A Randomised, Double-blind, Parallel Group Study to Evaluate the Safety, Tolerability and Pharmacokinetics of a Single Dose of GSK2269557 Administered Via the ELLIPTA™ Dry Powder Inhaler to Healthy Participants
Phase: PHASE1
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: GlaxoSmithKline

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TITLE PAGE
Protocol Title: A randomised, double-blind, parallel group study to evaluate the safety, 
tolerability and pharmacokinetics of a single dose of GSK2269557 administered via the 
ELLIPTA™dry powder inhaler to healthy participants.
Protocol Number: 207674
Short Title: Double-blind study to evaluate the safety, tolerability and pharmacokinetics 
of a single dose of GSK2269557 in healthy participants.
Compound Number:
GSK2269557
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): EudraCT Number 2017-001073-16
Approval Date: 04-APR-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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TABLE OF CONTENTS
PAGE
1.
SYNOPSIS...............................................................................................................5
2.
SCHEDULE OF ACTIVITIES (SOA).........................................................................7
3.
INTRODUCTION....................................................................................................11
3.1.
Study Rationale ..........................................................................................11
3.2.
Background ................................................................................................11
3.3.
Benefit/Risk Assessment ............................................................................12
3.3.1.
Risk Assessment .........................................................................13
3.3.2.
Benefit Assessment.....................................................................14
3.3.3.
Overall Benefit: Risk Conclusion..................................................14
4.
OBJECTIVES AND ENDPOINTS...........................................................................14
5.
STUDY DESIGN ....................................................................................................15
5.1.
Overall Design ............................................................................................15
5.2.
Number of Participants ...............................................................................15
5.3.
Participant and Study Completion...............................................................15
5.4.
Scientific Rationale for Study Design ..........................................................15
5.5.
Dose Justification........................................................................................16
6.
STUDY POPULATION...........................................................................................17
6.1.
Inclusion Criteria.........................................................................................17
6.2.
Exclusion Criteria........................................................................................18
6.3.
Lifestyle Restrictions...................................................................................20
6.3.1.
Meals and Dietary Restrictions ....................................................20
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................20
6.3.3.
Activity .........................................................................................20
6.4.
Screen Failures...........................................................................................20
7.
TREATMENTS.......................................................................................................21
7.1.
Treatments Administered............................................................................21
7.2.
Dose Modification .......................................................................................21
7.3.
Method of Treatment Assignment ...............................................................22
7.4.
Blinding.......................................................................................................22
7.5.
Preparation/Handling/Storage/Accountability..............................................22
7.6.
Treatment Compliance................................................................................23
7.7.
Concomitant Therapy..................................................................................23
7.8.
Treatment after the End of the Study ..........................................................23
8.
DISCONTINUATION CRITERIA.............................................................................24
8.1.
Discontinuation of Study Treatment ............................................................24
8.1.1.
Liver Chemistry Stopping Criteria ................................................24
8.1.2.
QTc Stopping Criteria ..................................................................25
8.2.
Withdrawal from the Study..........................................................................25
8.3.
Lost to Follow Up........................................................................................25
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................26
9.1.
Adverse Events...........................................................................................26

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9.1.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................27
9.1.2.
Method of Detecting AEs and SAEs.............................................27
9.1.3.
Follow-up of AEs and SAEs.........................................................27
9.1.4.
Regulatory Reporting Requirements for SAEs .............................27
9.1.5.
Pregnancy ...................................................................................28
9.2.
Treatment of Overdose...............................................................................28
9.3.
Safety Assessments ...................................................................................29
9.3.1.
Physical Examinations.................................................................29
9.3.2.
Vital Signs....................................................................................29
9.3.3.
Electrocardiograms......................................................................29
9.3.4.
Spirometry ...................................................................................30
9.3.5.
Clinical Safety Laboratory Assessments ......................................30
9.4.
Pharmacokinetics .......................................................................................30
9.5.
Genetics .....................................................................................................31
9.6.
Biomarkers .................................................................................................31
9.7.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................31
10. STATISTICAL CONSIDERATIONS........................................................................31
10.1.
Sample Size Determination ........................................................................31
10.1.1.
Sample Size Sensitivity................................................................32
10.2.
Populations for Analyses ............................................................................32
10.3.
Statistical Analyses.....................................................................................32
10.3.1.
Pharmacokinetic (PK) Analyses...................................................33
10.3.2.
Safety Analyses...........................................................................33
11. REFERENCES.......................................................................................................34
12. APPENDICES........................................................................................................35
12.1.
Appendix 1: Abbreviations and Trademarks................................................35
12.2.
Appendix 2: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................37
12.3.
Appendix 3: Study Governance Considerations..........................................41
12.4.
Appendix 4: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................45
12.5.
Appendix 5: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................47
12.6.
Appendix 6: Clinical Laboratory Tests.........................................................52

