety of the molecule and preliminary 
information on target engagement to allow progression to further repeat dose and proof of 
mechanism studies.
Objectives and Endpoints:
Objective
Endpoint
Primary

To assess the safety and tolerability of 
single and repeat doses of GSK2292767 as 
a dry powder in healthy cigarette smokers.

Safety and tolerability of GSK2292767 as 
assessed by clinical monitoring of: 

Vital Signs 

Spirometry

Electrocardiogram (ECG) 

Laboratory safety data

Adverse events (AEs)
Secondary

To determine the pharmacokinetic profile of 
single and repeat doses of GSK2292767 
as a dry powder in healthy cigarette 
smokers.

GSK2292767 plasma concentration data 
and derived pharmacokinetic parameters 
including area under the plasma drug 
concentration versus time curve (AUC(0-t), 
AUC(0-24), AUC(0-∞)), maximum observed 
plasma drug concentration (Cmax), time to 
maximum observed plasma drug 
concentration (Tmax),terminal half-life (T1/2) 
and trough concentrations (C) following 
single and repeated dry powder doses, 
where data allow.

To investigate the steady-state trough 
concentration of GSK2292767 in lung 
epithelial lining fluid (ELF) and 
Bronchoalveolar lavage (BAL) cell pellet
after repeat inhaled dry powder 

BAL concentrations of GSK2292767 and 
derived lung ELF and cell pellet deposition 
parameters.

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Objective
Endpoint
administration in healthy cigarette smokers.
Exploratory

To determine the pharmacodynamic effect 
of GSK2292767 on the biomarker 
Phosphatidylinositol (3,4,5)-trisphosphate 
(PIP3) in induced sputum after single and 
repeat doses of GSK2292767administered 
as a dry powder in healthy cigarette 
smokers.

PIP3 peak area as a proportion of (PIP3 
peak area + PIP2 peak area) in induced 
sputum cells.

To explore the intracellular distribution, 
binding and lysosomal disposition of 
GSK2292767 from lung resident cells 
derived from bronchoalveolar lavage at 
steady-state following repeat administration 

Semi quantitative characterisation of 
intracellular distribution of GSK2292767 
within lung resident cells, binding and 
lysosomal uptake and retention.

To generate samples that will be used to 
characterise the metabolic profile of 
GSK2292767 in plasma, following single 
and repeat doses of GSK2292767 
administered as a dry powder in healthy 
cigarette smokers. 

Characterisation and quantification of 
metabolites in plasma.

To collect urine samples only at the highest 
proposed dose level to characterise the 
renal excretion of systemically available 
drug following inhaled delivery.

Semi-quantitative characterisation of 
amount of parent GSK2292767 excreted in 
urine
Overall Design: This is a two part, single site, randomised, double-blind (sponsor open), 
placebo controlled study in healthy smokers. 
Part A will consist of two 3-period interlocking cohorts to evaluate the safety, tolerability 
and pharmacokinetics of ascending single doses of GSK2292767 administered as a dry 
powder. Pharmacodynamic effects on biomarkers will also be assessed.

In each cohort 16 participants will be randomised to one of four treatment 
sequences. 12 participants will receive placebo in one of the periods, where as 
four participants will receive the active dose in all periods. 

The planned doses of GSK2292767 for this study are 50, 100, 200, 500, 1000 and 
2000 μg.

On the first day of dosing within each period, only two participants will be dosed 
(randomisation schedule designed so that one placebo and one active will be 
dosed on first day). Following review of the safety data for the first set of 

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participants, and assuming no safety concerns, the remaining participants will be 
dosed.

Following each dose level, safety data (AE, vital signs, ECG and clinical lab 
safety test) and PK data (up to 24h) for a minimum of 5 participants on active will 
be reviewed before proceeding to the next dose level.

A maximum total dose of 2000 μg over a 24 hour period will not be exceeded. 
Part B is planned to follow Part A and progression will be based on an acceptable safety, 
tolerability and pharmacokinetic profiles. The highest well tolerated dose achieved in Part 
A will be selected for Part B. 

Part B will evaluate the safety, tolerability and pharmacokinetics of repeat doses 
of GSK2292767 administered as a dry powder. Pharmacodynamic effects on 
biomarkers will also be assessed. 

Twelve participants will be randomised to receive GSK2292767 or the matching 
placebo, once daily for 14 consecutive days. Participants will be randomised to 
active or placebo in a 3:1 ratio.

On the first day of dosing, only two participants will be dosed for the 14 day 
period (randomisation schedule designed so that one placebo and one active will 
be dosed on first day). Following a review of the safety data for the first set of 
participants and assuming no safety concerns (after completion of the 14 day 
dosing) the remaining participants will be dosed.
Number of Participants: In Part A for each cohort, a sufficient number of participants 
will be screened to achieve 16 randomised participants. Participants will be randomised 
to one of four treatment sequences.
In Part B, a sufficient number of participants will be screened to achieve 12 randomised 
participants with the aim to achieve approximately 9 completed participants on the active 
treatment group and 3 on placebo. Participants will be randomised to either GSK2292767 
or placebo.
If participants prematurely discontinue the study, additional replacement participants may 
be recruited and assigned to the same treatment sequence/regimen at the discretion of the 
Sponsor in consultation with the investigator.
Treatment Groups and Duration:
In Part A (cohorts 1 & 2), participants will be randomised to one of 4 treatment 
sequences. Participants will be randomised such that in each period 12 participants will 
receive GSK2292767 and 4 participants will receive placebo. Sentinel dosing of the first 
2 participants in each period will be performed ensuring one participant will receive the 
active dose strength and the other on placebo. 
In Part B, 9 participants will be randomised to receive the selected dose strength of 
GSK2292767 and 3 participants will be randomised to receive placebo. The planned dose 
in Part B is 2000 g GSK2292767 once daily for 14 days. However, the actual dose will 
be selected only after review of the safety, tolerability and PK data from Part A. The dose 
will not exceed 2000 g GSK2292767 per day. Sentinel dosing of the first 2 participants 

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will be performed ensuring one participant will receive the active dose strength and the 
other on placebo for the 14 day treatment period.
Part A: Study Duration
Screening
Within 1 to 30 days prior to the first dose
Treatment Period
Each cohort will be comprised of three treatment periods. During each 
period, participants will be admitted to the unit the day before dosing and will 
be discharged after completion of 24h post-dose assessments.
Washout Period
Will be approximately 4 weeks between doses for an individual participant.
Follow-up
At least 7 days and no greater than 14 days after last study drug 
administration. If warranted, additional follow-up visits may be scheduled.
Part B: Study Duration
Screening
Within 1 to 30 days prior to the first dose
Treatment Period
Will be 14 days. Participants will remain in-house during the entire dosing 
period and be discharged on Day 15 after completion of all assessments.
Follow-up
At least 7 days and no greater than 14 days after last study drug 
administration. If warranted, additional follow-up visits may be scheduled.

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2.
SCHEDULE OF ACTIVITIES (SOA)

The timing and number of planned study assessments, including safety, 
pharmacokinetic, and pharmacodynamic/biomarker assessments may be altered 
during the course of the study based on newly available data (e.g., to obtain data 
closer to the time of peak plasma concentrations) to ensure appropriate 
monitoring. 

Any changes in the timing or addition of time points for any planned study 
assessments must be documented and approved by the relevant study team 
member and then archived in the sponsor and site study files, but will not 
constitute a protocol amendment. The Institutional Review Board (IRB)/ 
Independent Ethics Committee (IEC) will be informed of any safety issues that 
require alteration of the safety monitoring scheme or amendment of the 
Informed consent form (ICF).

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2.1.
SOA -Screening
Procedure
Screening 
(up to 30 days 
before Day 1)
Notes
Informed consent
X
Inclusion and exclusion criteria
X
Recheck clinical status before randomisation
Demography
X
Complete physical examination including 
height and weight
X
Medical history (includes substance usage)
X
Substances: Drugs, Alcohol, tobacco and 
caffeine
Urine Pregnancy test 
X
Human Immunodeficiency Virus (HIV), 
Hepatitis B and C screening
X
1.
If test performed within 3 months prior 
to first dose of study treatment, testing at 
screening is not required
Laboratory assessments 
X
12-lead ECG (in triplicate)
X
See Section 9.3.3
Vital signs (in triplicate)
X
See Section 9.3.2
Sputum induction
X
Requires >100mg for inclusion
Spirometry
X
Maximal amount of air forcefully exhaled in 1 
second (FEV1) and Forced Vital Capacity 
(FVC). Perform before sputum induction
Urine Drug, Alcohol and Smoking breath test
X
24h Holter monitor
X

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2.2.
SOA – Part A (Single Dose)
Procedure
Part A (Single Dose) Treatment Period
Notes
Da
y -1
Day 1 (time relative to dosing)
Pre 
dose
0h
5m
30m
45m
1h
2h
3h
4h
6h
8h
12h
24h
Admission to Unit
X
Urine Drug/Alcohol breath test
X
Urine Pregnancy test
X
Brief Physical Exam
X
X
Laboratory Assessments
X
X
Meals
X
X
X
See Section 6.3.1
12-lead ECG (single)
X
X
X
X
X
Vital signs (single)
X
X
X
X
X
X
Telemetry
=============================
Cardiac telemetry: To 
start approximately1hr 
Pre-dose and then 
continuously for the first 
5h post dose.
Spirometry (triplicate)
X
X

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Procedure
Part A (Single Dose) Treatment Period
Notes
Da
y -1
Day 1 (time relative to dosing)
Pre 
dose
0h
5m
30m
45m
1h
2h
3h
4h
6h
8h
12h
24h
Pharmacokinetic and Metabolite 
Profile Blood Sample 
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacokinetic Urine Sample
X
=============================
Only for the maximum 
proposed dose group if 
escalated up to (2000 
µg).
Inhaler Training
X
Dosing
X
Sputum induction
X
X
Adverse Event Review
=============================
Concomitant Medication Review
=============================
Discharge
X

