A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety, Efficacy and Changes in Induced Sputum and Blood Biomarkers Following Daily Repeat Doses of Inhaled GSK2269557 for 12 Weeks in Adult Subjects Diagnosed With an Acute Exacerbation of Chronic Obstructive Pulmonary Disease (COPD)
Phase: PHASE2
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: GlaxoSmithKline

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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A randomised, double-blind, placebo-controlled study to 
evaluate the safety, efficacy and changes in induced sputum and 
blood biomarkers following daily repeat doses of inhaled 
GSK2269557 for 12 weeks in adult subjects diagnosed with an 
acute exacerbation of Chronic Obstructive Pulmonary Disease 
(COPD).
Compound Number:
GSK2269557
Development Phase:
IIA
Effective Date:
22-MAR-2017
Protocol Amendment Number:  04
Author (s):
 (CCSE); 
 (CPSSO); 
 
(Respiratory CEDD); 
 (Exp Biology); 
 (Clinical Statistics); 
 (CPMS); 
(GCSP).
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2014N218070_00
2015-JUN-04
Original
2014N218070_01
2015-NOV-30
Amendment No. 1
Remove the specific equations for the prediction of percent predicted from spirometry 
from the inclusion criteria and in Section 7.7.2.  At screening it may not be possible to 
identify which correction method was used, or modify the correction method used, at the 
time. It therefore is not valid to stipulate that lung function values be corrected using any 
particular method.  Both FEV1 and FVC measurements (which are not entry criteria for 
the study) collected during the study will be collected as absolute values (uncorrected), so 
that consistency will be obtained across all sites in the study, and percent predicted will 
be calculated using a standard approach in house at the end of the study. 
2014N218070_02
2016-JAN-26
Amendment No. 2
Increase the body mass index (BMI) range in the inclusion criteria from 18-32 kg/m2
(inclusive) to 16- 35 kg/m2 (inclusive). The original BMI range from 18-32 kg/m2 is a 
typical range used in both healthy volunteer studies and general subject populations. The 
revised range is more appropriate for a COPD patient population.
2014N218070_03
2016-NOV-16
Amendment No. 3
To remove photo toxicity from the protocol and to include minor administrative and 
clarification changes.
2014N218070_04
2017-MAR-22
Amendment No. 4
Replace the administration of GSK2269557 via the DISKUSTM device (1000 g) by a 
comparable dose administered via the ELLIPTATM device (700 g).  GSK2269557 is no 
longer manufactured for use with the DISKUS device which will be replaced with 
ELLIPTA Device. To increase the number of patients to be recruited to obtain sufficient 
completers. Minor updates and clarifications.
 
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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information:
Role
Name
Day Time Phone 
Number and email 
address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site Address
Primary 
Medical 
Monitor
Discovery 
Medicine 
Respiratory 
CEDD 
GlaxoSmithKline 
Gumnnels Wood 
Rd. 
Stevenage, 
Herts, 
SG1 2NY
Secondary 
Medical 
Monitor
Discovery 
Medicine 
Respiratory 
CEDD 
GlaxoSmithKline 
Gumnnels Wood 
Rd. 
Stevenage, 
Herts, 
SG1 2NY
SAE contact  
information 
Medical 
monitor as 
above
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UKStructure and Content of a Clinical Study Protocol Amendment
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol 201928
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
 
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 201928........................................................9
2.
INTRODUCTION....................................................................................................12
2.1.
Study Rationale ..........................................................................................12
2.2.
Brief Background ........................................................................................12
2.2.1.
Use of mRNA transcriptomics by Affymetrix.................................14
2.2.2.
Use of HRCT Endpoints to characterise Lung Function ...............14
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................15
4.
STUDY DESIGN ....................................................................................................16
4.1.
Overall Design ............................................................................................16
4.2.
Treatment Arms and Duration.....................................................................16
4.3.
Type and Number of Subjects.....................................................................17
4.4.
Design Justification.....................................................................................18
4.5.
Dose Justification........................................................................................18
4.6.
Benefit:Risk Assessment ............................................................................18
4.6.1.
Risk Assessment .........................................................................19
4.6.2.
Benefit Assessment.....................................................................20
4.6.3.
Overall Benefit:Risk Conclusion...................................................20
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............21
5.1.
Inclusion Criteria.........................................................................................21
5.2.
Exclusion Criteria........................................................................................24
5.3.
Screening/Baseline/Run-in Failures............................................................25
5.4.
Withdrawal/Stopping Criteria.......................................................................26
5.4.1.
Liver Chemistry Stopping Criteria ................................................26
5.4.1.1.
Study Treatment Restart or Re-challenge...................27
5.4.2.
QTc Stopping Criteria ..................................................................27
5.4.3.
Other Stopping Safety Criteria .....................................................28
5.5.
Subject and Study Completion....................................................................28
6.
STUDY TREATMENT ............................................................................................29
6.1.
Investigational Product and Other Study Treatment....................................29
6.2.
Treatment Assignment................................................................................29
6.3.
Planned Dose Adjustments.........................................................................30
6.4.
Subject Specific Dose Adjustment Criteria..................................................30
6.5.
Blinding.......................................................................................................30
6.6.
Packaging and Labeling..............................................................................31
6.7.
Compliance with Study Treatment Administration.......................................31
6.8.
Treatment of Study Treatment Overdose....................................................32
6.9.
Treatment after the End of the Study ..........................................................32
6.10.
Lifestyle and/or Dietary Restrictions............................................................32
6.11.
Concomitant Medications and Non-Drug Therapies....................................33
6.11.1.
Permitted Medications and Non-Drug Therapies..........................33
6.11.2.
Prohibited Medications and Non-Drug Therapies.........................33
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................33
7.1.
Time and Events Table (Screening and Follow Up Visits)...........................34
 
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7.2.
Time and Events Table (Treatment Period) ................................................36
7.3.
Screening and Critical Baseline Assessments ............................................38
7.4.
Biomarker(s)/Pharmacodynamic Markers ...................................................38
7.4.1.
Pharmacodynamic Biomarkers in Sputum ...................................38
7.4.2.
mRNA in blood ............................................................................38
7.5.
Patient diary................................................................................................38
7.6.
Genetics .....................................................................................................39
7.7.
Efficacy.......................................................................................................39
7.7.1.
Functional Respiratory Imaging ...................................................39
7.7.2.
FEV1  and FVC.............................................................................39
7.7.3.
Peak Expiratory Flow PEF ...........................................................39
7.8.
Safety .........................................................................................................39
7.8.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........39
7.8.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................40
7.8.1.2.
Method of Detecting AEs and SAEs ...........................40
7.8.1.3.
Follow-up of AEs and SAEs........................................41
7.8.1.4.
Cardiovascular and Death Events ..............................41
7.8.1.5.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................41
7.8.1.6.
Regulatory Reporting Requirements for SAEs............41
7.8.2.
Pregnancy ...................................................................................42
7.8.3.
Physical Exams ...........................................................................42
7.8.4.
Vital Signs....................................................................................42
7.8.5.
Electrocardiogram (ECG).............................................................42
7.8.6.
Clinical Safety Laboratory Assessments ......................................43
7.9.
Pharmacokinetics .......................................................................................44
7.9.1.
Blood Sample Collection..............................................................44
7.9.2.
Sample Analysis ..........................................................................44
8.
DATA MANAGEMENT ...........................................................................................45
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................45
9.1.
Sample Size Considerations.......................................................................45
9.1.1.
Sample Size Re-estimation or Adjustment...................................46
9.2.
Data Analysis Considerations .....................................................................46
9.2.1.
Analysis Populations....................................................................46
9.2.2.
Interim Analysis ...........................................................................46
9.3.
Key Elements of Analysis Plan ...................................................................47
9.3.1.
Primary Analyses.........................................................................47
9.3.2.
Secondary Analyses ....................................................................47
10. STUDY GOVERNANCE CONSIDERATIONS........................................................47
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............47
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................47
10.3.
Quality Control (Study Monitoring) ..............................................................48
10.4.
Quality Assurance.......................................................................................48
10.5.
Study and Site Closure ...............................................................................49
10.6.
Records Retention......................................................................................49
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................50
 
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11. REFERENCES.......................................................................................................51
12. APPENDICES........................................................................................................52
12.1.
Appendix 1: Abbreviations and Trademarks................................................52
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................53
12.3.
Appendix 3: Genetic Research ...................................................................56
12.4.
Appendix 4: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................59
12.4.1.
Definition of Adverse Events........................................................59
12.4.2.
Definition of Serious Adverse Events...........................................60
12.4.3.
Definition of Cardiovascular Events .............................................61
12.4.4.
Recording of AEs and SAEs ........................................................62
12.4.5.
Evaluating AEs and SAEs............................................................62
12.4.6.
Reporting of SAEs to GSK...........................................................64
12.5.
Appendix 5: Collection of Pregnancy Information........................................65
12.6.
Appendix 6: Country Specific Requirements...............................................66
12.7.
Appendix 7: Protocol Amendment Changes................................................67
 
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1.
PROTOCOL SYNOPSIS FOR STUDY 201928
Rationale
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To establish the PI3K-dependent changes 
in previously identified immune cell 
mechanisms specifically related to 
neutrophil function using mRNA in sputum 
from patients with an exacerbation of 
COPD, with or without treatment with 
GSK2269557.

Alterations in previously identified immune 
cell mechanisms specifically related to 
neutrophil function as determined by 
changes in mRNA transcriptomics in 
induced sputum after 12, 28 and 84 days 
of treatment.
Secondary

To evaluate the effect of once daily repeat 
inhaled doses of GSK2269557 on lung 
parameters derived from HRCT scans in 
subjects with acute exacerbation of COPD, 
compared to placebo.

Change from baseline in siVaw, iVaw, 
iRaw, siRAW, total lung capacity, lung 
lobar volumes, trachea length and 
diameter at FRC and TLC after 12 days of 
treatment and after 28 days of treatment.

To assess the safety and tolerability of 
once daily repeat inhaled doses of 
GSK2269557 administered to subjects with 
acute exacerbation of COPD, compared to 
placebo.

Adverse events 

Haematology, clinical chemistry 

Vital signs

12-lead ECG

To evaluate the plasma PK of once daily 
repeat inhaled doses of GSK2269557 
administered to subjects with acute 
exacerbation of COPD.

Day 1 plasma Cmax and trough (24 hours) 
post dose for inpatients

Trough concentration after 12 days, 28 
days, 56 days and 84 days of treatment.

To evaluate the effect of once daily repeat 
inhaled doses of GSK2269557 on lung 
function parameters in subjects with acute 
exacerbation of COPD compared to 
placebo.

PEF

Reliever usage

FEV1 and  FVC at clinic prior to sputum 
induction
Exploratory

To establish any other PI3K-dependent 
changes in mRNA in sputum or blood from 
patients with an exacerbation of COPD, 
with or without treatment with 
GSK2269557.

To explore the pharmacodynamic effects in 
induced sputum of once daily repeat 
inhaled doses of GSK2269557 
administered to subjects with acute 

Alterations in immune cell mechanisms as 
determined by changes in mRNA 
transcriptomics in induced sputum or blood 
after 12, 28 and 84 days of treatment.

Endpoints may include, but not limited to 
cytokines (IL-6, IL-8, TNF), microbiome 
(by 16SrRNA), bacterial qPCR, viral qPCR.
 
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Objectives
Endpoints
exacerbation of COPD, compared to
placebo.

To assess the changes in other CT 
parameters such as low attenuation score 
after once daily repeat inhaled doses of 
GSK2269557 administered to subjects with 
acute exacerbation of COPD, compared to 
placebo.

Change from baseline for other CT 
parameters including low attenuation score
after 12 days of treatment and after 28 
days of treatment
Overall Design
This is a randomised, double-blind, placebo-controlled, parallel-group study.  All subjects 
will continue on their usual Chronic Obstructive Pulmonary Disease (COPD) medications 
throughout the entire duration of the study regardless of treatment arm assignment.  
Subjects will be on standard of care treatment (antibiotic and corticosteroids) upon 
diagnosis of a COPD exacerbation.
SCR
Signature 
ICF
Day 1
Randomisation / 
First dose GSK2269557
Day 12
(+/- 2 days) 
HRCT
Day 28
(+/- 2 days)
HRCT
Day 56
(-4 / + 2 days)
Safety visit
Day 84
(-4 / + 2 days)
End treatment
FU
Baseline
HRCT
Within 48h / discharge
Baseline lung function
Treatment Arms and Duration
Subjects will be required to participate in the following:
Screening: Following diagnosis during outpatient assessment by a Respirologist, 
Emergency Department visit or acute admission to hospital, and up to 3 days before start 
of study treatment. During this time:

The start of the standard of care (to include both antibiotics and corticosteroids) is 
expected to start shortly after diagnosis, though it is allowed to have already been 
started before the formal diagnosis of COPD exacerbation is made. 
 
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
The High-Resolution Computed Tomography (HRCT) scan should be conducted at 
the earliest opportunity after obtaining Informed Consent from the subject and within 
48 h of diagnosis by a Respirologist or physician with respiratory experience.  

Randomisation and first dose administration should take place as soon as possible 
following HRCT scan assessment has been performed and no later than 24h after 
completing the HRCT scan.
Treatment period:  Once daily study treatment administration will start on Day 1 (visit 1). 

For subjects who were hospitalized: 
o
If discharge takes place before Day 10, the subject must complete the 
assessments planned for visit 2 on discharge and must then visit the unit 
on Day 12 (2 days) (visit 3).
o
If discharge takes place between Day 10 and Day 14 (inclusive), the 
assessments planned for visit 2 and visit 3 may be completed on the day of 
discharge.
o
If discharge takes place from Day 15 (inclusive), the assessments planned 
for visit 2 and visit 3 should be completed as soon as it is safe for the 
patient to do so.

For subjects who were not hospitalized: the subject must complete the 
assessments planned for visit 2 within 48 hours of start of treatment, and must 
then visit the unit on Day 12 (2 days) to complete the assessments planned for 
visit 3.
Subjects will then dose at home until Day 84 (– 4 / + 2 days), with the exception of the 
days when subjects come to the clinic. On those days, they will dose at the clinic. On Day 
12 (± 2 days) (unless visit completed on discharge), Day 28 (± 2 days), Day 56 (– 4 / + 2 
days) and Day 84 (– 4 / + 2 days) subjects will return on an outpatient basis to complete 
the assessments described in the Time & Event table. Subjects will be discharged once all 
assessments have been performed and there are no safety concerns.
Follow up: 7-14 days after last dose.
The total duration of the study is 13-14 weeks including the screening visit.
Type and Number of Subjects
Approximately 45 subjects with an acute exacerbation of COPD will be randomized such 
that approximately 15 subjects on active and 15 subjects on placebo provide sputum at all 
the scheduled time points and complete the study.  If a higher than expected number of 
subjects prematurely discontinue the study, or fail to produce sufficient sputum post 
randomisation additional subjects may be randomised at the discretion of the sponsor.
 
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Analysis
To estimate differences in mRNA intensities within and between treatment groups, a 
repeated measures model will be fitted to the results of the analysis of each probe set at 
Day 12, Day 28 and Day 84 following a loge transformation of the data. The Day 1 
response will be fitted as a baseline covariate. A separate model will be fitted for each of 
the approximate 54000 probe sets.
Back transformed ratios versus screening along with 95% confidence intervals will be 
calculated for each treatment group and timepoint.  Additionally, baseline adjusted ratios 
of the change between active treatment and placebo will be calculated along with 95% 
confidence intervals.
2.
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.
2.1.
Study Rationale
The purpose of this study is to evaluate specific alterations in immune cell mechanisms
related to neutrophil function as detected by PI3K-dependent changes in mRNA 
extracted from induced sputum in patients experiencing an exacerbation of COPD. In 
addition this study will also further evaluate the plasma PK and assess the safety of 
GSK2269557 administered to patients diagnosed with an acute exacerbation of Chronic 
Obstructive Pulmonary Disease (COPD). The efficacy of treatment with GSK2269557 
will also be measured using functional respiratory imaging (FRI) and spirometry. 
This study will also explore the pharmacodynamic effects of once daily repeat doses of 
inhaled GSK2269557 on cytokines, mediators and microbiome in induced sputum 
samples. These will be obtained from subjects at entry, during their exacerbation, and at 
additional time points over the 12 week treatment period.  To understand patient efficacy, 
at entry, Day 12 and Day 28 the sputum biomarker data will be correlated with computed
tomography (CT).   
2.2.
Brief Background
PI3Kis a member of the Class IA family of phosphoinositides 3-kinases (PI3Ks) that 
convert the membrane phospholipid phosphatidylinositol 4,5-biphosphate (PIP2) into 
phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 is a second messenger in many 
cellular processes including cell growth, differentiation and migration. PI3Khas 
specific roles in mediating antigen receptor and cytokine signalling in T-cells, mast cells 
and B-cells [Okkenhaug, 2007] and roles in neutrophil chemotaxis and activation [Sadhu, 
2003].  A PI3Kinhibitor has the potential to inhibit major cell types responsible for the
inflammation associated with both COPD and asthma.
 
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In COPD, tobacco smoke or other irritants activate epithelial cells and macrophages to 
release inflammatory mediators such as chemokines that attract neutrophils and T cells to 
the lungs. PI3Kis thought to play a role in a number of epithelial responses relevant for 
the development of COPD.  Therefore a PI3Kinhibitor may be able to suppress a 
number of these processes [Kim, 2010].  A greater proportion of macrophages appear to
be alternatively activated in COPD and their ability to phagocytose infective pathogens is 
reduced as a result of this alternative activation.  PI3Kis one of the mediators involved 
in determining this alternative phenotype in macrophages and therefore it is proposed that 
inhibition of PI3Kmight rebalance macrophage activation towards a classic phagocytic
phenotype [Weisser, 2011] facilitating clearance of bacteria, a major cause of
exacerbation in COPD.  The neutrophil and T cell are the two major inflammatory cell 
types involved in the pathogenesis of COPD and both are targeted by PI3Kinhibitors. 
GSK2269557 has demonstrated the ability to protect against and control bacterial 
infections in preclinical rodent models. This is coupled with recent observations that 
PI3Kinhibition leads to a correction in vitro of aberrant neutrophil chemotaxis 
directionality in the blood of COPD patients. Furthermore, a human point mutation which 
results in a constitutively activated version of PI3Khas recently been characterised 
where the majority of affected patients have recurrent lung infections with the same 
bacterial species which are seen in COPD patients and are known to drive exacerbations. 
Collectively these data suggest that repeat dosing with GSK2269557 could potentially
reduce the impact of an acute exacerbation, or prevent the onset of a secondary bacterial 
exacerbation or recurrent exacerbation.
Proinflammatory cytokines were reduced by GSK2269557, both in preclinical rodent 
bacterial models, and COPD patient samples treated in vitro and in the study setting 
(PII115119).
GSK2269557 has been administered as single and repeat doses to healthy subjects as 
nebulized solution in the FTIH study PII115117 up to a dose of 6400 μg per day for 7 
days.  GSK2269557 has also been administered as single and repeat doses to healthy 
smokers as a dry powder formulation in study PII116617 up to a dose of 3000 μg as 
single dose and 2000 μg per day for 14 days.  GSK2269557 has been well tolerated 
across the range of doses used.  There is also an ongoing study (Study PII115119, non-
reported) where a total daily dose of up to 2000 µg of GSK2269557 is being administered 
to stable COPD patients via a dry powder inhaler for 14 days in a two part study.  Part A 
of this study has completed and Part B will characterise the steady-state (exposure) dose 
response following repeat inhaled doses of up to 2000µg for the same treatment duration.  
There is also a completed larger clinical study PII116678 which is almost identical in 
design to 201928 using 1000 µg of GSK2269557 per day administered via a Diskus dry 
powder inhaler to patients diagnosed with an acute exacerbation of COPD.   For 
simplicity study PII116678 did not capture induced sputum hence cannot analyse any 
changes in mRNA. The primary objective of the current study is to capture induced 
sputum to enable the mRNA analysis on a smaller cohort.
GSK2269557 has also now been administered in Study 201544 using the formulation 
now proposed in this study up to daily doses of 200 μg GSK2269557 via the ELLIPTATM
DPI for up to 10 days. No safety issues were identified with this new formulation.
 
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More information about the non-clinical and clinical studies is available in the 
GSK2269557 Investigator’s Brochure (IB) GlaxoSmithKline Document Number
2012N141231_06.
2.2.1.
Use of mRNA transcriptomics by Affymetrix
Analysis of changes in mRNA can be used to demonstrate alterations in biochemical 
pathways at the gene transcription level. This can be used to better understand the 
consequences of drug intervention on disease pathophysiology, and ultimately predict 
alterations which could translate to a positive clinical benefit for patients.  Messenger 
RNA can be extracted from a variety of biological samples (including induced sputum 
and blood) taken from patients before and after drug dosing to show the impact a drug is 
having. 
The advantage of using Affymetrix is the broad (~50k) gene set covered using this 
technology enabling great depth in exploring the biological consequences of drug 
intervention. This technology has been used in previous preclinical and clinical studies 
using GSK2269557 generating a fingerprint of PI3Kinhibition in disease.  Importantly 
these approaches allow areas of complex PI3K-dependent immune cell mechanisms and 
pathophysiology, specifically related to neutrophil function to be explored which are not 
easily quantified using other techniques.
2.2.2.
Use of HRCT Endpoints to characterise Lung Function
High-resolution computed tomography (HRCT) scans provide a highly detailed insight 
into the structure and architecture of the respiratory system. A clear distinction can be 
made between the lung parenchyma, the intraluminal air and alveolar spaces up to the 
level of the smaller airways with a diameter of 1-2mm. To model dynamic information, 
low dose HRCT scans can be taken at two lung volumes: after deep inhalation (total lung 
capacity or TLC) and after normal expiration (functional residual capacity or FRC). The 
patient’s breathing is monitored in real time during the scans to ensure the correct lung 
levels are scanned.  Due to the natural contrast between the intraluminal air and the 
surrounding tissue, it is possible to attain a significant reduction in radiation dose (1-2 
mSv per scan) compared to standard CT protocols (>4 mSv per scan) by reducing the 
tube current and the voltage.  Depending on the patient’s weight, a 6- to 10-fold reduction 
can be obtained per scan without losing image quality. As a comparison, in the USA, the 
average annual background radiation exposure is 6.2 mSv and a transatlantic flight results 
in 0.07 mSv exposure.
The high resolution images allow for a three dimensional reconstruction of the airway 
tree and vasculature by applying segmentation principles.  These three dimensional 
models can be used to measure airway dimensions as well as potentially allowing the 
phenotyping of patients by disease severity.  The three dimensional computer 
reconstructions can be used for fluid dynamic modelling.  This method is used to 
simulate flow through these airway models and determine the typical flow characteristics 
such as local pressure drops, velocities and resistance.  It can also be used to predict 
particle deposition in the airways of these patients when using inhaled drug products.
 
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This method consisting of 2 low dose HRCT scans at several time points has previously 
been used successfully in clinical trials involving COPD patients [De Backer, 2011; De 
Backer, 2012; De Backer, 2014; Goldin, 1999]. 
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To establish the PI3K-dependent changes 
in previously identified immune cell 
mechanisms specifically related to 
neutrophil function using mRNA in sputum 
from patients with an exacerbation of 
COPD, with or without treatment with 
GSK2269557.

Alterations in previously identified immune 
cell mechanisms specifically related to 
neutrophil function as determined by 
changes in mRNA transcriptomics in 
induced sputum after 12, 28 and 84 days 
of treatment.
Secondary

To evaluate the effect of once daily repeat 
inhaled doses of GSK2269557 on lung 
parameters derived from HRCT scans in 
subjects with acute exacerbation of COPD, 
compared to placebo

Change from baseline in siVaw, iVaw, 
iRaw, siRAW, total lung capacity, lung 
lobar volumes, trachea length and 
diameter at FRC and TLC after 12 days of 
treatment and after 28 days of treatment.

To assess the safety and tolerability of 
once daily repeat inhaled doses of 
GSK2269557 administered to subjects with 
acute exacerbation of COPD, compared to 
placebo.

Adverse events 

Hematology, clinical chemistry 

Vital signs

12-lead ECG

To evaluate the plasma PK of once daily 
repeat inhaled doses of GSK2269557 
administered to subjects with acute 
exacerbation of COPD

Day 1 plasma Cmax and trough (24 hours) 
post dose for inpatients

Trough concentration after 12 days, 28 
days, 56 days and 84 days of treatment.

To evaluate the effect of once daily repeat 
inhaled doses of GSK2269557 on lung 
function parameters in subjects with acute 
exacerbation of COPD, compared to 
placebo

PEF, Reliever usage.

FEV1 and FVC at clinic prior to sputum 
induction.
Exploratory 

To establish any other PI3K-dependent 
changes in mRNA in sputum or blood from 
patients with an exacerbation of COPD, 
with or without treatment with 
GSK2269557.

To explore the pharmacodynamic effects in 
induced sputum of once daily repeat 
inhaled doses of GSK2269557 

Alterations in immune cell mechanisms as 
determined by changes in mRNA 
transcriptomics in induced sputum or blood 
after 12, 28 and 84 days of treatment.

Endpoints may include, but not limited to 
cytokines (IL-6, IL-8, TNF), microbiome 
(by 16SrRNA), bacterial qPCR, viral qPCR.
 
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Objectives
Endpoints
administered to subjects with acute 
exacerbation of COPD, compared to 
placebo.

To assess the changes in other CT 
parameters such as low attenuation score 
after once daily repeat inhaled doses of 
GSK2269557 administered to subjects with 
acute exacerbation of COPD, compared to 
placebo.

Change from baseline for other CT 
parameters including low attenuation score
after 12 days of treatment and after 28 
days of treatment.
4.
STUDY DESIGN
4.1.
Overall Design
This is a randomised, double-blind, placebo-controlled, parallel-group study.  All subjects 
will continue on their usual COPD medications throughout the entire duration of the 
study regardless of treatment arm assignment.  Subjects will be on standard of care 
treatment (antibiotic and corticosteroids) upon diagnosis of a COPD exacerbation.
SCR
Signature 
ICF
Day 1
Randomisation / 
First dose GSK2269557
Day 12
(+/- 2 days) 
HRCT
Day 28
(+/- 2 days)
HRCT
Day 56
(-4 / + 2 days)
Safety visit
Day 84
(-4 / + 2 days)
End treatment
FU
Baseline
HRCT
Within 48h / discharge
Baseline lung function
4.2.
Treatment Arms and Duration
Subjects will be required to participate in the following:
Screening: Following diagnosis during outpatient assessment by a Respirologist, 
Emergency Department visit or acute admission to hospital, and up to 3 days before start 
of study treatment. During this time:

The start of the standard of care (to include both antibiotics and corticosteroids) is 
expected to start shortly after diagnosis, though it is allowed to have already been 
started before the formal diagnosis of COPD exacerbation is made. 
 
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
The HRCT scan should be conducted at the earliest opportunity after obtaining 
Informed Consent from the subject and within 48 h of diagnosis by a Respirologist or 
physician with respiratory experience. 

Randomisation and first dose administration should take place as soon as possible 
following HRCT scan assessment has been performed and no later than 24h after 
completing the HRCT scan.
Treatment period:  Once daily study treatment administration will start on Day 1 (visit 1). 

For subjects who were hospitalized: 
o
If discharge takes place before Day 10, the subject must complete the 
assessments planned for visit 2 on discharge and must then visit the unit 
on Day 12 (2 days) (visit 3).
o
If discharge takes place between Day 10 and Day 14 (inclusive), the 
assessments planned for visit 2 and visit 3 may be completed on the day of 
discharge.
o
If discharge takes place from Day 15 (inclusive), the assessments planned 
for visit 2 and visit 3 should be completed as soon as it is safe for the 
patient to do so.

For subjects who were not hospitalized: the subject must complete the 
assessments planned for visit 2 within 48 hours of start of treatment, and must 
then visit the unit on Day 12 (2 days) to complete the assessments planned for 
visit 3.
Subjects will then dose at home until Day 84 (– 4 / + 2 days), with the exception of the 
days when subjects come to the clinic. On those days, they will dose at the clinic. On Day 
12 (± 2 days) (unless visit completed on discharge), Day 28 (± 2 days), Day 56 (– 4 / + 2 
days) and Day 84 (– 4 / + 2 days) subjects will return on an outpatient basis to complete 
the assessments described in the Time & Event table (Section 7.1). Subjects will be 
discharged once all assessments have been performed and there are no safety concerns.
Follow up: 7 to 14 days after last dose.
The total duration of the study is 13-14 weeks including the screening visit.
4.3.
Type and Number of Subjects
Approximately 45 subjects with an acute exacerbation of COPD will be randomized such 
that approximately 15 subjects on active and 15 subjects on placebo provide sputum at all 
the scheduled time points and complete the study.   If a higher than expected number of 
subjects prematurely discontinue the study, or fail to produce sufficient sputum post 
randomisation additional subjects may be randomised at the discretion of the sponsor.
 
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4.4.
Design Justification
This study will include a placebo control to allow for a valid evaluation of the 
pharmacodynamic endpoints and adverse events attributable to treatment versus those 
independent of treatment. Subjects will also receive standard of care for their 
exacerbation and throughout the study.
4.5.
Dose Justification
The dose chosen for this study is 700 µg of GSK2269557 per day administered via a dry 
powder ELLIPTA inhaler for a duration of 84 days (– 4 / + 2 days) and is equivalent to 
the dose of 1000 g administered via DISKUS in terms of the dose deposited and 
systemic exposure.  This dose has been selected based on previous safety and tolerability 
data in man, obtained in healthy subjects, healthy smokers and COPD patients including 
patients suffering COPD exacerbations. Also dose selection is based on a healthy subjects 
study using the ELLIPTA™ DPI. It will be assumed for exposure predictions, unless 
otherwise stated, that patients suffering exacerbations will have a similar lung deposition, 
distribution and plasma exposure to that of the healthy volunteers. However it is accepted 
that these types of subjects may have reduced airway function and hence potentially 
reduced deposition. This can be appropriately defined in this study based on the actual 
plasma exposures achieved. 
For DISKUS, twice this dose level (2000 µg) using the same formulation has previously 
been given once daily to healthy male smokers for 14 days (study PII116617). There is 
also an ongoing study where a total daily dose of 1000 µg of GSK2269557 is 
administered to stable COPD subjects via a dry powder inhaler for 14 days (study 
PII115119) which at the time of writing of this protocol had successfully dosed 21 
subjects on active treatment and collected pharmacokinetics (PK) samples for analysis 
out to 14 days.
The target effect compartment for PI3Kinhibition is the intracellular compartment of 
the immune cells resident in the lung tissue and lumen.  GSK2269557 has a high potency 
and selectivity at the PI3Kenzyme (Ki value 0.1 ng/mL) which translates into an IC50 in 
a more complex system (PHA stimulated lung tissue) of approximately 120 ng/mL (or 
2.5 ng/mL free unbound drug).  Based on the measured steady-state cellular 
concentration of GSK2269557 collected at trough (24 h) from the lungs of healthy 
smokers at 2000 µg DPI (450 ng/mL) in the clinical study it is expected that at 1000 µg 
(225 ng/mL), concentrations will be sufficient and PI3Kinhibition maintained in the 
lung at 90% inhibition for 24 h. 
Target PI3Kinhibition is based on a wide range of pharmacology experiments.  Details 
of these as well as the pharmacokinetics and safety data can be found in the IB, 
[GlaxoSmithKline Document Number: 2012N141231_06].
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK2269557 can be found in the IB [GlaxoSmithKline Document Number 
 
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2012N141231_06]. The following section outlines the risk assessment and mitigation 
strategy for this protocol:  
4.6.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Investigational Product (IP) [e.g., GSK2269557]
Bronchospasm
Mucosal irritancy
A general risk with Inhaled 
treatment
Detected in 13 week toxicology 
study in the dog
Subjects will be allowed to 
continue regular COPD 
treatments and have standard 
of care for treatment of their 
exacerbation. More severe 
patients will have their 
treatment started in hospital. 
Patients will be regularly 
monitored for AEs and a 
patient diary kept. Thus far this 
has not been seen in clinical 
studies.
Study Procedures
Radiation risk as part of HRCT 
scans
The maximum amount of 
radiation dose a patient 
undergoing all six scans will 
receive is approximately 
12mSv. Six low dose HRCT 
scans (one at TLC and FRC on 
screening, Day 12 and Day 28 
visits) at are required 
throughout the study for the 
functional imaging protocol
Reduced tube voltage (100 
kV), and tube current are used.
Scanning time less than 5 s 
per scan.
Total radiation dose for a total 
of six CT scans will be 
approximately 12mSv.
Final radiation dose will be 
dependent on the patient 
weight, with a range of 
between 1-2mSv per scan per 
patient. This radiation dose 
falls into the International 
Commission on Radiological 
Protections [ICRP, 2007]
category IIb (minor to 
intermediate risk).
The outcomes of this study will 
provide information which 
would produce advances in 
knowledge, leading to a 
potential health benefit in the 
future for patients in this target 
 
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
population. The CT may also 
provide information for the 
patients general clinical 
management
Sputum induction
Standard sputum induction 
techniques using hypertonic 
saline can result in 
bronchospasm and therefore 
could potentially induce 
bronchospasm in a patient or 
impact a pre-existing 
exacerbation.
For patients during an 
exacerbation and for sputum 
induction during the recovery 
period, including the day 28 
visit, patients will be pre-dosed 
with nebulised or inhaled beta-
2-agonist (or ipratropium 
bromide if beta-2-agonist 
intolerant). Sputum induction 
will only be carried out using 
Normal (0.9%) saline, which is 
also often used in patients 
clinically to facilitate sputum 
clearance.  
For the final sputum induction 
patients will be pre-dosed with 
nebulised or inhaled beta-2-
agonist (or ipratropium bromide 
if beta-2-agonist intolerant) and 
the induction carried out with 
0.9% saline initially and only 
then followed by hypertonic (3-
5%) if required, and, in the 
opinion of the Investigator,  it is 
considered safe to do so.
4.6.2.
Benefit Assessment
The outcomes of this study will provide information which will produce advances in 
knowledge of the pathophysiology of COPD exacerbations, leading to a potential health 
benefit in the future for patients in this target population. The CT scan may also provide 
information for the patient’s general clinical management.
4.6.3.
Overall Benefit:Risk Conclusion
The overall benefit:risk is considered to be positive. There is an opportunity to determine 
if there may be a new drug developable for the treatment of acute exacerbations of COPD 
which has not seen any new treatments recently. The scientific value in obtaining 
functional CT information on the anatomy and pathophysiology of COPD exacerbations 
 
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and how the lung responds to therapy will be extremely valuable to the wider clinical 
community and justifies the limited radiation exposure (maximum 12 mSv in total) from 
the CT scan procedures. The CT will also be useful to provide clinical information about 
the patient for the patient’s physician and contribute to clinical management.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB [GlaxoSmithKline 
Document Number: 2012N141231_06] 
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
[1] AGE

Between 40 and 80 years of age inclusive, at the time of signing the informed 
consent.
[2] TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY

The subject has a confirmed and established diagnosis of COPD, as defined by the 
GOLD guidelines for at least 6 months prior to entry.

The subject is able to produce >100 mg of sputum at screening for processing, (ie, 
total weight of sputum plugs.).

The subject has a post-bronchodilator FEV1/FVC < 0.7 and FEV1 80 % of predicted 
documented in the last 5 years.

Disease severity: Acute exacerbation of COPD requiring an escalation in therapy to 
include both corticosteroid and antibiotics. Acute exacerbation to be confirmed by an 
experienced physician and represent a recent change in at least two major and one 
minor symptoms, one major and two minor symptoms, or all 3 major symptoms.
1. Major symptoms:

Subjective increase in dyspnea

Increase in sputum volume

Change in sputum colour
2.
Minor symptoms:
 
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
Cough

Wheeze

Sore throat

The subject is a smoker or an ex-smoker with a smoking history of at least 10 pack 
years (pack years = (cigarettes per day smoked/20 x number of years smoked)).
[3] WEIGHT

Body weight 45 kg and body mass index (BMI) within the range 16 – 35 kg/m2
(inclusive).
[4] SEX

Male

Female subject : is eligible to participate if she is not pregnant (as confirmed by a 
negative urine human chorionic gonadotrophin (hCG) test), not lactating, and at least 
one of the following conditions applies:
1. Non-reproductive potential defined as:
Pre-menopausal females with one of the following:
Documented tubal ligation
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 
Hysterectomy
Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea.  Females whose 
menopausal status is in doubt will be required to use, or have been using, one of the 
highly effective contraception methods as specified below from 30 days prior to the first 
dose of study medication and until completion of the follow-up visit.
2. Reproductive potential and agrees to follow one of the options listed 
below in the GSK Modified List of Highly Effective Methods for 
Avoiding Pregnancy in Females of Reproductive Potential (FRP) 
requirements from 30 days prior to the first dose of study medication 
and until completion of the follow-up visit.
GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females 
of Reproductive Potential (FRP)
This list does not apply to FRP with same sex partners, when this is their preferred and 
usual lifestyle or for subjects who are and will continue to be abstinent from penile-
vaginal intercourse on a long term and persistent basis.
1. Contraceptive subdermal implant that meets GSK standard criteria including a 
<1% rate of failure per year, as stated in the product label
2. Intrauterine device or intrauterine system that meets GSK standard criteria 
 
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including a <1% rate of failure per year, as stated in the product label [Hatcher, 
2007a]
3. Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007a] 
4. Injectable progestogen [Hatcher, 2007a]
5. Contraceptive vaginal ring [Hatcher, 2007a]
6. Percutaneous contraceptive patches [Hatcher, 2007a]
7. Male partner sterilization with documentation of azoospermia prior to the female 
subject’s entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2007a].  
8. Male condom combined with a vaginal spermicide (foam, gel, film, cream, or 
suppository) [Hatcher, 2007b]
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
Specific inclusion criteria for Male subjects with female partners of reproductive 
potential is outlined below:
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until after the completion of the follow up visit.
3. Vasectomy with documentation of azoospermia.  
4. Male condom plus partner use of one of the contraceptive options below:
Contraceptive subdermal implant that meets GSK standard criteria including a 
<1% rate of failure per year, as stated in the product label
Intrauterine device or intrauterine system that meets GSK standard criteria 
including a <1% rate of failure per year, as stated in the product label [Hatcher, 
2007a]
Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007a] 
Injectable progestogen [Hatcher, 2007a]
Contraceptive vaginal ring [Hatcher, 2007a]
Percutaneous contraceptive patches [Hatcher, 2007a]
5.
These allowed methods of contraception are only effective when used 
consistently, correctly and in accordance with the product label.  The 
investigator is responsible for ensuring that subjects understand how to properly 
use these methods of contraception.
[5] INFORMED CONSENT

Capable of giving signed informed consent as described in Section 10.2 which
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
 
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5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
[1]  CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL)

To avoid recruitment of subjects with a severe COPD exacerbation, the presence of 
any one of the following severity criteria will render the subject ineligible for 
inclusion in the study:

Need for invasive mechanical ventilation (short term (< 48h) NIV or CPAP is 
acceptable)

Haemodynamic instability or clinically significant heart failure

Confusion

Clinically significant pneumonia, identified by chest X-ray at screening, and as 
judged by the Investigator. 