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1.
SYNOPSIS
Protocol Title: A randomised, double-blind, parallel group study to evaluate the safety, 
tolerability and pharmacokinetics of a single dose of GSK2269557 administered via the 
ELLIPTA™ dry powder inhaler to healthy participants.
Short Title: Double-blind study to evaluate the safety, tolerability and pharmacokinetics 
of a single dose of GSK2269557 in healthy participants.
Rationale: This is the first study using a new formulation of GSK2269557 in healthy 
participants. GSK2269557 will be administered via the ELLIPTA™dry powder inhaler 
(DPI) formulated in a blend containing 0.4% MgSt (magnesium stearate). The previous 
formulation contained 0.6% MgSt. Healthy participants are considered appropriate to 
assess the new formulation since previous studies assessing device and formulation have 
been conducted in healthy participants. Furthermore no significant differences in the 
pharmacokinetic (PK) profiles have been observed between healthy participants and 
chronic obstructive pulmonary disease (COPD) patients. Therefore data derived from this 
study will inform on the PK profile and systemic exposure expected in patients during 
Ph2b.  
Objectives and Endpoints:
Objectives
Endpoints
Primary
To assess the pharmacokinetic profile of a 
single dose of GSK2269557 administered via 
the ELLIPTA™DPI to healthy participants.
GSK2269557 plasma concentration data and 
derived pharmacokinetic parameters including 
area under the plasma drug concentration 
versus time curve area under the plasma drug 
concentration versus time curve from zero to 
time t, area under the plasma drug 
concentration versus time curve from zero to 24 
hours, area under the plasma drug 
concentration versus time curve from zero to 
infinity (AUC(0-t), AUC(0-24), AUC(0-inf∞)),
maximum observed plasma drug concentration 
(Cmax), time to maximum observed plasma drug 
concentration (Tmax), Concentration at trough 
(Ctrough), terminal half-life (T1/2), where data 
allow.
Secondary
To assess the safety and tolerability of a single 
dose of GSK2269557 administered via the 
ELLIPTA™DPI to healthy participants.
Safety and tolerability of GSK2269557 as 
assessed by clinical monitoring of: 

Vital Signs 

Electrocardiogram (ECG)

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Objectives
Endpoints

Spirometry

Laboratory safety data

Adverse events (AEs)
Overall Design: The study is a randomised, double blind, parallel group, single dose 
study in healthy participants. The study will be conducted at a single centre. 
Approximately twelve participants will be randomised to receive a single dose of  
GSK2269557 750 µg or a single dose of GSK2269557 500 µg. Participants will be 
randomised to GSK2269557 750 µg or GSK2269557 500 µg in a 1:1 ratio.
Number of Participants: A sufficient number of participants will be screened in order to 
randomise approximately twelve participants such that six participants complete on the 
GSK2269557 750 µg treatment group and six participants complete on the GSK2269557 
500 µg treatment group. Participants will be replaced if necessary. 
Treatment Groups and Duration: Participants will be randomised to receive 750 µg of 
GSK2269557 or 500 µg of GSK2269557 in a 1:1 ratio.
The study consists of the following visits:

Screening: within 28 days of first dose

Treatment Period: 

Participants will be admitted on Day -1 

Study treatment will be administrated on Day 1. Participants will be 
discharged after completion of all 24h post dose assessments on Day 
2 and if there are no safety concerns.

On Day 3 and Day 6, participants will return to the study clinic on an 
outpatient basis, in order to complete the assessments described in the 
SOA (Section 2). 

Follow-up:  

Participants will receive a telephone call at 10-12 days post dose to 
ensure there are no AEs to report or safety concerns. 
The duration of the study for each participant (including screening and follow-up) will 
last up to 6 weeks.

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2.
SCHEDULE OF ACTIVITIES (SOA)
Procedure
Screening 
(up to 28
days 
before Day 
1)
Treatment Period [Days]
Follow-up
(10-12 days post dose)
Notes
–1
1
2
3
6
Informed consent
X
Inclusion and exclusion criteria
X
Recheck clinical 
status before 
randomization 
Demography
X
Full physical examination including 
height and weight
X
Medical history (includes 
substance usage and current 
medical conditions)
X
Substances: 
Drugs, Alcohol, 
tobacco and 
caffeine
Urine pregnancy test (WOCBP 
only)
X
X
HIV, Hepatitis B and C screening
X
If test otherwise 
performed 
within 3 
months prior 
to first dose of 
study 
treatment, 
testing at 
screening is 
not required

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Procedure
Screening 
(up to 28
days 
before Day 
1)
Treatment Period [Days]
Follow-up
(10-12 days post dose)
Notes
–1
1
2
3
6
Admission to unit
X
Outpatient visit
X
X
X
Discharge
X
Laboratory assessments (include 
liver chemistries)
X
X
X
Urine Drug, Alcohol and Smoking 
breath test
X
X
12-lead ECG 
X
X
X
Screening only: 
ECG in triplicate
Day 1: pre-dose, 5 
mins & 6 hrs post-
dose
Day 2: before 
discharge
Vital signs 
X
X
X
Screening only: 
blood pressure  
and pulse in 
triplicate
Day1: pre-dose, 1h 
and 6h post-dose