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2.3.
SOA – Part B (Repeat Dose)
Procedure
Part B (Repeat Dose) Study Day
Notes
D -2 or 
D -1
D1
D2
D3
D4
D5
D6
D7
D8
D9
D10
D11
D12
D13
D14
D15
(D14 
+24h)
D16
(D14 
+48h
D17
(D14 
+72h
D18
(D14 
+96h
Admission to Unit
X
Urine Drug/Alcohol
X
Urine Pregnancy test
X
Brief Physical Exam
X
Laboratory Assessments
X
X1
X1
X1
X1
X1
X1
X1
X
1. Perform 
assessment pre 
dose
Meals
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
See Section 6.3.1
12-lead ECG (single)
X
X2
X2
X2
X2
X2
X2
X2
X2
X2
X2
X2
X2
X2
X2
X
2. Perform 
assessments pre 
dose and at 30 mins 
post dose.
Vital signs (single)
X
X3
X3
X3
X3
X3
X3
X3
X3
X3
X3
X3
X3
X3
X3
X
3. Perform 
assessments pre 
dose.
Spirometry (triplicate)
X
X4
X4
X4
X4
X4
X4
X4
X4
X4
X4
X4
X4
X4
X4
.
4. Perform 
assessment pre 
dose and 1h post 
dose.
Pharmacokinetic Blood 
Sample 
X6
X5
X5
X5
X5
X5
X5
X5
X5
X5
X5
X5
X5
X6
X
X7
X7
X7
5. pre-dose and 5 
min post dose.
6. pre-dose, 5 mins, 
30 mins, 45 mins, 1, 
2, 3, 4, 6, 8 and 12h 
post dose
7. If following Single 
dose (SD) PK 
analysis deemed 
necessary.

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Procedure
Part B (Repeat Dose) Study Day
Notes
D -2 or 
D -1
D1
D2
D3
D4
D5
D6
D7
D8
D9
D10
D11
D12
D13
D14
D15
(D14 
+24h)
D16
(D14 
+48h
D17
(D14 
+72h
D18
(D14 
+96h
Blood Sample for 
Metabolic Profiling
X6
X
X7
X7
X7
Urea Blood Sample
X
Collect sample just 
before bronchoscopy
Inhaler Training
X
Dosing
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Sputum induction
X11
X8
X9 
10
8. 3h post dose
9. 3h and 24h
10. Should sputum 
induction fail or be 
insufficient at any 
time point then the 
participant will be 
allowed to return 24h 
later for a further 
attempt to obtain an 
adequate sample
11. Should sputum 
induction fail or be 
insufficient then the 
participant will be 
allowed to return 24h 
later for a further 
attempt to obtain an 
adequate sample. 
Failure to produce a 
baseline sample will 
result in participant 
withdrawal.
Bronchoscopy
X
Adverse Event Review
===========================================

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Procedure
Part B (Repeat Dose) Study Day
Notes
D -2 or 
D -1
D1
D2
D3
D4
D5
D6
D7
D8
D9
D10
D11
D12
D13
D14
D15
(D14 
+24h)
D16
(D14 
+48h
D17
(D14 
+72h
D18
(D14 
+96h
Concomitant Medication 
Review
===========================================
Discharge
X

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2.4.
SOA – Follow-up
Procedure
Follow-up (7-14 days post 
last study treatment 
administration)
Notes
Full physical Examination
X
12-lead ECG
X
Vital signs
X
Laboratory assessments
X
Adverse Event Review
X
Concomitant Medication Review
X

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3.
INTRODUCTION
Phosphoinositide 3 Kinase delta (PI3Kδ) is a lipid kinase expressed predominantly in 
leucocytes, which converts phosphatidylinositol (4,5)-bisphosphate (PIP2) into 
Phosphatidylinositol (3,4,5)-trisphosphate (PIP3), a powerful second messenger 
responsible for activation, proliferation and function of multiple cell types, thereby 
modulating immune responses [Fung-Leung WP, 2011]. PI3Kδ inhibition will potentially 
prevent recruitment of inflammatory cells, including T lymphocytes or eosinophils and 
also inhibits the release of pro-inflammatory mediators from neutrophils such as 
cytokines, chemokines, reactive oxygen species, and proteolytic enzymes. In addition, 
targeting the PI3Kδ pathway enhances innate immune responses to infections by 
promoting neutrophil and T cell mediated host defence. Of interest for the treatment of 
severe respiratory disease is the observation that inhibition of PI3Kδ may restore steroid 
effectiveness under conditions of oxidative stress [Okkenhaug, 2002]. An inhaled PI3Kδ 
inhibitor may be beneficial for both asthma and chronic obstructive pulmonary disease 
(COPD).
3.1.
Asthma
There are a number of immune cell types which contribute to allergen-induced asthma, 
including T-cells, eosinophils, B-cells and mast cells. In allergic asthma, the pre-
dominant subset of effector T-cells, type 2 T helper (Th2) cells produce IL (interleukin)-
4, IL-5, IL-9 and IL-13 [Holgat, 2008]. IL-4 promotes the secretion of allergen specific 
IgE, which activates mast cells to release mediators such as histamines, prostaglandins 
and leukotrienes, leading to tissue inflammation. Additionally, IL-5 stimulates B-cell 
growth and immunoglobulin (Ig) secretion as well as being a key mediator of eosinophil 
activation.
A selective PI3Kδ inhibitor is predicted to block T-cell activation in the lung, reducing 
the production of pro-inflammatory Th2 cytokines. PI3Kδ is also involved in B-cell and 
mast cell activation which are key contributors to asthma pathogenesis [Rowan, 2012]. 
Therefore the inhibition of PI3Kδ should dampen down the inflammatory cascade 
involved in the asthmatic response through a wide breadth of pharmacology.
A key role for PI3Kδ in asthma is supported by investigations which have followed the 
generation of p110δ kinase dead knock-in mice [Okkenhaug, 2002]. These studies 
demonstrated that PI3Kδ is required for cell activation downstream of the T Cell 
Receptor and B Cell Receptor and the mast cell high-affinity IgE receptor FcϵRI 
[Okkenhaug, 2007]. Functionally, PI3Kδ is required for cytokine production and 
proliferation in T-cells, for antibody production, including IgE, in B-cells, and for 
proliferation and migration as well as allergen-IgE-induced degranulation in mast cells 
[Ali, 2004]. In a Phase1 study of the PI3Kδ inhibitor Idelalisib in grass pollen challenged 
allergic rhinitis patients, allergic symptoms were reduced after drug treatment, consistent 
with a mast cell role for PI3Kδ, as were the percentage of ex vivo–activated basophils or 
the plasma concentrations of the Th2 attracting chemokines CCL17 and CCL22 [Horak, 
2016]. The dual PI3Kγ-PI3Kδ inhibitor duvelisib (IPI-145) inhibited key cytokines and 
chemokines involved in the asthmatic response in a Phase IIa allergen challenge study of 
patients with mild allergic asthma (NCT01653756). Although the study primary endpoint 

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of significantly improving the maximum asthmatic response as measured by Maximal 
amount of air forcefully exhaled in 1 second (FEV1) (a standard lung function test that 
measures the amount of air that can be exhaled in one second) was not met, multiple 
secondary efficacy endpoints were significantly positive including an improvement in 
FEV1 AUC over the entire assessment period (p = 0.013) and a decrease in airway hyper-
reactivity (p = 0.036) [Infinity Pharmaceuticals, 2014].
3.2.
COPD
As anti-inflammatory agents, PI3Kδ inhibitors act via mechanisms that are 
complementary to those of steroids, and it is thus anticipated that they could further 
reduce the inflammation underlying COPD, in particular through inhibitory effects on the 
inflammatory actions of neutrophils. Lung extracts or peripheral blood neutrophils 
isolated from COPD patients have been found to over-express PI3Kδ resulting in 
increased PI3Kδ activity [To, 2010; Milara, 2014]. Additionally, PI3Kδ activation has 
been reported to contribute to corticosteroid insensitivity leading to a loss of the anti-
inflammatory and immunosuppressive effects of steroids in COPD [Marwick, 2010]. 
In addition to anti-inflammatory properties, PI3Kδ inhibition improves neutrophil 
functionality and in particular corrects the aberrant migration directionality which is 
specifically observed in COPD neutrophils [Walton, 2015]. This aberrant migration could 
be in part responsible for the wide spread lung tissue damage associated with COPD, 
along with the high bacterial colonization seen in the lungs of COPD patients. While 
improvement in neutrophil functionality will result in a more effective anti-bacterial 
response, PI3Kδ inhibitors may also provide benefits in preventing infections by common 
airway bacterial pathogens such as S. pneumoniae [Fallah, 2011].
Recently, several inherited activating mutations in human PI3Kδ have been discovered 
[Angulo, 2013; Lucas, 2015]. Affected individuals have an immunodeficiency disorder 
with a reduced life expectancy, and suffer from progressive lung damage as a result of 
recurrent respiratory infections and persistent lung sepsis, caused by bacterial pathogens 
such as H. influenzae and S. pneumoniae. 
3.3.
Study Rationale
This study is the first administration of GSK2292767 to humans. The study will evaluate 
the safety, tolerability, pharmacokinetics and pharmacodynamics of single and repeat 
inhaled doses of GSK2292767 in healthy smokers. This study is intended to provide 
sufficient confidence in the safety of the molecule and preliminary information on target 
engagement to allow progression to further repeat dose and proof of mechanism studies. 
3.4.
Background
GSK2292767 has a similar pharmacological profile to GSK2269557, which has been 
administered to healthy participants (smokers and non-smokers), patients with stable 
COPD; patients experiencing a COPD exacerbation; and patients with persistent, 
uncontrolled asthma. GSK2292767 has a different chemical structure resulting in 
differentiated physical chemistry properties.

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A detailed description of the chemistry, pharmacology, efficacy, and safety of 
GSK2292767 is provided in the Investigator’s Brochure [GlaxoSmithKline Document 
Number 2016N281480_00].
3.5.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of GSK2292767 may be found in the Investigator’s 
Brochure [GlaxoSmithKline Document Number 2016N281480_00]. 