Subjects who have current medical conditions or diseases that are not well controlled 
and, which as judged by the Investigator, may affect subject safety or influence the 
outcome of the study. (Note: Patients with adequately treated and well controlled 
concurrent medical conditions (e.g. hypertension or NIDDM) are permitted to be 
entered into the study).

Subject has a diagnosis of active tuberculosis, lung cancer, clinically overt 
bronchiectasis, pulmonary fibrosis, asthma or any other respiratory condition that 
might, in the opinion of the investigator, compromise the safety of the subject or 
affect the interpretation of the results.

ALT >2xULN and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if 
bilirubin is fractionated and direct bilirubin <35%). 

A subject with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the exclusion criteria, outside of the reference range for the 
population being studied may be included if the Investigator [in consultation with the 
GSK Medical Monitor if required] documents that the finding is unlikely to 
introduce additional risk factors and will not interfere with the study procedures.

Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert’s syndrome or asymptomatic gallstones)

ECG indicative of an acute cardiac event (e.g. Myocardial Infarction) or 
demonstrating a clinically significant arrhythmia requiring treatment.

QTcF > 450 msec or QTcF > 480 msec in subjects with Bundle Branch Block, based 
on single QTcF value.

Subjects who have undergone lung volume reduction surgery.
 
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[2] CONCOMITANT MEDICATIONS

Subject is currently on chronic treatment with macrolides or long term antibiotics.

Subject is being treated with long term oxygen therapy - LTOT (> 15 hours/day).

The subject has been on chronic treatment with anti-Tumour Necrosis Factor (anti-
TNF), or any other immunosuppressive therapy (except corticosteroid) within 60 days 
prior to dosing.
[3] RELEVANT HABITS

History of regular alcohol consumption within 6 months of the study defined as an 
average weekly intake of >28 units for males or >21 units for 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.
[4]  CONTRAINDICATIONS 

History of sensitivity to any of the study medications, or components thereof (such as 
lactose) or a history of drug or other allergy that, in the opinion of the investigator or 
Medical Monitor, contraindicates their participation.
[5] DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA

A known (historical) positive test for HIV antibody.

Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test 
result at screening or within 3 months prior to first dose of study treatment.
NOTE: Because of the short window for screening, treatment with GSK2269557 
may start before receiving the result of the hepatitis tests. If subsequently the test is 
found to be positive, the subject may be withdrawn, as judged by the Principal 
Investigator in consultation with the Medical Monitor.

Where participation in the study would result in donation of blood or blood 
products in excess of 500 mL within 56 days.

The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the 
current study: 30 days, 5 half-lives or twice the duration of the biological effect of 
the investigational product (whichever is longer).

Exposure to more than 4 investigational medicinal products within 12 months 
prior to the first dosing day.
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized.  In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
 
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set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria Protocol Deviations, and any Serious Adverse Events.
5.4.
Withdrawal/Stopping Criteria
Subjects who are withdrawn from treatment will also be withdrawn from the study. 
If a higher than expected number of subjects prematurely discontinues the study, 
additional subjects may be randomised and assigned to the same treatment sequence, at 
the discretion of the Sponsor.  
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as soon 
as possible. 

The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 
telephone calls and if necessary a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
Subjects who are withdrawn should complete all the assessments planned, if possible.  
Subjects who are withdrawn on a study clinic visit after randomization should complete 
all the safety related assessment for that visit which includes at minimum, vital sign, lab 
assessments (if deem necessary by the PI), AE/SAEs, concomitant medication(s) and 
ECG.   A Follow up Visit should be scheduled 7-14 days post last dose.
Subjects who are withdrawn in between study clinic visits should complete the 
unscheduled visit and complete all the safety related assessment at minimum which 
includes, vital sign, lab assessments (if deem necessary by the PI), AEs/SAEs, 
concomitant medication(s) and ECG.   A Follow up Visit should be scheduled 7-14 post 
last dose.
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
 
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http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase II Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5, if 
measured*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
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 2.
5.4.1.1.
Study Treatment Restart or Re-challenge
Study treatment restart or re-challenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.4.2.
QTc Stopping Criteria

QTcF should be based on averaged QTcF values of triplicate electrocardiograms 
obtained over a brief (e.g., 5-10 minute) recording period. For example, if an ECG 
(Electrocardiogram) demonstrates a prolonged QTcF interval, obtain two more 
ECGs and use the averaged QTcF values of the three ECGs to determine whether the 
patient should be discontinued from the study.
A subject who meets either of the bulleted criteria below will be withdrawn from the 
study:

QTcF >500 msec OR Uncorrected QT >600 msec

Change from baseline of QTcF > 60 msec
 
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For patients with underlying bundle branch block, follow the discontinuation criteria 
listed below:
Baseline QTcF with Bundle Branch 
Block
Discontinuation QTcF with Bundle 
Branch Block
<450 msec
>500 msec
450 – 480 msec
≥530 msec
5.4.3.
Other Stopping Safety Criteria
For an individual study participant, stopping criteria include, but are not limited to:
Severe signs or symptoms, or significant changes in any of the safety assessments, that 
put the safety of the individual at risk (e.g. ECG, vital signs, laboratory tests, spirometry 
assessments, etc), as judged by the Principal Investigator in consultation with the Medical 
Monitor if necessary.
Treatment failure or recurrent exacerbation does not mandate withdrawal from the study, 
unless there is a safety concern as judged by the Investigator, in consultation with the 
Medical Monitor if necessary.
Subjects should be withdrawn from the study if confusion, acute respiratory acidosis (pH 
< 7.30), or need for invasive mechanical ventilation occurs.
5.5.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit.
The end of the study is defined as the last subject’s last visit.
 
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6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
Study Treatment Name:
GSK2269557 
ELLIPTATM DPI 
(100 μg)
GSK2269557 
ELLIPTATM DPI 
(500 μg)
Placebo ELLIPTATM
DPI
Formulation 
description:
GSK2269557 
blended with lactose 
and magnesium 
stearate
GSK2269557 
blended with lactose
and magnesium 
stearate
Lactose
Dosage formulation:
DPI
DPI
DPI
Unit dose 
strength(s)/Dosage 
level(s):
100 μg per blister
500 μg per blister
NA
Route of 
Administration:
Inhaled
Inhaled
Inhaled
Dosing instructions:
Inhale as directed
Inhale as directed
Inhale as directed
Physical description:
Dry white powder
Dry white powder
Dry white powder
Method for 
individualizing dosage:
DPI containing a 
single strip with 30 
blisters
DPI containing a 
single strip with 30 
blisters
DPI containing a 
single strip with 30 
blisters
Packaging and Labeling
Study Treatment will 
be labeled as 
required per country 
requirement. 
Study Treatment will 
be labeled as 
required per country 
requirement.
Study Treatment will 
be labeled as 
required per country 
requirement.
Manufacturer
GSK
GSK
GSK
6.2.
Treatment Assignment
Subjects will be assigned to treatments in accordance with the randomization schedule
generated by Clinical Statistics, prior to the start of the study, using validated internal 
software. Central based randomisation will be used.
 
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Subjects will be randomised to treatments A, B, C or D where:
A = Placebo 
B = GSK2269557 1000 µg 
C = Placebo via Ellipta
D = GSK2269557 700 µg via Ellipta
A web based interactive response system will be used to assign subjects to treatment.
6.3.
Planned Dose Adjustments
If adverse events, unrelated to COPD exacerbation, which are of moderate or severe 
intensity and are consistent across subjects in the group, or if unacceptable 
pharmacological effects, reasonably attributable in the opinion of the investigator to 
dosing with GSK2269557, are observed in more than 30% of the subjects then the study
will be halted and no further subject will be dosed until a full safety review of the study 
has taken place. Relevant reporting and discussion with the Medical Monitor, relevant 
GSK personnel, and with the Ethics Committees will then take place prior to any 
resumption of dosing. If the above is observed consideration may be given to reducing 
the dose of GSK2269557 to 500 µg O.D.
6.4.
Subject Specific Dose Adjustment Criteria
There are no subject specific dose adjustment criteria.
6.5.
Blinding
This will be a double blind study and the following will apply. 

The investigator or treating physician may un-blind a subject’s treatment assignment 
only in the case of an emergency OR in the event of a serious medical condition 
when knowledge of the study treatment is essential for the appropriate clinical 
management or welfare of the subject as judged by the investigator. 

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before un-blinding 
the subject’s treatment assignment. 

If GSK personnel are not contacted before the un-blinding, the investigator must 
notify GSK as soon as possible after un-blinding. 

The date and reason for the un-blinding must be fully documented in the Case Report 
Form (CRF)

A subject will be withdrawn if the subject’s treatment code is un-blinded by the 
investigator or treating physician. The primary reason for discontinuation (the event 
or condition which led to the un-blinding) will be recorded in the CRF.
 
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
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may un-blind the 
treatment assignment for any subject with a Serious Adverse Event (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 subject’s treatment assignment, may be 
sent to investigators in accordance with local regulations and/or GSK policy.
6.6.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

Only subjects 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 labelled storage conditions with access limited to the 
investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e. receipt, reconciliation and final disposition records).  

Further guidance and information for final disposition of unused study treatment are 
provided in the Study Reference Manual (SRM).

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, Medical Monitor and/or 
GSK study contact.

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
6.7.
Compliance with Study Treatment Administration
When subjects 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 subjects will be asked to complete a diary when dose administration takes place at 
home. The date, time and number of inhalations will be recorded. The compliance will be 
checked by the site staff at each planned visit. 
A record of the number of ELLIPTATM inhalers dispensed to each subject and the 
number of actuation administered, read from the dose counter for each ELLIPTATM
inhaler, must be maintained and reconciled with study treatment and compliance records.  
 
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Treatment start and stop dates, including dates for treatment delays and/or dose 
reductions will also be recorded in the CRF.
6.8.
Treatment of Study Treatment Overdose
For this study, any dose of GSK2269557 >2000 µg for DISKUS and >1400 µg for 
ELLIPTA within a 22 hour time period will be considered an overdose.
GSK does not recommend specific treatment for an overdose
In the event of an overdose the investigator should:
1) contact the Medical Monitor immediately
2) closely monitor the subject for adverse events (AEs)/serious adverse events 
(SAEs) and laboratory abnormalities until GSK2269557 can no longer be detected 
systemically (at least 14 days for GSK2269557)
3) obtain a plasma sample for pharmacokinetic (PK) analysis within 7 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 subject.
6.9.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because the indication being studied is not life threatening or seriously debilitating 
and/or other treatment options are available.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
Any clinical abnormalities identified during the conduct of the study will be locally 
managed by the Investigator.
6.10.
Lifestyle and/or Dietary Restrictions

Subjects should refrain from consumption of Seville oranges, grapefruit or grapefruit 
juice, exotic citrus fruits or grapefruit hybrids from first dose till the end of the study.

Subjects should abstain from alcohol on the day when they visit the clinical unit and 
until their discharge on that day.

Subjects should refrain from smoking for at least 2 hours prior to each pulmonary 
function test conducted at the clinical unit/site.
 
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6.11.
Concomitant Medications and Non-Drug Therapies
6.11.1.
Permitted Medications and Non-Drug Therapies
On entry to the study all treatment required for standard of care and additional medical 
problems is permitted to start and continue.
The subjects are allowed to continue their regular COPD treatments for the duration of 
the study. However, the subjects should refrain, if possible, from using relief 
bronchodilators for at least 4 hours prior to each spirometry conducted at the clinical unit, 
and HRCT scan assessment unless essential for clinical symptom relief.  Otherwise free 
use of reliever/rescue medication is allowed.  Rescue ventolin and aerochambers may be 
provided by GSK for this study and in such case, subjects should be advise to discontinue 
their own ventolin and use the study ventolin and aerochamber provided for the duration 
of the study.
All prior (up to 2 months prior to screening) and concomitant medications should be 
recorded in the subject’s CRF.
6.11.2.
Prohibited Medications and Non-Drug Therapies
Regular or chronic treatment with medications that are considered strong inhibitors of 
CYP3A4 or CYP2D6 are not permitted. This includes anti-epileptic treatments, 
macrolide antibiotics, oral antifungal treatments (single doses and courses up to 7 days 
are allowed) and anti-tuberculous therapy. These medications must all have been stopped 
at least 14 days prior to first dose.
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1
 
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7.1.
Time and Events Table (Screening and Follow Up Visits)
Procedure
Screening 
(up to 3 days prior to Visit 1)
Follow-up
(7-14 days post-last dose)
Notes
Informed consent
X
Demography
X
Inclusion and exclusion criteria
X
Full physical exam, including height and 
weight
X
Brief physical examination, including weight
X
Chest X-Ray
X
To be done before baseline HRCT to exclude significant 
pneumonia and other incidental serious underlying pathology.
Medical history (includes substance usage
and Family history of premature CV disease)
X
Substances: Drugs, Alcohol, tobacco via history.  No drug, alcohol 
screening is required.
Past and current medical conditions  
(including cardiovascular medical history and 
therapy history)
X
Laboratory assessments (include Hematology 
and biochemistry)1
X
X
Historical values analysed by local lab to be used for eligibility 
assessment. Another sample must be collected and sent to central 
lab as soon as informed consent is obtained. 
Hep B and Hep C screen2
X
Urine pregnancy test (only WCBP)
X
Before conducting the HRCT.  Done locally at the site.
12-lead ECG
X
X
Single assessment
Vital signs
X
X
Single assessment
HRCT (at TLC and FRC)
X
Within 48 h of diagnosis, if subject otherwise eligible. Includes 
electronic monitoring of breathing (if applicable).  Baseline HRCT 
will be reviewed by the local site’s radiologist to identify any 
significant occurring underlying medical conditions that require 
further clinical management or monitoring.
Induced Sputum3
X4
To include sputum culture pre-first dose. Culture to be done by the
local site laboratory.
Blood sample for mRNA Analysis
X4
Collected at any time on specified days
AE/SAE collection and review
X
 
 
 
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Procedure
Screening 
(up to 3 days prior to Visit 1)
Follow-up
(7-14 days post-last dose)
Notes
Concomitant medication review
X
X
1.
Due to the short screening window, central laboratory analysis results will not be available on time. Therefore the local laboratory results should be used for eligibility assessment 
(to exclude severe subjects and underlying medical conditions). If local laboratory results are already available from diagnosis of current exacerbation, there is no need to take 
another sample for local analysis. A sample for central laboratory analysis should also be obtained. See Section 7.8.6 for further details.
2.
If test otherwise performed within 3 months prior to first dose of study treatment, testing at screening is not required. Because of the short window for screening, treatment with 
GSK2269557 may start before receiving the result of the hepatitis tests. If subsequently the test is found to be positive, the subject may be withdrawn, as judged by the Principal 
Investigator in consultation with the Medical Monitor.
3.
Induced sputum collection may be attempted on several occasions if an adequate sample is not produced at the first attempt.
4.
To be collected at any time point before randomisation.
 
 
 
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7.2.
Time and Events Table (Treatment Period)
Procedure
Treatment Period 
Notes
Visit
1
21
3
4
5
6
Day
1
Within 48h 
/ discharge
12
28
56
84
Visit window
N/A
1 days
2 days
2 days
- 4 / +2 days
- 4 / +2 days
SAFETY ASSESSMENTS
AE/SAE collection and review
=========================================================
Concomitant medication review
=========================================================
Reliever usage
=========================================================
Brief physical exam, including weight
X2
X
X
X
X
Pre-dose
Laboratory assessments (include 
haematology and biochemistry)
X2
X
X
X
X
Pre-dose
12-lead ECG
X2
X
X
X
X
Pre-dose. Single assessment
Vital signs
X2
X
X
X
X
Pre-dose. Single assessment
Urine pregnancy test (only WCBP)
X
X
Before conducting the HRCT
STUDY TREATMENT
ELLIPTATM Inhaler Training
X
Training conducted by reviewing the 
Patient Information Leaflet with the 
subject (no device will be used). 
Additional training may be conducted at 
the discretion of the investigator
Randomisation
X
Study drug administration
=========================================================
Daily in the morning before breakfast, 
(with the exception of days when the 
subjects have a planned visit to the 
clinic. On those days, they will be 
dosed at the clinic).
Assessment of study treatment compliance
X
X
X
X
Diary Card dispense and review at clinic
X
X
X
X
X
Refer to SRM for details.
 
 
 
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Procedure
Treatment Period 
Notes
Visit
1
21
3
4
5
6
Day
1
Within 48h 
/ discharge
12
28
56
84
Visit window
N/A
1 days
2 days
2 days
- 4 / +2 days
- 4 / +2 days
EFFICACY ASSESSMENTS
HRCT (at TLC and FRC)
X
X
At any time on specified days. Includes 
electronic monitoring of breathing (if 
applicable).  The radiologist may review 
any of the scan(s) if they wish, but this 
is NOT required for the study.  A formal 
review is required at screening only by 
the radiologist.
FEV1  and FVC
X
X
X
X
X
X
In clinic only for all visits where 
possible.
PEF 
=========================================================
Daily before drug administration at 
home.  If subject in hospital, this may 
be collected using the handheld device 
provided prior to drug administration.
OTHER ASSESSMENTS
Blood sample for PK
X
X
X
X
X
Day 1:  5 min and 24 h post-dose. The 
24 h post-dose time-point is optional for 
subjects not hospitalised. Pre-dose at 
all other time-points.
Sputum induction3
X
X
X
Blood sample for mRNA analysis
X
X
X
Genetic sample (PGx)4
X
Collected at any time after 
randomisation
1.
On discharge if the subject was hospitalized. Within 48 hours of first dose administration if the subject was not hospitalised. See Section 4.2
2.
Assessments do not need to be completed if screening assessments conducted within 48 hours 
3.
Induced sputum collection may be repeated on several occasions if an adequate sample is not produced at the first attempt 
4.
Informed consent for optional sub-studies (e.g. ,genetics research) must be obtained before collecting a sample.  May be obtained at any visits.
 
 
 
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7.3.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.  
Procedures conducted as part of the subject’s routine clinical management and obtained 
prior to signing of informed consent may be utilized for Screening or baseline purposes 
provided the procedure meets the protocol-defined criteria and has been performed in the 
timeframe of the study.
If they are being utilised in the study, Patient Reported Outcomes questionnaires should 
be completed by subjects before any other assessment at a clinic visit, in the order 
specified.
7.4.
Biomarker(s)/Pharmacodynamic Markers
7.4.1.
Pharmacodynamic Biomarkers in Sputum

Collect sputum induction samples at the time-points shown in the time and events
table (Section 7.1).

The sputum induction collection process will follow local standard procedures and
guidelines outlined in the SRM.

The collection of induced sputum may be attempted on several occasions if an 
adequate sample is not produced at the first attempt.

Further information on collection, processing, storage and shipping procedures are 
provided in the SRM.
7.4.2.
mRNA in blood

Collect 2.5 mL of blood into a PAXgene mRNA tube.
Details of blood sample collection, processing, storage and shipping procedures are 
provided in the SRM.
7.5.
Patient diary
The subjects will be provided with a diary to record the following data when at home: 

Time and date of each dose administration and number of inhalations.

Adverse Events and concomitant medications taken (including daily rescue 
medication – if used and how many times used).
 
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
PEF from a handheld device.  The best/highest result is recorded.
Changes in Health and details of any concomitant medications as well as PEF assessment 
details will be collected in the paper diaries and later transcribed into the CRF. 
7.6.
Genetics
Information regarding genetic research is included in Appendix 3.
7.7.
Efficacy
7.7.1.
Functional Respiratory Imaging

A CT scan with a low radiation protocol at FRC and TLC will be conducted as listed 
in the Time and Events Table (Section 7.1). The same scanner should be used for 
baseline and post-treatment scans for an individual subject.

A urine pregnancy test should be performed before the CT scan in female subjects of 
childbearing potential.

Further information is provided in the SRM.
7.7.2.
FEV1  and FVC
A triplicate FEV1 and FVC measurement will be taken at the clinic before dosing using 
the site’s spirometer as soon as it is safe to do so. These will be recorded as absolute 
values.  The best/highest result is recorded.

Further details are provided in the SRM.
7.7.3.
Peak Expiratory Flow PEF

PEF measurements will be taken (in triplicate) daily in the morning before dose 
administration, as soon as it is safe for the subject to do so. The best/highest result is 
recorded.

Subjects will be provided with a handheld device.

Further details are provided in the SRM.
7.8.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests (such as vital signs, physical exams
and laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
7.8.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.
 
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7.8.1.1.
Time period and Frequency for collecting AE and SAE information

AEs and SAEs will be collected from the start of Study Treatment until the follow-
up contact (see Section 7.8.1.3), at the time-points specified in the Time and Events 
Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product 
will be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact. 

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 4.

Investigators are not obligated to actively seek AEs or SAEs in former study
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the investigator 
must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 4.
7.8.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
 
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7.8.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in
Appendix 4.
7.8.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
7.8.1.5.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
COPD exacerbations are associated with the disease to be studied and will not be 
recorded as AEs unless they meet the definition of an SAE as defined in Appendix 4
Exacerbations that meet the definition of an SAE will be recorded on the appropriate 
eCRF section and should be reported to GSK.
Medications used to treat a COPD exacerbation will be recorded in the exacerbation 
eCRF
7.8.1.6.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs and non-serious AEs related to 
study treatment (even for non- interventional post-marketing studies) is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and the safety 
of a product under clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
 
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Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.8.2.
Pregnancy

Details of all pregnancies in female subjects and female partners of male subjects 
will be collected after the start of dosing and until the follow-up visit

If a pregnancy is reported then the investigator should inform GSK within 2 weeks 
of learning of the pregnancy and should follow the procedures outlined in Appendix 
5. 
7.8.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems.  Height and 
weight will also be measured and recorded.

A brief physical examination will include, at a minimum assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
7.8.4.
Vital Signs

Vital signs will be measured in semi-supine position after 5 minutes rest and will
include temperature, systolic and diastolic blood pressure and pulse rate and 
respiratory rate.

Three readings of blood pressure and pulse rate will be taken

First reading should be rejected

Second and third readings should be averaged to give the measurement to be 
recorded in the CRF. 
7.8.5.
Electrocardiogram (ECG)

Single 12-lead ECGs will be obtained at screening and at each other timepoint during 
the study using an ECG machine that automatically calculates the heart rate and 
measures PR, QRS, QT, and QTcF intervals.  Refer to Section 5.4.2 for QTcF
withdrawal criteria and additional QTcF readings that may be necessary.
 
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7.8.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 1, must be conducted in
accordance with the Laboratory Manual, and Protocol Time and Events Schedule.
Laboratory requisition forms must be completed and samples must be clearly labelled 
with the subject number, protocol number, site/centre number, and visit date. Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the laboratory manual. Reference ranges for all safety parameters will be
provided to the site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Historical values (if the assessment was conducted as part of the standard of care) for 
blood gases, blood culture and sputum culture may also be collected if available.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
Table 1
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 1
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose (non 
fasted)
Calcium
Alkaline 
phosphatise
Albumin
CRP
Other 
Screening 
Tests

Urine hCG Pregnancy test (as needed for women of child bearing 
potential) 2

Hepatitis B (HBsAg)

Hepatitis C (Hep C antibody)
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 5.4.1 and Appendix 2
2. Local urine testing will be standard for the protocol unless serum testing is required by local regulation or ethics 
committee.
 
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All study-required laboratory assessments will be performed by a central laboratory, apart 
from:

Hematology and clinical chemistry at screening for excluding subjects with severe 
disease and uncontrolled medical conditions. The results of each test must be entered 
into the CRF.
NOTE:  Local laboratory results are only required in the event that the central laboratory
results are not available in time for either a treatment and/or response evaluation to be 
performed. If a local sample is required it is important that the sample for central 
analysis is obtained at the same time. Additionally if the local laboratory results are used 
to make either a treatment or response evaluation, the results must be entered into the 
CRF.
Hematology, clinical chemistry and additional parameters to be tested are listed in Table 
1. 
7.9.
Pharmacokinetics
7.9.1.
Blood Sample Collection
A 2 mL blood samples for pharmacokinetic (PK) analysis of GSK2269557 will be
collected at the time points indicated in Section 7.1, Time and Events Table.  The actual
date and time of each blood sample collection will be recorded.  The timing of PK 
samples may be altered and/or PK samples may be obtained at additional time points to 
ensure thorough PK monitoring.  
Processing, storage and shipping procedures are provided in the Study Reference Manual
(SRM). 
7.9.2.
Sample Analysis
Plasma analysis will be performed under the control of PTS-DMPK/Scinovo, 
GlaxoSmithKline, the details of which will be included in the SRM. Concentrations of 
GSK2269557 will be determined in plasma samples using the currently approved 
bioanalytical methodology. Raw data will be archived at the bioanalytical site (detailed 
in the SRM).
Once the plasma has been analyzed for GSK2269557 any remaining plasma may be
analyzed for other compound-related metabolites and the results reported under a 
separate PTS-DMPK/Scinovo, GlaxoSmithKline protocol.
 
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8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.

Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSK Drug.  

CRFs (including queries and audit trails) will be retained by GSK, and copies will be 
sent to the investigator to maintain as the investigator copy.  Subject initials will not 
be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
This study is designed to establish the PI3K-dependent alterations in immune cell 
mechanisms related to neutrophil function as detected by changes in mRNA 
transcriptomics in samples of induced sputum from patients admitted with an 
exacerbation of COPD. The primary comparison will be between subjects treated with 
GSK2269557 in addition to standard of care, and subjects treated with placebo in 
addition to standard of care. In addition, treatment comparisons between subjects at 
baseline and subsequent time points will also be produced. By first intent, the data from 
the different devices will be pooled and may also be investigated separately, full details 
will be specified in the RAP prior to unblinding.
9.1.
Sample Size Considerations
The sample size for this study has been based on feasibility. The sample size of 30 
subjects completing the trial, with approximately 15 of which will receive GSK2269557 
and 15 will receive placebo, is expected to be sufficient to provide a meaningful estimate 
of the mRNA alterations within the lungs.
Previous studies with similar sample size populations have yielded significant fold-
changes (fold-change>1.5 and p<0.05) in immune cell mechanisms using the changes in 
mRNA transcriptomics.
 
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Study Name
Sample
Study Design
Number of Subjects
Number of Differential 
probesets FC = >= 1.5, 
Pval <= 0.05
Notes
PII115117 FTIH 
Healthy Smoker 
nebulised 
GSK2269557
Sputum
Sputum N=12 3-
way x-over 
placebo 400ug, 
6400ug 
12 (9 with all data 
points)
57 probesets change with 
both doses = 44 Genes
Gene changes relate predominantly 
to a down regulation of infection and 
inflammation responses.
Link to Haemophilus influenzae and 
Moraxella catarrhalis infection 
biology – Identified prior to 
knowledge of Activated PI3Kδ 
Syndrome phenotype
200114 Enabler 
GSK2269557 on ex-
vivo COPD Sputum 
and Blood
Sputum
Ex vivo Sputum 
incubated with 
GSK2269557 
sampled at 
6hrs (Sputum 
producers)
15 Subjects
490 probesets change vs 
vehicle control = 295 
genes (of which 43 are 
dysregulated in COPD 
disease vs Healthy 
comparison)
43 genes altered in COPD and 
positively modulated by PI3Kδi 
GSK2269557. Biological themes in 
signature: Pro-cell 
movement/migration  and cell 
viability, anti-apoptotic. Additionally 
link to B/T cell function. Signature 
supports GSK2269557 correction of 
neutrophil migration 
200114 Enabler 
GSK2269557 on ex-
vivo COPD Sputum 
and Blood
Blood
Ex vivo blood 
incubated with 
GSK2269557 
sampled at 
6hrs (Sputum 
15 Subjects
19 probesets change vs 
vehicle control = 15 genes 
Infection and inflammation 
associated genes
200114 Enabler 
GSK2269557 on ex-
vivo COPD Sputum 
and Blood
Blood
Ex vivo blood 
incubated with 
GSK2269557 
sampled at 
6h
(N
15 Subjects
30 probesets change vs 
vehicle control = 25 genes 
Infection and inflammation 
associated genes
9.1.1.
Sample Size Re-estimation or Adjustment
No sample size re-estimation will be performed in this study. 
9.2.
Data Analysis Considerations
9.2.1.
Analysis Populations
Population
Definition / Criteria
Analyses Evaluated
Screened
All subjects who were screened.

Study Population
All subject
All randomised subjects who receive at least 
one dose of the study treatment.
This population will be based on the 
treatment the subject actually received.

Study Population

Pharmacodynamics

Safety

Efficacy
Pharmacokinetic
Subjects in the ‘All subject’ population for 
whom a pharmacokinetic sample was 
obtained and analysed.

PK
9.2.2.
Interim Analysis
No interim analyses will be performed.
 
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9.3.
Key Elements of Analysis Plan
9.3.1.
Primary Analyses
To estimate differences in mRNA intensities within and between treatment groups, a 
repeated measures model will be fitted to the results of the analysis of each probe set at 
Day 12, Day 28 and Day 84 following a loge transformation of the data. The Day 1 
response will be fitted as a baseline covariate. A separate model will be fitted for each of 
the approximate 54000 probe sets.
Back transformed ratios versus screening along with 95% confidence intervals will be 
calculated for each treatment group and timepoint.  Additionally, baseline adjusted ratios 
of the change between active treatment and placebo will be calculated along with 95% 
confidence intervals.
Further details around the analysis of the mRNA data will be provided in the RAP.
9.3.2.
Secondary Analyses
All secondary analyses will be described in full prior to unblinding in the RAP.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Signed informed consent  to be obtained for each subject before participation in the 
study (and for amendments as applicable)
 
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
Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, or 
both.

Signed informed consent must be obtained for each subject prior to participation in 
the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, written 
approval of the clinical protocol should state that approval of optional assessments is 
being deferred and the study, with the exception of the optional assessments, can be 
initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will
serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and the 
regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
 
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relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective 
and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard Operating 
Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this study 
at any time for reasons including, but not limited to, safety or ethical issues or severe 
non-compliance. For multicenter studies, this can occur at one or more or at all sites.  

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by 
local regulations to be maintained elsewhere), in a safe and secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review in 
conjunction with assessment of the facility, supporting systems, and relevant site 
staff.  

Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, including 
re-generating a hard copy, if required.  Furthermore, the investigator must ensure 
there is an acceptable back-up of these reproductions and that an acceptable quality 
control process exists for making these reproductions.
 
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
GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by any 
institutional requirements or local laws or regulations, GSK standards/procedures, 
and/or institutional requirements. 

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of ownership 
of the records in the event the investigator is no longer associated with the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
The procedures and timing for public disclosure of the 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.
 
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11.
REFERENCES
De Backer J, Vos W, Vinchurkar S, Van Holsbeke C, Poli, G, Claes R et al. The Effect of 
Extrafine Beclometasone/Formoterol (BDP/F) on Lung Function, Dyspnea, 
Hyperinflation, and Airway Geometry in COPD Patients:  Novel Insight Using 
Fundtional Respiratory Imaging. Journal of Aerosol Medicine and Pulmonary Drug 
Delivery. 2014;27:1-12. 
De Backer LA, Vos WG, Salgado R, De Backer JW, Devoldr A, Verhulst SL et al. 
Functional imaging using computer methods to compare the effect of salbutamol and 
ipratropium bromide in patient-specific airway models of COPD. International Journal 
of COPD. 2011;6:637-646. 
De Backer Lieve A, Vos Wim, Van Holsbeke C, Vinchurkar S, De Backer W. The acute 
effect of budesonide/formoterol in COPD:  a multi-slice computed tomography and lung 
function study. Eur Respir J. 2012;40:298-305. 
GlaxoSmithKline Document Number 2012N141231_06: GSK2269557 Investigator's 
Brochure. Report Date 16-AUG-2016. 
Goldin J, Tashkin D, Kleerup E, Greaser MS, Haywood U, Sayre J et al. Comparative 
effects of hydrofluoroalkane and chloroflurocarbon beclomethasone dipropionate 
inhalation on small airways: Assessment with functional helical thin-section computed 
tomography. J Allergy Clin Immunol. 1999;104 #6:S258-S267. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D et al. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007(a):24. Table 3-2. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D et al. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007(b): 28. 
ICRP. 2007 Recommendation of the International Commission on Radiological 
Protection. ICRP Publication 103. 2007;37:2-4. 
Kim SR, Lee KS, Park HS, et al. HIF -1 alpha inhibition ameliorates an allergic airway 
disease via VEGF suppression in bronchial epithelium. Eur J Immunol. 2010;40 
(10):2858-69. 
Okkenhaug K, Aki K, Vanhaesebroeck B. Antigen receptor signalling:  A distincive role 
for the p110 isoform of PI3K. Trends in Immunuology. 2007;28:80-7. 
Sadhu C, Dick K, Tino WT, Staunton DE. Selective role of PI13K delta in neutrophil 
inflammatory responses. Biochem Biophys Res Commun. 2003 Sep 5;308 (4):764-9. 
Weisser SB, McLarren KW, Voglmaier B, et al. Alternative activation of macrophages 
by IL-4 requires SHIP degradation. Eur J Immunol. 2011;41(6):1742-53. 
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
AE
Adverse Event
ALT
Alanine aminotransferase
COPD
Chronic Obstructive Pulmonary Disease
CRF
Case Report Form
CT
Computed Tomography
CV
Cardiovascular
ECG
Electrocardiogram
DPI
Dry Powder Inhaler
FEV1
Forced Expiratory Volume in One Second
FRC
Functional Residual Capacity
FRI
Functional Respiratory Imaging
GCP
ICH Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GSK
GlaxoSmithKline
HRCT
High-Resolution Computed Tomography
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
PEF
Peak Expiratory Flow
PI3K
Phosphoinositide 3-Kinase Delta
PK
Pharmacokinetic
QTcF
QT interval corrected using the Fridericia's formula
RAP
Reporting and Analysis Plan
SAE
Serious Adverse Event
SRM
Study Reference Manual
TLC
Total Lung Capacity
ULN
Upper Limit of Normal
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
DISKUS
None
ELLIPTA
 
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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Phase II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase II liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete an
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with study 
treatment unless allowed per protocol and GSK 
Medical Governance approval is granted (refer 
to Appendix 2).

If restart/rechallenge not allowed per protocol 
or not granted, permanently discontinue study 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained 7 days after last 
dose5

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 
 
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treatment and may continue subject in the study 
for any protocol specified follow up assessments 
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-72 
hrs 

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline
form including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in subjects with definite or likely 
acetaminophen use in the preceding 
week [James, 2009]). NOTE: not 
required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN.. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, 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 subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
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 
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.)  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.
 
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Phase II liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject safety. 

Subject can continue study treatment 

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
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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12.3.
Appendix 3: Genetic Research
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and:

Response to medicine, including any treatment regimens under investigation in this 
study or any concomitant medicines;

COPD susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.

A 6 mL blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. A 
Blood sample is collected at the baseline visit, after the subject has been randomized 
and provided informed consent for genetic research. Instructions for collection and 
shipping of the genetic sample are described in the laboratory manual. The DNA 
from the blood sample may undergo quality control analyses to confirm the integrity 
of the sample. If there are concerns regarding the quality of the sample, then the 
sample may be destroyed. The blood sample is taken on a single occasion unless a
duplicate sample is required due to an inability to utilize the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
 
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the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA sample 
is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will continue 
to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to
complete this process as it will be completed as part of the consent and sample 
 
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reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
 
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12.4.
Appendix 4: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.4.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

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 medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

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 prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected 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 this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).
Events NOT meeting definition of an AE include:

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 subject’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 
subject’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
 
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convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
12.4.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject 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 hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject 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 out-patient setting.  Complications that occur during 
hospitalization are AEs.  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 disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g. sprained ankle) which may interfere 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 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 subject or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition.  These should also be 
considered serious.

Examples of such events are 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
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.4.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
 
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12.4.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’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 instance, all subject identifiers, with the exception of 
the subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
12.4.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
 
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Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence 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 natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of 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 when 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 prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject 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 the designated 
reporting time frames.
 
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12.4.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data 
collection tool

If the electronic system is unavailable for greater than 24 hours, the site will use 
the paper SAE data collection tool and fax it to the Medical Monitor.

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission 
of the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes 
to existing data

If a site receives a report of a new SAE from a study subject or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, the site can report this information on a paper SAE form or to the 
Medical Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
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12.5.
Appendix 5: Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who 
becomes pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 
2 weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, 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. 

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 4. 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 subject who becomes pregnant while participating will discontinue 
study medication
Pregnancy information on female partner of male study subjects

Investigator will attempt to collect pregnancy information on any female partner of 
a male study subject who becomes pregnant while participating in this study.  This 
applies only to subjects who are randomized to receive study medication. 

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate 
form and submit it to GSK within 2 weeks of learning of the partner’s pregnancy

Partner will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded to GSK. 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date.  Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for procedure.
 
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12.6.
Appendix 6: Country Specific Requirements
No country-specific requirements exist.
 
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12.7.
Appendix 7: Protocol Amendment Changes
Protocol Amendment #1 Changes
The amendment was created to remove the specific equations for the prediction of 
percent predicted from spirometry from the inclusion criteria (European Community of 
Coal and Steel and European Respiratory Society Global Lung Function Initiative 
reference equations (Quanjer 2012) in Section 7.7.2.  At screening it may not be possible
to identify which correction method was used, or modify the correction method used, at 
the time.  As a result it may not be valid to stipulate that lung function values be 
corrected using any particular method.  Both FEV1 and FVC measurements (which are 
not entry criteria for the study) collected during the study will be collected as absolute 
values (uncorrected), so that consistency will be obtained across all sites in the study, and 
percent predicted will be calculated using a standard approach in house at the end of the 
study.
List of specific changes:
Page 22, Inclusion Criteria (#2 – Type of Subject and Diagnosis Including Disease 
Severity) - Third Bullet.
PREVIOUS TEXT

The subject has a post-bronchodilator FEV1/FVC < 0.7 and FEV1 80 % of 
predicted. Predictions should be according to the European Community of Coal and 
Steel (ECCS) equations OR the European Respiratory Society Global Lung Function 
Initiative reference equations [Quanjer, 2012] and documented in the last 5 years.
REVISED TEXT

The subject has a post-bronchodilator FEV1/FVC < 0.7 and FEV1 80 % of
predicted documented in the last 5 years.
Page 40, Section 7.7.2 (FEV1 and FVC)
PREVIOUS TEXT
A triplicate FEV1 and FVC measurement will be taken at the clinic before dosing using 
the site’s spirometer as soon as it is safe to do so.  Predicted values will be based upon the 
European Respiratory Society Global Lung Function Initiative reference equations
[Quanjer, 2012].
REVISED TEXT
A triplicate FEV1 and FVC measurement will be taken at the clinic before dosing using 
the site’s spirometer as soon as it is safe to do so.  These will be recorded as absolute 
values.  The best/highest result is recorded.
 