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Procedure
Screening 
(up to 28
days 
before Day 
1)
Treatment Period [Days]
Follow-up
(10-12 days post dose)
Notes
–1
1
2
3
6
Spirometry [FEV1 and FVC]
(triplicate)
X
X
Day 1: pre-dose, 
30 min post-dose
Brief physical examination
X
Inhaler training 
X
Training conducted 
by reviewing the 
Patient Information 
Leaflet with the
participant. 
Additional training 
may be conducted 
at the discretion of 
the investigator.
Dosing study treatment
X
AE review
=================================================================
SAE review
======================================================================
Concomitant medication review
X
X
X
X
X

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Procedure
Screening 
(up to 28
days 
before Day 
1)
Treatment Period [Days]
Follow-up
(10-12 days post dose)
Notes
–1
1
2
3
6
Pharmacokinetic blood sample
X
X
X
X
Day 1: pre-dose, 5 
min and 0.5, 2, 6 
and 12 hours post-
dose.
Day 2: 24 hours 
post-dose.
Day 3: 48 hours 
post-dose
Day 6: 120 hours 
post dose. 

The timing and number of planned study assessments, including safety and pharmacokinetic assessments may be altered during 
the course of the study based on newly available data (e.g., for safety purposes or 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 ICF.

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3.
INTRODUCTION
GSK2269557 is a potent and highly selective inhaled Phosphoinositide 3 Kinase delta 
(PI3K) inhibitor being developed as an anti-inflammatory and anti-infective agent for 
the treatment of inflammatory airways diseases.
3.1.
Study Rationale
This is the first study using a new formulation of GSK2269557 in healthy participants.  
GSK2269557 will be administered via the ELLIPTA™ dry powder inhaler (DPI)
formulated in a blend containing 0.4% MgSt (magnesium stearate). The previous 
formulation contained 0.6% MgSt. Healthy participants are considered appropriate to 
assess the new formulation since previous studies assessing device and formulation have 
been conducted in healthy participants. Furthermore no significant differences in the 
pharmacokinetic (PK) profiles have been observed between healthy participants and 
chronic obstructive pulmonary disease (COPD) patients. Therefore data derived from this 
study will inform on the PK profile and systemic exposure expected in patients during 
Ph2b.  
3.2.
Background
Phosphoinositide 3-kinase (PI3K), a lipid kinase expressed predominantly in 
leukocytes, is a potential therapeutic target for inflammatory conditions such as COPD 
and asthma.  Neutrophils and T cells are the two major inflammatory cell types involved 
in COPD, and both are targeted by inhibition of PI3K[Hatcher, 2011]; [Okkenhaug, 
2007]; [Sadhu, 2003].
GSK2269557 has been administered to healthy participants and healthy smokers in 
previous studies, as follows:

Study PII115117 (healthy participants):  single and repeat doses of a nebulised 
solution of GSK2269557 – daily doses up to 6400 g for 7 days.

Study PII116617 (healthy smokers):  single and repeat doses of a dry powder 
formulation (DISKUS DPI) of GSK2269557 – single doses up to 3000 g, and daily 
doses up to 2000 g for 14 days.

Study 201544 (healthy participants): single centre, three part, randomised, study to 
evaluate the safety, tolerability and pharmacokinetics of GSK2269557 administered
via the ELLIPTA™dry powder inhaler (0.6% MgSt formulation) – single doses up 
to 200 g, and daily doses of 200 g for 10 days (study completed but not yet 
reported).

Study 205759 (healthy Japanese participants): single and repeat doses of 
GSK2269557 administered via the ELLIPTA™ dry powder inhaler (0.6% MgSt 
formulation) – single doses up to 700 g, and daily doses up to 700 g for 10 days
(study completed but not yet reported).
GSK2269557 was well tolerated across the range of doses tested in all studies.  

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GSK2269557 has been administered to stable COPD patients, patients experiencing a 
COPD exacerbation and patients with persistent, uncontrolled asthma:

Study PII115119 (stable COPD patients): daily doses of up to 2000 g GSK2269557 
are being administered via the DISKUS DPI for 14 days. 

Study PII116678 (patients experiencing a COPD exacerbation): daily doses of 1000 
g GSK2269557 are being administered via the DISKUS DPI for 12 weeks.

Study 201543 (patients with persistent, uncontrolled asthma): daily doses of 1000 g
GSK2269557 are being administered via the DISKUS DPI for 28 days (study 
completed but not yet reported).
There are also two ongoing studies in the clinical phase, one in patients experiencing a 
COPD exacerbation and one in patients with activated PI3K delta syndrome (APDS)/
p110 delta-activating mutation causing senescent T cells, lymphadenopathy, and 
immunodeficiency (PASLI):

Study 201928 (patients experiencing a COPD exacerbation): daily doses of 1000 g 
GSK2269557 are being administered via the DISKUS DPI for 12 weeks.

Study 204745 (patients with APDS/PASLI): daily doses of 700g GSK2269557 are 
being administered via the ELLIPTA dry powder inhaler.
More information about the non-clinical and clinical studies is available in the 
Investigator’s Brochure (IB) [GlaxoSmithKline Document Number 2012N141231_06].
3.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of GSK2269557 may be found in the Investigator’s 
Brochure (IB) [GlaxoSmithKline Document Number 2012N141231_06].