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3.5.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [GSK2292767]
Bronchospasm
A general risk with Inhaled treatment
All doses of study treatment will be administered 
in the clinical pharmacology unit in the presence 
of trained clinical staff. Spirometry will be 
conducted pre and post dose.
Treat immediately with a short-acting inhaled 
bronchodilator. GSK2292767 should be 
discontinued immediately, the participants 
assessed and, if necessary, an alternative 
therapy instituted as deemed appropriate by the 
investigator or the attending physician. 
Participants will be withdrawn from the study.
Unknown risks to an embryo, fetus or nursing 
infant
There are no studies with GSK2292767 in 
pregnant or lactating women.
As specified in the protocol: 

Women who are pregnant, lactating or 
are planning on becoming pregnant 
during the study are not eligible to 
participate. Female participants must be 
postmenopausal. 

If a female participant becomes pregnant 
during the study, she must let the study 
doctor know immediately. The study 
medication will be stopped.
Male participants with female partners of 
reproductive potential must use highly effective 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
contraception methods to avoid pregnancy while 
in this study.
Study Procedures
Sputum induction
Standard sputum induction techniques using 
hypertonic saline can result in bronchospasm 
and therefore could potentially induce 
bronchospasm 
The lowest possible concentration of saline will 
be used first and the procedure terminated once 
sufficient sputum has been obtained. Participants 
will receive a dose of bronchodilator prior to 
starting the procedure.
The procedure will stopped immediately and the 
participant treated with a short-acting inhaled 
bronchodilator should bronchospasm occur and 
a significant reduction in FEV1 ( >25% from pre 
procedure baseline) observed
Bronchoscopy
Sore throat and transient cough can occur 
following bronchoscopy but are self limiting. 
Sedation is used for the procedure with 
associated risks and is with low dose midazolam 
and Fentanyl.
There is a small risk of transient pyrexia that 
typically occurs within 24 to48-hours of the BAL 
procedure. 
Bronchoscopy/BAL will be performed by an 
experienced bronchoscopist in accordance with 
the guidelines published by the British Thoracic 
Society [Du Rand, 2013] in a dedicated ward 
area.
The use of sedation and local anaesthetics for 
the bronchoscopy will be according to local 
practice. Participants will be continuously 
monitored throughout the procedure for pulse, 
blood pressure and pulse oximetry. 
In case of an adverse event following the BAL 
procedure participants will be kept under 
observation at the discretion of the investigator 
and a Respiratory Physician review obtained if 
indicated.

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3.5.2.
Overall Benefit Risk Conclusion
The study will be run in a GSK unit with expertise in conducting first time in human 
studies and with adequate equipment and staff training to manage clinical emergencies.
The GSK unit is based in a teaching hospital. Participant enrolment will be limited to 
otherwise healthy male and female (of non-childbearing potential) cigarette smokers who 
also agree to adhere to mandated contraception requirements.
In this single and repeat dose study; evidence for adverse events will be monitored 
closely, both via subjective reporting and by objective means, i.e. serial assessments of 
vital signs, ECGs and clinical laboratory information. The in-house periods as detailed in 
the SoA will allow for continuous medical monitoring for all participants following the 
first dose.
An interlocking cohort dose escalation design will be used for Part A which will ensure 
approximately fortnightly dose escalations to occur while allowing for a sufficient 
washout period (see Section 5 for a detailed discussion of the study design). Sentinel 
dosing will be used at each dose escalation and also for the repeat dose cohort. Dose 
escalation will only proceed after a blinded review of safety, tolerability and 
pharmacokinetics obtained in at least 5 active participants at the prior dose level. For 
further details of the dose escalation and stopping criteria see Section 7.2.
For Part B (the repeat dose component), the intention is to test only one dose. A review 
meeting will be held after Part A and prior to Part B to review the safety, tolerability and 
pharmacokinetic data of single doses up to 24 hours. Following review of this data the 
dose for Part B will be selected and will not exceed 2000 mcg.
Sputum induction will be performed and monitored by suitably trained medical staff. 
Bronchoscopy will be performed in Part B to assess airway drug levels. Bronchoscopy 
will be undertaken by an experienced bronchoscopist in accordance with the guidelines 
published by the British Thoracic Society [Du Rand, 2013] in a dedicated ward area.
Participants will return to the clinical unit for a follow up safety examination and adverse 
event reporting 7 to 14 days post the final dose. 

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4.
OBJECTIVES AND ENDPOINTS
Objective
Endpoint
Primary

To assess the safety and tolerability of 
single and repeat doses of GSK2292767 as 
a dry powder in healthy cigarette smokers.

Safety and tolerability of GSK2292767 as 
assessed by clinical monitoring of: 

Vital Signs 

Spirometry

ECG 

Laboratory safety data

Adverse events (AEs)
Secondary

To determine the pharmacokinetic profile of 
single and repeat doses of GSK2292767 
as a dry powder in healthy cigarette 
smokers.

GSK2292767 plasma concentration data 
and derived pharmacokinetic parameters 
including area under the plasma drug 
concentration versus time curve (AUC(0-t), 
AUC(0-24), AUC(0-∞)), maximum observed 
plasma drug concentration (Cmax), time to 
maximum observed plasma drug 
concentration (Tmax),terminal half-life (T1/2) 
and trough concentrations (C) following 
single and repeated dry powder doses, 
where data allow.

To investigate the steady-state trough 
concentration of GSK2292767 in lung 
epithelial lining fluid (ELF) and 
Bronchoalveolar lavage (BAL) cell pellet
after repeat inhaled dry powder 
administration in healthy cigarette smokers.

BAL concentrations of GSK2292767 and 
derived lung ELF and cell pellet deposition 
parameters.
Exploratory

To determine the pharmacodynamic effect 
of GSK2292767 on the biomarker PIP3 in 
induced sputum after single and repeat 
doses of GSK2292767administered as a 
dry powder in healthy cigarette smokers.

PIP3 peak area as a proportion of (PIP3 
peak area + PIP2 peak area) in induced 
sputum cells.

To explore the intracellular distribution, 
binding and lysosomal disposition of 
GSK2292767 from lung resident cells 
derived from bronchoalveolar lavage at 
steady-state following repeat administration 

Semi quantitative characterisation of 
intracellular distribution of GSK2292767 
within lung resident cells, binding and 
lysosomal uptake and retention.

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Objective
Endpoint

To generate samples that will be used to 
characterise the metabolic profile of 
GSK2292767 in plasma, following single 
and repeat doses of GSK2292767 
administered as a dry powder in healthy 
cigarette smokers. 

Characterisation and quantification of 
metabolites in plasma.

To collect urine samples only at the highest 
proposed dose level to characterise the 
renal excretion of systemically available 
drug following inhaled delivery.

Semi-quantitative characterisation of 
amount of parent GSK2292767 excreted in 
urine
5.
STUDY DESIGN
5.1.
Overall Design
This is a two part, single site, randomised, double-blind (sponsor open), placebo 
controlled study in healthy smokers.
Part A

Part A will consist of two 3-period interlocking cohorts to evaluate the safety, 
tolerability and pharmacokinetics of ascending single doses of GSK2292767 
administered as a dry powder. Pharmacodynamic effects on biomarkers will also 
be assessed.

In each cohort 16 participants will be randomised to one of four treatment 
sequences. 12 participants will receive placebo in one of the periods, where as 
four participants will receive the active dose in all periods. 

The planned doses of GSK2292767 for this study are 50, 100, 200, 500, 1000 and 
2000 μg, and these may be modified based on review of safety, tolerability and 
PK data . The two cohorts together are to achieve dose escalation from a low 
starting dose to a maximum safe and well-tolerated dose.

On the first day of dosing, only two participants will be dosed (randomisation 
schedule designed so that one placebo and one active will be dosed on first day). 
Following review of the safety data for the first set of participants, and assuming 
no safety concerns, the remaining participants will be dosed.

Following each dose level, safety data (AE, vital signs, ECG and clinical lab 
safety test) and PK data (up to 24h) for a minimum of 5 participants on active will 
be reviewed before proceeding to the next dose level.

A maximum total dose of 2000 μg over a 24 hour period will not be exceeded. 
Part B is planned to follow Part A and progression will be based on an acceptable safety, 
tolerability and pharmacokinetic profile. The selection of an appropriate dose for Part B 

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will be performed upon consideration of available safety and tolerability and PK data 
from Part A. 
The highest well tolerated dose achieved in Part A will be selected for Part B. Part A 
participants will be considered for Part B, with a washout period of at least 2 weeks 
between doses for an individual participant. These participants will be re-screened as 
detailed in the SoA with the exception of the sputum induction procedure.
Part B

Part B will evaluate the safety, tolerability and pharmacokinetics of repeat doses 
of GSK2292767 administered as a dry powder. Pharmacodynamic effects on 
biomarkers will also be assessed. 

Twelve participants will be randomised to receive GSK2292767 or the matching 
placebo, once daily for 14 consecutive days. Participants will be randomised to 
active or placebo in a 3:1 ratio.

The total daily dose will not exceed doses that are considered to be well tolerated 
in Part A.

On the first day of dosing, only two participants will be dosed for the 14 day 
period (randomisation schedule designed so that one placebo and one active will 
be dosed on first day). Following a review of the safety data for the first set of 
participants (after completion of the 14 day dosing) the remaining participants 
will be dosed.
Study medication will be administered in a fasted state for all parts of the study. 
Part A: Study Duration
Screening
Within 1 to 30 days prior to the first dose
Treatment Period
Each cohort will be comprised of three treatment periods. During each 
period, participants will be admitted to the unit the day before dosing and will 
be discharged after completion of 24h post-dose assessments.
Washout Period
Will be approximately 4 weeks between doses for an individual participant
Follow-up
At least 7 days and no greater than 14 days after last study drug 
administration. If warranted, additional follow-up visits may be scheduled.