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Page 54 – References
PREVIOUS TEXT
De Backer J, Vos W, Vinchurkar S, Van Holsbeke C, Poli, G, Claes R et al. The Effect of 
Extrafine Beclometasone/Formoterol (BDP/F) on Lung Function, Dyspnea, 
Hyperinflation, and Airway Geometry in COPD Patients:  Novel Insight Using 
Fundtional Respiratory Imaging. Journal of Aerosol Medicine and Pulmonary Drug 
Delivery. 2014;27:1-12. 
De Backer LA, Vos WG, Salgado R, De Backer JW, Devoldr A, Verhulst SL et al. 
Functional imaging using computer methods to compare the effect of salbutamol and 
ipratropium bromide in patient-specific airway models of COPD. International Journal 
of COPD. 2011;6:637-646. 
De Backer Lieve A, Vos Wim, Van Holsbeke C, Vinchurkar S, De Backer W. The acute 
effect of budesonide/formoterol in COPD:  a multi-slice computed tomography and lung 
function study. Eur Respir J. 2012;40:298-305. 
GlaxoSmithKline Document Number 2012N141231_06: GSK2269557 Investigator's 
Brochure. Report Date 12-FEB-2015. 
Goldin J, Tashkin D, Kleerup E, Greaser MS, Haywood U, Sayre J et al. Comparative 
effects of hydrofluoroalkane and chloroflurocarbon beclomethasone dipropionate 
inhalation on small airways: Assessment with functional helical thin-section computed 
tomography. J Allergy Clin Immunol. 1999;104 #6:S258-S267. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D et al. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007(a):24. Table 3-2. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D et al. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007(b): 28. 
ICRP. 2007 Recommendation of the International Commission on Radiological 
Protection. ICRP Publication 103. 2007;37:2-4. 
Kim SR, Lee KS, Park HS, et al. HIF -1 alpha inhibition ameliorates an allergic airway 
disease via VEGF suppression in bronchial epithelium. Eur J Immunol. 2010;40 
(10):2858-69. 
Okkenhaug K, Aki K, Vanhaesebroeck B. Antigen receptor signalling:  A distincive role 
for the p110 isoform of PI3K. Trends in Immunuology. 2007;28:80-7. 
Quanjer P, Stanojevic S, Cole T, Baur X, Hall G, et al. Multi-ethnic reference values for 
spirometry for the 3-95-yr age range:  The global lung function 2012 equations. 
European Respiratory Journal. 2012;40(6):1324-1343. 
Sadhu C, Dick K, Tino WT, Staunton DE. Selective role of PI13K delta in neutrophil 
inflammatory responses. Biochem Biophys Res Commun. 2003 Sep 5;308 (4):764-9. 
 
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Weisser SB, McLarren KW, Voglmaier B, et al. Alternative activation of macrophages 
by IL-4 requires SHIP degradation. Eur J Immunol. 2011;41(6):1742-53. 
REVISED TEXT
De Backer J, Vos W, Vinchurkar S, Van Holsbeke C, Poli, G, Claes R et al. The Effect of 
Extrafine Beclometasone/Formoterol (BDP/F) on Lung Function, Dyspnea, 
Hyperinflation, and Airway Geometry in COPD Patients:  Novel Insight Using 
Fundtional Respiratory Imaging. Journal of Aerosol Medicine and Pulmonary Drug 
Delivery. 2014;27:1-12. 
De Backer LA, Vos WG, Salgado R, De Backer JW, Devoldr A, Verhulst SL et al. 
Functional imaging using computer methods to compare the effect of salbutamol and 
ipratropium bromide in patient-specific airway models of COPD. International Journal 
of COPD. 2011;6:637-646. 
De Backer Lieve A, Vos Wim, Van Holsbeke C, Vinchurkar S, De Backer W. The acute 
effect of budesonide/formoterol in COPD:  a multi-slice computed tomography and lung 
function study. Eur Respir J. 2012;40:298-305. 
GlaxoSmithKline Document Number 2012N141231_06: GSK2269557 Investigator's 
Brochure. Report Date 12-FEB-2015. 
Goldin J, Tashkin D, Kleerup E, Greaser MS, Haywood U, Sayre J et al. Comparative 
effects of hydrofluoroalkane and chloroflurocarbon beclomethasone dipropionate 
inhalation on small airways: Assessment with functional helical thin-section computed 
tomography. J Allergy Clin Immunol. 1999;104 #6:S258-S267. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D et al. Contraceptive
Technology. 19th ed. New York:Ardent Media; 2007(a):24. Table 3-2. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D et al. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007(b): 28. 
ICRP. 2007 Recommendation of the International Commission on Radiological 
Protection. ICRP Publication 103. 2007;37:2-4. 
Kim SR, Lee KS, Park HS, et al. HIF -1 alpha inhibition ameliorates an allergic airway 
disease via VEGF suppression in bronchial epithelium. Eur J Immunol. 2010;40 
(10):2858-69. 
Okkenhaug K, Aki K, Vanhaesebroeck B. Antigen receptor signalling:  A distincive role 
for the p110 isoform of PI3K. Trends in Immunuology. 2007;28:80-7. 
Sadhu C, Dick K, Tino WT, Staunton DE. Selective role of PI13K delta in neutrophil 
inflammatory responses. Biochem Biophys Res Commun. 2003 Sep 5;308 (4):764-9. 
Weisser SB, McLarren KW, Voglmaier B, et al. Alternative activation of macrophages 
by IL-4 requires SHIP degradation. Eur J Immunol. 2011;41(6):1742-53. 
 
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Protocol Amendment #2 Changes
This amendment was created to widen the Body Mass Index (BMI) range at the screening 
visit as the propose range from 16 – 35 kg/m2 would be appropriate for the COPD subject 
population. 
List of specific changes:
Page 22, Inclusion Criteria (#3 – Weight).
PREVIOUS TEXT

Body weight 45 kg and body mass index (BMI) within the range 18 – 32 kg/m2
(inclusive).
REVISED TEXT

Body weight 45 kg and body mass index (BMI) within the range 16 – 35 kg/m2
(inclusive).
 
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Protocol Amendment #3 Changes
This amendment was created to remove the photo toxicity from the protocol as a result of 
the updated Investigator Brochure, Version 7.0, August16, 2016.  It also contains minor 
administrative and clarification changes.
List of specific changes:
PREVIOUS TEXT
Section 4.6.1 (Table) – Risk assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Investigational Product (IP) [e.g., GSK2269557]
Bronchospasm
Mucosal irritancy
A general risk with Inhaled 
treatment
Detected in 13 week toxicology 
study in the dog
Subjects will be allowed to 
continue regular COPD 
treatments and have standard 
of care for treatment of their 
exacerbation. More severe 
patients will have their 
treatment started in hospital. 
Patients will be regularly 
monitored for AEs and a 
patient diary kept. Thus far this 
has not been seen in clinical 
studies.
Potential photosensitivity  
In the absorption spectrum for 
GSK2269557 there are peaks 
at the boundary of the 
ultraviolet (UV) light 
[UVA/UVB] region with a 
lambda max at 320 nm (molar 
extinction coefficient 
43800 L/Mol/cm), with smaller 
peaks at 305 nm and 332 nm.
Subjects will be advised to 
take UV protection measures 
(see Section 6.11).
Study Procedures
Radiation risk as part of HRCT 
scans
The maximum amount of 
radiation dose a patient 
undergoing all six scans will 
receive is approximately 
12mSv. Six low dose HRCT 
scans (one at TLC and FRC on 
screening, Day 12 and Day 28 
visits) at are required 
Reduced tube voltage (100 
kV), and tube current are used.
Scanning time less than 5 s 
per scan.
Total radiation dose for a total 
of six CT scans will be 
approximately 12mSv.
Final radiation dose will be 
 
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
throughout the study for the 
functional imaging protocol
dependent on the patient 
weight, with a range of 
between 1-2mSv per scan per 
patient. This radiation dose 
falls into the International 
Commission on Radiological 
Protections [ICRP, 2007]
category IIb (minor to 
intermediate risk).
The outcomes of this study will 
provide information which 
would produce advances in 
knowledge, leading to a 
potential health benefit in the 
future for patients in this target 
population. The CT may also 
provide information for the 
patients general clinical 
management
Sputum induction
Standard sputum induction 
techniques using hypertonic 
saline can result in 
bronchospasm and therefore 
could potentially induce 
bronchospasm in a patient or 
impact a pre-existing 
exacerbation.
For patients during an 
exacerbation and for sputum 
induction during the recovery 
period, including the day 28 
visit, patients will be pre-dosed 
with nebulised or inhaled beta-
2-agonist (or ipratropium 
bromide if beta-2-agonist 
intolerant). Sputum induction 
will only be carried out using 
Normal (0.9%) saline, which is 
also often used in patients 
clinically to facilitate sputum 
clearance.  
For the final sputum induction 
patients will be pre-dosed with 
nebulised or inhaled beta-2-
agonist (or ipratropium bromide 
if beta-2-agonist intolerant) and 
the induction carried out with 
0.9% saline initially and only 
then followed by hypertonic (3-
5%) if required, and, in the 
opinion of the Investigator,  it is 
considered safe to do so.
 
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
REVISED TEXT
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Investigational Product (IP) [e.g., GSK2269557]
Bronchospasm
Mucosal irritancy
A general risk with Inhaled 
treatment
Detected in 13 week toxicology 
study in the dog
Subjects will be allowed to 
continue regular COPD 
treatments and have standard 
of care for treatment of their 
exacerbation. More severe 
patients will have their 
treatment started in hospital. 
Patients will be regularly 
monitored for AEs and a 
patient diary kept. Thus far this 
has not been seen in clinical 
studies.
Study Procedures
Radiation risk as part of HRCT 
scans
The maximum amount of 
radiation dose a patient 
undergoing all six scans will 
receive is approximately 
12mSv. Six low dose HRCT 
scans (one at TLC and FRC on 
screening, Day 12 and Day 28 
visits) at are required 
throughout the study for the 
functional imaging protocol
Reduced tube voltage (100 
kV), and tube current are used.
Scanning time less than 5 s 
per scan.
Total radiation dose for a total 
of six CT scans will be 
approximately 12mSv.
Final radiation dose will be 
dependent on the patient 
weight, with a range of 
between 1-2mSv per scan per 
patient. This radiation dose 
falls into the International 
Commission on Radiological 
Protections [ICRP, 2007]
category IIb (minor to 
intermediate risk).
The outcomes of this study will 
provide information which 
would produce advances in 
 
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
knowledge, leading to a 
potential health benefit in the 
future for patients in this target 
population. The CT may also 
provide information for the 
patients general clinical 
management
Sputum induction
Standard sputum induction 
techniques using hypertonic 
saline can result in 
bronchospasm and therefore 
could potentially induce 
bronchospasm in a patient or 
impact a pre-existing 
exacerbation.
For patients during an 
exacerbation and for sputum 
induction during the recovery 
period, including the day 28 
visit, patients will be pre-dosed 
with nebulised or inhaled beta-
2-agonist (or ipratropium 
bromide if beta-2-agonist 
intolerant). Sputum induction 
will only be carried out using 
Normal (0.9%) saline, which is 
also often used in patients 
clinically to facilitate sputum 
clearance.  
For the final sputum induction 
patients will be pre-dosed with 
nebulised or inhaled beta-2-
agonist (or ipratropium bromide 
if beta-2-agonist intolerant) and 
the induction carried out with 
0.9% saline initially and only 
then followed by hypertonic (3-
5%) if required, and, in the 
opinion of the Investigator,  it is 
considered safe to do so.
PREVIOUS TEXT
Apply to ALL sections with reference to IB, [GlaxoSmithKline Document Number:
2012N141231_04].
 
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REVISED TEXT
Replace with:
IB, [GlaxoSmithKline Document Number: 2012N141231_06].
PREVIOUS TEXT
SECTION 5.4 – Withdrawal/Stopping Criteria
Subjects who are withdrawn from treatment will also be withdrawn from the study. 
If a higher than expected number of subjects prematurely discontinues the study, 
additional subjects may be randomised and assigned to the same treatment sequence, at 
the discretion of the Sponsor.  
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as soon 
as possible. 

The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 
telephone calls and if necessary a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
Subjects who are withdrawn should complete the assessments planned for the follow up 
visit.
REVISED TEXT
Subjects who are withdrawn from treatment will also be withdrawn from the study. 
If a higher than expected number of subjects prematurely discontinues the study, 
additional subjects may be randomised and assigned to the same treatment sequence, at 
the discretion of the Sponsor.  
 
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The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as soon 
as possible. 

The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 
telephone calls and if necessary a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
Subjects who are withdrawn should complete all the assessments planned, if possible.  
Subjects who are withdrawn on a study clinic visit after randomization should complete 
all the safety related assessment for that visit which includes at minimum, vital sign, lab 
assessments (if deem necessary by the PI), AE/SAEs, concomitant medication(s) and 
ECG.   A Follow up Visit should be scheduled 7-14 days post last dose.
Subjects who are withdrawn in between study clinic visits should complete the 
unscheduled visit and complete all the safety related assessment at mininum which 
includes, vital sign, lab assessments (if deem necessary by the PI), AEs/SAEs, 
concomitant medication(s) and ECG.  A Follow up Visit should be scheduled 7-14 post 
last dose.
PREVIOUS TEXT
SECTION 6.11 – Lifestyle and/or Dietary Restrictions

Subjects must not sunbathe or use a tanning device (e.g. sunbed or solarium) whilst 
taking the study medication and until at least 2 weeks after their last dose. Subjects 
are to be advised that they should cover exposed areas of skin (e.g. use sun hat, long 
sleeves) and use a broad spectrum UVA/UVB sunscreen (SPF ≥30) on exposed areas 
of skin when outdoors.

Subjects should refrain from consumption of Seville oranges, grapefruit or grapefruit 
juice, exotic citrus fruits or grapefruit hybrids from first dose till the end of the study.

Subjects should abstain from alcohol on the day when they visit the clinical unit and 
until their discharge on that day.
 
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
Subjects should refrain from smoking for at least 2 hours prior to each pulmonary 
function test conducted at the clinical unit/site.
REVISED TEXT

Subjects should refrain from consumption of Seville oranges, grapefruit or grapefruit 
juice, exotic citrus fruits or grapefruit hybrids from first dose till the end of the study.

Subjects should abstain from alcohol on the day when they visit the clinical unit and 
until their discharge on that day.

Subjects should refrain from smoking for at least 2 hours prior to each pulmonary 
function test conducted at the clinical unit/site.
PREVIOUS TEXT
SECTION 6.12.1 – Permitted Medications and Non-Drug Therapies
On entry to the study all treatment required for standard of care and additional medical 
problems is permitted to start and continue.
The subjects are allowed to continue their regular COPD treatments for the duration of 
the study. However, the subjects should refrain, if possible, from using relief 
bronchodilators for at least 4 hours prior to each spirometry conducted at the clinical unit, 
and HRCT scan assessment unless essential for clinical symptom relief. Otherwise free 
use of reliever/rescue medication is allowed.  Rescue ventolin and aerochambers may be 
provided by GSK for this study.
All prior (up to 2 months prior to screening) and concomitant medications should be 
recorded in the subject’s CRF.
REVISED TEXT
On entry to the study all treatment required for standard of care and additional medical 
problems is permitted to start and continue.
The subjects are allowed to continue their regular COPD treatments for the duration of 
the study. However, the subjects should refrain, if possible, from using relief 
bronchodilators for at least 4 hours prior to each spirometry conducted at the clinical unit, 
and HRCT scan assessment unless essential for clinical symptom relief.  Otherwise free 
use of reliever/rescue medication is allowed.  Rescue ventolin and aerochambers may be 
provided by GSK for this study and in such case,subjects should be advise to discontinue 
their own ventolin and use the study ventolin and aerochamber provided for the duration 
of the study.
All prior (up to 2 months prior to screening) and concomitant medications should be 
recorded in the subject’s CRF.
 
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PREVIOUS TEXT
SECTION 7.2 – Time and Events Table (Treatment Period)
Procedure
Treatment Period 
Notes
Visit
1
21
3
4
5
6
Day
1
Within 48h 
/ discharge
12
28
56
84
Visit window
N/A
1 days
2 days
2 days
- 4 / +2 days
- 4 / +2 days
SAFETY ASSESSMENTS
AE/SAE collection and review
=========================================================
Concomitant medication review
=========================================================
Reliever usage
=========================================================
Brief physical exam, including weight
X2
X
X
X
X
Pre-dose
Laboratory assessments (include 
haematology and biochemistry)
X2
X
X
X
X
Pre-dose
12-lead ECG
X2
X
X
X
X
Pre-dose. Single assessment
Vital signs
X2
X
X
X
X
Pre-dose. Single assessment
Urine pregnancy test (only WCBP)
X
X
Before conducting the HRCT
STUDY TREATMENT
Randomisation
X
Study drug administration
=========================================================
Daily in the morning before breakfast, 
(with the exception of days when the 
subjects have a planned visit to the 
clinic. On those days, they will be 
dosed at the clinic).
Assessment of study treatment compliance
X
X
X
X
 
 
 
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Procedure
Treatment Period 
Notes
Visit
1
21
3
4
5
6
Day
1
Within 48h 
/ discharge
12
28
56
84
Visit window
N/A
1 days
2 days
2 days
- 4 / +2 days
- 4 / +2 days
EFFICACY ASSESSMENTS
HRCT (at TLC and FRC)
X
X
At any time on specified days. Includes 
electronic monitoring of breathing (if 
applicable).  The radiologist may review 
any of the scan(s) if they wish, but this 
is NOT required for the study.  A formal 
review is required at screening only by 
the radiologist.
FEV1  and FVC
X
X
X
X
X
X
In clinic only for all visits where 
possible.
PEF 
=========================================================
Daily before drug administration at 
home.  If subject in hospital, this may 
be collected using the handheld device 
provided prior to drug administration.
OTHER ASSESSMENTS
Blood sample for PK
X
X
X
X
X
Day 1:  5 min and 24 h post-dose. The 
24 h post-dose time-point is optional for 
subjects not hospitalised. Pre-dose at 
all other time-points.
Sputum induction3
X
X
X
Blood sample for mRNA analysis
X
X
X
Genetic sample (PGx)4
X
Collected at any time after 
randomisation
5.
On discharge if the subject was hospitalized. Within 48 hours of first dose administration if the subject was not hospitalised. See Section 4.2
6.
Assessments do not need to be completed if screening assessments conducted within 48 hours 
7.
Induced sputum collection may be repeated on several occasions if an adequate sample is not produced at the first attempt 
8.
Informed consent for optional sub-studies (e.g. ,genetics research) must be obtained before collecting a sample.  May be obtained at any visits.
 
 
 
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REVISED TEXT
Procedure
Treatment Period 
Notes
Visit
1
21
3
4
5
6
Day
1
Within 48h 
/ discharge
12
28
56
84
Visit window
N/A
1 days
2 days
2 days
- 4 / +2 days
- 4 / +2 days
SAFETY ASSESSMENTS
AE/SAE collection and review
=========================================================
Concomitant medication review
=========================================================
Reliever usage
=========================================================
Brief physical exam, including weight
X2
X
X
X
X
Pre-dose
Laboratory assessments (include 
haematology and biochemistry)
X2
X
X
X
X
Pre-dose
12-lead ECG
X2
X
X
X
X
Pre-dose. Single assessment
Vital signs
X2
X
X
X
X
Pre-dose. Single assessment
Urine pregnancy test (only WCBP)
X
X
Before conducting the HRCT
STUDY TREATMENT
Randomisation
X
Study drug administration
=========================================================
Daily in the morning before breakfast, 
(with the exception of days when the 
subjects have a planned visit to the 
clinic. On those days, they will be 
dosed at the clinic).
Assessment of study treatment compliance
X
X
X
X
Diary Card dispense and review at clinic
X
X
X
X
X
Refer to SRM for details.
 
 
 
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Procedure
Treatment Period 
Notes
Visit
1
21
3
4
5
6
Day
1
Within 48h 
/ discharge
12
28
56
84
Visit window
N/A
1 days
2 days
2 days
- 4 / +2 days
- 4 / +2 days
EFFICACY ASSESSMENTS
HRCT (at TLC and FRC)
X
X
At any time on specified days. Includes 
electronic monitoring of breathing (if 
applicable).  The radiologist may review 
any of the scan(s) if they wish, but this 
is NOT required for the study.  A formal 
review is required at screening only by 
the radiologist.
FEV1  and FVC
X
X
X
X
X
X
In clinic only for all visits where 
possible.
PEF 
=========================================================
Daily before drug administration at 
home.  If subject in hospital, this may 
be collected using the handheld device 
provided prior to drug administration.
OTHER ASSESSMENTS
Blood sample for PK
X
X
X
X
X
Day 1:  5 min and 24 h post-dose. The 
24 h post-dose time-point is optional for 
subjects not hospitalised. Pre-dose at 
all other time-points.
Sputum induction3
X
X
X
Blood sample for mRNA analysis
X
X
X
Genetic sample (PGx)4
X
Collected at any time after 
randomisation
9.
On discharge if the subject was hospitalized. Within 48 hours of first dose administration if the subject was not hospitalised. See Section 4.2
10. Assessments do not need to be completed if screening assessments conducted within 48 hours 
11. Induced sputum collection may be repeated on several occasions if an adequate sample is not produced at the first attempt 
12. Informed consent for optional sub-studies (e.g. ,genetics research) must be obtained before collecting a sample.  May be obtained at any visits.
 
 
 
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PREVIOUS TEXT
SECTION 11 – References
GlaxoSmithKline Document Number 2012N141231_04: GSK2269557 Investigator's 
Brochure. Report Date 12-FEB-2015. 
REVISED TEXT
GlaxoSmithKline Document Number 2012N141231_06: GSK2269557 Investigator's 
Brochure. Report Date 16-AUG-2016. 
 
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Protocol Amendment #4 Changes
Replace the administration of GSK2269557 via the DISKUSTM device (1000 g) by a 
comparable dose administered via the ELLIPTATM device (700 g).  GSK2269557 is no 
longer manufactured for use with the DISKUS device which will be replaced with 
ELLIPTA Device. To increase the number of patients to be recruited to obtain sufficient 
completers. Minor updates and clarifications.
SECTION 1 – Type and Number of Subjects
PREVIOUS TEXT
Approximately 35 subjects with an acute exacerbation of COPD will be randomized such 
that approximately 15 subjects on active and 15 subjects on placebo provide sputum at all 
the scheduled time points and complete the study.  If a higher than expected numbers of 
subjects prematurely discontinue the study, or fail to produce sufficient sputum post 
randomisation additional subjects may be randomised at the discretion of the sponsor.
REVISED TEXT
Approximately 45 subjects with an acute exacerbation of COPD will be randomized such 
that approximately 15 subjects on active and 15 subjects on placebo provide sputum at all 
the scheduled time points and complete the study.  If a higher than expected number of 
subjects prematurely discontinue the study, or fail to produce sufficient sputum post 
randomisation additional subjects may be randomised at the discretion of the sponsor.
SECTION 2.2 – Brief Background (5th Paragraph)
PREVIOUS TEXT
GSK2269557 has been administered as single and repeat doses to healthy subjects as 
nebulized solution in the FTIH study PII115117 up to a dose of 6400 μg per day for 7 
days. GSK2269557 has also been administered as single and repeat doses to healthy 
smokers as a dry powder formulation in study PII116617 up to a dose of 3000 μg as 
single dose and 2000 μg per day for 14 days.  GSK2269557 has been well tolerated 
across the range of doses used.  There is also an ongoing study (Study PII115119, non-
reported) where a total daily dose of up to 2000 µg of GSK2269557 is being administered 
to stable COPD patients via a dry powder inhaler for 14 days in a two part study.  Part A 
of this study has completed and Part B will characterise the steady-state (exposure) dose 
response following repeat inhaled doses of up to 2000µg for the same treatment duration.  
There is also a completed larger clinical study PII116678 which is almost identical in 
design to 201928 using 1000 µg of GSK2269557 per day administered via a Diskus dry 
powder inhaler to patients diagnosed with an acute exacerbation of COPD.  For 
simplicity study PII116678 does not capture induced sputum hence cannot analyse any 
changes in mRNA. The primary objective of the current study is to capture induced 
sputum to enable the mRNA analysis on a smaller cohort.   
 
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REVISED TEXT
GSK2269557 has been administered as single and repeat doses to healthy subjects as 
nebulized solution in the FTIH study PII115117 up to a dose of 6400 μg per day for 7 
days. GSK2269557 has also been administered as single and repeat doses to healthy 
smokers as a dry powder formulation in study PII116617 up to a dose of 3000 μg as 
single dose and 2000 μg per day for 14 days.  GSK2269557 has been well tolerated 
across the range of doses used.  There is also an ongoing study (Study PII115119, non-
reported) where a total daily dose of up to 2000 µg of GSK2269557 is being administered 
to stable COPD patients via a dry powder inhaler for 14 days in a two part study.  Part A 
of this study has completed and Part B will characterise the steady-state (exposure) dose 
response following repeat inhaled doses of up to 2000µg for the same treatment duration.  
There is also a completed larger clinical study PII116678 which is almost identical in 
design to 201928 using 1000 µg of GSK2269557 per day administered via a Diskus dry 
powder inhaler to patients diagnosed with an acute exacerbation of COPD.  For 
simplicity study PII116678 did not capture induced sputum hence cannot analyse any 
changes in mRNA. The primary objective of the current study is to capture induced 
sputum to enable the mRNA analysis on a smaller cohort.
GSK2269557 has also now been administered in Study 201544 using the formulation 
now proposed in this study up to daily doses of 200 μg GSK2269557 via the ELLIPTATM
DPI for up to 10 days. No safety issues were identified with this new formulation.
SECTION 4.3 – Type and Number of Subjects
PREVIOUS TEXT
Approximately 35 subjects with an acute exacerbation of COPD will be randomized such 
that approximately 15 subjects on active and 15 subjects on placebo provide sputum at all 
the scheduled time points and complete the study.   If a higher than expected number of 
subjects prematurely discontinue the study, or fail to produce sufficient sputum post 
randomisation additional subjects may be randomised at the discretion of the sponsor.
REVISED TEXT
Approximately 45 subjects with an acute exacerbation of COPD will be randomized such 
that approximately 15 subjects on active and 15 subjects on placebo provide sputum at all 
the scheduled time points and complete the study.   If a higher than expected number of 
subjects prematurely discontinue the study, or fail to produce sufficient sputum post 
randomisation additional subjects may be randomised at the discretion of the sponsor.
SECTION 4.5 – Dose Justification
PREVIOUS TEXT
The dose chosen for this study is 1000 µg of GSK2269557 per day administered via a dry 
powder inhaler for a duration of 84 days (– 4 / + 2 days). This dose has been selected 
based on previous safety and tolerability data in man (healthy subjects and COPD 
subjects) as well as demonstration of target (PI3K) inhibition by observed changes in 
 
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biomarkers. Together with an additional study to be run in parallel (PII116678), this dose 
of GSK2269557 is being dosed to subjects in PII116678 with an exacerbation of COPD,
so it will be assumed for exposure predictions, unless otherwise stated, that these subjects 
will have a similar lung deposition, distribution and plasma exposure to that of the 
healthy volunteers. However it is accepted that these types of subjects may have reduced 
airway conductance and hence likely reduced deposition. This can be appropriately 
defined in this study based on the actual plasma exposures achieved. 
Twice this dose level (2000 µg) using the same formulation has previously been given 
once daily to healthy male smokers for 14 days (study PII116617). There is also an 
ongoing study where a total daily dose of 1000 µg of GSK2269557 is administered to 
stable COPD subjects via a dry powder inhaler for 14 days (study PII115119) which at 
the time of writing of this protocol had successfully dosed 21 subjects on active treatment 
and collected pharmacokinetics (PK) samples for analysis out to 14 days.
The target effect compartment for PI3Kinhibition is the intracellular compartment of 
the immune cells resident in the lung tissue and lumen.  GSK2269557 has a high potency 
and selectivity at the PI3Kenzyme (Ki value 0.1 ng/mL) which translates into an IC50 in 
a more complex system (PHA stimulated lung tissue) of approximately 120 ng/mL (or 
2.5 ng/mL free unbound drug).  Based on the measured steady-state cellular 
concentration of GSK2269557 collected at trough (24 h) from the lungs of healthy 
smokers at 2000 µg DPI (450 ng/mL) in the clinical study it is expected that at 1000 µg 
(225 ng/mL), concentrations will be sufficient and PI3Kinhibition maintained in the 
lung at 90% inhibition for 24 h. 
Target PI3Kinhibition is based on a wide range of pharmacology experiments.  Details 
of these as well as the pharmacokinetics and safety data can be found in the IB, 
[GlaxoSmithKline Document Number: 2012N141231_06].
REVISED TEXT
The dose chosen for this study is 700 µg of GSK2269557 per day administered via a dry 
powder ELLIPTA inhaler for a duration of 84 days (– 4 / + 2 days) and is equivalent to 
the dose of 1000 g administered via DISKUS in terms of the dose deposited and 
systemic exposure.. This dose has been selected based on previous safety and tolerability 
data in man, obtained in healthy subjects, healthy smokers and COPD patients including 
patients suffering COPD exacerbations. Also dose selection is based on a healthy subjects 
study using the ELLIPTA™ DPI. It will be assumed for exposure predictions, unless 
otherwise stated, that patients suffering exacerbations will have a similar lung deposition, 
distribution and plasma exposure to that of the healthy volunteers. However it is accepted 
that these types of subjects may have reduced airway function and hence potentially 
reduced deposition. This can be appropriately defined in this study based on the actual 
plasma exposures achieved. 
For DISKUS, twice this dose level (2000 µg) using the same formulation has previously 
been given once daily to healthy male smokers for 14 days (study PII116617). There is 
also an ongoing study where a total daily dose of 1000 µg of GSK2269557 is 
administered to stable COPD subjects via a dry powder inhaler for 14 days (study 
 
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PII115119) which at the time of writing of this protocol had successfully dosed 21 
subjects on active treatment and collected pharmacokinetics (PK) samples for analysis 
out to 14 days.
The target effect compartment for PI3Kinhibition is the intracellular compartment of 
the immune cells resident in the lung tissue and lumen.  GSK2269557 has a high potency 
and selectivity at the PI3Kenzyme (Ki value 0.1 ng/mL) which translates into an IC50 in 
a more complex system (PHA stimulated lung tissue) of approximately 120 ng/mL (or 
2.5 ng/mL free unbound drug).  Based on the measured steady-state cellular 
concentration of GSK2269557 collected at trough (24 h) from the lungs of healthy 
smokers at 2000 µg DPI (450 ng/mL) in the clinical study it is expected that at 1000 µg 
(225 ng/mL), concentrations will be sufficient and PI3Kinhibition maintained in the 
lung at 90% inhibition for 24 h. 
Target PI3Kinhibition is based on a wide range of pharmacology experiments.  Details 
of these as well as the pharmacokinetics and safety data can be found in the IB, 
[GlaxoSmithKline Document Number: 2012N141231_06].
SECTION 6.1 – Investigational Product and Other Study Treatment
PREVIOUS TEXT
Study Treatment
Product name:
GSK2269557
Placebo
Formulation description:
Lactose blend containing 
GSK2269557 in Diskus™device
Lactose in Diskus device
Dosage form:
Dry powder for inhalation
Dry powder for inhalation
Unit dose 
strength(s)/Dosage 
level(s):
500 µg / blister
N/A
Route of Administration
Inhalation
Inhalation
Dosing instructions:
2 inhalations to be taken every 
day before breakfast (with the 
exception of days when the 
subjects have a planned visit to 
the clinic. On those days, they 
will be dosed at the clinic). The 
subject should hold their breath 
for approximately 10 seconds 
before exhaling. Inhalations 
should be taken approximately 
30 seconds apart. 
2 inhalations to be taken every 
day before breakfast (with the 
exception of days when the 
subjects have a planned visit to 
the clinic. On those days, they 
will be dosed at the clinic). The 
subject should hold their breath 
for approximately 10 seconds 
before exhaling. Inhalations 
should be taken approximately 
30 seconds apart.
 
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REVISED TEXT
Study Treatment Name:
GSK2269557 
ELLIPTATM DPI 
(100 μg)
GSK2269557 
ELLIPTATM DPI 
(500 μg)
Placebo ELLIPTATM
DPI
Formulation 
description:
GSK2269557 
blended with lactose 
and magnesium 
stearate
GSK2269557 
blended with lactose 
and magnesium 
stearate
Lactose
Dosage formulation:
DPI
DPI
DPI
Unit dose 
strength(s)/Dosage 
level(s):
100 μg per blister
500 μg per blister
NA
Route of 
Administration:
Inhaled
Inhaled
Inhaled
Dosing instructions:
Inhale as directed
Inhale as directed
Inhale as directed
Physical description:
Dry white powder
Dry white powder
Dry white powder
Method for 
individualizing dosage:
DPI containing a 
single strip with 30 
blisters
DPI containing a 
single strip with 30 
blisters
DPI containing a 
single strip with 30 
blisters
Packaging and Labeling
Study Treatment will 
be labeled as 
required per country 
requirement. 
Study Treatment will 
be labeled as 
required per country 
requirement.
Study Treatment will 
be labeled as 
required per country 
requirement.
Manufacturer
GSK
GSK
GSK
PREVIOUS TEXT
SECTION 6.2 – Treatment Assignment
Subjects will be assigned to treatments in accordance with the randomization schedule
generated by Clinical Statistics, prior to the start of the study, using validated internal 
software. Central based randomisation will be used.
Subjects will be randomised to treatments A or B where:
A = Placebo 
 
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B = GSK2269557 1000 µg 
A web based interactive response system will be used to assign subjects to treatment.
REVISED TEXT
Subjects will be assigned to treatments in accordance with the randomization schedule
generated by Clinical Statistics, prior to the start of the study, using validated internal 
software. Central based randomisation will be used.
Subjects will be randomised to treatments A, B, C or D where:
A = Placebo 
B = GSK2269557 1000 µg 
C = Placebo via Ellipta
D = GSK2269557 700 µg via Ellipta 
A web based interactive response system will be used to assign subjects to treatment.
PREVIOUS TEXT
SECTION 6.8 – Compliance with Study Treatment Administration
When subjects 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 subjects will be asked to complete a diary when dose administration takes place at 
home. The date, time and number of inhalations will be recorded. The compliance will be 
checked by the site staff at each planned visit. 
A record of the number of Diskus inhalers dispensed to each subject and the number of 
actuation administered, read from the dose counter for each Diskus inhaler, must be 
maintained and reconciled with study treatment and compliance records.  Treatment start 
and stop dates, including dates for treatment delays and/or dose reductions will also be
recorded in the CRF.
REVISED TEXT
When subjects 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 subjects will be asked to complete a diary when dose administration takes place at 
home. The date, time and number of inhalations will be recorded. The compliance will be 
checked by the site staff at each planned visit. 
 
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A record of the number of ELLIPTATM inhalers dispensed to each subject and the 
number of actuation administered, read from the dose counter for each ELLIPTATM
inhaler, must be maintained and reconciled with study treatment and compliance records.  
Treatment start and stop dates, including dates for treatment delays and/or dose 
reductions will also be recorded in the CRF.
PREVIOUS TEXT
SECTION 6.9 – Treatment of Study Treatment Overdose
For this study, any dose of GSK2269557 >2000 µg within a 22 hour time period will be 
considered an overdose.
GSK does not recommend specific treatment for an overdose
In the event of an overdose the investigator should:
1) contact the Medical Monitor immediately
2) closely monitor the subject for adverse events (AEs)/serious adverse events 
(SAEs) and laboratory abnormalities until GSK2269557 can no longer be detected 
systemically (at least 14 days for GSK2269557)
3) obtain a plasma sample for pharmacokinetic (PK) analysis within 7 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 subject.
REVISED TEXT
For this study, any dose of GSK2269557 >2000 µg for DISKUS and >1400 µg for 
ELLIPTA within a 22 hour time period will be considered an overdose.
GSK does not recommend specific treatment for an overdose
In the event of an overdose the investigator should:
1) contact the Medical Monitor immediately
2) closely monitor the subject for adverse events (AEs)/serious adverse events 
(SAEs) and laboratory abnormalities until GSK2269557 can no longer be detected 
systemically (at least 14 days for GSK2269557)
3) obtain a plasma sample for pharmacokinetic (PK) analysis within 7 days from the 
date of the last dose of study treatment if requested by the Medical Monitor 
(determined on a case-by-case basis)
 
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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 subject.
 