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3.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [GSK2269557]
Bronchospasm
A general risk with all Inhaled treatments
Study treatment will be administered in the 
clinical pharmacology unit in the presence of 
trained clinical staff. 
Treat immediately with a short-acting inhaled 
bronchodilator. 
Participants will be withdrawn from the study.
Mucosal irritancy
Detected in 13 week toxicology study in the dog
Participants will be monitored for AEs. Thus far 
this has not been seen in clinical studies.
Unknown risks to an embryo, foetus or nursing 
infant
There are no studies with GSK2269557 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. 

If a female participant becomes pregnant 
during the study, she must let the study 
doctor know immediately. 

For women of reproductive potential, a 
pregnancy test will be performed at 
Screening and Day-1.

Male participants with female partners of 
reproductive potential must use highly 
effective contraception methods to avoid 
pregnancy while in this study.

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3.3.2.
Benefit Assessment
Healthy participants participating in this study will receive no direct medical benefit.  
They might benefit from the thorough medical examination and assessments they receive 
during the course of the study.
3.3.3.
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in 
this study, the potential risks identified in association with GSK2269557 are considered 
justified.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To assess the pharmacokinetic profile 
of a single dose of GSK2269557 administered 
via the ELLIPTA™DPI to healthy participants.

GSK2269557 plasma concentration 
data and derived pharmacokinetic parameters 
including area under the plasma drug 
concentration versus time curve area under the 
plasma drug concentration versus time curve 
from zero to time t, area under the plasma drug 
concentration versus time curve from zero to 24 
hours, area under the plasma drug 
concentration versus time curve from zero to 
infinity (AUC(0-t), AUC(0-24), AUC(0-inf∞)), 
maximum observed plasma drug concentration 
(Cmax), time to maximum observed plasma drug 
concentration (Tmax), Concentration at trough
(Ctrough), terminal half-life (T1/2), where data 
allow.
Secondary

To assess the safety and tolerability of a 
single dose of GSK2269557 administered via 
the ELLIPTA™DPI to healthy participants.

Safety and tolerability of GSK2269557 as 
assessed by clinical monitoring of: 

Vital Signs 

Electrocardiogram (ECG)

Spirometry

Laboratory safety data

Adverse events (AEs)

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5.
STUDY DESIGN
5.1.
Overall Design
This is a randomised, double-blind, parallel group, single centre study to evaluate the 
safety, tolerability and pharmacokinetics of a single dose of GSK2269557 administered 
via the ELLIPTA™ dry powder inhaler to healthy participants.
Eligible participants will be admitted on Day -1 and receive GSK2269557 on Day 1.
Participants will be discharged after completion of all 24 h post dose assessments on 
Day 2 and if there are no safety concerns.
On Day 3 and Day 6, participants will return to the study clinic on an outpatient basis. 
Participants will receive a telephone call at 10-12 days post dose to ensure there have 
been no safety issues since discharge. 
The duration of the study for each participant (including screening and follow-up) will 
last up to 6 weeks.
5.2.
Number of Participants
A sufficient number of healthy participants will be screened in order to randomise
approximately twelve participants such that six participants on the GSK2269557 750 µg 
treatment group and six participants on the GSK2269557 500 µg treatment group
complete the final sampling timepoint (120 hours post-dose). 
An evaluable participant is a participant who takes at least one dose of study treatment 
and for whom a pharmacokinetic sample was obtained and analysed. 
If participants prematurely discontinue the study, additional replacement participants may 
be recruited and assigned to the same treatment 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 Phone Call.
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.4.
Scientific Rationale for Study Design
This is the first study that GSK2269557 will be administered via the ELLIPTA DPI 
formulated in a blend containing 0.4% MgSt. Magnesium stearate has been reduced in 
this final formulation from that studied in previous trials and has resulted in a change in 
the respirable mass of the drug product. It is anticipated that this will impact the PK 
profile in man and resulting in an increase in systemic exposure. Cmax may increase, by
an average of approximately 50%-70% compared to the previously studied MgSt 
containing formulation. The final sampling timepoint (120 hours post-dose) has been 