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Part B: Study Duration
Screening
Within 1 to 30 days prior to the first dose
Treatment Period
Will be 14 days. Participants will remain in-house during the entire dosing 
period and be discharged on Day 15 after completion of all assessments.
Follow-up
At least 7 days and no greater than 14 days after last study drug 
administration. If warranted, additional follow-up visits may be scheduled.
5.2.
Number of Participants
In Part A for each cohort, a sufficient number of participants will be screened to achieve 
16 randomised participants. Participants will be randomised to one of four treatment 
sequences as detailed in Section 7.3. 
In Part B, a sufficient number of participants will be screened to achieve 12 randomised 
participants with the aim to achieve approximately 9 completed participants on the active 
treatment group and 3 on placebo. Participants will be randomised to either GSK2292767 
or placebo as detailed in Section 7.3.
If participants prematurely discontinue the study, additional replacement participants may 
be recruited and assigned to the same treatment sequence/regimen at the discretion of the 
Sponsor in consultation with the investigator.
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the follow up visit. 
The end of the study is defined as the date of the last follow-up visit of the last participant 
in the study. 
5.4.
Scientific Rationale for Study Design
The study design has addressed regulatory recommendations for First Time in Human 
(FTIH) studies and preclinical findings for GSK2292767, contributing to the frequency, 
type and duration of safety assessment and monitoring during treatment periods. This 
study will include placebo control within each treatment period to allow for a valid 
evaluation of adverse events attributable to treatment versus those independent of 
treatment.
This study will recruit healthy smokers to remain consistent with previous studies, and 
increase the likelihood of obtaining sputum samples.
Part A will be utilising placebo replacement, and the interlocking design has been set-up 
such that dose escalations are able to occur approximately every 2 weeks and participants 
approximately have a 4 week wash out period between treatment periods. This will allow 
for any adjustment needed based on emerging safety, tolerability and pharmacokinetic 

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information, and sufficient time between doses to eliminate most if not all the drug from 
the previous dose.
As this is a FTIH study, the doses in Part A will be staggered and participants will be 
divided into several groups. On Day 1 of each treatment period two participants will be 
dosed, 1 on active and 1 on placebo. Assuming adequate clinical safety from the Day 1 
participants, the remaining 14 participants will be subsequently dosed in staggered
groups. 
Dose escalation decisions, including the definition of the next dose, will be made by the 
GSK Study Team with agreement of the Principal Investigator or delegate, based upon 
review of safety and available PK data from the previous dose(s). The Principal 
Investigator or delegate and other relevant clinical staff will attend the first part of each 
review meeting to update the GSK Study Team on clinical observations from the 
previous dose level and to participate in the blinded data review. The review data set will 
at minimum consist of the listings of any adverse events, liver function test results, 
flagged vital signs, ECG and laboratory findings, and PK results derived from 24 hour 
plasma profiles.
Initial dosing in Part B will not commence until results from Part A have been fully 
reviewed. 
On Day 1, two participants will be dosed; 1 on active and 1 on placebo. Assuming 
adequate safety upon completion at Day 15, the remaining 10 participants will be 
subsequently dosed in staggered groups. In addition for Part B additional blood samples 
may be taken at 48, 72 and 96 hours post Day 14 dose to adequately assess the terminal
elimination rate from plasma of GSK2292767. The preliminary PK data for the dose 
escalation process will be used and the decision documented within this communication 
to the site at the end of Part A and before the commencement and selection of the dose 
for Part B.
Measurement of pharmacodynamic (PD) endpoints for the effects of GSK2292767 on 
PI3Kδ and its downstream pathway has the potential to provide information on the level 
of target engagement. This should help guide appropriate pharmacodynamic assessments 
and possibly determine dose selection for subsequent studies in participants with active 
PI3Kδ pharmacology.
5.5.
Dose Justification
To support dose selection for the proposed study, predictions for the effects of 
GSK2292767 are based on observed pharmacokinetic (PK) and pharmacodynamic (PD) 
data in rats (systemic and lung), in vitro metabolism in rats and in vitro PD assessments 
in human tissues and cell lines. The assumptions made in the development of the model 
to predict systemic exposure and lung deposition are described in the section below.
GSK2292767 is likely to have moderate volume of distribution in human, a moderate-
high plasma clearance (12 to 15 mL/min/kg) and a moderate terminal half-life (11h). Oral 
bioavailability is likely to be low (as for the rat) suggesting that systemic exposure will 
result predominantly from the fraction directly absorbed from the lung.

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GSK2292767 plasma concentration profiles at steady-state in human were predicted from 
the compartmental analysis of the rat data. Human exposure predictions are based on this 
extrapolation and a number of assumptions, taking a conservative approach were 
possible, are detailed as follows:

Lung deposition as a ratio of the amount swallowed is expected to be 1:4 (or 80% 
swallowed of the delivered dose)

Instant dissolution of the dry powder (making drug more available for appearance 
in plasma)

Complete and rapid absorption across the lungs

No attributable oral absorption and contribution to systemic exposure from 
swallowed fraction

Same drug distribution (volume of distribution, Vd) in human as in rat

Human clearance scaled from rat using standard allometry

Linear pharmacokinetics across dose range 50 to 2000 µg

No appreciable (not greater than 2-fold) accumulation on repeat administration 
The following table below contains the output of this simulation for the predicted 
systemic exposures (for Cmax and AUC24) for the proposed dose range in this study:
Table 1
Predicted human systemic PK exposure (plasma) following single 
doses of GSK2292767
Nominal Dose1 (µg)
Predicted2 AUC 
(0-24) (ng.h/mL)
Predicted2 
Cmax (ng/mL)
50
0.125
0.075
100
0.25
0.15
200
0.5
0.3
500
1.25
0.75
1000
2.5
1.5
2000
5
3
1. Amount of GSK2292767 in Ellipta™device
2. Prediction based on the maximum possible 20% of nominal dose deposited in lungs and then being 
systemically available
These predicted exposures represent the most likely systemic exposure in human based 
on the available data and knowledge of inhaled dry powders. However to generate the 
most conservative exposure estimate to humans against the non clinical toxicology data 
and toxicokinetic parameters a 100% lung deposition with 100% bioavailability (as 
opposed to the approximate 20% which is typical for an inhaled dry powder estimate) has 
been used to generate the following Table 2 which shows the relative margins against 
both rat and dog 13 week GLP studies. 

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Table 2
Human safety margins based on the predicted maximum systemic 
exposures (plasma) following a single inhaled administration of 
GSK2292767 to healthy volunteers via Ellipta™compared to the 
NOAEL exposures from rat and dog toxicology studies.
Dose (g)1
Steady-state AUC(0-24)
(ng.h/mL)
Steady-state Cmax
(ng/mL)
Lung Concentrations 
(ng/g)5
Rat2
Dog3
Rat2
Dog3
Rat2
Dog3
Safety cover multiple4
Safety cover multiple4
Safety cover multiple4
50
208
473
115
191
757
1342
100
104
240
58
96
379
671
200
52
120
28
48
189
336
500
21
47
12
19
76
134
1000
10
24
6
10
38
67
2000
5
12
3
5
19
34
1. Nominal Ellipta™dose
2. Based on rat day 13 week GLP tox data (males and females combined) at 3240 µg/kg/day with a No Observed 
Adverse Effect Level (NOAEL) exposure of 43.3 ng/mL and 130 ng.h/mL for Cmax and AUC respectively.
3. Based on dog day 13 week GLP tox data (males and females combined) at 2950 µg/kg/day with a NOAEL 
exposure of 71.5 ng/mL and 296 ng.h/mL for Cmax and AUC respectively.
4. Assuming 100% of the delivered dose is bioavailable in human
5. Assuming 7 or 25% of delivered dose in tox studies is deposited in the lungs and lung weights of 6 or 11 g/kg 
for rat and dog respectively. Human lung weight is 14.3 g/kg (based on 70kg body weight and the maximum 
possible deposition is used for multiples of 100% of nominal dose)
5.5.1.
Starting dose and maximum dose justification
The dose justification for this PI3Kδ asset is guided by not only our understanding of the 
pre-clinical testing of GSK2292767 but also specifically in terms of target pharmacology 
information from another GSK PI3Kδ asset GSK2269557 has also been used. 
GSK2269557 has so far been administered once daily to healthy volunteers, COPD 
patients (both mild/moderate and exacerbating populations) as well as asthmatics. 
Healthy volunteers have received doses up to 6400 µg via nebulisation, 3000 µg via dry 
powder for up to 14 days and mild/moderate COPD patients have received maximum 
doses of 2000 µg up to 14 days and exacerbating COPD patients at 1000 µg doses for 3 
months.
Achieved steady-state plasma exposures at 2000 µg in the 14 day study in healthy 
volunteers achieved an approximate maximum 44% inhibition of PI3Kδ by day 7. Based 
on lung lavage data and intracellular effect compartment concentrations of GSK2269557 
the estimated PI3Kδ inhibition in this study was approximately ≥ 95% by Day 7.
The starting dose of 50 µg is expected to result in at worst (100% systemic exposure) a 
level of systemic exposure in humans that would be at least 100-fold lower than the level 
of exposure deemed as the NOAEL in toxicology species. The predicted Cmax at 50 µg 
would only be expected to give a maximum PI3Kδ inhibition of approximately 10%.

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The maximum dose of 2000 µg is expected to result in at worst (100% systemic 
exposure) a level of plasma exposure in humans that would be in the range of 3-12-fold 
lower than the level of exposure deemed as the NOAEL in toxicology species. The 
predicted Cmax at 2000 µg would give a maximum PI3Kδ inhibition of approximately 
81%.
In terms of topical lung exposure in humans to GSK2292767 this molecule has not been 
in human before and therefore the standard assessment of deposition to the lungs is used, 
using a conservative estimate of 100% for human, as well as relevant toxicology 
information. The minimum lung safety cover based on the maximum proposed dose is 
approximately 19-fold based on the rat data. This is higher than the standard 10-fold 
minimum safety margin for an unmonitorable finding in toxicology for which there was 
NO such finding for GSK2292767.
The systemic exposure will be assessed at each dose level whilst the trial is being 
conducted using the blinded nominal time data to review and update the predictions using 
actual data in particular to make predictions for the higher dose levels in Part A as well as 
the Part B repeat dose phase. Please see Section 7.2 for dose adjustment details.