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PREVIOUS TEXT
SECTION 7.2 – Time and Events Table (Treatment Period)
Procedure
Treatment Period 
Notes
Visit
1
21
3
4
5
6
Day
1
Within 48h / 
discharge
12
28
56
84
Visit window
N/A
1 days
2 days
2 days
- 4 / +2 
days
- 4 / +2 days
SAFETY ASSESSMENTS
AE/SAE collection and review
=========================================================
Concomitant medication review
=========================================================
Reliever usage
=========================================================
Brief physical exam, including weight
X2
X
X
X
X
Pre-dose
Laboratory assessments (include haematology 
and biochemistry)
X2
X
X
X
X
Pre-dose
12-lead ECG
X2
X
X
X
X
Pre-dose. Single assessment
Vital signs
X2
X
X
X
X
Pre-dose. Single assessment
Urine pregnancy test (only WCBP)
X
X
Before conducting the HRCT
STUDY TREATMENT
Randomisation
X
Study drug administration
=========================================================
Daily in the morning before 
breakfast, (with the exception of 
days when the subjects have a 
planned visit to the clinic. On 
those days, they will be dosed 
at the clinic).
Assessment of study treatment compliance
X
X
X
X
 
 
 
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Procedure
Treatment Period 
Notes
Visit
1
21
3
4
5
6
Day
1
Within 48h / 
discharge
12
28
56
84
Visit window
N/A
1 days
2 days
2 days
- 4 / +2 
days
- 4 / +2 days
EFFICACY ASSESSMENTS
HRCT (at TLC and FRC)
X
X
At any time on specified 
days. Includes electronic 
monitoring of breathing (if 
applicable).  The radiologist 
may review any of the 
scan(s) if they wish, but this 
is NOT required for the 
study.  A formal review is 
required at screening only 
by the radiologist.
FEV1  and FVC
X
X
X
X
X
X
In clinic only for all visits 
where possible.
PEF 
=========================================================
Daily before drug 
administration at home.  If 
subject in hospital, this may 
be collected using the 
handheld device provided 
prior to drug administration.
OTHER ASSESSMENTS
Blood sample for PK
X
X
X
X
X
Day 1:  5 min and 24 h post-
dose. The 24 h post-dose 
time-point is optional for 
subjects not hospitalised. 
Pre-dose at all other time-
points.
Sputum induction3
X
X
X
 
 
 
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Procedure
Treatment Period 
Notes
Visit
1
21
3
4
5
6
Day
1
Within 48h / 
discharge
12
28
56
84
Visit window
N/A
1 days
2 days
2 days
- 4 / +2 
days
- 4 / +2 days
Blood sample for mRNA analysis
X
X
X
Genetic sample (PGx)4
X
Collected at any time after 
randomisation
13. On discharge if the subject was hospitalized. Within 48 hours of first dose administration if the subject was not hospitalised. See Section 4.2
14. Assessments do not need to be completed if screening assessments conducted within 48 hours 
15. Induced sputum collection may be repeated on several occasions if an adequate sample is not produced at the first attempt 
16. Informed consent for optional sub-studies (e.g. ,genetics research) must be obtained before collecting a sample.  May be obtained at any visits.
REVISED TEXT
Procedure
Treatment Period 
Notes
Visit
1
21
3
4
5
6
Day
1
Within 
48h / 
discharge
12
28
56
84
Visit window
N/A
1 days
2 days
2 days
- 4 / +2 
days
- 4 / +2 days
SAFETY ASSESSMENTS
AE/SAE collection and review
=========================================================
Concomitant medication review
=========================================================
Reliever usage
=========================================================
Brief physical exam, including weight
X2
X
X
X
X
Pre-dose
Laboratory assessments (include 
haematology and biochemistry)
X2
X
X
X
X
Pre-dose
12-lead ECG
X2
X
X
X
X
Pre-dose. Single assessment
 
 
 
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Procedure
Treatment Period 
Notes
Visit
1
21
3
4
5
6
Day
1
Within 
48h / 
discharge
12
28
56
84
Visit window
N/A
1 days
2 days
2 days
- 4 / +2 
days
- 4 / +2 days
Vital signs
X2
X
X
X
X
Pre-dose. Single assessment
Urine pregnancy test (only WCBP)
X
X
Before conducting the HRCT
STUDY TREATMENT
ELLIPTATM Inhaler Training
X
Training conducted by reviewing the Patient 
Information Leaflet with the subject (no device 
will be used). Additional training may be 
conducted at the discretion of the investigator
Randomisation
X
Study drug administration
=========================================================
Daily in the morning before breakfast, (with the 
exception of days when the subjects have a 
planned visit to the clinic. On those days, they 
will be dosed at the clinic).
Assessment of study treatment 
compliance
X
X
X
X
Diary Card dispense and review at clinic
X
X
X
X
X
Refer to SRM for details.
 
 
 
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Procedure
Treatment Period 
Notes
Visit
1
21
3
4
5
6
Day
1
Within 
48h / 
discharge
12
28
56
84
Visit window
N/A
1 days
2 days
2 days
- 4 / +2 
days
- 4 / +2 days
EFFICACY ASSESSMENTS
HRCT (at TLC and FRC)
X
X
At any time on specified days. Includes 
electronic monitoring of breathing (if 
applicable).  The radiologist may review any of 
the scan(s) if they wish, but this is NOT 
required for the study.  A formal review is 
required at screening only by the radiologist.
FEV1  and FVC
X
X
X
X
X
X
In clinic only for all visits where possible.
PEF 
=========================================================
Daily before drug administration at home.  If 
subject in hospital, this may be collected using 
the handheld device provided prior to drug 
administration.
OTHER ASSESSMENTS
Blood sample for PK
X
X
X
X
X
Day 1:  5 min and 24 h post-dose. The 24 h 
post-dose time-point is optional for subjects not 
hospitalised. Pre-dose at all other time-points.
Sputum induction3
X
X
X
Blood sample for mRNA analysis
X
X
X
Genetic sample (PGx)4
X
Collected at any time after randomisation
17. On discharge if the subject was hospitalized. Within 48 hours of first dose administration if the subject was not hospitalised. See Section 4.2
18. Assessments do not need to be completed if screening assessments conducted within 48 hours 
19. Induced sputum collection may be repeated on several occasions if an adequate sample is not produced at the first attempt 
20. Informed consent for optional sub-studies (e.g. ,genetics research) must be obtained before collecting a sample.  May be obtained at any visits.
 
 
 
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SECTION 9 – Statistical Considerations and Data Analyses
PREVIOUS TEXT
This study is designed to establish the PI3K-dependent alterations in immune cell 
mechanisms related to neutrophil function as detected by changes in mRNA 
transcriptomics in samples of induced sputum from patients admitted with an 
exacerbation of COPD. The primary comparison will be between  subjects treated with 
GSK2269557 in addition to standard of care, and subjects treated with placebo in 
addition to standard of care. In addition, treatment comparisons between subjects at 
baseline and subsequent time points will also be produced.
REVISED TEXT
This study is designed to establish the PI3K-dependent alterations in immune cell 
mechanisms related to neutrophil function as detected by changes in mRNA 
transcriptomics in samples of induced sputum from patients admitted with an 
exacerbation of COPD. The primary comparison will be between subjects treated with 
GSK2269557 in addition to standard of care, and subjects treated with placebo in 
addition to standard of care. In addition, treatment comparisons between subjects at 
baseline and subsequent time points will also be produced. By first intent, the data from 
the different devices will be pooled and may also be investigated separately, full details 
will be specified in the RAP prior to unblinding.
SECTION 12.1 – Appendix 1 (Abbreviation and Trademarks)
Dry Powder Inhaler (DPI) included as an abbreviation within Appendix 1 of the Protocol 
Amendment.
PREVIOUS TEXT
12.1
Appendix 1: Abbreviations and Trademarks
AE
Adverse Event
ALT
Alanine aminotransferase
COPD
Chronic Obstructive Pulmonary Disease
CRF
Case Report Form
CT
Computed Tomography
CV
Cardiovascular
ECG
Electrocardiogram
FEV1
Forced Expiratory Volume in One Second
FRC
Functional Residual Capacity
FRI
Functional Respiratory Imaging
GCP
ICH Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GSK
GlaxoSmithKline
HRCT
High-Resolution Computed Tomography
IB
Investigator’s Brochure
 
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IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
PEF
Peak Expiratory Flow
PI3K
Phosphoinositide 3-Kinase Delta
PK
Pharmacokinetic
QTcF
QT interval corrected using the Fridericia's formula
RAP
Reporting and Analysis Plan
SAE
Serious Adverse Event
SRM
Study Reference Manual
TLC
Total Lung Capacity
ULN
Upper Limit of Normal
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
DISKUS
None
REVISED TEXT
12.1
Appendix 1: Abbreviations and Trademarks
AE
Adverse Event
ALT
Alanine aminotransferase
COPD
Chronic Obstructive Pulmonary Disease
CRF
Case Report Form
CT
Computed Tomography
CV
Cardiovascular
ECG
Electrocardiogram
DPI
Dry Powder Inhaler
FEV1
Forced Expiratory Volume in One Second
FRC
Functional Residual Capacity
FRI
Functional Respiratory Imaging
GCP
ICH Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GSK
GlaxoSmithKline
HRCT
High-Resolution Computed Tomography
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
PEF
Peak Expiratory Flow
PI3K
Phosphoinositide 3-Kinase Delta
 
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PK
Pharmacokinetic
QTcF
QT interval corrected using the Fridericia's formula
RAP
Reporting and Analysis Plan
SAE
Serious Adverse Event
SRM
Study Reference Manual
TLC
Total Lung Capacity
ULN
Upper Limit of Normal
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
DISKUS
None
ELLIPTA
 
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A randomised, double-blind, placebo-controlled study to 
evaluate the safety, efficacy and changes in induced sputum and 
blood biomarkers following daily repeat doses of inhaled 
GSK2269557 for 12 weeks in adult subjects diagnosed with an 
acute exacerbation of Chronic Obstructive Pulmonary Disease 
(COPD).
Compound Number:
GSK2269557
Development Phase:
IIA
Effective Date:
16-NOV-2016
Protocol Amendment Number:  03
Author (s):
 (CCSE); 
 (CPSSO); 
 
(Respiratory CEDD); 
 (Exp Biology); 
 (Clinical Statistics); 
 (CPMS); 
 (GCSP).
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2014N218070_00
2015-JUN-04
Original
2014N218070_01
2015-NOV-30
Amendment No. 1
Remove the specific equations for the prediction of percent predicted from spirometry 
from the inclusion criteria and in Section 7.7.2.  At screening it may not be possible to 
identify which correction method was used, or modify the correction method used, at the 
time. It therefore is not valid to stipulate that lung function values be corrected using any 
particular method.  Both FEV1 and FVC measurements (which are not entry criteria for 
the study) collected during the study will be collected as absolute values (uncorrected), so 
that consistency will be obtained across all sites in the study, and percent predicted will 
be calculated using a standard approach in house at the end of the study. 
2014N218070_02
2016-JAN-26
Amendment No. 2
Increase the body mass index (BMI) range in the inclusion criteria from 18-32 kg/m2
(inclusive) to 16- 35 kg/m2 (inclusive). The original BMI range from 18-32 kg/m2 is a 
typical range used in both healthy volunteer studies and general subject populations. The 
revised range is more appropriate for a COPD patient population.
2014N218070_03
2016-NOV-16
Amendment No. 3
To remove photo toxicity from the protocol and to include minor administrative and 
clarification changes.
 
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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information:
Role
Name
Day Time Phone 
Number and email 
address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site Address
Primary 
Medical 
Monitor
Discovery 
Medicine 
Respiratory 
CEDD 
GlaxoSmithKline 
Gumnnels Wood 
Rd. 
Stevenage, 
Herts, 
SG1 2NY
Secondary 
Medical 
Monitor
Discovery 
Medicine 
Respiratory 
CEDD 
GlaxoSmithKline 
Gumnnels Wood 
Rd. 
Stevenage, 
Herts, 
SG1 2NY
SAE contact  
information 
Medical 
monitor as 
above
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol 201928
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
 
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 201928........................................................9
2.
INTRODUCTION....................................................................................................12
2.1.
Study Rationale ..........................................................................................12
2.2.
Brief Background ........................................................................................12
2.2.1.
Use of mRNA transcriptomics by Affymetrix.................................14
2.2.2.
Use of HRCT Endpoints to characterise Lung Function ...............14
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................15
4.
STUDY DESIGN ....................................................................................................16
4.1.
Overall Design ............................................................................................16
4.2.
Treatment Arms and Duration.....................................................................16
4.3.
Type and Number of Subjects.....................................................................17
4.4.
Design Justification.....................................................................................17
4.5.
Dose Justification........................................................................................18
4.6.
Benefit:Risk Assessment ............................................................................18
4.6.1.
Risk Assessment .........................................................................19
4.6.2.
Benefit Assessment.....................................................................20
4.6.3.
Overall Benefit:Risk Conclusion...................................................20
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............21
5.1.
Inclusion Criteria.........................................................................................21
5.2.
Exclusion Criteria........................................................................................24
5.3.
Screening/Baseline/Run-in Failures............................................................25
5.4.
Withdrawal/Stopping Criteria.......................................................................26
5.4.1.
Liver Chemistry Stopping Criteria ................................................26
5.4.1.1.
Study Treatment Restart or Re-challenge...................27
5.4.2.
QTc Stopping Criteria ..................................................................27
5.4.3.
Other Stopping Safety Criteria .....................................................28
5.5.
Subject and Study Completion....................................................................28
6.
STUDY TREATMENT ............................................................................................28
6.1.
Investigational Product and Other Study Treatment....................................28
6.2.
Treatment Assignment................................................................................29
6.3.
Planned Dose Adjustments.........................................................................29
6.4.
Subject Specific Dose Adjustment Criteria..................................................30
6.5.
Blinding.......................................................................................................30
6.6.
Packaging and Labeling..............................................................................30
6.7.
Preparation/Handling/Storage/Accountability..............................................31
6.8.
Compliance with Study Treatment Administration.......................................31
6.9.
Treatment of Study Treatment Overdose....................................................32
6.10.
Treatment after the End of the Study ..........................................................32
6.11.
Lifestyle and/or Dietary Restrictions............................................................32
6.12.
Concomitant Medications and Non-Drug Therapies....................................33
6.12.1.
Permitted Medications and Non-Drug Therapies..........................33
6.12.2.
Prohibited Medications and Non-Drug Therapies.........................33
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................33
 
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7.1.
Time and Events Table (Screening and Follow Up Visits)...........................34
7.2.
Time and Events Table (Treatment Period) ................................................36
7.3.
Screening and Critical Baseline Assessments ............................................38
7.4.
Biomarker(s)/Pharmacodynamic Markers ...................................................38
7.4.1.
Pharmacodynamic Biomarkers in Sputum ...................................38
7.4.2.
mRNA in blood ............................................................................38
7.5.
Patient diary................................................................................................38
7.6.
Genetics .....................................................................................................39
7.7.
Efficacy.......................................................................................................39
7.7.1.
Functional Respiratory Imaging ...................................................39
7.7.2.
FEV1  and FVC.............................................................................39
7.7.3.
Peak Expiratory Flow PEF ...........................................................39
7.8.
Safety .........................................................................................................39
7.8.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........39
7.8.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................40
7.8.1.2.
Method of Detecting AEs and SAEs ...........................40
7.8.1.3.
Follow-up of AEs and SAEs........................................41
7.8.1.4.
Cardiovascular and Death Events ..............................41
7.8.1.5.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................41
7.8.1.6.
Regulatory Reporting Requirements for SAEs............41
7.8.2.
Pregnancy ...................................................................................42
7.8.3.
Physical Exams ...........................................................................42
7.8.4.
Vital Signs....................................................................................42
7.8.5.
Electrocardiogram (ECG).............................................................42
7.8.6.
Clinical Safety Laboratory Assessments ......................................43
7.9.
Pharmacokinetics .......................................................................................44
7.9.1.
Blood Sample Collection..............................................................44
7.9.2.
Sample Analysis ..........................................................................44
8.
DATA MANAGEMENT ...........................................................................................45
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................45
9.1.
Sample Size Considerations.......................................................................45
9.1.1.
Sample Size Re-estimation or Adjustment...................................46
9.2.
Data Analysis Considerations .....................................................................46
9.2.1.
Analysis Populations....................................................................46
9.2.2.
Interim Analysis ...........................................................................46
9.3.
Key Elements of Analysis Plan ...................................................................47
9.3.1.
Primary Analyses.........................................................................47
9.3.2.
Secondary Analyses ....................................................................47
10. STUDY GOVERNANCE CONSIDERATIONS........................................................47
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............47
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................47
10.3.
Quality Control (Study Monitoring) ..............................................................48
10.4.
Quality Assurance.......................................................................................48
10.5.
Study and Site Closure ...............................................................................49
10.6.
Records Retention......................................................................................49
 
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10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................50
11. REFERENCES.......................................................................................................51
12. APPENDICES........................................................................................................52
12.1.
Appendix 1: Abbreviations and Trademarks................................................52
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................53
12.3.
Appendix 3: Genetic Research ...................................................................56
12.4.
Appendix 4: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................59
12.4.1.
Definition of Adverse Events........................................................59
12.4.2.
Definition of Serious Adverse Events...........................................60
12.4.3.
Definition of Cardiovascular Events .............................................61
12.4.4.
Recording of AEs and SAEs ........................................................62
12.4.5.
Evaluating AEs and SAEs............................................................62
12.4.6.
Reporting of SAEs to GSK...........................................................64
12.5.
Appendix 5: Collection of Pregnancy Information........................................65
12.6.
Appendix 6: Country Specific Requirements...............................................66
12.7.
Appendix 7: Protocol Amendment Changes................................................67
 
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1.
PROTOCOL SYNOPSIS FOR STUDY 201928
Rationale
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To establish the PI3K-dependent changes 
in previously identified immune cell 
mechanisms specifically related to 
neutrophil function using mRNA in sputum 
from patients with an exacerbation of 
COPD, with or without treatment with 
GSK2269557.

Alterations in previously identified immune 
cell mechanisms specifically related to 
neutrophil function as determined by 
changes in mRNA transcriptomics in 
induced sputum after 12, 28 and 84 days 
of treatment.
Secondary

To evaluate the effect of once daily repeat 
inhaled doses of GSK2269557 on lung 
parameters derived from HRCT scans in 
subjects with acute exacerbation of COPD, 
compared to placebo.

Change from baseline in siVaw, iVaw, 
iRaw, siRAW, total lung capacity, lung 
lobar volumes, trachea length and 
diameter at FRC and TLC after 12 days of 
treatment and after 28 days of treatment.

To assess the safety and tolerability of 
once daily repeat inhaled doses of 
GSK2269557 administered to subjects with 
acute exacerbation of COPD, compared to 
placebo.

Adverse events 

Haematology, clinical chemistry 

Vital signs

12-lead ECG

To evaluate the plasma PK of once daily 
repeat inhaled doses of GSK2269557 
administered to subjects with acute 
exacerbation of COPD.

Day 1 plasma Cmax and trough (24 hours) 
post dose for inpatients

Trough concentration after 12 days, 28 
days, 56 days and 84 days of treatment.

To evaluate the effect of once daily repeat 
inhaled doses of GSK2269557 on lung 
function parameters in subjects with acute 
exacerbation of COPD compared to 
placebo.

PEF

Reliever usage

FEV1 and  FVC at clinic prior to sputum 
induction
Exploratory

To establish any other PI3K-dependent 
changes in mRNA in sputum or blood from 
patients with an exacerbation of COPD, 
with or without treatment with 
GSK2269557.

To explore the pharmacodynamic effects in 
induced sputum of once daily repeat 
inhaled doses of GSK2269557 
administered to subjects with acute 

Alterations in immune cell mechanisms as 
determined by changes in mRNA 
transcriptomics in induced sputum or blood 
after 12, 28 and 84 days of treatment.

Endpoints may include, but not limited to 
cytokines (IL-6, IL-8, TNF), microbiome 
(by 16SrRNA), bacterial qPCR, viral qPCR.
 
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Objectives
Endpoints
exacerbation of COPD, compared to 
placebo.

To assess the changes in other CT 
parameters such as low attenuation score 
after once daily repeat inhaled doses of 
GSK2269557 administered to subjects with 
acute exacerbation of COPD, compared to 
placebo.

Change from baseline for other CT 
parameters including low attenuation score 
after 12 days of treatment and after 28 
days of treatment
Overall Design
This is a randomised, double-blind, placebo-controlled, parallel-group study.  All subjects 
will continue on their usual Chronic Obstructive Pulmonary Disease (COPD) medications 
throughout the entire duration of the study regardless of treatment arm assignment.  
Subjects will be on standard of care treatment (antibiotic and corticosteroids) upon 
diagnosis of a COPD exacerbation.
SCR
Signature 
ICF
Day 1
Randomisation / 
First dose GSK2269557
Day 12
(+/- 2 days) 
HRCT
Day 28
(+/- 2 days)
HRCT
Day 56
(-4 / + 2 days)
Safety visit
Day 84
(-4 / + 2 days)
End treatment
FU
Baseline
HRCT
Within 48h / discharge
Baseline lung function
Treatment Arms and Duration
Subjects will be required to participate in the following:
Screening: Following diagnosis during outpatient assessment by a Respirologist, 
Emergency Department visit or acute admission to hospital, and up to 3 days before start 
of study treatment. During this time:

The start of the standard of care (to include both antibiotics and corticosteroids) is 
expected to start shortly after diagnosis, though it is allowed to have already been 
started before the formal diagnosis of COPD exacerbation is made. 
 
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
The High-Resolution Computed Tomography (HRCT) scan should be conducted at 
the earliest opportunity after obtaining Informed Consent from the subject and within 
48 h of diagnosis by a Respirologist or physician with respiratory experience.  

Randomisation and first dose administration should take place as soon as possible 
following HRCT scan assessment has been performed and no later than 24h after 
completing the HRCT scan.
Treatment period:  Once daily study treatment administration will start on Day 1 (visit 1). 

For subjects who were hospitalized: 
o
If discharge takes place before Day 10, the subject must complete the 
assessments planned for visit 2 on discharge and must then visit the unit 
on Day 12 (2 days) (visit 3).
o
If discharge takes place between Day 10 and Day 14 (inclusive), the 
assessments planned for visit 2 and visit 3 may be completed on the day of 
discharge.
o
If discharge takes place from Day 15 (inclusive), the assessments planned 
for visit 2 and visit 3 should be completed as soon as it is safe for the 
patient to do so.

For subjects who were not hospitalized: the subject must complete the 
assessments planned for visit 2 within 48 hours of start of treatment, and must 
then visit the unit on Day 12 (2 days) to complete the assessments planned for 
visit 3.
Subjects will then dose at home until Day 84 (– 4 / + 2 days), with the exception of the 
days when subjects come to the clinic. On those days, they will dose at the clinic. On Day 
12 (± 2 days) (unless visit completed on discharge), Day 28 (± 2 days), Day 56 (– 4 / + 2 
days) and Day 84 (– 4 / + 2 days) subjects will return on an outpatient basis to complete 
the assessments described in the Time & Event table. Subjects will be discharged once all 
assessments have been performed and there are no safety concerns.
Follow up: 7-14 days after last dose.
The total duration of the study is 13-14 weeks including the screening visit.
Type and Number of Subjects
Approximately 35 subjects with an acute exacerbation of COPD will be randomized such 
that approximately 15 subjects on active and 15 subjects on placebo provide sputum at all 
the scheduled time points and complete the study.  If a higher than expected numbers of 
subjects prematurely discontinue the study, or fail to produce sufficient sputum post 
randomisation additional subjects may be randomised at the discretion of the sponsor.
 
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Analysis
To estimate differences in mRNA intensities within and between treatment groups, a 
repeated measures model will be fitted to the results of the analysis of each probe set at 
Day 12, Day 28 and Day 84 following a loge transformation of the data. The Day 1 
response will be fitted as a baseline covariate. A separate model will be fitted for each of 
the approximate 54000 probe sets.
Back transformed ratios versus screening along with 95% confidence intervals will be 
calculated for each treatment group and timepoint.  Additionally, baseline adjusted ratios 
of the change between active treatment and placebo will be calculated along with 95% 
confidence intervals.
2.
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.
2.1.
Study Rationale
The purpose of this study is to evaluate specific alterations in immune cell mechanisms
related to neutrophil function as detected by PI3K-dependent changes in mRNA 
extracted from induced sputum in patients experiencing an exacerbation of COPD. In 
addition this study will also further evaluate the plasma PK and assess the safety of 
GSK2269557 administered to patients diagnosed with an acute exacerbation of Chronic 
Obstructive Pulmonary Disease (COPD). The efficacy of treatment with GSK2269557 
will also be measured using functional respiratory imaging (FRI) and spirometry. 
This study will also explore the pharmacodynamic effects of once daily repeat doses of 
inhaled GSK2269557 on cytokines, mediators and microbiome in induced sputum 
samples. These will be obtained from subjects at entry, during their exacerbation, and at 
additional time points over the 12 week treatment period.  To understand patient efficacy, 
at entry, Day 12 and Day28 the sputum biomarker data will be correlated with computed 
tomography (CT).   
2.2.
Brief Background
PI3Kis a member of the Class IA family of phosphoinositides 3-kinases (PI3Ks) that 
convert the membrane phospholipid phosphatidylinositol 4,5-biphosphate (PIP2) into 
phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 is a second messenger in many 
cellular processes including cell growth, differentiation and migration. PI3Khas 
specific roles in mediating antigen receptor and cytokine signalling in T-cells, mast cells 
and B-cells [Okkenhaug, 2007] and roles in neutrophil chemotaxis and activation [Sadhu, 
2003].  A PI3Kinhibitor has the potential to inhibit major cell types responsible for the
inflammation associated with both COPD and asthma.
 
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In COPD, tobacco smoke or other irritants activate epithelial cells and macrophages to 
release inflammatory mediators such as chemokines that attract neutrophils and T cells to 
the lungs. PI3Kis thought to play a role in a number of epithelial responses relevant for 
the development of COPD.  Therefore a PI3Kinhibitor may be able to suppress a 
number of these processes [Kim, 2010].  A greater proportion of macrophages appear to
be alternatively activated in COPD and their ability to phagocytose infective pathogens is 
reduced as a result of this alternative activation.  PI3Kis one of the mediators involved 
in determining this alternative phenotype in macrophages and therefore it is proposed that 
inhibition of PI3Kmight rebalance macrophage activation towards a classic phagocytic
phenotype [Weisser, 2011] facilitating clearance of bacteria, a major cause of
exacerbation in COPD.  The neutrophil and T cell are the two major inflammatory cell 
types involved in the pathogenesis of COPD and both are targeted by PI3Kinhibitors. 
GSK2269557 has demonstrated the ability to protect against and control bacterial 
infections in preclinical rodent models. This is coupled with recent observations that 
PI3Kinhibition leads to a correction in vitro of aberrant neutrophil chemotaxis 
directionality in the blood of COPD patients. Furthermore, a human point mutation which 
results in a constitutively activated version of PI3Khas recently been characterised 
where the majority of affected patients have recurrent lung infections with the same 
bacterial species which are seen in COPD patients and are known to drive exacerbations. 
Collectively these data suggest that repeat dosing with GSK2269557 could potentially
reduce the impact of an acute exacerbation, or prevent the onset of a secondary bacterial 
exacerbation or recurrent exacerbation.
Proinflammatory cytokines were reduced by GSK2269557, both in preclinical rodent 
bacterial models, and COPD patient samples treated in vitro and in the study setting 
(PII115119).
GSK2269557 has been administered as single and repeat doses to healthy subjects as 
nebulized solution in the FTIH study PII115117 up to a dose of 6400 μg per day for 7 
days. GSK2269557 has also been administered as single and repeat doses to healthy 
smokers as a dry powder formulation in study PII116617 up to a dose of 3000 μg as 
single dose and 2000 μg per day for 14 days.  GSK2269557 has been well tolerated 
across the range of doses used.  There is also an ongoing study (Study PII115119, non-
reported) where a total daily dose of up to 2000 µg of GSK2269557 is being administered 
to stable COPD patients via a dry powder inhaler for 14 days in a two part study.  Part A 
of this study has completed and Part B will characterise the steady-state (exposure) dose 
response following repeat inhaled doses of up to 2000µg for the same treatment duration.  
There is also an on-going larger clinical study PII116678 which is almost identical in 
design to 201928 using 1000 µg of GSK2269557 per day administered via a Diskus dry 
powder inhaler to patients diagnosed with an acute exacerbation of COPD.  For 
simplicity study PII116678 does not capture induced sputum hence cannot analyse any 
changes in mRNA. The primary objective of the current study is to capture induced 
sputum to enable the mRNA analysis on a smaller cohort.   
More information about the non-clinical and clinical studies is available in the 
GSK2269557 Investigator’s Brochure (IB) GlaxoSmithKline Document Number
2012N141231_06.
 
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2.2.1.
Use of mRNA transcriptomics by Affymetrix
Analysis of changes in mRNA can be used to demonstrate alterations in biochemical 
pathways at the gene transcription level. This can be used to better understand the 
consequences of drug intervention on disease pathophysiology, and ultimately predict 
alterations which could translate to a positive clinical benefit for patients.  Messenger 
RNA can be extracted from a variety of biological samples (including induced sputum 
and blood) taken from patients before and after drug dosing to show the impact a drug is 
having. 
The advantage of using Affymetrix is the broad (~50k) gene set covered using this 
technology enabling great depth in exploring the biological consequences of drug 
intervention. This technology has been used in previous preclinical and clinical studies 
using GSK2269557 generating a fingerprint of PI3Kinhibition in disease.  Importantly 
these approaches allow areas of complex PI3K-dependent immune cell mechanisms and 
pathophysiology, specifically related to neutrophil function to be explored which are not 
easily quantified using other techniques.
2.2.2.
Use of HRCT Endpoints to characterise Lung Function
High-resolution computed tomography (HRCT) scans provide a highly detailed insight 
into the structure and architecture of the respiratory system. A clear distinction can be 
made between the lung parenchyma, the intraluminal air and alveolar spaces up to the 
level of the smaller airways with a diameter of 1-2mm. To model dynamic information, 
low dose HRCT scans can be taken at two lung volumes: after deep inhalation (total lung 
capacity or TLC) and after normal expiration (functional residual capacity or FRC). The 
patient’s breathing is monitored in real time during the scans to ensure the correct lung 
levels are scanned.  Due to the natural contrast between the intraluminal air and the 
surrounding tissue, it is possible to attain a significant reduction in radiation dose (1-2 
mSv per scan) compared to standard CT protocols (>4 mSv per scan) by reducing the 
tube current and the voltage.  Depending on the patient’s weight, a 6- to 10-fold reduction 
can be obtained per scan without losing image quality. As a comparison, in the USA, the 
average annual background radiation exposure is 6.2 mSv and a transatlantic flight results 
in 0.07 mSv exposure.
The high resolution images allow for a three dimensional reconstruction of the airway 
tree and vasculature by applying segmentation principles.  These three dimensional 
models can be used to measure airway dimensions as well as potentially allowing the 
phenotyping of patients by disease severity.  The three dimensional computer 
reconstructions can be used for fluid dynamic modelling.  This method is used to 
simulate flow through these airway models and determine the typical flow characteristics 
such as local pressure drops, velocities and resistance.  It can also be used to predict 
particle deposition in the airways of these patients when using inhaled drug products.
This method consisting of 2 low dose HRCT scans at several time points has previously 
been used successfully in clinical trials involving COPD patients [De Backer, 2011; De 
Backer, 2012; De Backer, 2014; Goldin, 1999]. 
 
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3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To establish the PI3K-dependent changes 
in previously identified immune cell 
mechanisms specifically related to 
neutrophil function using mRNA in sputum 
from patients with an exacerbation of 
COPD, with or without treatment with 
GSK2269557.

Alterations in previously identified immune 
cell mechanisms specifically related to 
neutrophil function as determined by 
changes in mRNA transcriptomics in 
induced sputum after 12, 28 and 84 days 
of treatment.
Secondary

To evaluate the effect of once daily repeat 
inhaled doses of GSK2269557 on lung 
parameters derived from HRCT scans in 
subjects with acute exacerbation of COPD, 
compared to placebo

Change from baseline in siVaw, iVaw, 
iRaw, siRAW, total lung capacity, lung 
lobar volumes, trachea length and 
diameter at FRC and TLC after 12 days of 
treatment and after 28 days of treatment.

To assess the safety and tolerability of 
once daily repeat inhaled doses of 
GSK2269557 administered to subjects with 
acute exacerbation of COPD, compared to 
placebo.

Adverse events 

Hematology, clinical chemistry 

Vital signs

12-lead ECG

To evaluate the plasma PK of once daily 
repeat inhaled doses of GSK2269557 
administered to subjects with acute 
exacerbation of COPD

Day 1 plasma Cmax and trough (24 hours) 
post dose for inpatients

Trough concentration after 12 days, 28 
days, 56 days and 84 days of treatment.

To evaluate the effect of once daily repeat 
inhaled doses of GSK2269557 on lung 
function parameters in subjects with acute 
exacerbation of COPD, compared to 
placebo

PEF, Reliever usage.

FEV1 and FVC at clinic prior to sputum 
induction.
Exploratory 

To establish any other PI3K-dependent 
changes in mRNA in sputum or blood from 
patients with an exacerbation of COPD, 
with or without treatment with 
GSK2269557.

To explore the pharmacodynamic effects in 
induced sputum of once daily repeat 
inhaled doses of GSK2269557 
administered to subjects with acute 
exacerbation of COPD, compared to 
placebo.

Alterations in immune cell mechanisms as 
determined by changes in mRNA 
transcriptomics in induced sputum or blood 
after 12, 28 and 84 days of treatment.

Endpoints may include, but not limited to 
cytokines (IL-6, IL-8, TNF), microbiome 
(by 16SrRNA), bacterial qPCR, viral qPCR.
 
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Objectives
Endpoints

To assess the changes in other CT 
parameters such as low attenuation score 
after once daily repeat inhaled doses of 
GSK2269557 administered to subjects with 
acute exacerbation of COPD, compared to 
placebo.

Change from baseline for other CT 
parameters including low attenuation score 
after 12 days of treatment and after 28 
days of treatment.
4.
STUDY DESIGN
4.1.
Overall Design
This is a randomised, double-blind, placebo-controlled, parallel-group study.  All subjects 
will continue on their usual COPD medications throughout the entire duration of the 
study regardless of treatment arm assignment.  Subjects will be on standard of care 
treatment (antibiotic and corticosteroids) upon diagnosis of a COPD exacerbation.
SCR
Signature 
ICF
Day 1
Randomisation / 
First dose GSK2269557
Day 12
(+/- 2 days) 
HRCT
Day 28
(+/- 2 days)
HRCT
Day 56
(-4 / + 2 days)
Safety visit
Day 84
(-4 / + 2 days)
End treatment
FU
Baseline
HRCT
Within 48h / discharge
Baseline lung function
4.2.
Treatment Arms and Duration
Subjects will be required to participate in the following:
Screening: Following diagnosis during outpatient assessment by a Respirologist, 
Emergency Department visit or acute admission to hospital, and up to 3 days before start 
of study treatment. During this time:

The start of the standard of care (to include both antibiotics and corticosteroids) is 
expected to start shortly after diagnosis, though it is allowed to have already been 
started before the formal diagnosis of COPD exacerbation is made. 

The HRCT scan should be conducted at the earliest opportunity after obtaining 
Informed Consent from the subject and within 48 h of diagnosis by a Respirologist or 
physician with respiratory experience. 
 
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
Randomisation and first dose administration should take place as soon as possible 
following HRCT scan assessment has been performed and no later than 24h after 
completing the HRCT scan.
Treatment period:  Once daily study treatment administration will start on Day 1 (visit 1). 

For subjects who were hospitalized: 
o
If discharge takes place before Day 10, the subject must complete the 
assessments planned for visit 2 on discharge and must then visit the unit 
on Day 12 (2 days) (visit 3).
o
If discharge takes place between Day 10 and Day 14 (inclusive), the 
assessments planned for visit 2 and visit 3 may be completed on the day of 
discharge.
o
If discharge takes place from Day 15 (inclusive), the assessments planned 
for visit 2 and visit 3 should be completed as soon as it is safe for the 
patient to do so.

For subjects who were not hospitalized: the subject must complete the 
assessments planned for visit 2 within 48 hours of start of treatment, and must 
then visit the unit on Day 12 (2 days) to complete the assessments planned for 
visit 3.
Subjects will then dose at home until Day 84 (– 4 / + 2 days), with the exception of the 
days when subjects come to the clinic. On those days, they will dose at the clinic. On Day 
12 (± 2 days) (unless visit completed on discharge), Day 28 (± 2 days), Day 56 (– 4 / + 2 
days) and Day 84 (– 4 / + 2 days) subjects will return on an outpatient basis to complete 
the assessments described in the Time & Event table (Section 7.1). Subjects will be 
discharged once all assessments have been performed and there are no safety concerns.
Follow up: 7 to 14 days after last dose.
The total duration of the study is 13-14 weeks including the screening visit.
4.3.
Type and Number of Subjects
Approximately 35 subjects with an acute exacerbation of COPD will be randomized such 
that approximately 15 subjects on active and 15 subjects on placebo provide sputum at all 
the scheduled time points and complete the study.   If a higher than expected number of 
subjects prematurely discontinue the study, or fail to produce sufficient sputum post 
randomisation additional subjects may be randomised at the discretion of the sponsor.
4.4.
Design Justification
This study will include a placebo control to allow for a valid evaluation of the 
pharmacodynamic endpoints and adverse events attributable to treatment versus those 
 
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independent of treatment. Subjects will also receive standard of care for their 
exacerbation and throughout the study.
4.5.
Dose Justification
The dose chosen for this study is 1000 µg of GSK2269557 per day administered via a dry 
powder inhaler for a duration of 84 days (– 4 / + 2 days). This dose has been selected 
based on previous safety and tolerability data in man (healthy subjects and COPD 
subjects) as well as demonstration of target (PI3K) inhibition by observed changes in 
biomarkers. Together with an additional study to be run in parallel (PII116678), this dose 
of GSK2269557 is being dosed to subjects in PII116678 with an exacerbation of COPD,
so it will be assumed for exposure predictions, unless otherwise stated, that these subjects 
will have a similar lung deposition, distribution and plasma exposure to that of the 
healthy volunteers. However it is accepted that these types of subjects may have reduced 
airway conductance and hence likely reduced deposition. This can be appropriately 
defined in this study based on the actual plasma exposures achieved. 
Twice this dose level (2000 µg) using the same formulation has previously been given 
once daily to healthy male smokers for 14 days (study PII116617). There is also an 
ongoing study where a total daily dose of 1000 µg of GSK2269557 is administered to 
stable COPD subjects via a dry powder inhaler for 14 days (study PII115119) which at 
the time of writing of this protocol had successfully dosed 21 subjects on active treatment 
and collected pharmacokinetics (PK) samples for analysis out to 14 days.
The target effect compartment for PI3Kinhibition is the intracellular compartment of 
the immune cells resident in the lung tissue and lumen.  GSK2269557 has a high potency 
and selectivity at the PI3Kenzyme (Ki value 0.1 ng/mL) which translates into an IC50 in 
a more complex system (PHA stimulated lung tissue) of approximately 120 ng/mL (or 
2.5 ng/mL free unbound drug).  Based on the measured steady-state cellular 
concentration of GSK2269557 collected at trough (24 h) from the lungs of healthy 
smokers at 2000 µg DPI (450 ng/mL) in the clinical study it is expected that at 1000 µg 
(225 ng/mL), concentrations will be sufficient and PI3Kinhibition maintained in the 
lung at 90% inhibition for 24 h. 
Target PI3Kinhibition is based on a wide range of pharmacology experiments.  Details 
of these as well as the pharmacokinetics and safety data can be found in the IB, 
[GlaxoSmithKline Document Number: 2012N141231_06].
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK2269557 can be found in the IB [GlaxoSmithKline Document Number 
2012N141231_06]. The following section outlines the risk assessment and mitigation 
strategy for this protocol:  
 
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4.6.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Investigational Product (IP) [e.g., GSK2269557]
Bronchospasm
Mucosal irritancy
A general risk with Inhaled 
treatment
Detected in 13 week toxicology 
study in the dog
Subjects will be allowed to 
continue regular COPD 
treatments and have standard 
of care for treatment of their 
exacerbation. More severe 
patients will have their 
treatment started in hospital. 
Patients will be regularly 
monitored for AEs and a 
patient diary kept. Thus far this 
has not been seen in clinical 
studies.
Study Procedures
Radiation risk as part of HRCT 
scans
The maximum amount of 
radiation dose a patient 
undergoing all six scans will 
receive is approximately 
12mSv. Six low dose HRCT 
scans (one at TLC and FRC on 
screening, Day 12 and Day 28 
visits) at are required 
throughout the study for the 
functional imaging protocol
Reduced tube voltage (100 
kV), and tube current are used.
Scanning time less than 5 s 
per scan.
Total radiation dose for a total 
of six CT scans will be 
approximately 12mSv.
Final radiation dose will be 
dependent on the patient 
weight, with a range of 
between 1-2mSv per scan per 
patient. This radiation dose 
falls into the International 
Commission on Radiological 
Protections [ICRP, 2007]
category IIb (minor to 
intermediate risk).
The outcomes of this study will 
provide information which 
would produce advances in 
knowledge, leading to a 
potential health benefit in the 
future for patients in this target 
population. The CT may also 
provide information for the 
patients general clinical 
 
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
management
Sputum induction
Standard sputum induction 
techniques using hypertonic 
saline can result in 
bronchospasm and therefore 
could potentially induce 
bronchospasm in a patient or 
impact a pre-existing 
exacerbation.
For patients during an 
exacerbation and for sputum 
induction during the recovery 
period, including the day 28 
visit, patients will be pre-dosed 
with nebulised or inhaled beta-
2-agonist (or ipratropium 
bromide if beta-2-agonist 
intolerant). Sputum induction 
will only be carried out using 
Normal (0.9%) saline, which is 
also often used in patients 
clinically to facilitate sputum 
clearance.  
For the final sputum induction 
patients will be pre-dosed with 
nebulised or inhaled beta-2-
agonist (or ipratropium bromide 
if beta-2-agonist intolerant) and 
the induction carried out with 
0.9% saline initially and only 
then followed by hypertonic (3-
5%) if required, and, in the 
opinion of the Investigator,  it is 
considered safe to do so.
4.6.2.
Benefit Assessment
The outcomes of this study will provide information which will produce advances in 
knowledge of the pathophysiology of COPD exacerbations, leading to a potential health 
benefit in the future for patients in this target population. The CT scan may also provide 
information for the patient’s general clinical management.
4.6.3.
Overall Benefit:Risk Conclusion
The overall benefit:risk is considered to be positive. There is an opportunity to determine 
if there may be a new drug developable for the treatment of acute exacerbations of COPD 
which has not seen any new treatments recently. The scientific value in obtaining 
functional CT information on the anatomy and pathophysiology of COPD exacerbations 
and how the lung responds to therapy will be extremely valuable to the wider clinical 
community and justifies the limited radiation exposure (maximum 12 mSv in total) from 
 
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the CT scan procedures. The CT will also be useful to provide clinical information about 
the patient for the patient’s physician and contribute to clinical management.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB [GlaxoSmithKline 
Document Number: 2012N141231_06] 
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
[1] AGE

Between 40 and 80 years of age inclusive, at the time of signing the informed 
consent.
[2] TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY

The subject has a confirmed and established diagnosis of COPD, as defined by the 
GOLD guidelines for at least 6 months prior to entry.