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selected to confirm the terminal half-life based on preliminary data from study 205759 in 
healthy Japanese participants which has shown a half-life of approximately 46 hours. 
This study will inform on the exposure of GSK2269557 administered via the ELLIPTA 
DPI formulated in the new blend containing 0.4% MgSt. Previous studies conducted 
across healthy participants and patients have shown no major differences in exposure.
5.5.
Dose Justification
This study is planned to test two separate dose strengths, 750 and 500 g via a single 
dose of GSK2269557.  Higher doses of other formulations of GSK2269557 as well as 
longer treatment duration have been tested in previous healthy participant studies:  twice 
daily doses of 3200 g were tested as a nebulised solution in healthy participants for 7 
days; and daily doses of 2000 g were tested using the DISKUS DPI in healthy smokers 
for 14 days and in healthy non-smokers for 10 days at a once daily dose of 200 g using 
the ELLIPTA DPI containing 0.6% magnesium stearate (preliminary data, not reported 
yet).  For more detailed information, see the GSK2269557 IB [GlaxoSmithKline 
Document Number 2012N141231_06].
This is the first study that GSK2269557 will be administered via the ELLIPTA DPI 
formulated in a blend containing 0.4% MgSt. The change in formulation is expected to 
increase systemic exposure by up to 50% based on an observed increase in respirable 
mass as measured by in vitro drug product performance (Aerodynamic Particle Size 
Distribution).
Table 1 below shows the expected multiples of the predicted clinical exposure following 
a single inhalation of 750 µg or 500 µg compared to both pre-clinical margins and in 
relation to previously observed clinical exposure. The number presented is the most 
conservative estimate of cover using the highest exposed individual within study 201544 
and compared to the expected geometric mean value derived from pre-clinical data (rat 3 
month no observed adverse effect level [NOAEL] exposures) as well as the data from the 
highest exposed clinical data to date (PII115117; 7 days dosing bid of 3200 µg nebulised 
GSK2269557 to steady-state). 
Table 1
GSK2269557 Systemic Exposure Margins to Pre-Clinical Safety and 
Clinical Data Following Administration via ELLIPTA DPI Containing 
Either 0.4% Magnesium Stearate
Dose
Parameter1
Exposure Margin
Pre-clinical2
Clinical3
500 g
Cmax (ng/mL)
17
2.0
500 g
AUC0−24h (ng.h/mL)
23
6.9
750 g
Cmax (ng/mL)
11
1.4
750 g
AUC0−24h (ng.h/mL)
15
4.6

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1. Using the highest measured exposed individual based on study 201544 (200 µg top dose) to generate 
(linear extrapolation including an increase of 1.71 fold for Cmax and 1.54-fold on AUC) the most 
conservative multiple for either a 500 µg or a 750 µg single dose based on Day 1 data. Cmax and AUC0-
24h of 2.6 ng/mL and 12.4 ng.h/mL for 500 µg and a Cmax and AUC0-24h of 3.9 ng/mL and 18.6 ng.h/mL 
for 750 µg respectively.
2. Based on the NOAEL derived from the rat 3 month toxicology study R29876 with a Cmax and AUC of 
43.7 ng/mL and 286 ng.h/mL respectively.
3. Based on the highest achieved geometric mean value derived from reported trials to date of 5.3 ng/mL and 
85 ng.h/mL based on exposure on Day 7 following repeat daily single doses.
Based on the above calculations the exposure following a single 750 µg inhaled dose is 
expected to be well within pre-clinical safety margins and in addition is expected to be 
lower than the maximum exposure seen to date in reported studies with no adverse events 
of note associated with that clinical systemic exposure.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be 18 to 75 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant 
2.
Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests, and ECG tests. Re-screening 
will be allowed once, at the discretion of the Principal Investigator in consultation 
with GSK medical monitor (see Section 6.4).
3.
Normal spirometry at Screening forced expiratory volume in 1 second (FEV1) and 
forced vital capacity (FVC) ≥80% of predicted – measurements to be taken in
triplicate and the highest value for each component must be ≥80% of predicted).
Weight
4.
Body weight 50 kg and body mass index (BMI) within the range 18.0 – 35.0 kg/m2
(inclusive).

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Sex
5.
Male or female
a. Male participants:
A male participant must agree to use contraception as detailed in Appendix 2 of this 
protocol during the treatment period for at least 5 half-lives + 90 days after the last 
dose of study treatment and refrain from donating sperm during this period.
b. Female participants: 
A female participant is eligible to participate if she is not pregnant (see Appendix 2), 
not breastfeeding, and at least one of the following conditions applies:
(i)
Not a woman of childbearing potential (WOCBP) as defined in Appendix 2
OR
(ii)
A WOCBP who agrees to follow the contraceptive guidance in Appendix 2
during the treatment period for at least 5 half-lives + 90 days after the last 
dose of study treatment .
Informed Consent
6.
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.
Asthma or a history of asthma (except in childhood, which has now remitted)
2.
Significant history of or current cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematological, or neurological disorders capable of 
significantly altering the absorption, metabolism, or elimination of drugs; 
constituting a risk when taking the study treatment; or interfering with the 
interpretation of data
3.
Abnormal blood pressure [as determined by the investigator]
4.
Alanine transaminase (ALT) >1.5x upper limit of normal (ULN) 
5.
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 
6.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones)
7.
Corrected QT interval (QTc) >450 msec

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NOTES:

The QTc is the QT interval corrected for heart rate according to Bazett’s 
formula (QTcB), Fridericia’s formula (QTcF), and/or another method, machine-
read or manually over-read.