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6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1. Participant must be 18 to 50 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2. Participants who are overtly healthy as determined by medical evaluation 
including (medical history, physical examination, laboratory tests, and cardiac 
monitoring). A participant with a clinical abnormality or laboratory parameters 
outside the reference range expected for them and the population being studied 
may be included only if the Investigator believes that the finding is unlikely to 
introduce additional risk factors and will not interfere with the study procedures 
or outcomes. 
3. Participants who are current daily cigarette smokers (manufactured and self-
rolled). Must have smoked regularly in the 12-month period preceding the 
screening visit.
4. Normal spirometry (FEV1 80% of predicted) at screening. Predictions will be 
based upon [Quanjer, 2012].
Weight
5. Body weight 50kg and body mass index (BMI) within the range 18 to 31 kg/m2 
(inclusive).
Sex
6. Male and female
a.
Male participants:
A male participant must agree to use contraception as detailed in Appendix 5 of this 
protocol during the treatment period and for at least from the time of first dose of 
study medication until at least 55 (5x11) hours plus an additional 90 days after the 
last dose of study medication and refrain from donating sperm during this period.
GSK2292767 has a predicted half-life of approximately 11 hours.
b.
Female participants: 
A female participant is eligible to participate if she is not pregnant (see Appendix 5), 
not breastfeeding, and:
(i)
Not a woman of childbearing potential (WOCBP) as defined in Appendix 5

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Informed Consent
7.
Capable of giving signed informed consent as described in Appendix 3 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. History or presence of current cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, haematological, or neurological disorders capable of 
significantly altering the absorption, metabolism, or elimination of drugs; 
constituting a risk when taking the study treatment; or interfering with the 
interpretation of data
2. Abnormal blood pressure as determined by the investigator
3. Alanine transaminase (ALT) >1.5x upper limit of normal (ULN) 
4. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 
5. Current or chronic history of liver disease, or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic 
gallstones)
6. Average QTcF >450 msec (based on triplicate ECGs)
NOTES:

The QTc is the QT interval corrected for heart rate according to Fridericia’s 
formula (QTcF) machine-read or manually over-read.

The specific formula that will be used to determine eligibility and 
discontinuation for an individual participant should be determined prior to 
initiation of the study. In other words, several different formulae cannot be used 
to calculate the QTc for an individual participant and then the lowest QTc value 
used to include or discontinue the participant from the trial.

For purposes of data analysis,QTcF, will be used as specified in the Reporting 
and Analysis Plan (RAP).
7. Participants who have asthma or a history of asthma (except in childhood and 
which has now remitted).
Prior/Concomitant Therapy
8. Past or intended use of over-the-counter or prescription medication including 
herbal medications within 14 days prior to dosing. Specific medications listed in 
Section 7.7 may be allowed.
9. Live vaccine(s) within 1 month prior to screening, or plans to receive such 
vaccines during the study

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Prior/Concurrent Clinical Study Experience
10. Participation in the study would result in loss of blood or blood products in 
excess of 500 mL within 56 days.
11. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day
12. Current enrolment or past participation within the last 90 days of exposure to any 
other clinical study involving an investigational study treatment or any other type 
of medical research 
Diagnostic assessments
13. Presence of Hepatitis B surface antigen (HBsAg) at screening Positive Hepatitis 
C antibody test result at screening.
NOTE: Participants with positive Hepatitis C antibody due to prior resolved disease can 
be enrolled, only if a confirmatory negative Hepatitis C Ribonucleic Acid (RNA) test is 
obtained
14. Positive Hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study treatment
NOTE: Test is optional and participants with negative Hepatitis C antibody test are not 
required to also undergo Hepatitis C RNA testing
15. Positive pre-study drug/alcohol screen
16. Positive human immunodeficiency virus (HIV) antibody test
17. Regular use of known drugs of abuse
Other Exclusions
18. Regular alcohol consumption within 3 months prior to the study defined as: An 
average weekly intake of >14 units for males and females. One unit is equivalent 
to 8 g of alcohol: a half-pint (~240 mL of beer, 1 glass (125 mL) of wine or 1 (25 
mL) measure of spirits. 
19. Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy that, in the opinion of the investigator or medical monitor, contraindicates 
participation in the study
20. Participants who are unable to produce a total weight of at least 100 mg of 
selected sputum during sputum induction at screening.
21. Participants whose primary consumption of tobacco is via methods other than 
cigarettes (manufactured or self-rolled). Primary methods of tobacco 
consumption that are excluded include, but are not limited to pipes and cigars. 
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit 
juice, pomelos, exotic citrus fruits, grapefruit hybrids from 7 days before the start of 
study treatment until after the final dose.

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
In all Parts, on all dosing days, participants will be required to fast from at least 2 
hours before drug administration and until 2 hours after administration of study 
treatment. At other times, snacks and meals will be provided by the clinical unit. 
Water will be allowed as desired except for 2 hours before and 2 hours after drug 
administration.
6.3.2.
Caffeine, Alcohol, and Tobacco

During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for 6 hours 
before the start of dosing until after collection of the final pharmacokinetic (PK) 
and/or pharmacodynamic sample.

During each dosing session, participants will abstain from alcohol for 24 hours 
before the start of dosing until after collection of the final PK and/or 
pharmacodynamic sample. 

Smoking is permitted during the study, whilst resident in the unit participants will be 
escorted to a designated smoking area.
6.3.3.
Activity

Participants will abstain from strenuous exercise for a minimum of 48 hours before 
each blood collection for clinical laboratory tests. Participants may participate in 
light recreational activities during studies (eg, watching television, reading).
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomised. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse events 
(SAEs).
Individuals who were reserved and not subsequently dosed and individuals who do not 
meet the criteria for participation in this study (screen failure) may be rescreened once. 
Rescreened participants should be assigned a new participant number.
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.

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7.1.
Treatments Administered
Study Treatment 
Name:
GSK2292767 
ELLIPTA™Drug 
Powder Inhaler (DPI) 
(50 μg)
GSK2292767 
ELLIPTA™DPI (500 
μg)
Placebo ELLIPTA™
DPI
Formulation 
description:
GSK2292767 blended 
with lactose and 
magnesium stearate
GSK2292767 blended 
with lactose and 
magnesium stearate
Lactose
Dosage 
formulation:
DPI
DPI
DPI
Unit dose 
strength(s)/Dosa
ge level(s):
50 μg per blister X µg / 
blister
500 μg per blister
N/A
Route of 
Administration 
Inhaled
Inhaled
Inhaled
Dosing 
instructions:
Inhale as directed
Inhale as directed
Inhale as directed
Method for 
individualizing 
dosage:
DPI containing a single 
strip with 30 blisters
DPI containing a single 
strip with 30 blisters
DPI containing a single 
strip with 30 blisters
Packaging and 
Labeling
Do not include a 
sample of the 
label text or 
details of pack 
design in the 
protocol. 
Study Treatment will be 
labelled as required per 
country requirement.
Study Treatment will be 
labelled as required per 
country requirement.
Study Treatment will be 
labelled as required per 
country requirement.
Manufacturer
GSK
GSK
GSK
7.2.
Dose Modification
This protocol allows some alteration from the currently outlined dosing schedule, 
however in this study, the maximum total daily dose will not exceed 2000 µg (nominal) 
GSK2292767 and the maximum daily exposure of GSK2292767 is not intended to 
exceed the steady-state exposure at the NOAEL in the 13 week rat toxicology studies 
(AUC(0-24h) 130 ng.h/mL; Cmax 43.3 ng/mL). 
The following dose adjustment/PK stopping criteria will be employed:

If exposure in a participant reaches or is predicted to reach 130 ng.h/mL for AUC(0-
24h) and/or 43.3 ng/mL for Cmax, the participant will be withdrawn from the study. 

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
If mean group exposure reaches or is predicted to reach 130 ng.h/mL for AUC(0-24h) 
and/or 43.3 ng/mL for Cmax, dose escalation will be stopped.
If 3 or more participants withdraw based on PK stopping criteria, dose escalation will be 
temporarily halted and no further participants will be dosed until review of all the data 
has taken place.
7.3.
Method of Treatment Assignment
Study using 
Pre-Coded 
Randomisation 
provided to 
site
On Day 1, participants will be assigned a unique number 
(randomisation number) in ascending numerical order at each study 
site. The randomisation number encodes the participant’s 
assignment to one of the treatment sequences (Part A) or treatment 
arms (Part B) of the study, according to the randomisation schedule 
generated prior to the study by the Clinical Statistics Department at 
GSK. Each participant will be dispensed blinded study treatment, 
labelled with their unique randomisation number, throughout the 
study. Once a randomisation number has been assigned, it must not 
be reassigned.
7.3.1.
Part A
In Cohorts 1 & 2, participants will be randomised to one of 4 treatment sequences as 
described in Table 3. Participants will be randomised such that in each period 12 
participants will receive GSK2292767 and 4 participants will receive placebo. Sentinel 
dosing of the first 2 participants in each period will be performed ensuring one 
participants will receive the active dose strength and the other on placebo. No participant 
will be a sentinel participant on more than one occasion. 
Table 3
Part A: Treatment Sequences
1
1
4
Placebo
Dose Level 3
Dose Level 5
2
4
Dose Level 1
Placebo
Dose Level 5
3
4
Dose Level 1
Dose Level 3
Placebo
4
4
Dose Level 1
Dose Level 3
Dose Level 5
2
5
4
Placebo
Dose Level 4
Dose Level 6
6
4
Dose Level 2
Placebo
Dose Level 6
7
4
Dose Level 2
Dose Level 4
Placebo
8
4
Dose Level 2
Dose Level 4
Dose Level 6

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The planned treatments are as indicated in Table 4:
Table 4
Part A: Planned Treatments
Treatment
Dose Level
Description (Planned dose level)
A
Placebo
Placebo inhaled single dose
B
Dose Level 1
50 g GSK2292767 inhaled single dose
C
Dose Level 2
100 g GSK2292767 inhaled single dose
D
Dose Level 3
200 g GSK2292767 inhaled single dose
E
Dose Level 4
500 g GSK2292767 inhaled single dose
F
Dose Level 5
1000 g GSK2292767 inhaled single dose
G
Dose Level 6
2000 g GSK2292767 inhaled single dose
1.
Note: Doses may be modified based on emerging data.
7.3.2.
Part B
Nine participants will be randomised to receive the selected dose strength of 
GSK2292767 and 3 participants will be randomised to receive placebo. The planned dose 
in Part B is 2000 g GSK2292767 once daily for 14 days. However, the actual dose will 
be selected only after review of the safety, tolerability and PK data from Part A. The dose 
will not exceed 2000 g GSK2292767 per day. Sentinel dosing of the first 2 participants 
will be performed ensuring one participant will receive the active dose strength and the 
other on placebo for the 14 day treatment period.
Table 5
Part B Planned Treatments
Treatment
Dose Level
Description (Planned dose level)
H
Placebo
Placebo inhaled repeat dose
I
Dose Level 7
2000 g GSK2292767 inhaled repeat dose
1.
Note: Dose may be modified based on emerging data.