The subject is able to produce >100 mg of sputum at screening for processing, (ie, 
total weight of sputum plugs.).

The subject has a post-bronchodilator FEV1/FVC < 0.7 and FEV1 80 % of predicted 
documented in the last 5 years.

Disease severity: Acute exacerbation of COPD requiring an escalation in therapy to 
include both corticosteroid and antibiotics. Acute exacerbation to be confirmed by an 
experienced physician and represent a recent change in at least two major and one 
minor symptoms, one major and two minor symptoms, or all 3 major symptoms.
1. Major symptoms:

Subjective increase in dyspnea

Increase in sputum volume

Change in sputum colour
2.
Minor symptoms:

Cough
 
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
Wheeze

Sore throat

The subject is a smoker or an ex-smoker with a smoking history of at least 10 pack 
years (pack years = (cigarettes per day smoked/20 x number of years smoked)).
[3] WEIGHT

Body weight 45 kg and body mass index (BMI) within the range 16 – 35 kg/m2
(inclusive).
[4] SEX

Male

Female subject : is eligible to participate if she is not pregnant (as confirmed by a 
negative urine human chorionic gonadotrophin (hCG) test), not lactating, and at least 
one of the following conditions applies:
1. Non-reproductive potential defined as:
Pre-menopausal females with one of the following:
Documented tubal ligation
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 
Hysterectomy
Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea.  Females whose 
menopausal status is in doubt will be required to use, or have been using, one of the 
highly effective contraception methods as specified below from 30 days prior to the first 
dose of study medication and until completion of the follow-up visit.
2. Reproductive potential and agrees to follow one of the options listed 
below in the GSK Modified List of Highly Effective Methods for 
Avoiding Pregnancy in Females of Reproductive Potential (FRP) 
requirements from 30 days prior to the first dose of study medication 
and until completion of the follow-up visit.
GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females 
of Reproductive Potential (FRP)
This list does not apply to FRP with same sex partners, when this is their preferred and 
usual lifestyle or for subjects who are and will continue to be abstinent from penile-
vaginal intercourse on a long term and persistent basis.
1. Contraceptive subdermal implant that meets GSK standard criteria including a 
<1% rate of failure per year, as stated in the product label
2. Intrauterine device or intrauterine system that meets GSK standard criteria 
including a <1% rate of failure per year, as stated in the product label [Hatcher, 
 
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2007a]
3. Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007a] 
4. Injectable progestogen [Hatcher, 2007a]
5. Contraceptive vaginal ring [Hatcher, 2007a]
6. Percutaneous contraceptive patches [Hatcher, 2007a]
7. Male partner sterilization with documentation of azoospermia prior to the female 
subject’s entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2007a].  
8. Male condom combined with a vaginal spermicide (foam, gel, film, cream, or 
suppository) [Hatcher, 2007b]
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
Specific inclusion criteria for Male subjects with female partners of reproductive 
potential is outlined below:
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until after the completion of the follow up visit.
3. Vasectomy with documentation of azoospermia.  
4. Male condom plus partner use of one of the contraceptive options below:
Contraceptive subdermal implant that meets GSK standard criteria including a 
<1% rate of failure per year, as stated in the product label
Intrauterine device or intrauterine system that meets GSK standard criteria 
including a <1% rate of failure per year, as stated in the product label [Hatcher, 
2007a]
Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007a] 
Injectable progestogen [Hatcher, 2007a]
Contraceptive vaginal ring [Hatcher, 2007a]
Percutaneous contraceptive patches [Hatcher, 2007a]
5.
These allowed methods of contraception are only effective when used 
consistently, correctly and in accordance with the product label.  The 
investigator is responsible for ensuring that subjects understand how to properly 
use these methods of contraception.
[5] INFORMED CONSENT

Capable of giving signed informed consent as described in Section 10.2 which
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
 
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5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
[1]  CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL)

To avoid recruitment of subjects with a severe COPD exacerbation, the presence of 
any one of the following severity criteria will render the subject ineligible for 
inclusion in the study:

Need for invasive mechanical ventilation (short term (< 48h) NIV or CPAP is 
acceptable)

Haemodynamic instability or clinically significant heart failure

Confusion

Clinically significant pneumonia, identified by chest X-ray at screening, and as 
judged by the Investigator. 

Subjects who have current medical conditions or diseases that are not well controlled 
and, which as judged by the Investigator, may affect subject safety or influence the 
outcome of the study. (Note: Patients with adequately treated and well controlled 
concurrent medical conditions (e.g. hypertension or NIDDM) are permitted to be 
entered into the study).

Subject has a diagnosis of active tuberculosis, lung cancer, clinically overt 
bronchiectasis, pulmonary fibrosis, asthma or any other respiratory condition that 
might, in the opinion of the investigator, compromise the safety of the subject or 
affect the interpretation of the results.

ALT >2xULN and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if 
bilirubin is fractionated and direct bilirubin <35%). 

A subject with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the exclusion criteria, outside of the reference range for the 
population being studied may be included if the Investigator [in consultation with the 
GSK Medical Monitor if required] documents that the finding is unlikely to 
introduce additional risk factors and will not interfere with the study procedures.

Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert’s syndrome or asymptomatic gallstones)

ECG indicative of an acute cardiac event (e.g. Myocardial Infarction) or 
demonstrating a clinically significant arrhythmia requiring treatment.

QTcF > 450 msec or QTcF > 480 msec in subjects with Bundle Branch Block, based 
on single QTcF value.

Subjects who have undergone lung volume reduction surgery.
 
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[2] CONCOMITANT MEDICATIONS

Subject is currently on chronic treatment with macrolides or long term antibiotics.

Subject is being treated with long term oxygen therapy - LTOT (> 15 hours/day).

The subject has been on chronic treatment with anti-Tumour Necrosis Factor (anti-
TNF), or any other immunosuppressive therapy (except corticosteroid) within 60 days 
prior to dosing.
[3] RELEVANT HABITS

History of regular alcohol consumption within 6 months of the study defined as an 
average weekly intake of >28 units for males or >21 units for 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.
[4]  CONTRAINDICATIONS 

History of sensitivity to any of the study medications, or components thereof (such as 
lactose) or a history of drug or other allergy that, in the opinion of the investigator or 
Medical Monitor, contraindicates their participation.
[5] DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA

A known (historical) positive test for HIV antibody.

Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test 
result at screening or within 3 months prior to first dose of study treatment.
NOTE: Because of the short window for screening, treatment with GSK2269557 
may start before receiving the result of the hepatitis tests. If subsequently the test is 
found to be positive, the subject may be withdrawn, as judged by the Principal 
Investigator in consultation with the Medical Monitor.

Where participation in the study would result in donation of blood or blood 
products in excess of 500 mL within 56 days.

The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the 
current study: 30 days, 5 half-lives or twice the duration of the biological effect of 
the investigational product (whichever is longer).

Exposure to more than 4 investigational medicinal products within 12 months 
prior to the first dosing day.
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized.  In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
 
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set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria Protocol Deviations, and any Serious Adverse Events.
5.4.
Withdrawal/Stopping Criteria
Subjects who are withdrawn from treatment will also be withdrawn from the study. 
If a higher than expected number of subjects prematurely discontinues the study, 
additional subjects may be randomised and assigned to the same treatment sequence, at 
the discretion of the Sponsor.  
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as soon 
as possible. 

The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 
telephone calls and if necessary a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
Subjects who are withdrawn should complete all the assessments planned, if possible.  
Subjects who are withdrawn on a study clinic visit after randomization should complete 
all the safety related assessment for that visit which includes at minimum, vital sign, lab 
assessments (if deem necessary by the PI), AE/SAEs, concomitant medication(s) and 
ECG.   A Follow up Visit should be scheduled 7-14 days post last dose.
Subjects who are withdrawn in between study clinic visits should complete the 
unscheduled visit and complete all the safety related assessment at minimum which 
includes, vital sign, lab assessments (if deem necessary by the PI), AEs/SAEs, 
concomitant medication(s) and ECG.   A Follow up Visit should be scheduled 7-14 post 
last dose.
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
 
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http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase II Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5, if 
measured*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
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 2.
5.4.1.1.
Study Treatment Restart or Re-challenge
Study treatment restart or re-challenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.4.2.
QTc Stopping Criteria

QTcF should be based on averaged QTcF values of triplicate electrocardiograms 
obtained over a brief (e.g., 5-10 minute) recording period. For example, if an ECG 
(Electrocardiogram) demonstrates a prolonged QTcF interval, obtain two more 
ECGs and use the averaged QTcF values of the three ECGs to determine whether the 
patient should be discontinued from the study.
A subject who meets either of the bulleted criteria below will be withdrawn from the 
study:

QTcF >500 msec OR Uncorrected QT >600 msec

Change from baseline of QTcF > 60 msec
 
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For patients with underlying bundle branch block, follow the discontinuation criteria 
listed below:
Baseline QTcF with Bundle Branch 
Block
Discontinuation QTcF with Bundle 
Branch Block
<450 msec
>500 msec
450 – 480 msec
≥530 msec
5.4.3.
Other Stopping Safety Criteria
For an individual study participant, stopping criteria include, but are not limited to:
Severe signs or symptoms, or significant changes in any of the safety assessments, that 
put the safety of the individual at risk (e.g. ECG, vital signs, laboratory tests, spirometry 
assessments, etc), as judged by the Principal Investigator in consultation with the Medical 
Monitor if necessary.
Treatment failure or recurrent exacerbation does not mandate withdrawal from the study, 
unless there is a safety concern as judged by the Investigator, in consultation with the 
Medical Monitor if necessary.
Subjects should be withdrawn from the study if confusion, acute respiratory acidosis (pH 
< 7.30), or need for invasive mechanical ventilation occurs.
5.5.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit.
The end of the study is defined as the last subject’s last visit.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
 
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Study Treatment
Product name:
GSK2269557
Placebo
Formulation description:
Lactose blend containing 
GSK2269557 in Diskus™device
Lactose in Diskus device
Dosage form:
Dry powder for inhalation
Dry powder for inhalation
Unit dose 
strength(s)/Dosage 
level(s):
500 µg / blister
N/A
Route of Administration
Inhalation
Inhalation
Dosing instructions:
2 inhalations to be taken every 
day before breakfast (with the 
exception of days when the 
subjects have a planned visit to 
the clinic. On those days, they 
will be dosed at the clinic). The 
subject should hold their breath 
for approximately 10 seconds 
before exhaling. Inhalations 
should be taken approximately 
30 seconds apart. 
2 inhalations to be taken every 
day before breakfast (with the 
exception of days when the 
subjects have a planned visit to 
the clinic. On those days, they 
will be dosed at the clinic). The 
subject should hold their breath 
for approximately 10 seconds 
before exhaling. Inhalations 
should be taken approximately
30 seconds apart.
6.2.
Treatment Assignment
Subjects will be assigned to treatments in accordance with the randomization schedule
generated by Clinical Statistics, prior to the start of the study, using validated internal 
software. Central based randomisation will be used.
Subjects will be randomised to treatments A or B where:
A = Placebo 
B = GSK2269557 1000 µg 
A web based interactive response system will be used to assign subjects to treatment.
6.3.
Planned Dose Adjustments
If adverse events, unrelated to COPD exacerbation, which are of moderate or severe 
intensity and are consistent across subjects in the group, or if unacceptable 
pharmacological effects, reasonably attributable in the opinion of the investigator to 
dosing with GSK2269557, are observed in more than 30% of the subjects then the study
will be halted and no further subject will be dosed until a full safety review of the study 
has taken place. Relevant reporting and discussion with the Medical Monitor, relevant 
GSK personnel, and with the Ethics Committees will then take place prior to any 
resumption of dosing. If the above is observed consideration may be given to reducing 
the dose of GSK2269557 to 500 µg O.D.
 
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6.4.
Subject Specific Dose Adjustment Criteria
There are no subject specific dose adjustment criteria.
6.5.
Blinding
This will be a double blind study and the following will apply. 

The investigator or treating physician may un-blind a subject’s treatment assignment 
only in the case of an emergency OR in the event of a serious medical condition 
when knowledge of the study treatment is essential for the appropriate clinical 
management or welfare of the subject as judged by the investigator. 

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before un-blinding 
the subject’s treatment assignment. 

If GSK personnel are not contacted before the un-blinding, the investigator must 
notify GSK as soon as possible after un-blinding. 

The date and reason for the un-blinding must be fully documented in the Case Report 
Form (CRF)

A subject will be withdrawn if the subject’s treatment code is un-blinded by the 
investigator or treating physician. The primary reason for discontinuation (the event 
or condition which led to the un-blinding) will be recorded in the CRF.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may un-blind the 
treatment assignment for any subject with a Serious Adverse Event (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 subject’s treatment assignment, may be 
sent to investigators in accordance with local regulations and/or GSK policy.
6.6.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
 
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6.7.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

Only subjects 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 labelled storage conditions with access limited to the 
investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e. receipt, reconciliation and final disposition records).  

Further guidance and information for final disposition of unused study treatment are 
provided in the Study Reference Manual (SRM).

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, Medical Monitor and/or 
GSK study contact.

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
6.8.
Compliance with Study Treatment Administration
When subjects 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 subjects will be asked to complete a diary when dose administration takes place at 
home. The date, time and number of inhalations will be recorded. The compliance will be 
checked by the site staff at each planned visit. 
A record of the number of Diskus inhalers dispensed to each subject and the number of 
actuation administered, read from the dose counter for each Diskus inhaler, must be 
maintained and reconciled with study treatment and compliance records.  Treatment start 
and stop dates, including dates for treatment delays and/or dose reductions will also be
recorded in the CRF.
 
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6.9.
Treatment of Study Treatment Overdose
For this study, any dose of GSK2269557 >2000 µg within a 22 hour time period will be 
considered an overdose.
GSK does not recommend specific treatment for an overdose
In the event of an overdose the investigator should:
1) contact the Medical Monitor immediately
2) closely monitor the subject for adverse events (AEs)/serious adverse events 
(SAEs) and laboratory abnormalities until GSK2269557 can no longer be detected 
systemically (at least 14 days for GSK2269557)
3) obtain a plasma sample for pharmacokinetic (PK) analysis within 7 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 subject.
6.10.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because the indication being studied is not life threatening or seriously debilitating 
and/or other treatment options are available.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
Any clinical abnormalities identified during the conduct of the study will be locally 
managed by the Investigator.
6.11.
Lifestyle and/or Dietary Restrictions

Subjects should refrain from consumption of Seville oranges, grapefruit or grapefruit 
juice, exotic citrus fruits or grapefruit hybrids from first dose till the end of the study.

Subjects should abstain from alcohol on the day when they visit the clinical unit and 
until their discharge on that day.

Subjects should refrain from smoking for at least 2 hours prior to each pulmonary 
function test conducted at the clinical unit/site.
 
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6.12.
Concomitant Medications and Non-Drug Therapies
6.12.1.
Permitted Medications and Non-Drug Therapies
On entry to the study all treatment required for standard of care and additional medical 
problems is permitted to start and continue.
The subjects are allowed to continue their regular COPD treatments for the duration of 
the study. However, the subjects should refrain, if possible, from using relief 
bronchodilators for at least 4 hours prior to each spirometry conducted at the clinical unit, 
and HRCT scan assessment unless essential for clinical symptom relief. Otherwise free 
use of reliever/rescue medication is allowed.  Rescue ventolin and aerochambers may be 
provided by GSK for this study and in such case, subjects should be advise to discontinue 
their own ventolin and use the study ventolin and aerochamber provided for the duration 
of the study.
All prior (up to 2 months prior to screening) and concomitant medications should be 
recorded in the subject’s CRF.
6.12.2.
Prohibited Medications and Non-Drug Therapies
Regular or chronic treatment with medications that are considered strong inhibitors of 
CYP3A4 or CYP2D6 are not permitted. This includes anti-epileptic treatments, 
macrolide antibiotics, oral antifungal treatments (single doses and courses up to 7 days 
are allowed) and anti-tuberculous therapy. These medications must all have been stopped 
at least 14 days prior to first dose.
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1
 
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7.1.
Time and Events Table (Screening and Follow Up Visits)
Procedure
Screening 
(up to 3 days prior to Visit 1)
Follow-up
(7-14 days post-last dose)
Notes
Informed consent
X
Demography
X
Inclusion and exclusion criteria
X
Full physical exam, including height and 
weight
X
Brief physical examination, including weight
X
Chest X-Ray
X
To be done before baseline HRCT to exclude significant 
pneumonia and other incidental serious underlying pathology.
Medical history (includes substance usage
and Family history of premature CV disease)
X
Substances: Drugs, Alcohol, tobacco via history.  No drug, alcohol 
screening is required.
Past and current medical conditions  
(including cardiovascular medical history and 
therapy history)
X
Laboratory assessments (include Hematology 
and biochemistry)1
X
X
Historical values analysed by local lab to be used for eligibility 
assessment. Another sample must be collected and sent to central 
lab as soon as informed consent is obtained. 
Hep B and Hep C screen2
X
Urine pregnancy test (only WCBP)
X
Before conducting the HRCT.  Done locally at the site.
12-lead ECG
X
X
Single assessment
Vital signs
X
X
Single assessment
HRCT (at TLC and FRC)
X
Within 48 h of diagnosis, if subject otherwise eligible. Includes 
electronic monitoring of breathing (if applicable).  Baseline HRCT 
will be reviewed by the local site’s radiologist to identify any 
significant occurring underlying medical conditions that require 
further clinical management or monitoring.
Induced Sputum3
X4
To include sputum culture pre-first dose. Culture to be done by the
local site laboratory.
Blood sample for mRNA Analysis
X4
Collected at any time on specified days
AE/SAE collection and review
X
 
 
 
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Procedure
Screening 
(up to 3 days prior to Visit 1)
Follow-up
(7-14 days post-last dose)
Notes
Concomitant medication review
X
X
1.
Due to the short screening window, central laboratory analysis results will not be available on time. Therefore the local laboratory results should be used for eligibility assessment 
(to exclude severe subjects and underlying medical conditions). If local laboratory results are already available from diagnosis of current exacerbation, there is no need to take 
another sample for local analysis. A sample for central laboratory analysis should also be obtained. See Section 7.8.6 for further details.
2.
If test otherwise performed within 3 months prior to first dose of study treatment, testing at screening is not required. Because of the short window for screening, treatment with 
GSK2269557 may start before receiving the result of the hepatitis tests. If subsequently the test is found to be positive, the subject may be withdrawn, as judged by the Principal 
Investigator in consultation with the Medical Monitor.
3.
Induced sputum collection may be attempted on several occasions if an adequate sample is not produced at the first attempt.
4.
To be collected at any time point before randomisation.
 
 
 
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7.2.
Time and Events Table (Treatment Period)
Procedure
Treatment Period 
Notes
Visit
1
21
3
4
5
6
Day
1
Within 48h 
/ discharge
12
28
56
84
Visit window
N/A
1 days
2 days
2 days
- 4 / +2 days
- 4 / +2 days
SAFETY ASSESSMENTS
AE/SAE collection and review
=========================================================
Concomitant medication review
=========================================================
Reliever usage
=========================================================
Brief physical exam, including weight
X2
X
X
X
X
Pre-dose
Laboratory assessments (include 
haematology and biochemistry)
X2
X
X
X
X
Pre-dose
12-lead ECG
X2
X
X
X
X
Pre-dose. Single assessment
Vital signs
X2
X
X
X
X
Pre-dose. Single assessment
Urine pregnancy test (only WCBP)
X
X
Before conducting the HRCT
STUDY TREATMENT
Randomisation
X
Study drug administration
=========================================================
Daily in the morning before breakfast, 
(with the exception of days when the 
subjects have a planned visit to the 
clinic. On those days, they will be 
dosed at the clinic).
Assessment of study treatment compliance
X
X
X
X
Diary Card dispense and review at clinic
X
X
X
X
X
Refer to SRM for details.
 
 
 
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Procedure
Treatment Period 
Notes
Visit
1
21
3
4
5
6
Day
1
Within 48h 
/ discharge
12
28
56
84
Visit window
N/A
1 days
2 days
2 days
- 4 / +2 days
- 4 / +2 days
EFFICACY ASSESSMENTS
HRCT (at TLC and FRC)
X
X
At any time on specified days. Includes 
electronic monitoring of breathing (if 
applicable).  The radiologist may review 
any of the scan(s) if they wish, but this 
is NOT required for the study.  A formal 
review is required at screening only by 
the radiologist.
FEV1  and FVC
X
X
X
X
X
X
In clinic only for all visits where 
possible.
PEF 
=========================================================
Daily before drug administration at 
home.  If subject in hospital, this may 
be collected using the handheld device 
provided prior to drug administration.
OTHER ASSESSMENTS
Blood sample for PK
X
X
X
X
X
Day 1:  5 min and 24 h post-dose. The 
24 h post-dose time-point is optional for 
subjects not hospitalised. Pre-dose at 
all other time-points.
Sputum induction3
X
X
X
Blood sample for mRNA analysis
X
X
X
Genetic sample (PGx)4
X
Collected at any time after 
randomisation
1.
On discharge if the subject was hospitalized. Within 48 hours of first dose administration if the subject was not hospitalised. See Section 4.2
2.
Assessments do not need to be completed if screening assessments conducted within 48 hours 
3.
Induced sputum collection may be repeated on several occasions if an adequate sample is not produced at the first attempt 
4.
Informed consent for optional sub-studies (e.g. ,genetics research) must be obtained before collecting a sample.  May be obtained at any visits.
 
 
 
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7.3.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.  
Procedures conducted as part of the subject’s routine clinical management and obtained 
prior to signing of informed consent may be utilized for Screening or baseline purposes 
provided the procedure meets the protocol-defined criteria and has been performed in the 
timeframe of the study.
If they are being utilised in the study, Patient Reported Outcomes questionnaires should 
be completed by subjects before any other assessment at a clinic visit, in the order 
specified.
7.4.
Biomarker(s)/Pharmacodynamic Markers
7.4.1.
Pharmacodynamic Biomarkers in Sputum

Collect sputum induction samples at the time-points shown in the time and events 
table (Section 7.1).

The sputum induction collection process will follow local standard procedures and
guidelines outlined in the SRM.

The collection of induced sputum may be attempted on several occasions if an 
adequate sample is not produced at the first attempt.

Further information on collection, processing, storage and shipping procedures are 
provided in the SRM.
7.4.2.
mRNA in blood

Collect 2.5 mL of blood into a PAXgene mRNA tube.
Details of blood sample collection, processing, storage and shipping procedures are 
provided in the SRM.
7.5.
Patient diary
The subjects will be provided with a diary to record the following data when at home: 

Time and date of each dose administration and number of inhalations.

Adverse Events and concomitant medications taken (including daily rescue 
medication – if used and how many times used).
 
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
PEF from a handheld device.  The best/highest result is recorded.
Changes in Health and details of any concomitant medications as well as PEF assessment 
details will be collected in the paper diaries and later transcribed into the CRF. 
7.6.
Genetics
Information regarding genetic research is included in Appendix 3.
7.7.
Efficacy
7.7.1.
Functional Respiratory Imaging

A CT scan with a low radiation protocol at FRC and TLC will be conducted as listed 
in the Time and Events Table (Section 7.1). The same scanner should be used for 
baseline and post-treatment scans for an individual subject.

A urine pregnancy test should be performed before the CT scan in female subjects of 
childbearing potential.

Further information is provided in the SRM.
7.7.2.
FEV1  and FVC
A triplicate FEV1 and FVC measurement will be taken at the clinic before dosing using 
the site’s spirometer as soon as it is safe to do so. These will be recorded as absolute 
values.  The best/highest result is recorded.

Further details are provided in the SRM.
7.7.3.
Peak Expiratory Flow PEF

PEF measurements will be taken (in triplicate) daily in the morning before dose 
administration, as soon as it is safe for the subject to do so. The best/highest result is 
recorded.

Subjects will be provided with a handheld device.

Further details are provided in the SRM.
7.8.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests (such as vital signs, physical exams
and laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
7.8.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.
 
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7.8.1.1.
Time period and Frequency for collecting AE and SAE information

AEs and SAEs will be collected from the start of Study Treatment until the follow-
up contact (see Section 7.8.1.3), at the time-points specified in the Time and Events 
Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product 
will be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact. 

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 4.

Investigators are not obligated to actively seek AEs or SAEs in former study
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the investigator 
must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 4.
7.8.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
 
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7.8.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in
Appendix 4.
7.8.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
7.8.1.5.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
COPD exacerbations are associated with the disease to be studied and will not be 
recorded as AEs unless they meet the definition of an SAE as defined in Appendix 4
Exacerbations that meet the definition of an SAE will be recorded on the appropriate 
eCRF section and should be reported to GSK.
Medications used to treat a COPD exacerbation will be recorded in the exacerbation 
eCRF
7.8.1.6.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs and non-serious AEs related to 
study treatment (even for non- interventional post-marketing studies) is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and the safety 
of a product under clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
 
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Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.8.2.
Pregnancy

Details of all pregnancies in female subjects and female partners of male subjects 
will be collected after the start of dosing and until the follow-up visit

If a pregnancy is reported then the investigator should inform GSK within 2 weeks 
of learning of the pregnancy and should follow the procedures outlined in Appendix 
5. 
7.8.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems.  Height and 
weight will also be measured and recorded.

A brief physical examination will include, at a minimum assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
7.8.4.
Vital Signs

Vital signs will be measured in semi-supine position after 5 minutes rest and will
include temperature, systolic and diastolic blood pressure and pulse rate and 
respiratory rate.

Three readings of blood pressure and pulse rate will be taken

First reading should be rejected

Second and third readings should be averaged to give the measurement to be 
recorded in the CRF. 
7.8.5.
Electrocardiogram (ECG)

Single 12-lead ECGs will be obtained at screening and at each other timepoint during 
the study using an ECG machine that automatically calculates the heart rate and 
measures PR, QRS, QT, and QTcF intervals.  Refer to Section 5.4.2 for QTcF
withdrawal criteria and additional QTcF readings that may be necessary.
 
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7.8.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 1, must be conducted in
accordance with the Laboratory Manual, and Protocol Time and Events Schedule.
Laboratory requisition forms must be completed and samples must be clearly labelled
with the subject number, protocol number, site/centre number, and visit date. Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the laboratory manual. Reference ranges for all safety parameters will be
provided to the site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Historical values (if the assessment was conducted as part of the standard of care) for 
blood gases, blood culture and sputum culture may also be collected if available.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
Table 1
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 1
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose (non 
fasted)
Calcium
Alkaline 
phosphatise
Albumin
CRP
Other 
Screening 
Tests

Urine hCG Pregnancy test (as needed for women of child bearing 
potential) 2

Hepatitis B (HBsAg)

Hepatitis C (Hep C antibody)
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 5.4.1 and Appendix 2
2. Local urine testing will be standard for the protocol unless serum testing is required by local regulation or ethics 
committee.
 
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All study-required laboratory assessments will be performed by a central laboratory, apart 
from:

Hematology and clinical chemistry at screening for excluding subjects with severe 
disease and uncontrolled medical conditions. The results of each test must be entered 
into the CRF.
NOTE:  Local laboratory results are only required in the event that the central laboratory
results are not available in time for either a treatment and/or response evaluation to be 
performed. If a local sample is required it is important that the sample for central 
analysis is obtained at the same time. Additionally if the local laboratory results are used 
to make either a treatment or response evaluation, the results must be entered into the 
CRF.
Hematology, clinical chemistry and additional parameters to be tested are listed in Table 
1. 
7.9.
Pharmacokinetics
7.9.1.
Blood Sample Collection
A 2 mL blood samples for pharmacokinetic (PK) analysis of GSK2269557 will be
collected at the time points indicated in Section 7.1, Time and Events Table.  The actual
date and time of each blood sample collection will be recorded.  The timing of PK 
samples may be altered and/or PK samples may be obtained at additional time points to 
ensure thorough PK monitoring.  
Processing, storage and shipping procedures are provided in the Study Reference Manual
(SRM). 
7.9.2.
Sample Analysis
Plasma analysis will be performed under the control of PTS-DMPK/Scinovo, 
GlaxoSmithKline, the details of which will be included in the SRM. Concentrations of 
GSK2269557 will be determined in plasma samples using the currently approved 
bioanalytical methodology. Raw data will be archived at the bioanalytical site (detailed 
in the SRM).
Once the plasma has been analyzed for GSK2269557 any remaining plasma may be
analyzed for other compound-related metabolites and the results reported under a 
separate PTS-DMPK/Scinovo, GlaxoSmithKline protocol.
 
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8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.

Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSK Drug.  

CRFs (including queries and audit trails) will be retained by GSK, and copies will be 
sent to the investigator to maintain as the investigator copy.  Subject initials will not 
be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
This study is designed to establish the PI3K-dependent alterations in immune cell 
mechanisms related to neutrophil function as detected by changes in mRNA 
transcriptomics in samples of induced sputum from patients admitted with an 
exacerbation of COPD. The primary comparison will be between  subjects treated with 
GSK2269557 in addition to standard of care, and subjects treated with placebo in 
addition to standard of care. In addition, treatment comparisons between subjects at 
baseline and subsequent time points will also be produced.
9.1.
Sample Size Considerations
The sample size for this study has been based on feasibility. The sample size of 30 
subjects completing the trial, with approximately 15 of which will receive GSK2269557 
and 15 will receive placebo, is expected to be sufficient to provide a meaningful estimate 
of the mRNA alterations within the lungs.
Previous studies with similar sample size populations have yielded significant fold-
changes (fold-change>1.5 and p<0.05) in immune cell mechanisms using the changes in 
mRNA transcriptomics.
 
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Study Name
Sample
Study Design
Number of Subjects
Number of Differential 
probesets FC = >= 1.5, 
Pval <= 0.05
Notes
PII115117 FTIH 
Healthy Smoker 
nebulised 
GSK2269557
Sputum
Sputum N=12 3-
way x-over 
placebo 400ug, 
6400ug 
12 (9 with all data 
points)
57 probesets change with 
both doses = 44 Genes
Gene changes relate predominantly 
to a down regulation of infection and 
inflammation responses.
Link to Haemophilus influenzae and 
Moraxella catarrhalis infection 
biology – Identified prior to 
knowledge of Activated PI3Kδ 
Syndrome phenotype
200114 Enabler 
GSK2269557 on ex-
vivo COPD Sputum 
and Blood
Sputum
Ex vivo Sputum 
incubated with 
GSK2269557 
sampled at 
6hrs (Sputum 
producers)
15 Subjects
490 probesets change vs 
vehicle control = 295 
genes (of which 43 are 
dysregulated in COPD 
disease vs Healthy 
comparison)
43 genes altered in COPD and 
positively modulated by PI3Kδi 
GSK2269557. Biological themes in 
signature: Pro-cell 
movement/migration  and cell 
viability, anti-apoptotic. Additionally 
link to B/T cell function. Signature 
supports GSK2269557 correction of 
neutrophil migration 
200114 Enabler 
GSK2269557 on ex-
vivo COPD Sputum 
and Blood
Blood
Ex vivo blood 
incubated with 
GSK2269557 
sampled at 
6hrs (Sputum 
15 Subjects
19 probesets change vs 
vehicle control = 15 genes 
Infection and inflammation 
associated genes
200114 Enabler 
GSK2269557 on ex-
vivo COPD Sputum 
and Blood
Blood
Ex vivo blood 
incubated with 
GSK2269557 
sampled at 
6h
(N
15 Subjects
30 probesets change vs 
vehicle control = 25 genes 
Infection and inflammation 
associated genes
9.1.1.
Sample Size Re-estimation or Adjustment
No sample size re-estimation will be performed in this study. 
9.2.
Data Analysis Considerations
9.2.1.
Analysis Populations
Population
Definition / Criteria
Analyses Evaluated
Screened
All subjects who were screened.

Study Population
All subject
All randomised subjects who receive at least 
one dose of the study treatment.
This population will be based on the 
treatment the subject actually received.

Study Population

Pharmacodynamics

Safety

Efficacy
Pharmacokinetic
Subjects in the ‘All subject’ population for 
whom a pharmacokinetic sample was 
obtained and analysed.

PK
9.2.2.
Interim Analysis
No interim analyses will be performed.
 
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9.3.
Key Elements of Analysis Plan
9.3.1.
Primary Analyses
To estimate differences in mRNA intensities within and between treatment groups, a 
repeated measures model will be fitted to the results of the analysis of each probe set at 
Day 12, Day 28 and Day 84 following a loge transformation of the data. The Day 1 
response will be fitted as a baseline covariate. A separate model will be fitted for each of 
the approximate 54000 probe sets.
Back transformed ratios versus screening along with 95% confidence intervals will be 
calculated for each treatment group and timepoint.  Additionally, baseline adjusted ratios 
of the change between active treatment and placebo will be calculated along with 95% 
confidence intervals.
Further details around the analysis of the mRNA data will be provided in the RAP.
9.3.2.
Secondary Analyses
All secondary analyses will be described in full prior to unblinding in the RAP.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Signed informed consent  to be obtained for each subject before participation in the 
study (and for amendments as applicable)
 
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
Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, or 
both.

Signed informed consent must be obtained for each subject prior to participation in 
the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, written 
approval of the clinical protocol should state that approval of optional assessments is 
being deferred and the study, with the exception of the optional assessments, can be 
initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will
serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and the 
regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
 
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relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective 
and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard Operating 
Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this study 
at any time for reasons including, but not limited to, safety or ethical issues or severe 
non-compliance. For multicenter studies, this can occur at one or more or at all sites.  

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by 
local regulations to be maintained elsewhere), in a safe and secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review in 
conjunction with assessment of the facility, supporting systems, and relevant site 
staff.  

Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, including 
re-generating a hard copy, if required.  Furthermore, the investigator must ensure 
there is an acceptable back-up of these reproductions and that an acceptable quality 
control process exists for making these reproductions.
 
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
GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by any 
institutional requirements or local laws or regulations, GSK standards/procedures, 
and/or institutional requirements. 

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of ownership 
of the records in the event the investigator is no longer associated with the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
The procedures and timing for public disclosure of the 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.
 
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11.
REFERENCES
De Backer J, Vos W, Vinchurkar S, Van Holsbeke C, Poli, G, Claes R et al. The Effect of 
Extrafine Beclometasone/Formoterol (BDP/F) on Lung Function, Dyspnea, 
Hyperinflation, and Airway Geometry in COPD Patients:  Novel Insight Using 
Fundtional Respiratory Imaging. Journal of Aerosol Medicine and Pulmonary Drug 
Delivery. 2014;27:1-12. 
De Backer LA, Vos WG, Salgado R, De Backer JW, Devoldr A, Verhulst SL et al. 
Functional imaging using computer methods to compare the effect of salbutamol and 
ipratropium bromide in patient-specific airway models of COPD. International Journal 
of COPD. 2011;6:637-646. 
De Backer Lieve A, Vos Wim, Van Holsbeke C, Vinchurkar S, De Backer W. The acute 
effect of budesonide/formoterol in COPD:  a multi-slice computed tomography and lung 
function study. Eur Respir J. 2012;40:298-305. 
GlaxoSmithKline Document Number 2012N141231_06: GSK2269557 Investigator's 
Brochure. Report Date 16-AUG-2016. 
Goldin J, Tashkin D, Kleerup E, Greaser MS, Haywood U, Sayre J et al. Comparative 
effects of hydrofluoroalkane and chloroflurocarbon beclomethasone dipropionate 
inhalation on small airways: Assessment with functional helical thin-section computed 
tomography. J Allergy Clin Immunol. 1999;104 #6:S258-S267. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D et al. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007(a):24. Table 3-2. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D et al. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007(b): 28. 
ICRP. 2007 Recommendation of the International Commission on Radiological 
Protection. ICRP Publication 103. 2007;37:2-4. 
Kim SR, Lee KS, Park HS, et al. HIF -1 alpha inhibition ameliorates an allergic airway 
disease via VEGF suppression in bronchial epithelium. Eur J Immunol. 2010;40 
(10):2858-69. 
Okkenhaug K, Aki K, Vanhaesebroeck B. Antigen receptor signalling:  A distincive role 
for the p110 isoform of PI3K. Trends in Immunuology. 2007;28:80-7. 
Sadhu C, Dick K, Tino WT, Staunton DE. Selective role of PI13K delta in neutrophil 
inflammatory responses. Biochem Biophys Res Commun. 2003 Sep 5;308 (4):764-9. 
Weisser SB, McLarren KW, Voglmaier B, et al. Alternative activation of macrophages 
by IL-4 requires SHIP degradation. Eur J Immunol. 2011;41(6):1742-53. 
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
AE
Adverse Event
ALT
Alanine aminotransferase
COPD
Chronic Obstructive Pulmonary Disease
CRF
Case Report Form
CT
Computed Tomography
CV
Cardiovascular
ECG
Electrocardiogram
FEV1
Forced Expiratory Volume in One Second
FRC
Functional Residual Capacity
FRI
Functional Respiratory Imaging
GCP
ICH Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GSK
GlaxoSmithKline
HRCT
High-Resolution Computed Tomography
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
PEF
Peak Expiratory Flow
PI3K
Phosphoinositide 3-Kinase Delta
PK
Pharmacokinetic
QTcF
QT interval corrected using the Fridericia's formula
RAP
Reporting and Analysis Plan
SAE
Serious Adverse Event
SRM
Study Reference Manual
TLC
Total Lung Capacity
ULN
Upper Limit of Normal
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
DISKUS
None
 
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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Phase II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase II liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete an
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with study 
treatment unless allowed per protocol and GSK 
Medical Governance approval is granted (refer 
to Appendix 2).