The specific formula that will be used to determine eligibility and 
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, QTcB, QTcF, another QT correction formula, or a 
composite of available values of QTc will be used as specified in the Reporting 
and Analysis Plan (RAP).
Prior/Concomitant Therapy
8.
Past or intended use of over-the-counter or prescription medication including herbal 
medications within 7 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
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
Consider adding the following criteria if participants can only be enrolled once per study.
12. Current enrollment or past participation within the last 90 days before signing of 
consent in 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

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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. Current smoker or a history of smoking within 6 months of Screening, or a total pack 
year history of >5 pack years.
[number of pack years = (number of cigarettes per day/20) x number of years 
smoked]
20. Sensitivity to any of the study treatments, or components thereof (including lactose 
and MgSt), or drug or other allergy that, in the opinion of the investigator or medical 
monitor, contraindicates participation in the study
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

Refrain from consumption of  Seville oranges, grapefruit or grapefruit juice from 7
days before the start of study treatment until collection of the final pharmacokinetic 
(PK) sample.
6.3.2.
Caffeine, Alcohol, and Tobacco

Participants will abstain from ingesting caffeine- or xanthine-containing products 
(eg, coffee and cola drinks) for 6 hours before the start of dosing until after 
collection of the final pharmacokinetic (PK) and/or pharmacodynamic sample.

Participants will abstain from alcohol for 12 hours before the start of dosing until 
after collection of the final PK and/or pharmacodynamic sample. 

Smoking is not permitted during the study.
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 randomized. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 

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demography, screen failure details, eligibility criteria, and any serious adverse events 
(SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened. 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.
7.1.
Treatments Administered
Study Treatment Name:
GSK2269557 ELLIPTA™ DPI 
(500 µg)
GSK2269557 ELLIPTA™ DPI 
(750 µg)
Dosage formulation:
DPI
DPI
Unit dose 
strength(s)/Dosage 
level(s):
500 µg
750 µg 
Route of Administration 
Inhalation
Inhalation
Dosing instructions:
Inhale as directed
Inhale as directed
Packaging and Labelling
Study Treatment will be labelled 
as required per country 
requirement.
Study Treatment will be labelled 
as required per country 
requirement.
Manufacturer
GSK
GSK
Device:
ELLIPTA™
ELLIPTA™
7.2.
Dose Modification
This protocol does not allow alteration from the currently outlined dosing schedule.

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7.3.
Method of Treatment Assignment
Study using 
Pre-Coded 
Randomization 
On Day 1, participants will be assigned a unique number 
(randomization number) in ascending numerical order by the 
Interactive Voice Recognition System/ Web Response Centre 
(IVRS/IWRS). The randomization number encodes the participant’s 
assignment to one of the treatment arms of the study, according to 
the randomization schedule generated prior to the study by the 
Clinical Statistics Department at GSK. Each participant will be 
dispensed blinded study treatment, labelled with a unique container 
number.
7.4.
Blinding
Blind Break 
(IVRS/IWRS)
The IVRS/IWRS will be programmed with blind-breaking 
instructions. The blind may be broken by the investigator or 
treating physician in the case of an emergency, or if, in the 
opinion of the investigator, it is in the participant’s best interest 
for the investigator to know the study treatment assignment. The 
investigator is encouraged to discuss with the GSK Medical 
Monitor or appropriate GSK study personnel before the blind is 
broken If GSK is not notified before the blind is broken, they 
must be notified as soon as possible after breaking the blind. The 
date and reason that the blind was broken must be recorded in the 
source documentation and CRF, as applicable.
A participant may continue in the study if that participant’s treatment assignment is 
unblinded.  The primary reason for discontinuation (the event or condition which led to 
the unblinding) will be recorded in the case report form (CRF).
GlaxoSmithKline’s (GSK) Global Clinical Safety and Pharmacovigilance (GCSP) staff 
may unblind the treatment assignment for any participant with an SAE. If the SAE 
requires that an expedited regulatory report be sent to one or more regulatory agencies, a 
copy of the report, identifying the participant’s treatment assignment, may be sent to 
investigators in accordance with local regulations and/or GSK policy.
7.5.
Preparation/Handling/Storage/Accountability
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.
2.
Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized site staff.

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3.
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).
4.
Further guidance and information for the final disposition of unused study treatment 
are provided in the Study Reference Manual. 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
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.  
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 non-prescription drugs (including 
dietary or herbal supplements but excluding simple analgesics and vitamins) within 7 
days 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
There is no treatment following the end of the study.

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8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
8.1.1.
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:
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 4.

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8.1.2.
QTc Stopping Criteria

The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may not 
be changed or substituted once the participant has been enrolled.

For example, if a participant is eligible for the protocol based on QTcB, then 
QTcB must be used for discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, 
the same formula must continue to be used for that participant for all QTc data 
being collected for data analysis.  Safety ECGs and other non-protocol specified 
ECGs are an exception.  

The 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.  

QTc, QTcB, QTcF >500 msec,

Change from baseline: QTc >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.
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.

Participants who are withdrawn will receive a follow-up telephone call at 10 –
12 days post dose. Refer to the SoA for data to be collected at the follow-up 
telephone call. 
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:

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
The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES

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.
9.1.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 5.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study (see Section 8). 

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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) and 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 5. 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 5.
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 5.
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 

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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 post 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 2.