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7.4.
Blinding
Blind Break 
(Envelopes)
A sealed envelope that contains the study treatment assignment for 
each participant will be provided to the investigator. The sealed 
envelope will be retained by the investigator (or representative) in a 
secured area.
GSK must be notified before the blind is broken unless 
identification of the study treatment is required for a medical 
emergency in which the knowledge of the specific blinded study 
treatment will affect the immediate management of the participant’s 
condition (eg, antidote is available). In this case, GSK must be 
notified within 24 hours after breaking the blind. The date and 
reason that the blind was broken must be recorded in the source 
documentation and electronic case report form (eCRF), as 
applicable.
Once the study is complete, all envelopes (sealed and opened) must 
be inventoried and returned to the GSK.
Blinded study 
with unblinded 
site pharmacy 
staff who are 
labelling and 
ensuring release 
of the study drug
In Part A participants will be randomised to one of four treatment 
sequences, and in Part B participants will be randomised in a [3:1] 
ratio to receive study treatment. Investigators will remain blinded to 
each participant’s assigned study treatment throughout the course 
of the study. In order to maintain this blind, unblinded site 
pharmacy staff will be responsible for labelling and ensuring 
release of the blinded study treatment to the investigator or 
designee.
Unblinded monitors and in the event of a Quality Assurance audit, 
the auditor(s) will be allowed access to un-blinded study treatment 
records at the site(s) to verify that randomization/dispensing has 
been done accurately.
A participant will be withdrawn if the participant’s treatment code is unblinded by the 
investigator or treating physician. The primary reason for discontinuation (the event or 
condition which led to the unblinding) will be recorded in the Case Report Form (CRF).
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any participant with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s treatment assignment, may be sent to investigators in 
accordance with local regulations and/or GSK policy.

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7.5.
Preparation/Handling/Storage/Accountability

The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received and any 
discrepancies are reported and resolved before use of the study treatment.

Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study 
treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions 
with access limited to the investigator and authorized site staff.

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (ie, receipt, reconciliation, and final disposition records).

Further guidance and information for the final disposition of unused study 
treatment are provided in the Study Reference Manual (SRM). 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff. Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case 
of unintentional occupational exposure notify the monitor, Medical Monitor 
and/or GSK study contact.

A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the investigator, where this is required by local laws, or is available 
upon request from GSK.
7.6.
Treatment Compliance

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. 

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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 
enrolment or receives during the study must be recorded along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
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. 
Paracetamol/Acetaminophen, at doses of 2 grams/day, is permitted for use any time 
during the study. Other concomitant medication may be considered on a case-by-case 
basis by the investigator in consultation with the Medical Monitor if required.
7.8.
Treatment after the End of the Study
Participants will not receive any additional treatment from GSK after completion of the 
study because the safety and efficacy of GSK2292767has not yet been defined.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
8.1.1.
Pharmacokinetic Stopping Criteria
This protocol allows some alteration from the currently outlined dosing schedule, please 
refer to Section 7.2 for more details.
8.1.2.
Liver Chemistry Stopping Criteria
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 or if 
the investigator believes that it is in the best interest of the participant. 
Study treatment will be discontinued for a participant if liver chemistry stopping criteria 
are met:

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Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6.
8.1.3.
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. 

The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period. 
A participant that meets the bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from study treatment. 

QTcF >500 msec,

Increase from baseline: QTcF >60 msec
See the SoA for data to be collected at the time of treatment discontinuation and follow-
up and for any further evaluations that need to be completed.
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*

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8.1.4.
Safety Stopping Criteria
Dose escalation stopping criteria include the following:

A serious adverse event (SAE) occurring in 1 or more participants receiving 
GSK2292767 that is considered at least possibly related to study drug;

Two or more severe adverse events occurring in a group of participants receiving 
GSK2292767 that are considered at least possibly related to study drug.
8.1.5.
Temporary Discontinuation
Participants withdrawn from study treatment will be withdrawn from the study.
8.1.6.
Rechallenge
8.1.6.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
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 taken and not tested, and the investigator must document this in the site 
study records.

Refer to the SoA for data to be collected at 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. 
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.

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
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. 

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9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. 

Protocol waivers or exemptions are not allowed 

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA.

The maximum amount of blood collected from each participant over the 
duration of the study, including any extra assessments that may be required, will 
not exceed 500 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.

If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order:
1. pregnancy test
2. physical examinations
3. vital signs
4. 12-lead ECG
5. lung function tests (spirometry)
6. blood draws
7. sputum induction
Note: The timing of the assessments must allow the blood draw to occur at the 
exact nominal time.

The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamic/biomarker 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 change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File which is approved by the 

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relevant GSK study team member and then archived in the study sponsor and 
site study files, but this will not constitute a protocol amendment.

The institutional review board (IRB)/ Independent Ethics Committee (IEC) will 
be informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the Informed Consent Form.
9.1.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
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 (see Section 8).
9.1.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the signing of the ICF until the follow-up visit
at the time points specified in the SoA (Section 2).

All AEs will be collected from the start of treatment until [the follow-up visit] at 
the time points specified in the SoA (Section 2).

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (CRF) not the AE section.

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstances should this exceed 24 hours, as indicated in 
Appendix 4. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs 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.

The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 4.

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9.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
9.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 8.3). Further information on follow-up procedures is given in 
Appendix 4.
9.1.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information eg, summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
9.1.5.
Pregnancy

Details of all pregnancies in female partners of male participants will be collected 
after the start of study treatment and until 7 days after the last dose.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.2.
Treatment of Overdose
For this study, any dose of GSK2292767 greater than 2000 µg within a 24-hour time 
period 2 hour will be considered an overdose.
Sponsor does not recommend specific treatment for an overdose.

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In the event of an overdose, the investigator should:
1. Contact the Medical Monitor immediately.
2. Closely monitor the participant for AE/SAE and laboratory abnormalities 
until study treatment can no longer be detected systemically (at least 3 days).
3. Obtain a plasma sample for PK analysis within 3 days from the date of the 
last dose of study treatment if requested by the Medical Monitor (determined 
on a case-by-case basis).
4. Document the quantity of the excess dose as well as the duration of the 
overdosing in the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
9.3.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA. 
9.3.1.
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 (at screening only).

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.
9.3.2.
Vital Signs

Tympanic temperature, pulse rate, respiratory rate, and blood pressure will be 
assessed.

Blood pressure and pulse measurements will be assessed semi supine with a 
completely automated device. Manual techniques will be used only if an 
automated device is not available or in the case of an emergency.

Blood pressure and pulse measurements should be preceded by at least 5 
minutes of rest for the participant in a quiet setting without distractions (eg, 
television, cell phones).

Vital signs will be measured (triplicate at screening) in a semi-supine position 
after 5 minutes rest and will include temperature (single reading), systolic and 
diastolic blood pressure, and pulse (recorded at intervals of no more than 2-5 
minutes apart). The first reading should be rejected. The second and third 
readings should be averaged to give the measurement to be recorded in the CRF.

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9.3.3.
Electrocardiograms

Triplicate/Single 12-lead ECG will be obtained as outlined in the SoA using an 
ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTFc intervals. Refer to Section 8.1.3 for QTc withdrawal 
criteria and additional QTc readings that may be necessary.

At each time point at which triplicate ECG are required, 3 individual ECG 
tracings should be obtained as closely as possible in succession, but no more 
than 2 to 5 minutes apart. 
9.3.4.
Spirometry

The maximal amount of air forcefully exhaled in 1 second (FEV1) and forced 
vital capacity (FVC) will be measured using a spirometer at the time indicated in 
the SoA.

All sites will use their existing spirometry equipment.

FEV1 and FVC measurements will be repeated until three technically acceptable 
measurements (within 150 mL of each other) have been made. Only the best 3 
measurements will be recorded in the eCRF.

A full description of the timing and conduct of spirometry procedures will be 
provided in the SRM.
9.3.5.
Cardiac Telemetry

Continuous cardiac telemetry will be performed in Part A, from approximately 1 
hr pre-dose to 5 hours post dosing in each period. Full disclosures will be 
maintained as part of the participant’s source documents and will be reviewed in 
detail.

Cardiac telemetry might also be done in Part B depending on emerging data (lead 
II real-time display ECG monitoring is acceptable).
9.3.6.
Holter Monitoring

Holter monitoring will be performed in Parts A & B at screening only. (3 lead 
holter monitoring is acceptable) for the duration of 24hrs.
9.3.7.
Bronchoscopy

Bronchoscopy assessments will be performed as described in the SoA table.

Standard procedures for the bronchoscopy assessments described in full in the 
SRM.

Bronchial alveolar lavage (BAL) will be collected at bronchoscopy.

BAL samples for GSK2292767 and urea analysis will be collected at the time 
points listed in the SoA. 

Details of BAL sample collection, processing, storage and shipping procedures 
are provided in the SRM.

GSK2292767 concentration in BAL will need to be corrected for dilution using 
urea concentration as a correction factor. Consequently a plasma sample taken as 
soon as practically possible before the BAL samples will be used to determine 
both plasma and BAL urea concentrations in order to determine the dilution 
factor.