If restart/rechallenge not allowed per protocol 
or not granted, permanently discontinue study 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained 7 days after last 
dose5

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 
 
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treatment and may continue subject in the study 
for any protocol specified follow up assessments 
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-72 
hrs 

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline
form including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in subjects with definite or likely 
acetaminophen use in the preceding 
week [James, 2009]). NOTE: not 
required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN.. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, 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 subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
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 
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.)  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.
 
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Phase II liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject safety. 

Subject can continue study treatment 

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
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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12.3.
Appendix 3: Genetic Research
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and:

Response to medicine, including any treatment regimens under investigation in this 
study or any concomitant medicines;

COPD susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.

A 6 mL blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. A 
Blood sample is collected at the baseline visit, after the subject has been randomized 
and provided informed consent for genetic research. Instructions for collection and 
shipping of the genetic sample are described in the laboratory manual. The DNA 
from the blood sample may undergo quality control analyses to confirm the integrity 
of the sample. If there are concerns regarding the quality of the sample, then the 
sample may be destroyed. The blood sample is taken on a single occasion unless a
duplicate sample is required due to an inability to utilize the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
 
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the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA sample 
is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will continue 
to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
 
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reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
 
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12.4.
Appendix 4: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.4.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

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 medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

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 prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected 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 this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).
Events NOT meeting definition of an AE include:

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 subject’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 
subject’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
 
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convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
12.4.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject 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 hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject 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 out-patient setting.  Complications that occur during 
hospitalization are AEs.  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 disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g. sprained ankle) which may interfere 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 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 subject or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition.  These should also be 
considered serious.

Examples of such events are 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
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.4.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
 
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12.4.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’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 instance, all subject identifiers, with the exception of 
the subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
12.4.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
 
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Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence 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 natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of 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 when 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 prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject 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 the designated 
reporting time frames.
 
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12.4.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data 
collection tool

If the electronic system is unavailable for greater than 24 hours, the site will use 
the paper SAE data collection tool and fax it to the Medical Monitor.

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission 
of the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes 
to existing data

If a site receives a report of a new SAE from a study subject or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, the site can report this information on a paper SAE form or to the 
Medical Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
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12.5.
Appendix 5: Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who 
becomes pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 
2 weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, 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. 

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 4. 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 subject who becomes pregnant while participating will discontinue 
study medication
Pregnancy information on female partner of male study subjects

Investigator will attempt to collect pregnancy information on any female partner of 
a male study subject who becomes pregnant while participating in this study.  This 
applies only to subjects who are randomized to receive study medication. 

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate 
form and submit it to GSK within 2 weeks of learning of the partner’s pregnancy

Partner will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded to GSK. 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date.  Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for procedure.
 
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12.6.
Appendix 6: Country Specific Requirements
No country-specific requirements exist.
 
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12.7.
Appendix 7: Protocol Amendment Changes
Protocol Amendment #1 Changes
The amendment was created to remove the specific equations for the prediction of 
percent predicted from spirometry from the inclusion criteria (European Community of 
Coal and Steel and European Respiratory Society Global Lung Function Initiative 
reference equations (Quanjer 2012) in Section 7.7.2.  At screening it may not be possible
to identify which correction method was used, or modify the correction method used, at 
the time.  As a result it may not be valid to stipulate that lung function values be 
corrected using any particular method.  Both FEV1 and FVC measurements (which are 
not entry criteria for the study) collected during the study will be collected as absolute 
values (uncorrected), so that consistency will be obtained across all sites in the study, and 
percent predicted will be calculated using a standard approach in house at the end of the 
study.
List of specific changes:
Page 22, Inclusion Criteria (#2 – Type of Subject and Diagnosis Including Disease 
Severity) - Third Bullet.
PREVIOUS TEXT

The subject has a post-bronchodilator FEV1/FVC < 0.7 and FEV1 80 % of 
predicted. Predictions should be according to the European Community of Coal and 
Steel (ECCS) equations OR the European Respiratory Society Global Lung Function 
Initiative reference equations [Quanjer, 2012] and documented in the last 5 years.
REVISED TEXT

The subject has a post-bronchodilator FEV1/FVC < 0.7 and FEV1 80 % of
predicted documented in the last 5 years.
Page 40, Section 7.7.2 (FEV1 and FVC)
PREVIOUS TEXT
A triplicate FEV1 and FVC measurement will be taken at the clinic before dosing using
the site’s spirometer as soon as it is safe to do so.  Predicted values will be based upon the 
European Respiratory Society Global Lung Function Initiative reference equations
[Quanjer, 2012].
REVISED TEXT
A triplicate FEV1 and FVC measurement will be taken at the clinic before dosing using 
the site’s spirometer as soon as it is safe to do so.  These will be recorded as absolute 
values.  The best/highest result is recorded.
 
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Page 54 – References
PREVIOUS TEXT
De Backer J, Vos W, Vinchurkar S, Van Holsbeke C, Poli, G, Claes R et al. The Effect of 
Extrafine Beclometasone/Formoterol (BDP/F) on Lung Function, Dyspnea, 
Hyperinflation, and Airway Geometry in COPD Patients:  Novel Insight Using 
Fundtional Respiratory Imaging. Journal of Aerosol Medicine and Pulmonary Drug 
Delivery. 2014;27:1-12. 
De Backer LA, Vos WG, Salgado R, De Backer JW, Devoldr A, Verhulst SL et al. 
Functional imaging using computer methods to compare the effect of salbutamol and 
ipratropium bromide in patient-specific airway models of COPD. International Journal 
of COPD. 2011;6:637-646. 
De Backer Lieve A, Vos Wim, Van Holsbeke C, Vinchurkar S, De Backer W. The acute 
effect of budesonide/formoterol in COPD:  a multi-slice computed tomography and lung 
function study. Eur Respir J. 2012;40:298-305. 
GlaxoSmithKline Document Number 2012N141231_06: GSK2269557 Investigator's 
Brochure. Report Date 12-FEB-2015. 
Goldin J, Tashkin D, Kleerup E, Greaser MS, Haywood U, Sayre J et al. Comparative 
effects of hydrofluoroalkane and chloroflurocarbon beclomethasone dipropionate 
inhalation on small airways: Assessment with functional helical thin-section computed 
tomography. J Allergy Clin Immunol. 1999;104 #6:S258-S267. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D et al. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007(a):24. Table 3-2. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D et al. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007(b): 28. 
ICRP. 2007 Recommendation of the International Commission on Radiological 
Protection. ICRP Publication 103. 2007;37:2-4. 
Kim SR, Lee KS, Park HS, et al. HIF -1 alpha inhibition ameliorates an allergic airway 
disease via VEGF suppression in bronchial epithelium. Eur J Immunol. 2010;40 
(10):2858-69. 
Okkenhaug K, Aki K, Vanhaesebroeck B. Antigen receptor signalling:  A distincive role 
for the p110 isoform of PI3K. Trends in Immunuology. 2007;28:80-7. 
Quanjer P, Stanojevic S, Cole T, Baur X, Hall G, et al. Multi-ethnic reference values for 
spirometry for the 3-95-yr age range:  The global lung function 2012 equations. 
European Respiratory Journal. 2012;40(6):1324-1343. 
Sadhu C, Dick K, Tino WT, Staunton DE. Selective role of PI13K delta in neutrophil 
inflammatory responses. Biochem Biophys Res Commun. 2003 Sep 5;308 (4):764-9. 
 
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Weisser SB, McLarren KW, Voglmaier B, et al. Alternative activation of macrophages 
by IL-4 requires SHIP degradation. Eur J Immunol. 2011;41(6):1742-53. 
REVISED TEXT
De Backer J, Vos W, Vinchurkar S, Van Holsbeke C, Poli, G, Claes R et al. The Effect of 
Extrafine Beclometasone/Formoterol (BDP/F) on Lung Function, Dyspnea, 
Hyperinflation, and Airway Geometry in COPD Patients:  Novel Insight Using 
Fundtional Respiratory Imaging. Journal of Aerosol Medicine and Pulmonary Drug 
Delivery. 2014;27:1-12. 
De Backer LA, Vos WG, Salgado R, De Backer JW, Devoldr A, Verhulst SL et al. 
Functional imaging using computer methods to compare the effect of salbutamol and 
ipratropium bromide in patient-specific airway models of COPD. International Journal 
of COPD. 2011;6:637-646. 
De Backer Lieve A, Vos Wim, Van Holsbeke C, Vinchurkar S, De Backer W. The acute 
effect of budesonide/formoterol in COPD:  a multi-slice computed tomography and lung 
function study. Eur Respir J. 2012;40:298-305. 
GlaxoSmithKline Document Number 2012N141231_06: GSK2269557 Investigator's 
Brochure. Report Date 12-FEB-2015. 
Goldin J, Tashkin D, Kleerup E, Greaser MS, Haywood U, Sayre J et al. Comparative 
effects of hydrofluoroalkane and chloroflurocarbon beclomethasone dipropionate 
inhalation on small airways: Assessment with functional helical thin-section computed 
tomography. J Allergy Clin Immunol. 1999;104 #6:S258-S267. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D et al. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007(a):24. Table 3-2. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D et al. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007(b): 28. 
ICRP. 2007 Recommendation of the International Commission on Radiological 
Protection. ICRP Publication 103. 2007;37:2-4. 
Kim SR, Lee KS, Park HS, et al. HIF -1 alpha inhibition ameliorates an allergic airway 
disease via VEGF suppression in bronchial epithelium. Eur J Immunol. 2010;40 
(10):2858-69. 
Okkenhaug K, Aki K, Vanhaesebroeck B. Antigen receptor signalling:  A distincive role 
for the p110 isoform of PI3K. Trends in Immunuology. 2007;28:80-7. 
Sadhu C, Dick K, Tino WT, Staunton DE. Selective role of PI13K delta in neutrophil 
inflammatory responses. Biochem Biophys Res Commun. 2003 Sep 5;308 (4):764-9. 
Weisser SB, McLarren KW, Voglmaier B, et al. Alternative activation of macrophages 
by IL-4 requires SHIP degradation. Eur J Immunol. 2011;41(6):1742-53. 
 
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Protocol Amendment #2 Changes
This amendment was created to widen the Body Mass Index (BMI) range at the screening 
visit as the propose range from 16 – 35 kg/m2 would be appropriate for the COPD subject 
population. 
List of specific changes:
Page 22, Inclusion Criteria (#3 – Weight).
PREVIOUS TEXT

Body weight 45 kg and body mass index (BMI) within the range 18 – 32 kg/m2
(inclusive).
REVISED TEXT

Body weight 45 kg and body mass index (BMI) within the range 16 – 35 kg/m2
(inclusive).
 
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Protocol Amendment #3 Changes
This amendment was created to remove the photo toxicity from the protocol as a result of 
the updated Investigator Brochure, Version 7.0, August16, 2016.  It also contains minor 
administrative and clarification changes.
List of specific changes:
PREVIOUS TEXT
Section 4.6.1 (Table) – Risk assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Investigational Product (IP) [e.g., GSK2269557]
Bronchospasm
Mucosal irritancy
A general risk with Inhaled 
treatment
Detected in 13 week toxicology 
study in the dog
Subjects will be allowed to 
continue regular COPD 
treatments and have standard 
of care for treatment of their 
exacerbation. More severe 
patients will have their 
treatment started in hospital. 
Patients will be regularly 
monitored for AEs and a 
patient diary kept. Thus far this 
has not been seen in clinical 
studies.
Potential photosensitivity  
In the absorption spectrum for 
GSK2269557 there are peaks 
at the boundary of the 
ultraviolet (UV) light 
[UVA/UVB] region with a 
lambda max at 320 nm (molar 
extinction coefficient 
43800 L/Mol/cm), with smaller 
peaks at 305 nm and 332 nm.
Subjects will be advised to 
take UV protection measures 
(see Section 6.11).
Study Procedures
Radiation risk as part of HRCT 
scans
The maximum amount of 
radiation dose a patient 
undergoing all six scans will 
receive is approximately 
12mSv. Six low dose HRCT 
scans (one at TLC and FRC on 
Reduced tube voltage (100 
kV), and tube current are used.
Scanning time less than 5 s 
per scan.
Total radiation dose for a total 
of six CT scans will be 
 
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
screening, Day 12 and Day 28 
visits) at are required 
throughout the study for the 
functional imaging protocol
approximately 12mSv.
Final radiation dose will be 
dependent on the patient 
weight, with a range of 
between 1-2mSv per scan per 
patient. This radiation dose 
falls into the International 
Commission on Radiological 
Protections [ICRP, 2007]
category IIb (minor to 
intermediate risk).
The outcomes of this study will 
provide information which 
would produce advances in 
knowledge, leading to a 
potential health benefit in the 
future for patients in this target 
population. The CT may also 
provide information for the 
patients general clinical 
management
Sputum induction
Standard sputum induction 
techniques using hypertonic 
saline can result in 
bronchospasm and therefore 
could potentially induce 
bronchospasm in a patient or 
impact a pre-existing 
exacerbation.
For patients during an 
exacerbation and for sputum 
induction during the recovery 
period, including the day 28 
visit, patients will be pre-dosed 
with nebulised or inhaled beta-
2-agonist (or ipratropium 
bromide if beta-2-agonist 
intolerant). Sputum induction 
will only be carried out using 
Normal (0.9%) saline, which is 
also often used in patients 
clinically to facilitate sputum 
clearance.  
For the final sputum induction 
patients will be pre-dosed with 
nebulised or inhaled beta-2-
agonist (or ipratropium bromide 
if beta-2-agonist intolerant) and 
the induction carried out with 
0.9% saline initially and only 
then followed by hypertonic (3-
5%) if required, and, in the 
 
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
opinion of the Investigator,  it is 
considered safe to do so.
REVISED TEXT
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Investigational Product (IP) [e.g., GSK2269557]
Bronchospasm
Mucosal irritancy
A general risk with Inhaled 
treatment
Detected in 13 week toxicology 
study in the dog
Subjects will be allowed to 
continue regular COPD 
treatments and have standard 
of care for treatment of their 
exacerbation. More severe 
patients will have their 
treatment started in hospital. 
Patients will be regularly 
monitored for AEs and a 
patient diary kept. Thus far this 
has not been seen in clinical 
studies.
Study Procedures
Radiation risk as part of HRCT 
scans
The maximum amount of 
radiation dose a patient 
undergoing all six scans will 
receive is approximately 
12mSv. Six low dose HRCT 
scans (one at TLC and FRC on 
screening, Day 12 and Day 28 
visits) at are required 
throughout the study for the 
functional imaging protocol
Reduced tube voltage (100 
kV), and tube current are used.
Scanning time less than 5 s 
per scan.
Total radiation dose for a total 
of six CT scans will be 
approximately 12mSv.
Final radiation dose will be 
dependent on the patient 
weight, with a range of 
between 1-2mSv per scan per 
patient. This radiation dose 
falls into the International 
Commission on Radiological 
Protections [ICRP, 2007]
category IIb (minor to 
intermediate risk).
The outcomes of this study will 
 
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
provide information which 
would produce advances in 
knowledge, leading to a 
potential health benefit in the 
future for patients in this target 
population. The CT may also 
provide information for the 
patients general clinical 
management
Sputum induction
Standard sputum induction 
techniques using hypertonic 
saline can result in 
bronchospasm and therefore 
could potentially induce 
bronchospasm in a patient or 
impact a pre-existing 
exacerbation.
For patients during an 
exacerbation and for sputum 
induction during the recovery 
period, including the day 28 
visit, patients will be pre-dosed 
with nebulised or inhaled beta-
2-agonist (or ipratropium 
bromide if beta-2-agonist 
intolerant). Sputum induction 
will only be carried out using 
Normal (0.9%) saline, which is 
also often used in patients 
clinically to facilitate sputum 
clearance.  
For the final sputum induction 
patients will be pre-dosed with 
nebulised or inhaled beta-2-
agonist (or ipratropium bromide 
if beta-2-agonist intolerant) and 
the induction carried out with 
0.9% saline initially and only 
then followed by hypertonic (3-
5%) if required, and, in the 
opinion of the Investigator,  it is 
considered safe to do so.
PREVIOUS TEXT
Apply to ALL sections with reference to IB, [GlaxoSmithKline Document Number:
2012N141231_04].
 
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REVISED TEXT
Replace with:
IB, [GlaxoSmithKline Document Number: 2012N141231_06].
PREVIOUS TEXT
SECTION 5.4 – Withdrawal/Stopping Criteria
Subjects who are withdrawn from treatment will also be withdrawn from the study. 
If a higher than expected number of subjects prematurely discontinues the study, 
additional subjects may be randomised and assigned to the same treatment sequence, at 
the discretion of the Sponsor.  
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as soon 
as possible. 

The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 
telephone calls and if necessary a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
Subjects who are withdrawn should complete the assessments planned for the follow up 
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REVISED TEXT
Subjects who are withdrawn from treatment will also be withdrawn from the study. 
If a higher than expected number of subjects prematurely discontinues the study, 
additional subjects may be randomised and assigned to the same treatment sequence, at 
the discretion of the Sponsor.  
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as soon 
as possible. 

The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 
telephone calls and if necessary a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
Subjects who are withdrawn should complete all the assessments planned, if possible.  
Subjects who are withdrawn on a study clinic visit after randomization should complete 
all the safety related assessment for that visit which includes at minimum, vital sign, lab 
assessments (if deem necessary by the PI), AE/SAEs, concomitant medication(s) and 
ECG.   A Follow up Visit should be scheduled 7-14 days post last dose.
Subjects who are withdrawn in between study clinic visits should complete the 
unscheduled visit and complete all the safety related assessment at mininum which 
includes, vital sign, lab assessments (if deem necessary by the PI), AEs/SAEs, 
concomitant medication(s) and ECG.   A Follow up Visit should be scheduled 7-14 post 
last dose.
 
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PREVIOUS TEXT
SECTION 6.11 – Lifestyle and/or Dietary Restrictions

Subjects must not sunbathe or use a tanning device (e.g. sunbed or solarium) whilst 
taking the study medication and until at least 2 weeks after their last dose. Subjects 
are to be advised that they should cover exposed areas of skin (e.g. use sun hat, long 
sleeves) and use a broad spectrum UVA/UVB sunscreen (SPF ≥30) on exposed areas 
of skin when outdoors.

Subjects should refrain from consumption of Seville oranges, grapefruit or grapefruit 
juice, exotic citrus fruits or grapefruit hybrids from first dose till the end of the study.

Subjects should abstain from alcohol on the day when they visit the clinical unit and 
until their discharge on that day.

Subjects should refrain from smoking for at least 2 hours prior to each pulmonary 
function test conducted at the clinical unit/site.
REVISED TEXT

Subjects should refrain from consumption of Seville oranges, grapefruit or grapefruit 
juice, exotic citrus fruits or grapefruit hybrids from first dose till the end of the study.

Subjects should abstain from alcohol on the day when they visit the clinical unit and 
until their discharge on that day.

Subjects should refrain from smoking for at least 2 hours prior to each pulmonary 
function test conducted at the clinical unit/site.
PREVIOUS TEXT
SECTION 6.12.1 – Permitted Medications and Non-Drug Therapies
On entry to the study all treatment required for standard of care and additional medical 
problems is permitted to start and continue.
The subjects are allowed to continue their regular COPD treatments for the duration of 
the study. However, the subjects should refrain, if possible, from using relief 
bronchodilators for at least 4 hours prior to each spirometry conducted at the clinical unit, 
and HRCT scan assessment unless essential for clinical symptom relief. Otherwise free 
 
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use of reliever/rescue medication is allowed.  Rescue ventolin and aerochambers may be 
provided by GSK for this study.
All prior (up to 2 months prior to screening) and concomitant medications should be 
recorded in the subject’s CRF.
REVISED TEXT
On entry to the study all treatment required for standard of care and additional medical 
problems is permitted to start and continue.
The subjects are allowed to continue their regular COPD treatments for the duration of 
the study. However, the subjects should refrain, if possible, from using relief 
bronchodilators for at least 4 hours prior to each spirometry conducted at the clinical unit, 
and HRCT scan assessment unless essential for clinical symptom relief.  Otherwise free 
use of reliever/rescue medication is allowed.  Rescue ventolin and aerochambers may be 
provided by GSK for this study and in such case,subjects should be advise to discontinue 
their own ventolin and use the study ventolin and aerochamber provided for the duration 
of the study.
All prior (up to 2 months prior to screening) and concomitant medications should be 
recorded in the subject’s CRF.
 
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PREVIOUS TEXT
SECTION 7.2 – Time and Events Table (Treatment Period)
Procedure
Treatment Period 
Notes
Visit
1
21
3
4
5
6
Day
1
Within 48h 
/ discharge
12
28
56
84
Visit window
N/A
1 days
2 days
2 days
- 4 / +2 days
- 4 / +2 days
SAFETY ASSESSMENTS
AE/SAE collection and review
=========================================================
Concomitant medication review
=========================================================
Reliever usage
=========================================================
Brief physical exam, including weight
X2
X
X
X
X
Pre-dose
Laboratory assessments (include 
haematology and biochemistry)
X2
X
X
X
X
Pre-dose
12-lead ECG
X2
X
X
X
X
Pre-dose. Single assessment
Vital signs
X2
X
X
X
X
Pre-dose. Single assessment
Urine pregnancy test (only WCBP)
X
X
Before conducting the HRCT
STUDY TREATMENT
Randomisation
X
Study drug administration
=========================================================
Daily in the morning before breakfast, 
(with the exception of days when the 
subjects have a planned visit to the 
clinic. On those days, they will be 
dosed at the clinic).
Assessment of study treatment compliance
X
X
X
X
 
 
 
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Procedure
Treatment Period 
Notes
Visit
1
21
3
4
5
6
Day
1
Within 48h 
/ discharge
12
28
56
84
Visit window
N/A
1 days
2 days
2 days
- 4 / +2 days
- 4 / +2 days
EFFICACY ASSESSMENTS
HRCT (at TLC and FRC)
X
X
At any time on specified days. Includes 
electronic monitoring of breathing (if 
applicable).  The radiologist may review 
any of the scan(s) if they wish, but this 
is NOT required for the study.  A formal 
review is required at screening only by 
the radiologist.
FEV1  and FVC
X
X
X
X
X
X
In clinic only for all visits where 
possible.
PEF 
=========================================================
Daily before drug administration at 
home.  If subject in hospital, this may 
be collected using the handheld device 
provided prior to drug administration.
OTHER ASSESSMENTS
Blood sample for PK
X
X
X
X
X
Day 1:  5 min and 24 h post-dose. The 
24 h post-dose time-point is optional for 
subjects not hospitalised. Pre-dose at 
all other time-points.
Sputum induction3
X
X
X
Blood sample for mRNA analysis
X
X
X
Genetic sample (PGx)4
X
Collected at any time after 
randomisation
5.
On discharge if the subject was hospitalized. Within 48 hours of first dose administration if the subject was not hospitalised. See Section 4.2
6.
Assessments do not need to be completed if screening assessments conducted within 48 hours 
7.
Induced sputum collection may be repeated on several occasions if an adequate sample is not produced at the first attempt 
8.
Informed consent for optional sub-studies (e.g. ,genetics research) must be obtained before collecting a sample.  May be obtained at any visits.
 
 
 
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REVISED TEXT
Procedure
Treatment Period 
Notes
Visit
1
21
3
4
5
6
Day
1
Within 48h 
/ discharge
12
28
56
84
Visit window
N/A
1 days
2 days
2 days
- 4 / +2 days
- 4 / +2 days
SAFETY ASSESSMENTS
AE/SAE collection and review
=========================================================
Concomitant medication review
=========================================================
Reliever usage
=========================================================
Brief physical exam, including weight
X2
X
X
X
X
Pre-dose
Laboratory assessments (include 
haematology and biochemistry)
X2
X
X
X
X
Pre-dose
12-lead ECG
X2
X
X
X
X
Pre-dose. Single assessment
Vital signs
X2
X
X
X
X
Pre-dose. Single assessment
Urine pregnancy test (only WCBP)
X
X
Before conducting the HRCT
STUDY TREATMENT
Randomisation
X
Study drug administration
=========================================================
Daily in the morning before breakfast, 
(with the exception of days when the 
subjects have a planned visit to the 
clinic. On those days, they will be 
dosed at the clinic).
Assessment of study treatment compliance
X
X
X
X
Diary Card dispense and review at clinic
X
X
X
X
X
Refer to SRM for details.
 
 
 
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Procedure
Treatment Period 
Notes
Visit
1
21
3
4
5
6
Day
1
Within 48h 
/ discharge
12
28
56
84
Visit window
N/A
1 days
2 days
2 days
- 4 / +2 days
- 4 / +2 days
EFFICACY ASSESSMENTS
HRCT (at TLC and FRC)
X
X
At any time on specified days. Includes 
electronic monitoring of breathing (if 
applicable).  The radiologist may review 
any of the scan(s) if they wish, but this 
is NOT required for the study. A formal 
review is required at screening only by 
the radiologist.
FEV1  and FVC
X
X
X
X
X
X
In clinic only for all visits where 
possible.
PEF 
=========================================================
Daily before drug administration at 
home.  If subject in hospital, this may 
be collected using the handheld device 
provided prior to drug administration.
OTHER ASSESSMENTS
Blood sample for PK
X
X
X
X
X
Day 1:  5 min and 24 h post-dose. The 
24 h post-dose time-point is optional for 
subjects not hospitalised. Pre-dose at 
all other time-points.
Sputum induction3
X
X
X
Blood sample for mRNA analysis
X
X
X
Genetic sample (PGx)4
X
Collected at any time after 
randomisation
9.
On discharge if the subject was hospitalized. Within 48 hours of first dose administration if the subject was not hospitalised. See Section 4.2
10. Assessments do not need to be completed if screening assessments conducted within 48 hours 
11. Induced sputum collection may be repeated on several occasions if an adequate sample is not produced at the first attempt 
12. Informed consent for optional sub-studies (e.g. ,genetics research) must be obtained before collecting a sample.  May be obtained at any visits.
 
 
 
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PREVIOUS TEXT
SECTION 11 – References
GlaxoSmithKline Document Number 2012N141231_04: GSK2269557 Investigator's 
Brochure. Report Date 12-FEB-2015. 
REVISED TEXT
GlaxoSmithKline Document Number 2012N141231_06: GSK2269557 Investigator's 
Brochure. Report Date 16-AUG-2016. 
 
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A randomised, double-blind, placebo-controlled study to 
evaluate the safety, efficacy and changes in induced sputum and 
blood biomarkers following daily repeat doses of inhaled 
GSK2269557 for 12 weeks in adult subjects diagnosed with an 
acute exacerbation of Chronic Obstructive Pulmonary Disease 
(COPD).
Compound Number:
GSK2269557
Development Phase:
IIA
Effective Date:
26-JAN-2016
Protocol Amendment Number:  02
Author (s):
 (CCSE); 
 (CPSSO); 
 
(Respiratory CEDD); 
 (Exp Biology); 
 (Clinical Statistics); 
 (CPMS); 
 (GCSP).
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2014N218070_00
2015-JUN-04
Original
2014N218070_01
2015-NOV-30
Amendment No. 1
Remove the specific equations for the prediction of percent predicted from spirometry 
from the inclusion criteria and in Section 7.7.2.  At screening it may not be possible
to identify which correction method was used, or modify the correction method used, 
at the time. It therefore is not valid to stipulate that lung function values be corrected 
using any particular method.  Both FEV1 and FVC measurements (which are not 
entry criteria for the study) collected during the study will be collected as absolute 
values (uncorrected), so that consistency will be obtained across all sites in the study, 
and percent predicted will be calculated using a standard approach in house at the end 
of the study. 
2014N218070_02
2016-JAN-26
Amendment No. 2
Increase the body mass index (BMI) range in the inclusion criteria from 18-32 kg/m2
(inclusive) to 16- 35 kg/m2 (inclusive). The original BMI range from 18-32 kg/m2 is a 
typical range used in both healthy volunteer studies and general subject populations. The 
revised range is more appropriate for a COPD patient population.
 
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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information:
Role
Name
Day Time Phone 
Number and email 
address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site Address
Primary 
Medical 
Monitor
Discovery 
Medicine 
Respiratory 
CEDD 
GlaxoSmithKline 
Gumnnels Wood 
Rd. 
Stevenage, 
Herts, 
SG1 2NY
Secondary 
Medical 
Monitor
Discovery 
Medicine 
Respiratory 
CEDD 
GlaxoSmithKline 
Gumnnels Wood 
Rd. 
Stevenage, 
Herts, 
SG1 2NY
SAE contact  
information 
Medical 
monitor as 
above
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
 
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PROTOCOL AGREEMENT PAGE
For protocol 201928
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
 
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 201928........................................................9
2.
INTRODUCTION....................................................................................................12
2.1.
Study Rationale ..........................................................................................12
2.2.
Brief Background ........................................................................................12
2.2.1.
Use of mRNA transcriptomics by Affymetrix.................................14
2.2.2.
Use of HRCT Endpoints to characterise Lung Function ...............14
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................15
4.
STUDY DESIGN ....................................................................................................16
4.1.
Overall Design ............................................................................................16
4.2.
Treatment Arms and Duration.....................................................................16
4.3.
Type and Number of Subjects.....................................................................17
4.4.
Design Justification.....................................................................................17
4.5.
Dose Justification........................................................................................18
4.6.
Benefit:Risk Assessment ............................................................................18
4.6.1.
Risk Assessment .........................................................................19
4.6.2.
Benefit Assessment.....................................................................20
4.6.3.
Overall Benefit:Risk Conclusion...................................................21
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............21
5.1.
Inclusion Criteria.........................................................................................21
5.2.
Exclusion Criteria........................................................................................24
5.3.
Screening/Baseline/Run-in Failures............................................................26
5.4.
Withdrawal/Stopping Criteria.......................................................................26
5.4.1.
Liver Chemistry Stopping Criteria ................................................27
5.4.1.1.
Study Treatment Restart or Re-challenge...................27
5.4.2.
QTc Stopping Criteria ..................................................................28
5.4.3.
Other Stopping Safety Criteria .....................................................28
5.5.
Subject and Study Completion....................................................................28
6.
STUDY TREATMENT ............................................................................................29
6.1.
Investigational Product and Other Study Treatment....................................29
6.2.
Treatment Assignment................................................................................29
6.3.
Planned Dose Adjustments.........................................................................29
6.4.
Subject Specific Dose Adjustment Criteria..................................................30
6.5.
Blinding.......................................................................................................30
6.6.
Packaging and Labeling..............................................................................30
6.7.
Preparation/Handling/Storage/Accountability..............................................31
6.8.
Compliance with Study Treatment Administration.......................................31
6.9.
Treatment of Study Treatment Overdose....................................................32
6.10.
Treatment after the End of the Study ..........................................................32
6.11.
Lifestyle and/or Dietary Restrictions............................................................32
6.12.
Concomitant Medications and Non-Drug Therapies....................................33
6.12.1.
Permitted Medications and Non-Drug Therapies..........................33
6.12.2.
Prohibited Medications and Non-Drug Therapies.........................33
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................33
 
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7.1.
Time and Events Table (Screening and Follow Up Visits)...........................34
7.2.
Time and Events Table (Treatment Period) ................................................36
7.3.
Screening and Critical Baseline Assessments ............................................38
7.4.
Biomarker(s)/Pharmacodynamic Markers ...................................................38
7.4.1.
Pharmacodynamic Biomarkers in Sputum ...................................38
7.4.2.
mRNA in blood ............................................................................38
7.5.
Patient diary................................................................................................38
7.6.
Genetics .....................................................................................................39
7.7.
Efficacy.......................................................................................................39
7.7.1.
Functional Respiratory Imaging ...................................................39
7.7.2.
FEV1 and FVC.............................................................................39
7.7.3.
Peak Expiratory Flow PEF ...........................................................39
7.8.
Safety .........................................................................................................39
7.8.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........40
7.8.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................40
7.8.1.2.
Method of Detecting AEs and SAEs ...........................40
7.8.1.3.
Follow-up of AEs and SAEs........................................41
7.8.1.4.
Cardiovascular and Death Events ..............................41
7.8.1.5.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................41
7.8.1.6.
Regulatory Reporting Requirements for SAEs............41
7.8.2.
Pregnancy ...................................................................................42
7.8.3.
Physical Exams ...........................................................................42
7.8.4.
Vital Signs....................................................................................42
7.8.5.
Electrocardiogram (ECG).............................................................42
7.8.6.
Clinical Safety Laboratory Assessments ......................................43
7.9.
Pharmacokinetics .......................................................................................44
7.9.1.
Blood Sample Collection..............................................................44
7.9.2.
Sample Analysis ..........................................................................44
8.
DATA MANAGEMENT ...........................................................................................45
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................45
9.1.
Sample Size Considerations.......................................................................45
9.1.1.
Sample Size Re-estimation or Adjustment...................................46
9.2.
Data Analysis Considerations .....................................................................46
9.2.1.
Analysis Populations....................................................................46
9.2.2.
Interim Analysis ...........................................................................46
9.3.
Key Elements of Analysis Plan ...................................................................47
9.3.1.
Primary Analyses.........................................................................47
9.3.2.
Secondary Analyses ....................................................................47
10. STUDY GOVERNANCE CONSIDERATIONS........................................................47
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............47
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................47
10.3.
Quality Control (Study Monitoring) ..............................................................48
10.4.
Quality Assurance.......................................................................................48
10.5.
Study and Site Closure ...............................................................................49
10.6.
Records Retention......................................................................................49
 
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10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................50
11. REFERENCES.......................................................................................................51
12. APPENDICES........................................................................................................52
12.1.
Appendix 1: Abbreviations and Trademarks................................................52
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................53
12.3.
Appendix 3: Genetic Research ...................................................................56
12.4.
Appendix 4: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................59
12.4.1.
Definition of Adverse Events........................................................59
12.4.2.
Definition of Serious Adverse Events...........................................60
12.4.3.
Definition of Cardiovascular Events .............................................61
12.4.4.
Recording of AEs and SAEs ........................................................62
12.4.5.
Evaluating AEs and SAEs............................................................62
12.4.6.
Reporting of SAEs to GSK...........................................................64
12.5.
Appendix 5: Collection of Pregnancy Information........................................65
12.6.
Appendix 6: Country Specific Requirements...............................................66
12.7.
Appendix 7: Protocol Amendment Changes................................................67
 
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1.
PROTOCOL SYNOPSIS FOR STUDY 201928
Rationale
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To establish the PI3K-dependent 
changes in previously identified immune 
cell mechanisms specifically related to 
neutrophil function using mRNA in 
sputum from patients with an 
exacerbation of COPD, with or without 
treatment with GSK2269557.

Alterations in previously identified
immune cell mechanisms specifically 
related to neutrophil function as 
determined by changes in mRNA
transcriptomics in induced sputum after 
12, 28 and 84 days of treatment.
Secondary

To evaluate the effect of once daily 
repeat inhaled doses of GSK2269557 on 
lung parameters derived from HRCT 
scans in subjects with acute 
exacerbation of COPD, compared to 
placebo.

Change from baseline in siVaw, iVaw, 
iRaw, siRAW, total lung capacity, lung 
lobar volumes, trachea length and 
diameter at FRC and TLC after 12 days 
of treatment and after 28 days of 
treatment.

To assess the safety and tolerability of 
once daily repeat inhaled doses of 
GSK2269557 administered to subjects 
with acute exacerbation of COPD, 
compared to placebo.

Adverse events 

Haematology, clinical chemistry 

Vital signs

12-lead ECG

To evaluate the plasma PK of once daily 
repeat inhaled doses of GSK2269557 
administered to subjects with acute 
exacerbation of COPD.

Day 1 plasma Cmax and trough (24 
hours) post dose for inpatients

Trough concentration after 12 days, 28 
days, 56 days and 84 days of treatment.

To evaluate the effect of once daily 
repeat inhaled doses of GSK2269557 on 
lung function parameters in subjects with 
acute exacerbation of COPD compared 
to placebo.

PEF

Reliever usage

FEV1 and  FVC at clinic prior to sputum 
induction
Exploratory

To establish any other PI3K-dependent 
changes in mRNA in sputum or blood 
from patients with an exacerbation of 
COPD, with or without treatment with 
GSK2269557.

To explore the pharmacodynamic effects 
in induced sputum of once daily repeat 

Alterations in immune cell mechanisms 
as determined by changes in mRNA 
transcriptomics in induced sputum or 
blood after 12, 28 and 84 days of 
treatment.

Endpoints may include, but not limited to 
 
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Objectives
Endpoints
inhaled doses of GSK2269557 
administered to subjects with acute 
exacerbation of COPD, compared to 
placebo.
cytokines (IL-6, IL-8, TNF), microbiome 
(by 16SrRNA), bacterial qPCR, viral 
qPCR.

To assess the changes in other CT 
parameters such as low attenuation 
score after once daily repeat inhaled 
doses of GSK2269557 administered to 
subjects with acute exacerbation of 
COPD, compared to placebo.