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 GSK2269557 greater than 750 µg within a 24-hour time 
period 2 hour will be considered an overdose.
Sponsor does not recommend specific treatment for an overdose and may be used in case 
of overdose.
In the event of an overdose, the investigator should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
GSK2269557 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.

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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, assessments of the 
Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. 
Height and weight will also be measured and recorded.

A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
9.3.2.
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.

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 in a semi-supine position after 5 minutes rest and 
will include temperature (single reading), systolic and diastolic blood pressure
and pulse. Three readings of blood pressure and pulse will be taken at screening 
only. They will be 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. Single readings 
will be recorded at all other timepoints.
9.3.3.
Electrocardiograms

Triplicate OR 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 QTc intervals. Refer to Section 8.1.2. 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 2-5 minutes apart. The full set of triplicates should be completed in less 
than 5-10 minutes.

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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.

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 of each component will be recorded in the electronic case report 
form (eCRF).

A full description of the timing and conduct of spirometry procedures will be 
provided in the study reference manual (SRM).
9.3.5.
Clinical Safety Laboratory Assessments

Refer to Appendix 6 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency. 

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study should be repeated until the values return to 
normal or baseline or are no longer considered significantly abnormal by the 
investigator or medical monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 6, 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 2 mL will be collected for measurement 
of plasma concentrations of GSK2269557 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. Processing, storage and shipping procedures are provided in the SRM.

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
Samples will be used to evaluate the PK of GSK2269557. Samples collected for 
analyses of GSK2269557 plasma concentration may also be used to evaluate 
safety or efficacy aspects related to concerns arising during or after the study.

Plasma analysis for GSK2269557 will be performed under the control 
Bioanalysis, Immunogenicity, Biomarkers,  BIB /Third Party Resourcing, TPR, 
GlaxoSmithKline.

Genetic analyses will not be performed on these whole blood samples. 
Participant confidentiality will be maintained. At visits during which whole 
blood samples for the determination of plasma concentrations of GSK2269557
will be taken, one sample of sufficient volume can be used.
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.
Genetics
Genetics are not evaluated in this study.
9.6.
Biomarkers
Biomarkers are not evaluated in this study.
9.7.
Health Economics OR Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
The objective is to assess the pharmacokinetic profile of a single dose of GSK2269557 
administered via the ELLIPTA™ DPI to healthy participants.
An evaluable participant is a participant who takes at least one dose of study treatment 
and for whom a pharmacokinetic sample was obtained and analysed. 
10.1.
Sample Size Determination
The total number of participants for this study is 12 ; 6 on the GSK2269557 750 µg arm
and 6 on the GSK2269557 500 µg arm. The objective of the trial is to obtain a 
preliminary assessment of safety, tolerability and PK of GSK2269557 administered via 
the ELLIPTA DPI with the addition of 0.4% MgSt.
The sample size has been chosen based on feasibility. However, consideration has been 
given to the level of precision we would expect to achieve for the main PK parameters 
assuming the variability is the same as seen previously using the ELLIPTA DPI with the 
addition of 0.6% MgSt in Japanese participants.

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Assuming estimates of the between participant standard deviation, obtained from the 
most variable estimate between the 500 µg and 700 µg single doses from GSK study 
(Study 205759), of 0.346 (log scale) for Cmax and 0.382 (log scale) for AUC(0-24), the 
precision estimate for the half width of a 90% confidence interval is 0.285 for Cmax and 
0.314 for AUC(0-24).
10.1.1.
Sample Size Sensitivity
If the between participant standard deviation observed in the PK parameters is 10% or 
20% higher than standard deviation in Study 205759, the precision estimate for the half 
width of the 90% confidence interval will be 0.313 and 0.342, respectively for Cmax, and 
0.346 and 0.377, respectively for AUC(0-24).
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Screened
All participants screened and for whom a record exists on the study 
database. 
Safety
All participants randomised to treatment and who received at least 
one dose of study medication. Participants will be analysed 
according to the treatment they received.
Pharmacokinetic
All randomised participants who take at least 1 dose of study 
treatment and for whom a pharmacokinetic sample was obtained 
and analysed. Participants will be analysed according to the 
treatment they received.
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).

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10.3.1.
Pharmacokinetic (PK) Analyses
All PK analyses will be performed on the Pharmacokinetic Population.
Endpoint
Statistical Analysis Methods
Primary
Plasma GSK2269557 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) and apparent terminal phase half-life (t½).
Pharmacokinetic data will be presented in graphical and/or tabular form and will 
be summarised descriptively. 
Listings will be generated and summary statistics (n, arithmetic mean with 
associated 95% CI, standard deviation, minimum, median, maximum, geometric 
mean with associated 95% CI, single dose (SD) on loge-scale and between 
subject coefficient [%CVb]) will be calculated for each derived plasma PK 
parameter for each treatment group.
10.3.2.
Safety Analyses
All safety analyses will be performed on the Safety Population. 
Endpoint
Statistical Analysis Methods
Secondary
Adverse events (AE), clinical laboratory values, vital signs, electrocardiogram 
(ECG), Spirometry, will be summarized by treatment

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11.
REFERENCES
GlaxoSmithKline Document Number 2012N141231_06: GSK2269557 Investigator’s 
Brochure. 31-AUG-2015
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, et al. Contraceptive 
Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc., 2011: 50. Table 3-2.
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.
Okkenhaug K, Ali K and Vanhaesebroeck B.  Antigen receptor signalling:  A distinctive 
role for the p110isoform of PI3K.  Trends in Immunology, 2007; 28: 80-7.
Sadhu C, Dick K, Tino WT, Staunton DE. Selective role of PI3K delta in neutrophil 
inflammatory responses. Biochem Biophys Res Commun. 2003; 308(4): 764-769.