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9.3.8.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency. 

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or at follow-up should be repeated until the 
values return to normal or baseline or are no longer considered significantly 
abnormal by the investigator or medical monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the aetiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.

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 (eg, SAE 
or AE or dose modification), then the results must be recorded in the CRF.
9.4.
Pharmacokinetics

Whole blood samples of approximately 3mL will be collected for measurement of 
plasma concentrations of GSK2292767 as specified in the SoA. Instructions for 
the collection and handling of biological samples will be provided by the sponsor. 
The actual date and time (24-hour clock time) of each sample will be recorded.

Samples will be used to measure GSK2292767 for PK analysis and to evaluate for 
the presence of drug-related metabolites. Drug-related metabolites will only be 
assessed at the top dose level in Part A (single dose phase). Each plasma sample 
will be divided into 2 aliquots (1 each for PK and metabolite analysis). Urine will 
also be collected only from the maximum proposed dose group if escalated up to 
(2000 µg) for semi quantitative assessment of the contribution of the kidney in 
renal elimination if possible based on detection. Samples may also be used to 
evaluate safety or efficacy aspects related to concerns arising during or after the 
study.

Plasma and BAL analysis of GSK2292767 will be performed under the 
management of the Bioanalysis, Immunogenicity and Biomarkers department, 
GlaxoSmithKline. Concentrations of GSK2292767 will be determined in all 
samples using the currently approved analytical methodology. Metabolite analysis 
and a semi-quantitative assessment of unchanged drug in urine will be performed 
under the management of the Analytical Sciences & Development department, 

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GlaxoSmithKline and the results will reported under a separate protocol. All raw 
data will be stored in the GLP Archives, GlaxoSmithKline.

BAL cells will be investigated further if possible (depending on cell amount 
obtained and cell health) for cellular uptake, distribution and binding of 
GSK2292767. Priority will be given to BAL analysis of GSK2292767 and cell 
pellet deposition parameters. This work if possible will be conducted under the 
management of the Platform Technology and Science (PTS) department within 
GlaxoSmithKline and documented and reported out within the main study 
outputs.

Further information on collection, processing, storage and shipping procedures 
are provided in the Study Reference Manual (SRM).
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
9.5.
Pharmacodynamics
Pharmacodynamic parameters evaluated in this study are detailed in Section 9.5.
9.6.
Genetics
Genetics are not evaluated in this study.
9.7.
Biomarkers
9.7.1.
Induced Sputum

Saline induced sputum samples will be captured at all of the time points shown in the 
SoA.

The sputum induction process will follow local standard procedures in the presence 
of a trained physician. 

At screening no analysis of the sputum sample is required, only the weight of the 
sputum sample is required to confirm that the participant is able to produce an 
adequate induced sputum sample (>100 mg).

In Parts A and B samples will be processed and analysed for the detection of PIP2 
and PIP3 levels at all time points.

Further information on collection, processing, storage and shipping procedures are 
provided in the Study Reference Manual (SRM).
9.8.
Health Economics OR Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.

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10.
STATISTICAL CONSIDERATIONS
10.1.
Sample Size Determination
Part A
The sample size of 16 participants per cohort for the single dose, dose escalation (cohorts 
1 and 2), is based on feasibility and is deemed an adequate number to provide a 
preliminary assessment of PK and safety prior to progression into the repeat dose cohort. 
However, to illustrate the level of precision that could be expected, a sample size 
calculation has been performed based on PIP3 data collected from GSK2269557 studies.
In PII115117 [GlaxoSmithKline Document Number 2011N124265_00] Part C Cohort 4, 
between and within participant variances for PIP3 (as a proportion of PIP2 and PIP3) at 3 
hours post dose were estimated to be 0.045 and 0.034 respectively on the log scale. 
Applying these estimates to the design of Part A yields a predicted treatment comparison 
standard error of each active dose to placebo of approximately 0.1140 on a log scale. This 
would enable half widths of the 95% confidence interval (CI). to be achieved of 0.1898 
on the log scale which translates to (-17%, 21%) assuming no difference between 
treatments for the comparison of PIP3 proportion of each active dose over placebo. 
Assuming a smaller PIP3 proportion, standard error on a logged scale of 0.071 (as 
observed in PII116617 Parts B and C combined), the half-widths of the 95% CI would 
reduce to 0.1182 on the log-scale which translates to (-11%, 13%) assuming no 
difference between treatments.
Part B:
It is anticipated that a sufficient number of participants will be enrolled in the study such 
that data are obtained from 12 participants (9 participants on active and 3 on placebo). 
These numbers; together with the participants in Part A, are deemed adequate in order to 
provide a preliminary assessment of safety and PK prior to progression into longer 
duration studies However, to illustrate the level of precision that could be expected, a 
sample size calculation has been performed based on PIP3 data collected from 
GSK2269557 studies.
In PII116617 [GlaxoSmithKline Document Number 2013N183586_00] Part B, the 
between participant standard deviation of the differences in treatments of change from 
baseline at Day 1 3H was estimated to be 0.187 on the log scale. Using this as the 
estimate along with the study design for Part B, this would enable half widths of the 95% 
C.I. to be achieved of 0.2283 on the log scale which translates to (-20%, 26%) 
assuming no difference between treatments for the comparison of PIP3 proportion of 
active dose over placebo. 
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:

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Population
Description
Screened
All participants who were screened
Safety
All randomised participants who take at least 1 dose of study 
treatment. Participants will be analyzed according to the treatment 
they actually received.
Pharmacokinetics
Participants in the ‘All participant’ population for whom a 
pharmacokinetic sample was obtained and analysed.
10.3.
Statistical Analyses
Statistical analysis will be performed by, or under the direct auspices of Clinical 
Statistics, GlaxoSmithKline. 
Complete details of the planned statistical analyses will be provided in the Reporting and 
Analysis Plan (RAP).
10.3.1.
Safety Analyses
All safety analyses will be performed on the Safety Population.Safety data will be 
presented in tabular and/or graphical format and summarised descriptively according to 
GSK’s Integrated Data Standards Library (IDSL) standards.
10.3.2.
Pharmacokinetic Analyses
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacokinetics 
Modelling and Simulation (CPMS) department within GlaxoSmithKline. Plasma 
GSK2292767 concentration-time data will be analysed by non-compartmental methods 
with WinNonlin. Calculations will be based on the actual sampling times recorded during 
the study. From the plasma concentration-time data, the following pharmacokinetic 
parameters will be determined, as data permit: maximum observed plasma concentration 
(Cmax), time to Cmax (Tmax), area under the plasma concentration-time curve [AUC(0-t), 
AUC(0-24), and AUC(0-∞)], concentration at trough (Ctrough is the sample with the lowest 
concentration which will be immediately before the next day’s dose) and apparent 
terminal phase half-life (t½).
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarised descriptively. All pharmacokinetic data will be stored in the Archives, 
GlaxoSmithKline Pharmaceuticals, R&D.
Statistical analyses of the pharmacokinetic parameter data will be the responsibility of 
Respiratory Clinical Statistics, GlaxoSmithKline.

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10.3.2.1.
Dose Proportionality, for Part A
A preliminary analysis will be conducted to assess the dose proportionality of loge-
transformed parameters AUC(0-t), Ctrough and Cmax, using the power model. If the power 
model indicates deviations from dose proportionality, further analyses may be performed 
using the Analysis of Variance (ANOVA) method.
10.3.2.2.
Dose Accumulation, for Part B
A preliminary assessment of dose accumulation of GSK2292767 will be made on AUC(0-
24), Ctrough and Cmax. Point estimates and 90% Confidence Intervals will be generated for 
the difference between the PK parameters for Day 1 and Day 14.
10.3.2.3.
Steady State, for Part B
Attainment of steady state will be assessed separately for each cohort through the visual 
inspection of individual Cmax and Ctrough values plotted over time.
10.3.2.4.
Peak to Trough Ratio
Peak to trough ratio will be calculated on each study day as the concentration 5 minutes 
after dosing divided by the Ctrough concentration on that study day. Peak to trough 
concentrations will be plotted over time. A longitudinal model may be fitted to explore 
the change in ratio over time.
10.3.3.
Other Analyses
Pharmacodynamic, and biomarker exploratory analyses will be described in the reporting 
and analysis plan. 
10.3.4.
Interim Analyses
No formal statistical analysis is planned.
A review of preliminary safety and pharmacokinetic data will be conducted prior to dose 
escalating within Part A and before confirmation of the dose for Part B. Safety data will 
be provided by the site at the end of each dosing session. Preliminary analysis of the PK 
data will be performed using nominal time information to justify the taking of additional 
blood samples in Part B at 48, 72 and 96 hours post Day 14 dose. If the half-life cannot 
be adequately determined from a 24 hour sampling regimen then these additional samples 
will be taken and documented in the dose escalation report before the commencement of 
Part B. Pharmacokinetic data will be provided by or under the auspices of Clinical 
Pharmacokinetics Modelling & Simulation (CPMS).
Pharmacodynamic data will be analysed on an ongoing basis as the data become 
available.