Change from baseline for other CT 
parameters including low attenuation 
score after 12 days of treatment and 
after 28 days of treatment
Overall Design
This is a randomised, double-blind, placebo-controlled, parallel-group study.  All subjects 
will continue on their usual Chronic Obstructive Pulmonary Disease (COPD) medications 
throughout the entire duration of the study regardless of treatment arm assignment.  
Subjects will be on standard of care treatment (antibiotic and corticosteroids) upon 
diagnosis of a COPD exacerbation.
SCR
Signature 
ICF
Day 1
Randomisation / 
First dose GSK2269557
Day 12
(+/- 2 days) 
HRCT
Day 28
(+/- 2 days)
HRCT
Day 56
(-4 / + 2 days)
Safety visit
Day 84
(-4 / + 2 days)
End treatment
FU
Baseline
HRCT
Within 48h / discharge
Baseline lung function
Treatment Arms and Duration
Subjects will be required to participate in the following:
Screening: Following diagnosis during outpatient assessment by a Respirologist, 
Emergency Department visit or acute admission to hospital, and up to 3 days before start 
of study treatment. During this time:

The start of the standard of care (to include both antibiotics and corticosteroids) is 
expected to start shortly after diagnosis, though it is allowed to have already been 
started before the formal diagnosis of COPD exacerbation is made. 
 
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
The High-Resolution Computed Tomography (HRCT) scan should be conducted at 
the earliest opportunity after obtaining Informed Consent from the subject and within 
48 h of diagnosis by a Respirologist or physician with respiratory experience.  

Randomisation and first dose administration should take place as soon as possible 
following HRCT scan assessment has been performed and no later than 24h after 
completing the HRCT scan.
Treatment period:  Once daily study treatment administration will start on Day 1 (visit 1). 

For subjects who were hospitalized: 
o
If discharge takes place before Day 10, the subject must complete the 
assessments planned for visit 2 on discharge and must then visit the unit 
on Day 12 (2 days) (visit 3).
o
If discharge takes place between Day 10 and Day 14 (inclusive), the 
assessments planned for visit 2 and visit 3 may be completed on the day of 
discharge.
o
If discharge takes place from Day 15 (inclusive), the assessments planned 
for visit 2 and visit 3 should be completed as soon as it is safe for the 
patient to do so.

For subjects who were not hospitalized: the subject must complete the 
assessments planned for visit 2 within 48 hours of start of treatment, and must 
then visit the unit on Day 12 (2 days) to complete the assessments planned for 
visit 3.
Subjects will then dose at home until Day 84 (– 4 / + 2 days), with the exception of the 
days when subjects come to the clinic. On those days, they will dose at the clinic. On Day 
12 (± 2 days) (unless visit completed on discharge), Day 28 (± 2 days), Day 56 (– 4 / + 2 
days) and Day 84 (– 4 / + 2 days) subjects will return on an outpatient basis to complete 
the assessments described in the Time & Event table. Subjects will be discharged once all 
assessments have been performed and there are no safety concerns.
Follow up: 7-14 days after last dose.
The total duration of the study is 13-14 weeks including the screening visit.
Type and Number of Subjects
Approximately 35 subjects with an acute exacerbation of COPD will be randomized such 
that approximately 15 subjects on active and 15 subjects on placebo provide sputum at all 
the scheduled time points and complete the study.  If a higher than expected numbers of 
subjects prematurely discontinue the study, or fail to produce sufficient sputum post 
randomisation additional subjects may be randomised at the discretion of the sponsor.
 
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Analysis
To estimate differences in mRNA intensities within and between treatment groups, a 
repeated measures model will be fitted to the results of the analysis of each probe set at 
Day 12, Day 28 and Day 84 following a loge transformation of the data. The Day 1 
response will be fitted as a baseline covariate. A separate model will be fitted for each of 
the approximate 54000 probe sets.
Back transformed ratios versus screening along with 95% confidence intervals will be 
calculated for each treatment group and timepoint.  Additionally, baseline adjusted ratios 
of the change between active treatment and placebo will be calculated along with 95% 
confidence intervals.
2.
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.
2.1.
Study Rationale
The purpose of this study is to evaluate specific alterations in immune cell mechanisms
related to neutrophil function as detected by PI3K-dependent changes in mRNA 
extracted from induced sputum in patients experiencing an exacerbation of COPD. In 
addition this study will also further evaluate the plasma PK and assess the safety of 
GSK2269557 administered to patients diagnosed with an acute exacerbation of Chronic 
Obstructive Pulmonary Disease (COPD). The efficacy of treatment with GSK2269557 
will also be measured using functional respiratory imaging (FRI) and spirometry. 
This study will also explore the pharmacodynamic effects of once daily repeat doses of 
inhaled GSK2269557 on cytokines, mediators and microbiome in induced sputum 
samples. These will be obtained from subjects at entry, during their exacerbation, and at 
additional time points over the 12 week treatment period.  To understand patient efficacy, 
at entry, Day 12 and Day28 the sputum biomarker data will be correlated with computed 
tomography (CT).   
2.2.
Brief Background
PI3Kis a member of the Class IA family of phosphoinositides 3-kinases (PI3Ks) that 
convert the membrane phospholipid phosphatidylinositol 4,5-biphosphate (PIP2) into 
phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 is a second messenger in many 
cellular processes including cell growth, differentiation and migration. PI3Khas 
specific roles in mediating antigen receptor and cytokine signalling in T-cells, mast cells 
and B-cells [Okkenhaug, 2007] and roles in neutrophil chemotaxis and activation [Sadhu, 
2003].  A PI3Kinhibitor has the potential to inhibit major cell types responsible for the
inflammation associated with both COPD and asthma.
 
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In COPD, tobacco smoke or other irritants activate epithelial cells and macrophages to 
release inflammatory mediators such as chemokines that attract neutrophils and T cells to 
the lungs. PI3Kis thought to play a role in a number of epithelial responses relevant for 
the development of COPD.  Therefore a PI3Kinhibitor may be able to suppress a 
number of these processes [Kim, 2010].  A greater proportion of macrophages appear to
be alternatively activated in COPD and their ability to phagocytose infective pathogens is 
reduced as a result of this alternative activation.  PI3Kis one of the mediators involved 
in determining this alternative phenotype in macrophages and therefore it is proposed that 
inhibition of PI3Kmight rebalance macrophage activation towards a classic phagocytic
phenotype [Weisser, 2011] facilitating clearance of bacteria, a major cause of
exacerbation in COPD.  The neutrophil and T cell are the two major inflammatory cell 
types involved in the pathogenesis of COPD and both are targeted by PI3Kinhibitors. 
GSK2269557 has demonstrated the ability to protect against and control bacterial 
infections in preclinical rodent models. This is coupled with recent observations that 
PI3Kinhibition leads to a correction in vitro of aberrant neutrophil chemotaxis 
directionality in the blood of COPD patients. Furthermore, a human point mutation which 
results in a constitutively activated version of PI3Khas recently been characterised 
where the majority of affected patients have recurrent lung infections with the same 
bacterial species which are seen in COPD patients and are known to drive exacerbations. 
Collectively these data suggest that repeat dosing with GSK2269557 could potentially
reduce the impact of an acute exacerbation, or prevent the onset of a secondary bacterial 
exacerbation or recurrent exacerbation.
Proinflammatory cytokines were reduced by GSK2269557, both in preclinical rodent 
bacterial models, and COPD patient samples treated in vitro and in the study setting 
(PII115119).
GSK2269557 has been administered as single and repeat doses to healthy subjects as 
nebulized solution in the FTIH study PII115117 up to a dose of 6400 μg per day for 7 
days. GSK2269557 has also been administered as single and repeat doses to healthy 
smokers as a dry powder formulation in study PII116617 up to a dose of 3000 μg as 
single dose and 2000 μg per day for 14 days.  GSK2269557 has been well tolerated 
across the range of doses used.  There is also an ongoing study (Study PII115119, non-
reported) where a total daily dose of up to 2000 µg of GSK2269557 is being administered 
to stable COPD patients via a dry powder inhaler for 14 days in a two part study.  Part A 
of this study has completed and Part B will characterise the steady-state (exposure) dose 
response following repeat inhaled doses of up to 2000µg for the same treatment duration.  
There is also an on-going larger clinical study PII116678 which is almost identical in 
design to 201928 using 1000 µg of GSK2269557 per day administered via a Diskus dry 
powder inhaler to patients diagnosed with an acute exacerbation of COPD.  For 
simplicity study PII116678 does not capture induced sputum hence cannot analyse any 
changes in mRNA. The primary objective of the current study is to capture induced 
sputum to enable the mRNA analysis on a smaller cohort.   
More information about the non-clinical and clinical studies is available in the 
GSK2269557 Investigator’s Brochure (IB) GlaxoSmithKline Document Number
2012N141231_04.
 
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2.2.1.
Use of mRNA transcriptomics by Affymetrix
Analysis of changes in mRNA can be used to demonstrate alterations in biochemical 
pathways at the gene transcription level. This can be used to better understand the 
consequences of drug intervention on disease pathophysiology, and ultimately predict 
alterations which could translate to a positive clinical benefit for patients.  Messenger 
RNA can be extracted from a variety of biological samples (including induced sputum 
and blood) taken from patients before and after drug dosing to show the impact a drug is 
having. 
The advantage of using Affymetrix is the broad (~50k) gene set covered using this 
technology enabling great depth in exploring the biological consequences of drug 
intervention. This technology has been used in previous preclinical and clinical studies 
using GSK2269557 generating a fingerprint of PI3Kinhibition in disease.  Importantly 
these approaches allow areas of complex PI3K-dependent immune cell mechanisms and 
pathophysiology, specifically related to neutrophil function to be explored which are not 
easily quantified using other techniques.
2.2.2.
Use of HRCT Endpoints to characterise Lung Function
High-resolution computed tomography (HRCT) scans provide a highly detailed insight 
into the structure and architecture of the respiratory system. A clear distinction can be 
made between the lung parenchyma, the intraluminal air and alveolar spaces up to the 
level of the smaller airways with a diameter of 1-2mm. To model dynamic information, 
low dose HRCT scans can be taken at two lung volumes: after deep inhalation (total lung 
capacity or TLC) and after normal expiration (functional residual capacity or FRC). The 
patient’s breathing is monitored in real time during the scans to ensure the correct lung 
levels are scanned.  Due to the natural contrast between the intraluminal air and the 
surrounding tissue, it is possible to attain a significant reduction in radiation dose (1-2 
mSv per scan) compared to standard CT protocols (>4 mSv per scan) by reducing the 
tube current and the voltage.  Depending on the patient’s weight, a 6- to 10-fold reduction 
can be obtained per scan without losing image quality. As a comparison, in the USA, the 
average annual background radiation exposure is 6.2 mSv and a transatlantic flight results 
in 0.07 mSv exposure.
The high resolution images allow for a three dimensional reconstruction of the airway 
tree and vasculature by applying segmentation principles.  These three dimensional 
models can be used to measure airway dimensions as well as potentially allowing the 
phenotyping of patients by disease severity.  The three dimensional computer 
reconstructions can be used for fluid dynamic modelling.  This method is used to 
simulate flow through these airway models and determine the typical flow characteristics 
such as local pressure drops, velocities and resistance.  It can also be used to predict 
particle deposition in the airways of these patients when using inhaled drug products.
This method consisting of 2 low dose HRCT scans at several time points has previously 
been used successfully in clinical trials involving COPD patients [De Backer, 2011; De 
Backer, 2012; De Backer, 2014; Goldin, 1999]. 
 
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3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To establish the PI3K-dependent 
changes in previously identified immune 
cell mechanisms specifically related to 
neutrophil function using mRNA in 
sputum from patients with an 
exacerbation of COPD, with or without 
treatment with GSK2269557.

Alterations in previously identified
immune cell mechanisms specifically 
related to neutrophil function as 
determined by changes in mRNA
transcriptomics in induced sputum after 
12, 28 and 84 days of treatment.
Secondary

To evaluate the effect of once daily 
repeat inhaled doses of GSK2269557 on 
lung parameters derived from HRCT 
scans in subjects with acute 
exacerbation of COPD, compared to 
placebo

Change from baseline in siVaw, iVaw, 
iRaw, siRAW, total lung capacity, lung 
lobar volumes, trachea length and 
diameter at FRC and TLC after 12 days 
of treatment and after 28 days of 
treatment.

To assess the safety and tolerability of 
once daily repeat inhaled doses of 
GSK2269557 administered to subjects 
with acute exacerbation of COPD, 
compared to placebo.

Adverse events 

Hematology, clinical chemistry 

Vital signs

12-lead ECG

To evaluate the plasma PK of once daily 
repeat inhaled doses of GSK2269557 
administered to subjects with acute 
exacerbation of COPD

Day 1 plasma Cmax and trough (24 
hours) post dose for inpatients

Trough concentration after 12 days, 28 
days, 56 days and 84 days of treatment.

To evaluate the effect of once daily 
repeat inhaled doses of GSK2269557 on 
lung function parameters in subjects with 
acute exacerbation of COPD, compared 
to placebo

PEF, Reliever usage.

FEV1 and FVC at clinic prior to sputum 
induction.
Exploratory 

To establish any other PI3K-dependent 
changes in mRNA in sputum or blood 
from patients with an exacerbation of 
COPD, with or without treatment with 
GSK2269557.

To explore the pharmacodynamic effects 
in induced sputum of once daily repeat 
inhaled doses of GSK2269557 
administered to subjects with acute 
exacerbation of COPD, compared to 

Alterations in immune cell mechanisms 
as determined by changes in mRNA 
transcriptomics in induced sputum or 
blood after 12, 28 and 84 days of 
treatment.

Endpoints may include, but not limited to 
cytokines (IL-6, IL-8, TNF), microbiome 
(by 16SrRNA), bacterial qPCR, viral 
qPCR.
 
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Objectives
Endpoints
placebo.

To assess the changes in other CT 
parameters such as low attenuation 
score after once daily repeat inhaled 
doses of GSK2269557 administered to 
subjects with acute exacerbation of 
COPD, compared to placebo.

Change from baseline for other CT 
parameters including low attenuation 
score after 12 days of treatment and 
after 28 days of treatment.
4.
STUDY DESIGN
4.1.
Overall Design
This is a randomised, double-blind, placebo-controlled, parallel-group study.  All subjects 
will continue on their usual COPD medications throughout the entire duration of the 
study regardless of treatment arm assignment.  Subjects will be on standard of care 
treatment (antibiotic and corticosteroids) upon diagnosis of a COPD exacerbation.
SCR
Signature 
ICF
Day 1
Randomisation / 
First dose GSK2269557
Day 12
(+/- 2 days) 
HRCT
Day 28
(+/- 2 days)
HRCT
Day 56
(-4 / + 2 days)
Safety visit
Day 84
(-4 / + 2 days)
End treatment
FU
Baseline
HRCT
Within 48h / discharge
Baseline lung function
4.2.
Treatment Arms and Duration
Subjects will be required to participate in the following:
Screening: Following diagnosis during outpatient assessment by a Respirologist, 
Emergency Department visit or acute admission to hospital, and up to 3 days before start 
of study treatment. During this time:

The start of the standard of care (to include both antibiotics and corticosteroids) is 
expected to start shortly after diagnosis, though it is allowed to have already been 
started before the formal diagnosis of COPD exacerbation is made. 

The HRCT scan should be conducted at the earliest opportunity after obtaining 
Informed Consent from the subject and within 48 h of diagnosis by a Respirologist or 
physician with respiratory experience. 
 
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
Randomisation and first dose administration should take place as soon as possible 
following HRCT scan assessment has been performed and no later than 24h after 
completing the HRCT scan.
Treatment period:  Once daily study treatment administration will start on Day 1 (visit 1). 

For subjects who were hospitalized: 
o
If discharge takes place before Day 10, the subject must complete the 
assessments planned for visit 2 on discharge and must then visit the unit 
on Day 12 (2 days) (visit 3).
o
If discharge takes place between Day 10 and Day 14 (inclusive), the 
assessments planned for visit 2 and visit 3 may be completed on the day of 
discharge.
o
If discharge takes place from Day 15 (inclusive), the assessments planned 
for visit 2 and visit 3 should be completed as soon as it is safe for the 
patient to do so.

For subjects who were not hospitalized: the subject must complete the 
assessments planned for visit 2 within 48 hours of start of treatment, and must 
then visit the unit on Day 12 (2 days) to complete the assessments planned for 
visit 3.
Subjects will then dose at home until Day 84 (– 4 / + 2 days), with the exception of the 
days when subjects come to the clinic. On those days, they will dose at the clinic. On Day 
12 (± 2 days) (unless visit completed on discharge), Day 28 (± 2 days), Day 56 (– 4 / + 2 
days) and Day 84 (– 4 / + 2 days) subjects will return on an outpatient basis to complete 
the assessments described in the Time & Event table (Section 7.1). Subjects will be 
discharged once all assessments have been performed and there are no safety concerns.
Follow up: 7 to 14 days after last dose.
The total duration of the study is 13-14 weeks including the screening visit.
4.3.
Type and Number of Subjects
Approximately 35 subjects with an acute exacerbation of COPD will be randomized such 
that approximately 15 subjects on active and 15 subjects on placebo provide sputum at all 
the scheduled time points and complete the study.   If a higher than expected number of 
subjects prematurely discontinue the study, or fail to produce sufficient sputum post 
randomisation additional subjects may be randomised at the discretion of the sponsor.
4.4.
Design Justification
This study will include a placebo control to allow for a valid evaluation of the 
pharmacodynamic endpoints and adverse events attributable to treatment versus those 
 
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independent of treatment. Subjects will also receive standard of care for their 
exacerbation and throughout the study.
4.5.
Dose Justification
The dose chosen for this study is 1000 µg of GSK2269557 per day administered via a dry 
powder inhaler for a duration of 84 days (– 4 / + 2 days). This dose has been selected 
based on previous safety and tolerability data in man (healthy subjects and COPD 
subjects) as well as demonstration of target (PI3K) inhibition by observed changes in 
biomarkers. Together with an additional study to be run in parallel (PII116678), this dose 
of GSK2269557 is being dosed to subjects in PII116678 with an exacerbation of COPD,
so it will be assumed for exposure predictions, unless otherwise stated, that these subjects 
will have a similar lung deposition, distribution and plasma exposure to that of the 
healthy volunteers. However it is accepted that these types of subjects may have reduced 
airway conductance and hence likely reduced deposition. This can be appropriately 
defined in this study based on the actual plasma exposures achieved. 
Twice this dose level (2000 µg) using the same formulation has previously been given 
once daily to healthy male smokers for 14 days (study PII116617). There is also an 
ongoing study where a total daily dose of 1000 µg of GSK2269557 is administered to 
stable COPD subjects via a dry powder inhaler for 14 days (study PII115119) which at 
the time of writing of this protocol had successfully dosed 21 subjects on active treatment 
and collected pharmacokinetics (PK) samples for analysis out to 14 days.
The target effect compartment for PI3Kinhibition is the intracellular compartment of 
the immune cells resident in the lung tissue and lumen.  GSK2269557 has a high potency 
and selectivity at the PI3Kenzyme (Ki value 0.1 ng/mL) which translates into an IC50 in 
a more complex system (PHA stimulated lung tissue) of approximately 120 ng/mL (or 
2.5 ng/mL free unbound drug).  Based on the measured steady-state cellular 
concentration of GSK2269557 collected at trough (24 h) from the lungs of healthy 
smokers at 2000 µg DPI (450 ng/mL) in the clinical study it is expected that at 1000 µg 
(225 ng/mL), concentrations will be sufficient and PI3Kinhibition maintained in the 
lung at 90% inhibition for 24 h. 
Target PI3Kinhibition is based on a wide range of pharmacology experiments.  Details 
of these as well as the pharmacokinetics and safety data can be found in the IB, 
[GlaxoSmithKline Document Number: 2012N141231_04].
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK2269557 can be found in the IB [GlaxoSmithKline Document Number 
2012N141231_04]. The following section outlines the risk assessment and mitigation 
strategy for this protocol:  
 
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4.6.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Investigational Product (IP) [e.g., GSK2269557]
Bronchospasm
Mucosal irritancy
A general risk with Inhaled 
treatment
Detected in 13 week toxicology 
study in the dog
Subjects will be allowed to 
continue regular COPD 
treatments and have standard 
of care for treatment of their 
exacerbation. More severe 
patients will have their 
treatment started in hospital. 
Patients will be regularly 
monitored for AEs and a 
patient diary kept. Thus far this 
has not been seen in clinical 
studies.
Potential photosensitivity  
In the absorption spectrum for 
GSK2269557 there are peaks 
at the boundary of the 
ultraviolet (UV) light 
[UVA/UVB] region with a 
lambda max at 320 nm (molar 
extinction coefficient 
43800 L/Mol/cm), with smaller 
peaks at 305 nm and 332 nm.
Subjects will be advised to 
take UV protection measures 
(see Section 6.11).
Study Procedures
Radiation risk as part of HRCT 
scans
The maximum amount of 
radiation dose a patient 
undergoing all six scans will 
receive is approximately 
12mSv. Six low dose HRCT 
scans (one at TLC and FRC on 
screening, Day 12 and Day 28 
visits) at are required 
throughout the study for the 
functional imaging protocol
Reduced tube voltage (100 
kV), and tube current are used.
Scanning time less than 5 s 
per scan.
Total radiation dose for a total 
of six CT scans will be 
approximately 12mSv.
Final radiation dose will be 
dependent on the patient 
weight, with a range of
between 1-2mSv per scan per 
patient. This radiation dose 
falls into the International 
Commission on Radiological 
Protections [ICRP, 2007]
category IIb (minor to 
intermediate risk).
 
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
The outcomes of this study will 
provide information which
would produce advances in 
knowledge, leading to a 
potential health benefit in the 
future for patients in this target 
population. The CT may also 
provide information for the 
patients general clinical 
management
Sputum induction
Standard sputum induction 
techniques using hypertonic 
saline can result in 
bronchospasm and therefore 
could potentially induce 
bronchospasm in a patient or 
impact a pre-existing 
exacerbation.
For patients during an 
exacerbation and for sputum 
induction during the recovery 
period, including the day 28 
visit, patients will be pre-dosed 
with nebulised or inhaled beta-
2-agonist (or ipratropium 
bromide if beta-2-agonist 
intolerant). Sputum induction 
will only be carried out using 
Normal (0.9%) saline, which is 
also often used in patients 
clinically to facilitate sputum 
clearance.  
For the final sputum induction 
patients will be pre-dosed with 
nebulised or inhaled beta-2-
agonist (or ipratropium bromide 
if beta-2-agonist intolerant) and 
the induction carried out with 
0.9% saline initially and only 
then followed by hypertonic (3-
5%) if required, and, in the 
opinion of the Investigator,  it is 
considered safe to do so.
4.6.2.
Benefit Assessment
The outcomes of this study will provide information which will produce advances in 
knowledge of the pathophysiology of COPD exacerbations, leading to a potential health 
benefit in the future for patients in this target population. The CT scan may also provide 
information for the patient’s general clinical management.
 
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4.6.3.
Overall Benefit:Risk Conclusion
The overall benefit:risk is considered to be positive. There is an opportunity to determine 
if there may be a new drug developable for the treatment of acute exacerbations of COPD 
which has not seen any new treatments recently. The scientific value in obtaining 
functional CT information on the anatomy and pathophysiology of COPD exacerbations 
and how the lung responds to therapy will be extremely valuable to the wider clinical 
community and justifies the limited radiation exposure (maximum 12 mSv in total) from 
the CT scan procedures. The CT will also be useful to provide clinical information about 
the patient for the patient’s physician and contribute to clinical management.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB [GlaxoSmithKline 
Document Number: 2012N141231_04] 
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
[1] AGE

Between 40 and 80 years of age inclusive, at the time of signing the informed 
consent.
[2] TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY

The subject has a confirmed and established diagnosis of COPD, as defined by the 
GOLD guidelines for at least 6 months prior to entry.

The subject is able to produce >100 mg of sputum at screening for processing, (ie, 
total weight of sputum plugs.).

The subject has a post-bronchodilator FEV1/FVC < 0.7 and FEV1 80 % of predicted 
documented in the last 5 years.

Disease severity: Acute exacerbation of COPD requiring an escalation in therapy to 
include both corticosteroid and antibiotics. Acute exacerbation to be confirmed by an 
experienced physician and represent a recent change in at least two major and one 
minor symptoms, one major and two minor symptoms, or all 3 major symptoms.
1. Major symptoms:
 
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
Subjective increase in dyspnea

Increase in sputum volume

Change in sputum colour
2.
Minor symptoms:

Cough

Wheeze

Sore throat

The subject is a smoker or an ex-smoker with a smoking history of at least 10 pack 
years (pack years = (cigarettes per day smoked/20 x number of years smoked)).
[3] WEIGHT

Body weight 45 kg and body mass index (BMI) within the range 16 – 35 kg/m2
(inclusive).
[4] SEX

Male

Female subject : is eligible to participate if she is not pregnant (as confirmed by a 
negative urine human chorionic gonadotrophin (hCG) test), not lactating, and at least 
one of the following conditions applies:
1. Non-reproductive potential defined as:
Pre-menopausal females with one of the following:
Documented tubal ligation
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 
Hysterectomy
Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea.  Females whose 
menopausal status is in doubt will be required to use, or have been using, one of the 
highly effective contraception methods as specified below from 30 days prior to the first 
dose of study medication and until completion of the follow-up visit.
2. Reproductive potential and agrees to follow one of the options listed 
below in the GSK Modified List of Highly Effective Methods for 
Avoiding Pregnancy in Females of Reproductive Potential (FRP) 
requirements from 30 days prior to the first dose of study medication 
and until completion of the follow-up visit.
 
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GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females 
of Reproductive Potential (FRP)
This list does not apply to FRP with same sex partners, when this is their preferred and 
usual lifestyle or for subjects who are and will continue to be abstinent from penile-
vaginal intercourse on a long term and persistent basis.
1. Contraceptive subdermal implant that meets GSK standard criteria including a 
<1% rate of failure per year, as stated in the product label
2. Intrauterine device or intrauterine system that meets GSK standard criteria 
including a <1% rate of failure per year, as stated in the product label [Hatcher, 
2007a]
3. Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007a] 
4. Injectable progestogen [Hatcher, 2007a]
5. Contraceptive vaginal ring [Hatcher, 2007a]
6. Percutaneous contraceptive patches [Hatcher, 2007a]
7. Male partner sterilization with documentation of azoospermia prior to the female 
subject’s entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2007a].  
8. Male condom combined with a vaginal spermicide (foam, gel, film, cream, or 
suppository) [Hatcher, 2007b]
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
Specific inclusion criteria for Male subjects with female partners of reproductive 
potential is outlined below:
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until after the completion of the follow up visit.
3. Vasectomy with documentation of azoospermia.  
4. Male condom plus partner use of one of the contraceptive options below:
Contraceptive subdermal implant that meets GSK standard criteria including a 
<1% rate of failure per year, as stated in the product label
Intrauterine device or intrauterine system that meets GSK standard criteria 
including a <1% rate of failure per year, as stated in the product label [Hatcher, 
2007a]
 
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Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007a] 
Injectable progestogen [Hatcher, 2007a]
Contraceptive vaginal ring [Hatcher, 2007a]
Percutaneous contraceptive patches [Hatcher, 2007a]
5.
These allowed methods of contraception are only effective when used 
consistently, correctly and in accordance with the product label.  The 
investigator is responsible for ensuring that subjects understand how to properly 
use these methods of contraception.
[5] INFORMED CONSENT

Capable of giving signed informed consent as described in Section 10.2 which
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
[1]  CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL)

To avoid recruitment of subjects with a severe COPD exacerbation, the presence of 
any one of the following severity criteria will render the subject ineligible for 
inclusion in the study:

Need for invasive mechanical ventilation (short term (< 48h) NIV or CPAP is 
acceptable)

Haemodynamic instability or clinically significant heart failure

Confusion

Clinically significant pneumonia, identified by chest X-ray at screening, and as 
judged by the Investigator. 

Subjects who have current medical conditions or diseases that are not well controlled 
and, which as judged by the Investigator, may affect subject safety or influence the 
outcome of the study. (Note: Patients with adequately treated and well controlled 
concurrent medical conditions (e.g. hypertension or NIDDM) are permitted to be 
entered into the study).

Subject has a diagnosis of active tuberculosis, lung cancer, clinically overt 
bronchiectasis, pulmonary fibrosis, asthma or any other respiratory condition that 
might, in the opinion of the investigator, compromise the safety of the subject or 
affect the interpretation of the results.

ALT >2xULN and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if 
 
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bilirubin is fractionated and direct bilirubin <35%). 

A subject with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the exclusion criteria, outside of the reference range for the 
population being studied may be included if the Investigator [in consultation with the 
GSK Medical Monitor if required] documents that the finding is unlikely to 
introduce additional risk factors and will not interfere with the study procedures.

Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert’s syndrome or asymptomatic gallstones)

ECG indicative of an acute cardiac event (e.g. Myocardial Infarction) or 
demonstrating a clinically significant arrhythmia requiring treatment.

QTcF > 450 msec or QTcF > 480 msec in subjects with Bundle Branch Block, based 
on single QTcF value.

Subjects who have undergone lung volume reduction surgery.
[2] CONCOMITANT MEDICATIONS

Subject is currently on chronic treatment with macrolides or long term antibiotics.

Subject is being treated with long term oxygen therapy - LTOT (> 15 hours/day).

The subject has been on chronic treatment with anti-Tumour Necrosis Factor (anti-
TNF), or any other immunosuppressive therapy (except corticosteroid) within 60 days 
prior to dosing.
[3] RELEVANT HABITS

History of regular alcohol consumption within 6 months of the study defined as an 
average weekly intake of >28 units for males or >21 units for 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.
[4]  CONTRAINDICATIONS 

History of sensitivity to any of the study medications, or components thereof (such as 
lactose) or a history of drug or other allergy that, in the opinion of the investigator or 
Medical Monitor, contraindicates their participation.
[5] DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA

A known (historical) positive test for HIV antibody.

Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test 
result at screening or within 3 months prior to first dose of study treatment.
NOTE: Because of the short window for screening, treatment with GSK2269557 
may start before receiving the result of the hepatitis tests. If subsequently the test is 
found to be positive, the subject may be withdrawn, as judged by the Principal 
 
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Investigator in consultation with the Medical Monitor.

Where participation in the study would result in donation of blood or blood 
products in excess of 500 mL within 56 days.

The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the 
current study: 30 days, 5 half-lives or twice the duration of the biological effect of 
the investigational product (whichever is longer).

Exposure to more than 4 investigational medicinal products within 12 months 
prior to the first dosing day.
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized.  In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria Protocol Deviations, and any Serious Adverse Events.
5.4.
Withdrawal/Stopping Criteria
Subjects who are withdrawn from treatment will also be withdrawn from the study. 
If a higher than expected number of subjects prematurely discontinues the study, 
additional subjects may be randomised and assigned to the same treatment sequence, at 
the discretion of the Sponsor.  
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as soon 
as possible. 

The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 
telephone calls and if necessary a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered to
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
 
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A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
Subjects who are withdrawn should complete the assessments planned for the follow up 
visit.
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase II Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5, if 
measured*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
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 2.
5.4.1.1.
Study Treatment Restart or Re-challenge
Study treatment restart or re-challenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
 
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5.4.2.
QTc Stopping Criteria

QTcF should be based on averaged QTcF values of triplicate electrocardiograms 
obtained over a brief (e.g., 5-10 minute) recording period. For example, if an ECG 
(Electrocardiogram) demonstrates a prolonged QTcF interval, obtain two more 
ECGs and use the averaged QTcF values of the three ECGs to determine whether the 
patient should be discontinued from the study.
A subject who meets either of the bulleted criteria below will be withdrawn from the 
study:

QTcF >500 msec OR Uncorrected QT >600 msec

Change from baseline of QTcF > 60 msec
For patients with underlying bundle branch block, follow the discontinuation criteria 
listed below:
Baseline QTcF with Bundle 
Branch Block
Discontinuation QTcF with 
Bundle Branch Block
<450 msec
>500 msec
450 – 480 msec
≥530 msec
5.4.3.
Other Stopping Safety Criteria
For an individual study participant, stopping criteria include, but are not limited to:
Severe signs or symptoms, or significant changes in any of the safety assessments, that 
put the safety of the individual at risk (e.g. ECG, vital signs, laboratory tests, spirometry 
assessments, etc), as judged by the Principal Investigator in consultation with the Medical 
Monitor if necessary.
Treatment failure or recurrent exacerbation does not mandate withdrawal from the study, 
unless there is a safety concern as judged by the Investigator, in consultation with the 
Medical Monitor if necessary.
Subjects should be withdrawn from the study if confusion, acute respiratory acidosis (pH 
< 7.30), or need for invasive mechanical ventilation occurs.
5.5.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit.
The end of the study is defined as the last subject’s last visit.
 
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6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
Study Treatment
Product name:
GSK2269557
Placebo
Formulation description:
Lactose blend containing 
GSK2269557 in Diskus™device
Lactose in Diskus device
Dosage form:
Dry powder for inhalation
Dry powder for inhalation
Unit dose 
strength(s)/Dosage 
level(s):
500 µg / blister
N/A
Route of Administration
Inhalation
Inhalation
Dosing instructions:
2 inhalations to be taken every 
day before breakfast (with the 
exception of days when the 
subjects have a planned visit to 
the clinic. On those days, they 
will be dosed at the clinic). The 
subject should hold their breath 
for approximately 10 seconds 
before exhaling. Inhalations 
should be taken approximately 
30 seconds apart. 
2 inhalations to be taken every 
day before breakfast (with the 
exception of days when the 
subjects have a planned visit to 
the clinic. On those days, they 
will be dosed at the clinic). The 
subject should hold their breath 
for approximately 10 seconds 
before exhaling. Inhalations 
should be taken approximately
30 seconds apart.
6.2.
Treatment Assignment
Subjects will be assigned to treatments in accordance with the randomization schedule
generated by Clinical Statistics, prior to the start of the study, using validated internal 
software. Central based randomisation will be used.
Subjects will be randomised to treatments A or B where:
A = Placebo 
B = GSK2269557 1000 µg 
A web based interactive response system will be used to assign subjects to treatment.
6.3.
Planned Dose Adjustments
If adverse events, unrelated to COPD exacerbation, which are of moderate or severe 
intensity and are consistent across subjects in the group, or if unacceptable 
 
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pharmacological effects, reasonably attributable in the opinion of the investigator to 
dosing with GSK2269557, are observed in more than 30% of the subjects then the study
will be halted and no further subject will be dosed until a full safety review of the study 
has taken place. Relevant reporting and discussion with the Medical Monitor, relevant 
GSK personnel, and with the Ethics Committees will then take place prior to any 
resumption of dosing. If the above is observed consideration may be given to reducing 
the dose of GSK2269557 to 500 µg O.D.
6.4.
Subject Specific Dose Adjustment Criteria
There are no subject specific dose adjustment criteria.
6.5.
Blinding
This will be a double blind study and the following will apply. 

The investigator or treating physician may un-blind a subject’s treatment assignment 
only in the case of an emergency OR in the event of a serious medical condition 
when knowledge of the study treatment is essential for the appropriate clinical 
management or welfare of the subject as judged by the investigator. 

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before un-blinding 
the subject’s treatment assignment. 

If GSK personnel are not contacted before the un-blinding, the investigator must 
notify GSK as soon as possible after un-blinding. 

The date and reason for the un-blinding must be fully documented in the Case Report 
Form (CRF)

A subject will be withdrawn if the subject’s treatment code is un-blinded by the 
investigator or treating physician. The primary reason for discontinuation (the event 
or condition which led to the un-blinding) will be recorded in the CRF.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may un-blind the 
treatment assignment for any subject with a Serious Adverse Event (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 subject’s treatment assignment, may be 
sent to investigators in accordance with local regulations and/or GSK policy.
6.6.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
 
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6.7.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

Only subjects 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 labelled storage conditions with access limited to the 
investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e. receipt, reconciliation and final disposition records).  

Further guidance and information for final disposition of unused study treatment are 
provided in the Study Reference Manual (SRM).

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, Medical Monitor and/or 
GSK study contact.

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
6.8.
Compliance with Study Treatment Administration
When subjects 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 subjects will be asked to complete a diary when dose administration takes place at 
home. The date, time and number of inhalations will be recorded. The compliance will be 
checked by the site staff at each planned visit. 
A record of the number of Diskus inhalers dispensed to each subject and the number of 
actuation administered, read from the dose counter for each Diskus inhaler, must be 
maintained and reconciled with study treatment and compliance records.  Treatment start 
and stop dates, including dates for treatment delays and/or dose reductions will also be
recorded in the CRF.
 
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6.9.
Treatment of Study Treatment Overdose
For this study, any dose of GSK2269557 >2000 µg within a 22 hour time period will be 
considered an overdose.
GSK does not recommend specific treatment for an overdose
In the event of an overdose the investigator should:
1) contact the Medical Monitor immediately
2) closely monitor the subject for adverse events (AEs)/serious adverse events 
(SAEs) and laboratory abnormalities until GSK2269557 can no longer be detected 
systemically (at least 14 days for GSK2269557)
3) obtain a plasma sample for pharmacokinetic (PK) analysis within 7 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 subject.
6.10.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because the indication being studied is not life threatening or seriously debilitating 
and/or other treatment options are available.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
Any clinical abnormalities identified during the conduct of the study will be locally 
managed by the Investigator.
6.11.
Lifestyle and/or Dietary Restrictions

Subjects must not sunbathe or use a tanning device (e.g. sunbed or solarium) whilst 
taking the study medication and until at least 2 weeks after their last dose. Subjects 
are to be advised that they should cover exposed areas of skin (e.g. use sun hat, long 
sleeves) and use a broad spectrum UVA/UVB sunscreen (SPF ≥30) on exposed areas 
of skin when outdoors.

Subjects should refrain from consumption of Seville oranges, grapefruit or grapefruit 
juice, exotic citrus fruits or grapefruit hybrids from first dose till the end of the study.

Subjects should abstain from alcohol on the day when they visit the clinical unit and 
until their discharge on that day.
 