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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
AE
Adverse Event
ALT
Alanine Aminotransferase/ Alanine Transaminase
APDS
Activated PI3K Delta Syndrome
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-inf∞)
Area Under the Plasma Drug Concentration versus Time Curve 
from zero to infinity
BMI
Body Mass Index
CIOMS
Council for International Organizations of Medical Sciences 
CFR
Code of Federal Regulations
Cmax
Maximum Observed Plasma Drug Concentration 
%CVb
Between subject coefficient
CONSORT
Consolidated Standards of Reporting Trials 
COPD
Chronic Obstructive Pulmonary Disease
CPK
Creatine phosphokinase 
CRF
Case Report Form 
DPI
Dry Powder Inhaler
ECG
Electrocardiogram
eCRF
electronic case report form
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FVC
Forced Vital Capacity
FSH
Follicle Stimulating Hormone 
GCP
Good Clinical Practice 
GCSP
Global Clinical Safety and Pharmacovigilance 
GSK
GlaxoSmithKline
Hrs/h
hours
hCG
Human chorionic gonadotropin 
HBsAg
Hepatitis B surface antigen 
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 
IEC
Independent Ethics Committee 
Ig
Immunoglobulin 
INR
International normalized ratio 

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IP
Investigational Product
IRB
Institutional Review Board 
IUD
Intrauterine Device 
IUS
Intrauterine Hormone-Releasing System 
IVRS/ IWRS
Interactive Voice Recognition System/ Web Response Centre
Kg
Kilogram
Kg/m2
Kilogram/square meter
LDH
Lactate dehydrogenase 
µg
Microgram
MgSt
Magnesium Stearate
mins
Minutes
mL
Milliliter
msec
Milliseconds
MSDS
Material Safety Data Sheet 
ng
Nanogram 
NOAEL
No Observed Adverse Effect Level
PASLI
p110 delta-activating mutation causing senescent T cells, 
lymphadenopathy, and immunodeficiency
PI3K
Phosphoinositide 3 Kinase delta 
PK
Pharmacokinetic 
QTc
Corrected QT interval
QTcB
QT interval corrected for heart rate according to Bazett’s formula
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
SRM
Study Reference Manual 
SUSAR
Suspected Unexpected Serious Adverse Reaction
T1/2
Terminal Half-life 
ULN
Upper Limit of Normal 
WOCBP
Woman Of Childbearing Potential 
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
DISKUS
WinNonlin
ELLIPTA™

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12.2.
Appendix 2: 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 during the protocol-defined 
time frame in Section 6.1: 

Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent 

Agree to use a male condom plus an additional method of contraception 
with a failure rate of <1% per year as described in Table 2 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 5 half-lives + 
90 days from last dose
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 2
Table 2
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulationb

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.) 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)

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NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies. 
b.
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case two highly effective methods of contraception should be utilized during the 
treatment period and for at least 5 half-lives + 90 days after the last dose of study treatment 
Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine pregnancy test 

Additional pregnancy testing is not required during the treatment period and at FU.

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 

Pregnancy testing, with a sensitivity of 25 mIU/mL will be performed using the test 
kit approved by the sponsor and 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. 
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

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
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK
as described in Appendix 5. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
Any female participant who becomes pregnant while participating  

will be withdrawn from the study 

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12.3.
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.
Dissemination of Clinical Study Data
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 

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opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge
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 from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. 

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Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in the Source Document 
Agreement (SDA).
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: Liver Safety: Required Actions and Follow-up 
Assessments
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or  INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

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 
liver event follow up assessments within 24-
72 hrs

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
If ALT≥3xULN AND bilirubin 2xULN  or 
INR >1.5:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 

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Liver Chemistry Stopping Criteria 

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
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 
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.

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12.5.
Appendix 5: 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.

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
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 

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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 
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

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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 
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.

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

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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 
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 the SRM.

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12.6.
Appendix 6: Clinical Laboratory Tests

The tests detailed in Table 3 will be performed by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 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 3
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
Mean corpuscular 
volume (MCV)
Mean corpuscular 
hemoglobin (MCH)
%Reticulocytes
White blood cell (WBC) 
count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Red blood cell (RBC) 
Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
Blood urea 
nitrogen (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 
for screening)
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 

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Laboratory 
Assessments
Parameters
needed for women of childbearing potential)2

Serology [(HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis 
C virus antibody) 

additional local laboratory assessments are needed, include  the following:  
and list the exceptions.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 Appendix 4 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.
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.