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11.
REFERENCES
Ali K, Bilancio A, Thomas M, Pearce W, Gilfillan AM, Tkaczyk C et al. Essential role 
for the p110δ phosphoinositide 3-kinase in the allergic response. Nature. 2004;431:1007–
1011.
Angulo I, Vadas O, Garçon F, Banham-Hall E, Plagnol V, Leahy TR et al. 
Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and 
airway damage. Science. 2013;342(6160):866-71. 
Du Rand IA, Blaikley J, Booton R, Chaudhuri N, Gupta V, Khalid S et al. British 
Thoracic Society guideline for diagnostic flexible bronchoscopy in adults. Thorax 
2013;68:i1–i44.
Fallah MP, Chelvarajan RL, Garvy BA, Bondada S. Role of phosphoinositide 3 kinase-
Akt signaling pathway in the age-related cytokine dysregulation in splenic macrophages 
stimulated via TLR-2 or TLR-4 receptors. Mech Ageing Dev. 2011;132(6-7):274-86.
Fung-Leung WP. Phosphoinositide 3-kinase delta (PI3Kδ) in leucocyte signaling and 
function. Cell Signal. 2011;23(4):603-8.
GlaxoSmithKline Document Number 2011N124265_00, Clinical Pharmacology Study 
report for study PII115117, dated 10-Apr-2013
GlaxoSmithKline Document Number 2013N183586_00, Clinical Pharmacology Study 
report for study PII116617, dated 19-Jun-2014
GlaxoSmithKline Document Number 2016N281480_00, GSK2292767 Investigator’s 
Brochure, dated 11-Oct-2016
Holgate ST. Pathogenesis of asthma. Clin. Exp. Allergy 2008;38:872–897.
Horak F, Puri KD, Steiner BH, Holes L, Xing G, Zieglmayer P et al. Randomized phase 1 
study of the phosphatidylinositol 3-kinase δ inhibitor idelalisib in patients with allergic 
rhinitis. J Allergy Clin Immunol. 2016;137(6):1733-41
Infinity Pharmaceuticals. Infinity Reports Topline Data from Phase 2a Exploratory Study 
of Duvelisib in Patients with Mild, Allergic Asthma, 2014.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U et al. Dominant-
activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ
result in T cell senescence and human immunodeficiency. Nat Immunol. 2015;15(1):88-
97.
Marwick JA, Caramori G, Casolari P, Mazzoni F, Kirkham PA, Adcock IM et al. A role 
for phosphoinositol 3-kinase delta in the impairment of glucocorticoid responsiveness in 
patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol. 
2010;125(5):1146-53.

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Milara J, Lluch J, Almudever P, Freire J, Xiaozhong Q, Cortijo J. Roflumilast N-oxide 
reverses corticosteroid resistance in neutrophils from patients with chronic obstructive 
pulmonary disease. J Allergy Clin Immunol. 2014;134(2):314-22.
Okkenhaug K, Ali K, Vanhaesebroeck B. Antigen receptor signalling: a distinctive role 
for the p110δ isoform of PI3K. Trends Immunol. 2007;28:80–87.
Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E et al. Impaired B and 
T cell antigen receptor signaling in p110δ PI 3-kinase mutant mice. Science 
2002;297:1031–1034.
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH et al. Multi-ethnic 
reference values for spirometry for the 3-95-yr age range: the global lung function 2012 
equations. Eur Respir J. 2012;40(6):1324-43.
Rossios, C, To, Y, Osoata, G, Ito M, Barnes PJ, Ito K. Corticosteroid insensitivity is 
reversed by formoterol via phosphoinositide-3-kinase inhibition. Br J Pharmacol. 
2012;167(4):775–786.
Rowan WC, Smith JL, Affleck K, Amour A. Targeting phosphoinositide 3-kinase δ for 
allergic asthma. Biochem Soc Trans. 2012;40(1):240-5.
To Y, Ito K, Kizawa Y, Failla M, Ito M, Kusama T et al. Targeting phosphoinositide-3-
kinase-delta with theophylline reverses corticosteroid insensitivity in chronic obstructive 
pulmonary disease. Am J Respir Crit Care Med. 2010;182(7):897-904.
Walton GM, Begg M, Amour A, Hessel EM, Usher AKH, Pottle M et al. Targeting 
Phosphoinositide 3 Kinase Reduces Damaging Neutrophil Functions Without Impairing 
Bacterial Phagocytosis In COPD. Am J Respir Crit Care Med 191;2015:A2740.

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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
μg
Microgram
AE
Adverse Event
aPTT
Activated Partial Thromboplastin Time 
ALT
Alanine Aminotransferase
ALT
Alanine Transaminase 
ANOVA
Analysis of Variance
AST
Aspartate Aminotransferase
AUC
Area Under the Plasma Drug Concentration versus Time Curve 
AUC(0-t)
Area Under the Plasma Drug Concentration versus Time Curve 
from zero to time t
AUC(0-24)
Area Under the Plasma Drug Concentration versus Time Curve 
from zero to 24 hours
AUC(0-∞)
Area Under the Plasma Drug Concentration versus Time Curve 
from zero to infinity
BAL
Bronchoalveolar Lavage 
BMI
Body Mass Index
CIOMS
Council for International Organizations of Medical Sciences 
CFR
Code of Federal Regulations
Cmax
Maximum Observed Plasma Drug Concentration 
COPD
Chronic Obstructive Pulmonary Disease
CONSORT
Consolidated Standards of Reporting Trials 
CPK
Creatine phosphokinase 
CPMS
Clinical Pharmacokinetics Modelling and Simulation
CRF
Case Report Form 
CV
Cardiovascular 
DPI
Drug Powder Inhaler
ECG
Electrocardiogram
eCRF
electronic case report form
ELF
Epithelial Lining Fluid 
FDA
Food and Drug Administration
FEV1
Maximal amount of air forcefully exhaled in 1 second
FSH
Follicle Stimulating Hormone 
FTIH
First Time in Human
FVC
Forced Vital Capacity
g
Gram
GCP
Good Clinical Practice 
GCSP
Global Clinical Safety and Pharmacovigilance 
GSK
GlaxoSmithKline
H
hour
hCG
Human chorionic gonadotropin 
HBsAg
Hepatitis B surface antigen 

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H. 
influenzae
Haemophilus influenzae
HIPAA
Health Insurance Portability and Accountability Act 
HIV
Human Immunodeficiency Virus 
HPLC
High performance liquid chromatography 
HRT
Hormonal Replacement Therapy 
IB
Investigator Brochure
ICF
Informed Consent Form 
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee 
Ig
Immunoglobulin 
IL
Interleukin
INR
International normalized ratio 
IP
Investigational Product
IRB
Institutional Review Board 
IUD
Intrauterine Device 
IUS
Intrauterine Hormone-Releasing System 
Kg
Kilogram
LDH
Lactate dehydrogenase 
mcg
Microgram
mg
Milligram 
mins
Minutes
mL
Milliliter
msec
Milliseconds
MSDS
Material Safety Data Sheet 
ng
Nanogram 
NOAEL
No Observed Adverse Effect Level
PD
Pharmacodynamic 
PI3Kδ
Phosphoinositide 3 Kinase delta 
PIP2
Phosphatidylinositol (4,5)-bisphosphate 
PIP3
Phosphatidylinositol (3,4,5)-trisphosphate 
PK
Pharmacokinetic 
PT
Prothrombin Time 
PTS
Platform Technology and Science
QTcF
QT interval corrected for heart rate according to Fridericia’s 
formula
RAP
Reporting and Analysis Plan 
RNA
Ribonucleic Acid
SAEs
Serious Adverse Events 
SD
Single dose
SDA
Source Document Agreement 
SGOT
Serum Glutamic-Oxaloacetic Transaminase 
SGPT
Serum Glutamic-Pyruvic Transaminase 
SOA
Schedule of Activities
S. 
pneumoniae
Streptococcus pneumoniae

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SRM
Study Reference Manual 
SUSAR
Suspected Unexpected Serious Adverse Reaction
T1/2
Terminal Half-life 
Th2
Type 2 T helper
Tmax
Time to Maximum Observed Plasma Drug Concentration 
C
Trough concentrations 
ULN
Upper Limit of Normal 
Vd
Volume of distribution
WOCBP
Woman Of Childbearing Potential 
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ELLIPTA
WinNonlin

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12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 6 will be performed by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 6
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Activated partial 
thromboplastin time 
(aPTT)3
Prothrombin time (PT)3
Clinical 
Chemistry1
BUN
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose fasting 
(screening only)/ 
non fasting 
Calcium
Alkaline 
phosphatase
Routine 
Urinalysis
Specific gravity
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick
Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests
Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)
Urine alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines).
Serum or urine human chorionic gonadotropin (hCG) pregnancy test (as needed 
for women of childbearing potential)2
Serology (Human Immunodeficiency Virus (HIV) antibody, hepatitis B surface 
antigen [HBsAg], and hepatitis C virus antibody)

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Laboratory 
Assessments
Parameters
The results of each test must be entered into the CRF.
NOTES :
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 8.1 and Section 12.6 (Appendix 6) All events of ALT 3 × upper limit of 
normal (ULN) and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio 
(INR) >1.5, if INR measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an 
SAE (excluding studies of hepatic impairment or cirrhosis).
2.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC.
3.
Part B (Screening) only.
Laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded.

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12.3.
Appendix 3: 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 (eg, 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 Code of Federal Regulations (CFR), ICH guidelines, 
the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 

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informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.

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Dissemination of Clinical Study Data
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 (eg, 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 after study completion 
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.

Definition of what constitutes source data can be found in Source Document 
Agreement (SDA).

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Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development

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12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 

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convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
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.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
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 

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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.
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes 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 

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

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this information to the SAE coordinator.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in SRM.

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12.5.
Appendix 5: 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
1. Premenarchal
2. 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.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, 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: 

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 as described in Table 7 when having penile-vaginal 
intercourse with a woman of childbearing potential 

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
Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration during the protocol-defined time frame. 

Refrain from donating sperm for duration of study and for at least 55 hours plus 
an additional 90 days after the last dose of drug.
Female participants
Table 7
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 ovulation 

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation 

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation

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.)
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. 

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Pregnancy Testing

Pregnancy testing, with a sensitivity of 25 mIU/mL will be performed and assayed in 
a certified laboratory in accordance with instructions provided in its package insert.
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. 

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12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments Guidelines
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue study treatment

Report the event to GSK within 24 hours

Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN or INR 
>1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 
hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN and INR 
≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for pharmacokinetic 
(PK) analysis, obtained [ 3days insert time 
interval recommended by clinical 
pharmacokinetics representative] of last 
dose4 

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
If ALT≥3xULN AND bilirubin 2xULN or INR 

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Liver Chemistry Stopping Criteria 
liver event follow up assessments within 24-
72 hrs

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
>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]. NOTE: not required in 
China.

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, 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
3.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); Hepatitis E IgM antibody 
4.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments. Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SRM. 

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12.7.
Appendix 7: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).