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
Subjects should refrain from smoking for at least 2 hours prior to each pulmonary 
function test conducted at the clinical unit/site.
6.12.
Concomitant Medications and Non-Drug Therapies
6.12.1.
Permitted Medications and Non-Drug Therapies
On entry to the study all treatment required for standard of care and additional medical 
problems is permitted to start and continue.
The subjects are allowed to continue their regular COPD treatments for the duration of 
the study. However, the subjects should refrain, if possible, from using relief 
bronchodilators for at least 4 hours prior to each spirometry conducted at the clinical unit, 
and HRCT scan assessment unless essential for clinical symptom relief. Otherwise free 
use of reliever/rescue medication is allowed.  Rescue ventolin and aerochambers may be 
provided by GSK for this study.
All prior (up to 2 months prior to screening) and concomitant medications should be 
recorded in the subject’s CRF.
6.12.2.
Prohibited Medications and Non-Drug Therapies
Regular or chronic treatment with medications that are considered strong inhibitors of 
CYP3A4 or CYP2D6 are not permitted. This includes anti-epileptic treatments, 
macrolide antibiotics, oral antifungal treatments (single doses and courses up to 7 days 
are allowed) and anti-tuberculous therapy. These medications must all have been stopped 
at least 14 days prior to first dose.
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1
 
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7.1.
Time and Events Table (Screening and Follow Up Visits)
Procedure
Screening 
(up to 3 days prior to Visit 1)
Follow-up
(7-14 days post-last dose)
Notes
Informed consent
X
Demography
X
Inclusion and exclusion criteria
X
Full physical exam, including height and 
weight
X
Brief physical examination, including weight
X
Chest X-Ray
X
To be done before baseline HRCT to exclude significant 
pneumonia and other incidental serious underlying 
pathology.
Medical history (includes substance usage
and Family history of premature CV disease)
X
Substances: Drugs, Alcohol, tobacco via history.  No drug, 
alcohol screening is required.
Past and current medical conditions  
(including cardiovascular medical history and 
therapy history)
X
Laboratory assessments (include Hematology 
and biochemistry)1
X
X
Historical values analysed by local lab to be used for 
eligibility assessment. Another sample must be collected 
and sent to central lab as soon as informed consent is 
obtained. 
Hep B and Hep C screen2
X
Urine pregnancy test (only WCBP)
X
Before conducting the HRCT.  Done locally at the site.
12-lead ECG
X
X
Single assessment
Vital signs
X
X
Single assessment
HRCT (at TLC and FRC)
X
Within 48 h of diagnosis, if subject otherwise eligible. 
Includes electronic monitoring of breathing (if applicable).  
Baseline HRCT will be reviewed by the local site’s 
radiologist to identify any significant occurring underlying 
medical conditions that require further clinical management 
or monitoring.
Induced Sputum3
X4
To include sputum culture pre-first dose. Culture to be done 
by the local site laboratory.
 
 
 
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Procedure
Screening 
(up to 3 days prior to Visit 1)
Follow-up
(7-14 days post-last dose)
Notes
Blood sample for mRNA Analysis
X4
Collected at any time on specified days
AE/SAE collection and review
X
Concomitant medication review
X
X
1.
Due to the short screening window, central laboratory analysis results will not be available on time. Therefore the local laboratory results should be used for eligibility assessment 
(to exclude severe subjects and underlying medical conditions). If local laboratory results are already available from diagnosis of current exacerbation, there is no need to take 
another sample for local analysis. A sample for central laboratory analysis should also be obtained. See Section 7.8.6 for further details.
2.
If test otherwise performed within 3 months prior to first dose of study treatment, testing at screening is not required. Because of the short window for screening, treatment with 
GSK2269557 may start before receiving the result of the hepatitis tests. If subsequently the test is found to be positive, the subject may be withdrawn, as judged by the Principal 
Investigator in consultation with the Medical Monitor.
3.
Induced sputum collection may be attempted on several occasions if an adequate sample is not produced at the first attempt.
4.
To be collected at any time point before randomisation.
 
 
 
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7.2.
Time and Events Table (Treatment Period)
Procedure
Treatment Period 
Notes
Visit
1
21
3
4
5
6
Day
1
Within 48h 
/ discharge
12
28
56
84
Visit window
N/A
1 days
2 days
2 days
- 4 / +2 days
- 4 / +2 days
SAFETY ASSESSMENTS
AE/SAE collection and review
=========================================================
Concomitant medication review
=========================================================
Reliever usage
=========================================================
Brief physical exam, including weight
X2
X
X
X
X
Pre-dose
Laboratory assessments (include 
haematology and biochemistry)
X2
X
X
X
X
Pre-dose
12-lead ECG
X2
X
X
X
X
Pre-dose. Single assessment
Vital signs
X2
X
X
X
X
Pre-dose. Single assessment
Urine pregnancy test (only WCBP)
X
X
Before conducting the HRCT
STUDY TREATMENT
Randomisation
X
Study drug administration
=========================================================
Daily in the morning before breakfast, 
(with the exception of days when the 
subjects have a planned visit to the 
clinic. On those days, they will be 
dosed at the clinic).
Assessment of study treatment compliance
X
X
X
X
 
 
 
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Procedure
Treatment Period 
Notes
Visit
1
21
3
4
5
6
Day
1
Within 48h 
/ discharge
12
28
56
84
Visit window
N/A
1 days
2 days
2 days
- 4 / +2 days
- 4 / +2 days
EFFICACY ASSESSMENTS
HRCT (at TLC and FRC)
X
X
At any time on specified days. Includes 
electronic monitoring of breathing (if 
applicable).  The radiologist may review 
any of the scan(s) if they wish, but this 
is NOT required for the study.  A formal 
review is required at screening only by 
the radiologist.
FEV1  and FVC
X
X
X
X
X
X
In clinic only for all visits where 
possible.
PEF 
=========================================================
Daily before drug administration at 
home.  If subject in hospital, this may 
be collected using the handheld device 
provided prior to drug administration.
OTHER ASSESSMENTS
Blood sample for PK
X
X
X
X
X
Day 1:  5 min and 24 h post-dose. The 
24 h post-dose time-point is optional for 
subjects not hospitalised. Pre-dose at 
all other time-points.
Sputum induction3
X
X
X
Blood sample for mRNA analysis
X
X
X
Genetic sample (PGx)4
X
Collected at any time after 
randomisation
1.
On discharge if the subject was hospitalized. Within 48 hours of first dose administration if the subject was not hospitalised. See Section 4.2
2.
Assessments do not need to be completed if screening assessments conducted within 48 hours 
3.
Induced sputum collection may be repeated on several occasions if an adequate sample is not produced at the first attempt 
4.
Informed consent for optional sub-studies (e.g. ,genetics research) must be obtained before collecting a sample.  May be obtained at any visits.
 
 
 
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7.3.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.  
Procedures conducted as part of the subject’s routine clinical management and obtained 
prior to signing of informed consent may be utilized for Screening or baseline purposes 
provided the procedure meets the protocol-defined criteria and has been performed in the 
timeframe of the study.
If they are being utilised in the study, Patient Reported Outcomes questionnaires should 
be completed by subjects before any other assessment at a clinic visit, in the order 
specified.
7.4.
Biomarker(s)/Pharmacodynamic Markers
7.4.1.
Pharmacodynamic Biomarkers in Sputum

Collect sputum induction samples at the time-points shown in the time and events 
table (Section 7.1).

The sputum induction collection process will follow local standard procedures and
guidelines outlined in the SRM.

The collection of induced sputum may be attempted on several occasions if an 
adequate sample is not produced at the first attempt.

Further information on collection, processing, storage and shipping procedures are 
provided in the SRM.
7.4.2.
mRNA in blood

Collect 2.5 mL of blood into a PAXgene mRNA tube.
Details of blood sample collection, processing, storage and shipping procedures are 
provided in the SRM.
7.5.
Patient diary
The subjects will be provided with a diary to record the following data when at home: 

Time and date of each dose administration and number of inhalations.
 
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
Adverse Events and concomitant medications taken (including daily rescue 
medication – if used and how many times used).

PEF from a handheld device.  The best/highest result is recorded.
Changes in Health and details of any concomitant medications as well as PEF assessment 
details will be collected in the paper diaries and later transcribed into the CRF. 
7.6.
Genetics
Information regarding genetic research is included in Appendix 3.
7.7.
Efficacy
7.7.1.
Functional Respiratory Imaging

A CT scan with a low radiation protocol at FRC and TLC will be conducted as listed 
in the Time and Events Table (Section 7.1). The same scanner should be used for 
baseline and post-treatment scans for an individual subject.

A urine pregnancy test should be performed before the CT scan in female subjects of 
childbearing potential.

Further information is provided in the SRM.
7.7.2.
FEV1  and FVC
A triplicate FEV1 and FVC measurement will be taken at the clinic before dosing using 
the site’s spirometer as soon as it is safe to do so. These will be recorded as absolute 
values.  The best/highest result is recorded.

Further details are provided in the SRM.
7.7.3.
Peak Expiratory Flow PEF

PEF measurements will be taken (in triplicate) daily in the morning before dose 
administration, as soon as it is safe for the subject to do so. The best/highest result is 
recorded.

Subjects will be provided with a handheld device.

Further details are provided in the SRM.
7.8.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests (such as vital signs, physical exams
and laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
 
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7.8.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.
7.8.1.1.
Time period and Frequency for collecting AE and SAE information

AEs and SAEs will be collected from the start of Study Treatment until the follow-
up contact (see Section 7.8.1.3), at the time-points specified in the Time and Events 
Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product 
will be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact. 

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 4.

Investigators are not obligated to actively seek AEs or SAEs in former study
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the investigator 
must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 4.
7.8.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
 
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7.8.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in
Appendix 4.
7.8.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
7.8.1.5.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
COPD exacerbations are associated with the disease to be studied and will not be 
recorded as AEs unless they meet the definition of an SAE as defined in Appendix 4
Exacerbations that meet the definition of an SAE will be recorded on the appropriate 
eCRF section and should be reported to GSK.
Medications used to treat a COPD exacerbation will be recorded in the exacerbation 
eCRF
7.8.1.6.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs and non-serious AEs related to 
study treatment (even for non- interventional post-marketing studies) is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and the safety 
of a product under clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
 
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Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.8.2.
Pregnancy

Details of all pregnancies in female subjects and female partners of male subjects 
will be collected after the start of dosing and until the follow-up visit

If a pregnancy is reported then the investigator should inform GSK within 2 weeks 
of learning of the pregnancy and should follow the procedures outlined in Appendix 
5. 
7.8.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems.  Height and 
weight will also be measured and recorded.

A brief physical examination will include, at a minimum assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
7.8.4.
Vital Signs

Vital signs will be measured in semi-supine position after 5 minutes rest and will
include temperature, systolic and diastolic blood pressure and pulse rate and 
respiratory rate.

Three readings of blood pressure and pulse rate will be taken

First reading should be rejected

Second and third readings should be averaged to give the measurement to be 
recorded in the CRF. 
7.8.5.
Electrocardiogram (ECG)

Single 12-lead ECGs will be obtained at screening and at each other timepoint during 
the study using an ECG machine that automatically calculates the heart rate and 
measures PR, QRS, QT, and QTcF intervals.  Refer to Section 5.4.2 for QTcF
withdrawal criteria and additional QTcF readings that may be necessary.
 
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7.8.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 1, must be conducted in
accordance with the Laboratory Manual, and Protocol Time and Events Schedule.
Laboratory requisition forms must be completed and samples must be clearly labelled 
with the subject number, protocol number, site/centre number, and visit date. Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the laboratory manual. Reference ranges for all safety parameters will be
provided to the site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Historical values (if the assessment was conducted as part of the standard of care) for 
blood gases, blood culture and sputum culture may also be collected if available.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
Table 1
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 1
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose (non 
fasted)
Calcium
Alkaline 
phosphatise
Albumin
CRP
Other 
Screening 
Tests

Urine hCG Pregnancy test (as needed for women of child bearing 
potential) 2

Hepatitis B (HBsAg)

Hepatitis C (Hep C antibody)
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 5.4.1 and Appendix 2
2. Local urine testing will be standard for the protocol unless serum testing is required by local regulation or ethics 
committee.
 
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All study-required laboratory assessments will be performed by a central laboratory, apart 
from:

Hematology and clinical chemistry at screening for excluding subjects with severe 
disease and uncontrolled medical conditions. The results of each test must be entered 
into the CRF.
NOTE:  Local laboratory results are only required in the event that the central laboratory
results are not available in time for either a treatment and/or response evaluation to be 
performed. If a local sample is required it is important that the sample for central 
analysis is obtained at the same time. Additionally if the local laboratory results are used 
to make either a treatment or response evaluation, the results must be entered into the 
CRF.
Hematology, clinical chemistry and additional parameters to be tested are listed in Table 
1. 
7.9.
Pharmacokinetics
7.9.1.
Blood Sample Collection
A 2 mL blood samples for pharmacokinetic (PK) analysis of GSK2269557 will be
collected at the time points indicated in Section 7.1, Time and Events Table.  The actual
date and time of each blood sample collection will be recorded.  The timing of PK 
samples may be altered and/or PK samples may be obtained at additional time points to 
ensure thorough PK monitoring.  
Processing, storage and shipping procedures are provided in the Study Reference Manual
(SRM). 
7.9.2.
Sample Analysis
Plasma analysis will be performed under the control of PTS-DMPK/Scinovo, 
GlaxoSmithKline, the details of which will be included in the SRM. Concentrations of 
GSK2269557 will be determined in plasma samples using the currently approved 
bioanalytical methodology. Raw data will be archived at the bioanalytical site (detailed 
in the SRM).
Once the plasma has been analyzed for GSK2269557 any remaining plasma may be
analyzed for other compound-related metabolites and the results reported under a 
separate PTS-DMPK/Scinovo, GlaxoSmithKline protocol.
 
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8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.

Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSK Drug.  

CRFs (including queries and audit trails) will be retained by GSK, and copies will be 
sent to the investigator to maintain as the investigator copy.  Subject initials will not 
be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
This study is designed to establish the PI3K-dependent alterations in immune cell 
mechanisms related to neutrophil function as detected by changes in mRNA 
transcriptomics in samples of induced sputum from patients admitted with an 
exacerbation of COPD. The primary comparison will be between  subjects treated with 
GSK2269557 in addition to standard of care, and subjects treated with placebo in 
addition to standard of care. In addition, treatment comparisons between subjects at 
baseline and subsequent time points will also be produced.
9.1.
Sample Size Considerations
The sample size for this study has been based on feasibility. The sample size of 30 
subjects completing the trial, with approximately 15 of which will receive GSK2269557 
and 15 will receive placebo, is expected to be sufficient to provide a meaningful estimate 
of the mRNA alterations within the lungs.
Previous studies with similar sample size populations have yielded significant fold-
changes (fold-change>1.5 and p<0.05) in immune cell mechanisms using the changes in 
mRNA transcriptomics.
 
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Study Name
Sample
Study Design
Number of Subjects
Number of Differential 
probesets FC = >= 1.5, 
Pval <= 0.05
Notes
PII115117 FTIH 
Healthy Smoker 
nebulised 
GSK2269557
Sputum
Sputum N=12 3-
way x-over 
placebo 400ug, 
6400ug 
12 (9 with all data 
points)
57 probesets change with 
both doses = 44 Genes
Gene changes relate predominantly 
to a down regulation of infection and 
inflammation responses.
Link to Haemophilus influenzae and 
Moraxella catarrhalis infection 
biology – Identified prior to 
knowledge of Activated PI3Kδ 
Syndrome phenotype
200114 Enabler 
GSK2269557 on ex-
vivo COPD Sputum 
and Blood
Sputum
Ex vivo Sputum 
incubated with 
GSK2269557 
sampled at 
6hrs (Sputum 
producers)
15 Subjects
490 probesets change vs 
vehicle control = 295 
genes (of which 43 are 
dysregulated in COPD 
disease vs Healthy 
comparison)
43 genes altered in COPD and 
positively modulated by PI3Kδi 
GSK2269557. Biological themes in 
signature: Pro-cell 
movement/migration  and cell 
viability, anti-apoptotic. Additionally 
link to B/T cell function. Signature 
supports GSK2269557 correction of 
neutrophil migration 
200114 Enabler 
GSK2269557 on ex-
vivo COPD Sputum 
and Blood
Blood
Ex vivo blood 
incubated with 
GSK2269557 
sampled at 
6hrs (Sputum 
15 Subjects
19 probesets change vs 
vehicle control = 15 genes 
Infection and inflammation 
associated genes
200114 Enabler 
GSK2269557 on ex-
vivo COPD Sputum 
and Blood
Blood
Ex vivo blood 
incubated with 
GSK2269557 
sampled at 
6h
(N
15 Subjects
30 probesets change vs 
vehicle control = 25 genes 
Infection and inflammation 
associated genes
9.1.1.
Sample Size Re-estimation or Adjustment
No sample size re-estimation will be performed in this study. 
9.2.
Data Analysis Considerations
9.2.1.
Analysis Populations
Population
Definition / Criteria
Analyses Evaluated
Screened
All subjects who were screened.

Study Population
All subject
All randomised subjects who receive at least 
one dose of the study treatment.
This population will be based on the 
treatment the subject actually received.

Study Population

Pharmacodynamics

Safety

Efficacy
Pharmacokinetic
Subjects in the ‘All subject’ population for 
whom a pharmacokinetic sample was 
obtained and analysed.

PK
9.2.2.
Interim Analysis
No interim analyses will be performed.
 
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9.3.
Key Elements of Analysis Plan
9.3.1.
Primary Analyses
To estimate differences in mRNA intensities within and between treatment groups, a 
repeated measures model will be fitted to the results of the analysis of each probe set at 
Day 12, Day 28 and Day 84 following a loge transformation of the data. The Day 1 
response will be fitted as a baseline covariate. A separate model will be fitted for each of 
the approximate 54000 probe sets.
Back transformed ratios versus screening along with 95% confidence intervals will be 
calculated for each treatment group and timepoint.  Additionally, baseline adjusted ratios 
of the change between active treatment and placebo will be calculated along with 95% 
confidence intervals.
Further details around the analysis of the mRNA data will be provided in the RAP.
9.3.2.
Secondary Analyses
All secondary analyses will be described in full prior to unblinding in the RAP.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable
 
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
Signed informed consent  to be obtained for each subject before participation in the 
study (and for amendments as applicable)

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, or 
both.

Signed informed consent must be obtained for each subject prior to participation in 
the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, written 
approval of the clinical protocol should state that approval of optional assessments is 
being deferred and the study, with the exception of the optional assessments, can be 
initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will
serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and the 
 
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regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective 
and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard Operating 
Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this study 
at any time for reasons including, but not limited to, safety or ethical issues or severe 
non-compliance. For multicenter studies, this can occur at one or more or at all sites.  

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by 
local regulations to be maintained elsewhere), in a safe and secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review in 
conjunction with assessment of the facility, supporting systems, and relevant site 
staff.  

Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  
 
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
The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, including 
re-generating a hard copy, if required.  Furthermore, the investigator must ensure 
there is an acceptable back-up of these reproductions and that an acceptable quality 
control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by any 
institutional requirements or local laws or regulations, GSK standards/procedures, 
and/or institutional requirements. 

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of ownership 
of the records in the event the investigator is no longer associated with the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
The procedures and timing for public disclosure of the 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.
 
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11.
REFERENCES
De Backer J, Vos W, Vinchurkar S, Van Holsbeke C, Poli, G, Claes R et al. The Effect of 
Extrafine Beclometasone/Formoterol (BDP/F) on Lung Function, Dyspnea, 
Hyperinflation, and Airway Geometry in COPD Patients:  Novel Insight Using 
Fundtional Respiratory Imaging. Journal of Aerosol Medicine and Pulmonary Drug 
Delivery. 2014;27:1-12. 
De Backer LA, Vos WG, Salgado R, De Backer JW, Devoldr A, Verhulst SL et al. 
Functional imaging using computer methods to compare the effect of salbutamol and 
ipratropium bromide in patient-specific airway models of COPD. International Journal 
of COPD. 2011;6:637-646. 
De Backer Lieve A, Vos Wim, Van Holsbeke C, Vinchurkar S, De Backer W. The acute 
effect of budesonide/formoterol in COPD:  a multi-slice computed tomography and lung 
function study. Eur Respir J. 2012;40:298-305. 
GlaxoSmithKline Document Number 2012N141231_04: GSK2269557 Investigator's 
Brochure. Report Date 12-FEB-2015. 
Goldin J, Tashkin D, Kleerup E, Greaser MS, Haywood U, Sayre J et al. Comparative 
effects of hydrofluoroalkane and chloroflurocarbon beclomethasone dipropionate
inhalation on small airways: Assessment with functional helical thin-section computed 
tomography. J Allergy Clin Immunol. 1999;104 #6:S258-S267. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D et al. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007(a):24. Table 3-2. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D et al. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007(b): 28. 
ICRP. 2007 Recommendation of the International Commission on Radiological 
Protection. ICRP Publication 103. 2007;37:2-4. 
Kim SR, Lee KS, Park HS, et al. HIF -1 alpha inhibition ameliorates an allergic airway 
disease via VEGF suppression in bronchial epithelium. Eur J Immunol. 2010;40 
(10):2858-69. 
Okkenhaug K, Aki K, Vanhaesebroeck B. Antigen receptor signalling:  A distincive role 
for the p110 isoform of PI3K. Trends in Immunuology. 2007;28:80-7. 
Sadhu C, Dick K, Tino WT, Staunton DE. Selective role of PI13K delta in neutrophil 
inflammatory responses. Biochem Biophys Res Commun. 2003 Sep 5;308 (4):764-9. 
Weisser SB, McLarren KW, Voglmaier B, et al. Alternative activation of macrophages 
by IL-4 requires SHIP degradation. Eur J Immunol. 2011;41(6):1742-53. 
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
AE
Adverse Event
ALT
Alanine aminotransferase
COPD
Chronic Obstructive Pulmonary Disease
CRF
Case Report Form
CT
Computed Tomography
CV
Cardiovascular
ECG
Electrocardiogram
FEV1
Forced Expiratory Volume in One Second
FRC
Functional Residual Capacity
FRI
Functional Respiratory Imaging
GCP
ICH Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GSK
GlaxoSmithKline
HRCT
High-Resolution Computed Tomography
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
PEF
Peak Expiratory Flow
PI3K
Phosphoinositide 3-Kinase Delta
PK
Pharmacokinetic
QTcF
QT interval corrected using the Fridericia's formula
RAP
Reporting and Analysis Plan
SAE
Serious Adverse Event
SRM
Study Reference Manual
TLC
Total Lung Capacity
ULN
Upper Limit of Normal
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
DISKUS
None
 
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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Phase II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase II liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete an
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with study 
treatment unless allowed per protocol and GSK 
Medical Governance approval is granted (refer 
to Appendix 2).

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained 7 days after last 
dose5

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 
 
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
If restart/rechallenge not allowed per protocol 
or not granted, permanently discontinue study 
treatment and may continue subject in the study 
for any protocol specified follow up assessments 
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-72 
hrs 

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline
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
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in subjects with definite or likely 
acetaminophen use in the preceding 
week [James, 2009]). NOTE: not 
required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN.. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, 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 subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
 
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4.
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 
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.)  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.
Phase II liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject safety. 

Subject can continue study treatment 

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
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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12.3.
Appendix 3: Genetic Research
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and:

Response to medicine, including any treatment regimens under investigation in this 
study or any concomitant medicines;

COPD susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.

A 6 mL blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. A 
Blood sample is collected at the baseline visit, after the subject has been randomized 
and provided informed consent for genetic research. Instructions for collection and 
shipping of the genetic sample are described in the laboratory manual. The DNA 
from the blood sample may undergo quality control analyses to confirm the integrity 
of the sample. If there are concerns regarding the quality of the sample, then the 
sample may be destroyed. The blood sample is taken on a single occasion unless a
duplicate sample is required due to an inability to utilize the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
 
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the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA sample 
is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will continue 
to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
 
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reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
 
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12.4.
Appendix 4: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.4.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

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 medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

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 prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected 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 this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).
Events NOT meeting definition of an AE include:

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 subject’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 
subject’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.
 
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
Situations where 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.
12.4.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject 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 hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject 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 out-patient setting.  Complications that occur during 
hospitalization are AEs.  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 disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g. sprained ankle) which may interfere or 
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e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether 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 subject or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition.  These should also be 
considered serious.

Examples of such events are 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
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.4.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
 
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12.4.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’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 instance, all subject identifiers, with the exception of 
the subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
12.4.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
 
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Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence 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 natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of 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 when 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 prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject 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 the designated 
reporting time frames.
 
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12.4.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data 
collection tool

If the electronic system is unavailable for greater than 24 hours, the site will use 
the paper SAE data collection tool and fax it to the Medical Monitor.

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission 
of the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes 
to existing data

If a site receives a report of a new SAE from a study subject or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, the site can report this information on a paper SAE form or to the 
Medical Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
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12.5.
Appendix 5: Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who 
becomes pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 
2 weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, 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. 

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 4. 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 subject who becomes pregnant while participating will discontinue 
study medication
Pregnancy information on female partner of male study subjects

Investigator will attempt to collect pregnancy information on any female partner of 
a male study subject who becomes pregnant while participating in this study.  This 
applies only to subjects who are randomized to receive study medication. 

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate 
form and submit it to GSK within 2 weeks of learning of the partner’s pregnancy

Partner will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded to GSK. 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date.  Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for procedure.
 
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12.6.
Appendix 6: Country Specific Requirements
No country-specific requirements exist.
 
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12.7.
Appendix 7: Protocol Amendment Changes
Protocol Amendment #1 Changes
The amendment was created to remove the specific equations for the prediction of 
percent predicted from spirometry from the inclusion criteria (European Community of 
Coal and Steel and European Respiratory Society Global Lung Function Initiative 
reference equations (Quanjer 2012) in Section 7.7.2.  At screening it may not be possible
to identify which correction method was used, or modify the correction method used, at 
the time.  As a result it may not be valid to stipulate that lung function values be 
corrected using any particular method.  Both FEV1 and FVC measurements (which are 
not entry criteria for the study) collected during the study will be collected as absolute 
values (uncorrected), so that consistency will be obtained across all sites in the study, and 
percent predicted will be calculated using a standard approach in house at the end of the 
study.
List of specific changes:
Page 22, Inclusion Criteria (#2 – Type of Subject and Diagnosis Including Disease 
Severity) - Third Bullet.
PREVIOUS TEXT

The subject has a post-bronchodilator FEV1/FVC < 0.7 and FEV1 80 % of 
predicted. Predictions should be according to the European Community of Coal and 
Steel (ECCS) equations OR the European Respiratory Society Global Lung Function 
Initiative reference equations [Quanjer, 2012] and documented in the last 5 years.
REVISED TEXT

The subject has a post-bronchodilator FEV1/FVC < 0.7 and FEV1 80 % of
predicted documented in the last 5 years.
Page 40, Section 7.7.2 (FEV1 and FVC)
PREVIOUS TEXT
A triplicate FEV1 and FVC measurement will be taken at the clinic before dosing using 
the site’s spirometer as soon as it is safe to do so.  Predicted values will be based upon the 
European Respiratory Society Global Lung Function Initiative reference equations
[Quanjer, 2012].
REVISED TEXT
A triplicate FEV1 and FVC measurement will be taken at the clinic before dosing using 
the site’s spirometer as soon as it is safe to do so.  These will be recorded as absolute
values.  The best/highest result is recorded.
 
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Page 54 – References
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Weisser SB, McLarren KW, Voglmaier B, et al. Alternative activation of macrophages 
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REVISED TEXT
De Backer J, Vos W, Vinchurkar S, Van Holsbeke C, Poli, G, Claes R et al. The Effect of 
Extrafine Beclometasone/Formoterol (BDP/F) on Lung Function, Dyspnea, 
Hyperinflation, and Airway Geometry in COPD Patients:  Novel Insight Using 
Fundtional Respiratory Imaging. Journal of Aerosol Medicine and Pulmonary Drug 
Delivery. 2014;27:1-12. 
De Backer LA, Vos WG, Salgado R, De Backer JW, Devoldr A, Verhulst SL et al. 
Functional imaging using computer methods to compare the effect of salbutamol and 
ipratropium bromide in patient-specific airway models of COPD. International Journal 
of COPD. 2011;6:637-646. 
De Backer Lieve A, Vos Wim, Van Holsbeke C, Vinchurkar S, De Backer W. The acute 
effect of budesonide/formoterol in COPD:  a multi-slice computed tomography and lung 
function study. Eur Respir J. 2012;40:298-305. 
GlaxoSmithKline Document Number 2012N141231_04: GSK2269557 Investigator's 
Brochure. Report Date 12-FEB-2015. 
Goldin J, Tashkin D, Kleerup E, Greaser MS, Haywood U, Sayre J et al. Comparative 
effects of hydrofluoroalkane and chloroflurocarbon beclomethasone dipropionate 
inhalation on small airways: Assessment with functional helical thin-section computed 
tomography. J Allergy Clin Immunol. 1999;104 #6:S258-S267. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D et al. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007(a):24. Table 3-2. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D et al. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007(b): 28. 
ICRP. 2007 Recommendation of the International Commission on Radiological 
Protection. ICRP Publication 103. 2007;37:2-4. 
Kim SR, Lee KS, Park HS, et al. HIF -1 alpha inhibition ameliorates an allergic airway 
disease via VEGF suppression in bronchial epithelium. Eur J Immunol. 2010;40 
(10):2858-69. 
Okkenhaug K, Aki K, Vanhaesebroeck B. Antigen receptor signalling:  A distincive role 
for the p110 isoform of PI3K. Trends in Immunuology. 2007;28:80-7. 
Sadhu C, Dick K, Tino WT, Staunton DE. Selective role of PI13K delta in neutrophil 
inflammatory responses. Biochem Biophys Res Commun. 2003 Sep 5;308 (4):764-9. 
Weisser SB, McLarren KW, Voglmaier B, et al. Alternative activation of macrophages 
by IL-4 requires SHIP degradation. Eur J Immunol. 2011;41(6):1742-53. 
 
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Protocol Amendment #2 Changes
This amendment was created to widen the Body Mass Index (BMI) range at the screening 
visit as the propose range from 16 – 35 kg/m2 would be appropriate for the COPD subject 
population. 
List of specific changes:
Page 22, Inclusion Criteria (#3 – Weight).
PREVIOUS TEXT

Body weight 45 kg and body mass index (BMI) within the range 18 – 32 kg/m2
(inclusive).
REVISED TEXT

Body weight 45 kg and body mass index (BMI) within the range 16 – 35 kg/m2
(inclusive).
 
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The GlaxoSmithKline group of companies
201928
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A randomised, double-blind, placebo-controlled study to 
evaluate the safety, efficacy and changes in induced sputum and 
blood biomarkers following daily repeat doses of inhaled 
GSK2269557 for 12 weeks in adult subjects diagnosed with an 
acute exacerbation of Chronic Obstructive Pulmonary Disease 
(COPD).
Compound Number:
GSK2269557
Development Phase:
IIA
Effective Date:
30-NOV-2015
Protocol Amendment Number:  01
Author (s):
 (CCSE); 
 (CPSSO); 
 
(Respiratory CEDD); 
 (Exp Biology); 
 (Clinical Statistics); 
 (CPMS); 
 (GCSP).
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2014N218070_00
2015-JUN-04
Original
2014N218070_01
2015-NOV-30
Amendment No. 1
Remove the specific equations for the prediction of percent predicted from spirometry 
from the inclusion criteria and in Section 7.7.2.  At screening it may not be possible
to identify which correction method was used, or modify the correction method used,
at the time. It therefore is not valid to stipulate that lung function values be corrected 
using any particular method.  Both FEV1 and FVC measurements (which are not 
entry criteria for the study) collected during the study will be collected as absolute 
values (uncorrected), so that consistency will be obtained across all sites in the study, 
and percent predicted will be calculated using a standard approach in house at the end 
of the study. 
Copyright 2015 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
2018N375139_00
PPD
PPD
PPD
PPD
PPD
PPD
PPD

 
2018N375139_00
PPD

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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information:
Role
Name
Day Time Phone 
Number and email 
address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site Address
Primary 
Medical 
Monitor
Discovery 
Medicine 
Respiratory 
CEDD 
GlaxoSmithKline 
Gumnnels Wood 
Rd. 
Stevenage, 
Herts, 
SG1 2NY
Secondary 
Medical 
Monitor
Discovery 
Medicine 
Respiratory 
CEDD 
GlaxoSmithKline 
Gumnnels Wood 
Rd. 
Stevenage, 
Herts, 
SG1 2NY
SAE contact  
information 
Medical 
monitor as 
above
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
 
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PROTOCOL AGREEMENT PAGE
For protocol 201928:
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
 
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 201928........................................................8
2.
INTRODUCTION....................................................................................................11
2.1.
Study Rationale ..........................................................................................11
2.2.
Brief Background ........................................................................................11
2.2.1.
Use of mRNA transcriptomics by Affymetrix.................................13
2.2.2.
Use of HRCT Endpoints to characterise Lung Function ...............13
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................14
4.
STUDY DESIGN ....................................................................................................15
4.1.
Overall Design ............................................................................................15
4.2.
Treatment Arms and Duration.....................................................................15
4.3.
Type and Number of Subjects.....................................................................16
4.4.
Design Justification.....................................................................................16
4.5.
Dose Justification........................................................................................17
4.6.
Benefit:Risk Assessment ............................................................................17
4.6.1.
Risk Assessment .........................................................................18
4.6.2.
Benefit Assessment.....................................................................19
4.6.3.
Overall Benefit:Risk Conclusion...................................................20
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............20
5.1.
Inclusion Criteria.........................................................................................20
5.2.
Exclusion Criteria........................................................................................23
5.3.
Screening/Baseline/Run-in Failures............................................................25
5.4.
Withdrawal/Stopping Criteria.......................................................................25
5.4.1.
Liver Chemistry Stopping Criteria ................................................26
5.4.1.1.
Study Treatment Restart or Re-challenge...................27
5.4.2.
QTc Stopping Criteria ..................................................................27
5.4.3.
Other Stopping Safety Criteria .....................................................27
5.5.
Subject and Study Completion....................................................................27
6.
STUDY TREATMENT ............................................................................................28
6.1.
Investigational Product and Other Study Treatment....................................28
6.2.
Treatment Assignment................................................................................28
6.3.
Planned Dose Adjustments.........................................................................29
6.4.
Subject Specific Dose Adjustment Criteria..................................................29
6.5.
Blinding.......................................................................................................29
6.6.
Packaging and Labeling..............................................................................29
6.7.
Preparation/Handling/Storage/Accountability..............................................30
6.8.
Compliance with Study Treatment Administration.......................................30
6.9.
Treatment of Study Treatment Overdose....................................................31
6.10.
Treatment after the End of the Study ..........................................................31
6.11.
Lifestyle and/or Dietary Restrictions............................................................31
6.12.
Concomitant Medications and Non-Drug Therapies....................................32
6.12.1.
Permitted Medications and Non-Drug Therapies..........................32
6.12.2.
Prohibited Medications and Non-Drug Therapies.........................32
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................32
 
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7.1.
Time and Events Table (Screening and Follow Up Visits)...........................33
7.2.
Time and Events Table (Treatment Period) ................................................35
7.3.
Screening and Critical Baseline Assessments ............................................37
7.4.
Biomarker(s)/Pharmacodynamic Markers ...................................................37
7.4.1.
Pharmacodynamic Biomarkers in Sputum ...................................37
7.4.2.
mRNA in blood ............................................................................37
7.5.
Patient diary................................................................................................37
7.6.
Genetics .....................................................................................................38
7.7.
Efficacy.......................................................................................................38
7.7.1.
Functional Respiratory Imaging ...................................................38
7.7.2.
FEV1  and FVC.............................................................................38
7.7.3.
Peak Expiratory Flow PEF ...........................................................38
7.8.
Safety .........................................................................................................38
7.8.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........39
7.8.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................39
7.8.1.2.
Method of Detecting AEs and SAEs ...........................39
7.8.1.3.
Follow-up of AEs and SAEs........................................40
7.8.1.4.
Cardiovascular and Death Events ..............................40
7.8.1.5.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................40
7.8.1.6.
Regulatory Reporting Requirements for SAEs............40
7.8.2.
Pregnancy ...................................................................................41
7.8.3.
Physical Exams ...........................................................................41
7.8.4.
Vital Signs....................................................................................41
7.8.5.
Electrocardiogram (ECG).............................................................41
7.8.6.
Clinical Safety Laboratory Assessments ......................................42
7.9.
Pharmacokinetics .......................................................................................43
7.9.1.
Blood Sample Collection..............................................................43
7.9.2.
Sample Analysis ..........................................................................43
8.
DATA MANAGEMENT ...........................................................................................44
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................44
9.1.
Sample Size Considerations.......................................................................44
9.1.1.
Sample Size Re-estimation or Adjustment...................................45
9.2.
Data Analysis Considerations .....................................................................45
9.2.1.
Analysis Populations....................................................................45
9.2.2.
Interim Analysis ...........................................................................45
9.3.
Key Elements of Analysis Plan ...................................................................46
9.3.1.
Primary Analyses.........................................................................46
9.3.2.
Secondary Analyses ....................................................................46
10. STUDY GOVERNANCE CONSIDERATIONS........................................................46
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............46
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................46
10.3.
Quality Control (Study Monitoring) ..............................................................47
10.4.
Quality Assurance.......................................................................................47
10.5.
Study and Site Closure ...............................................................................48
10.6.
Records Retention......................................................................................48
 
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10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................49
11. REFERENCES.......................................................................................................50
12. APPENDICES........................................................................................................51
12.1.
Appendix 1: Abbreviations and Trademarks................................................51
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................52
12.3.
Appendix 3: Genetic Research ...................................................................55
12.4.
Appendix 4: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................58
12.4.1.
Definition of Adverse Events........................................................58
12.4.2.
Definition of Serious Adverse Events...........................................59
12.4.3.
Definition of Cardiovascular Events .............................................60
12.4.4.
Recording of AEs and SAEs ........................................................61
12.4.5.
Evaluating AEs and SAEs............................................................61
12.4.6.
Reporting of SAEs to GSK...........................................................63
12.5.
Appendix 5: Collection of Pregnancy Information........................................64
12.6.
Appendix 6: Country Specific Requirements...............................................65
12.7.
Appendix 7: Protocol Amendment Changes................................................66
 
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1.
PROTOCOL SYNOPSIS FOR STUDY 201928
Rationale
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To establish the PI3K-dependent 
changes in previously identified immune 
cell mechanisms specifically related to 
neutrophil function using mRNA in 
sputum from patients with an 
exacerbation of COPD, with or without 
treatment with GSK2269557.

Alterations in previously identified
immune cell mechanisms specifically 
related to neutrophil function as 
determined by changes in mRNA
transcriptomics in induced sputum after 
12, 28 and 84 days of treatment.
Secondary

To evaluate the effect of once daily 
repeat inhaled doses of GSK2269557 on 
lung parameters derived from HRCT 
scans in subjects with acute 
exacerbation of COPD, compared to 
placebo.

Change from baseline in siVaw, iVaw, 
iRaw, siRAW, total lung capacity, lung 
lobar volumes, trachea length and 
diameter at FRC and TLC after 12 days 
of treatment and after 28 days of 
treatment.

To assess the safety and tolerability of 
once daily repeat inhaled doses of 
GSK2269557 administered to subjects 
with acute exacerbation of COPD, 
compared to placebo.

Adverse events 

Haematology, clinical chemistry 

Vital signs

12-lead ECG

To evaluate the plasma PK of once daily 
repeat inhaled doses of GSK2269557 
administered to subjects with acute 
exacerbation of COPD.

Day 1 plasma Cmax and trough (24 
hours) post dose for inpatients

Trough concentration after 12 days, 28 
days, 56 days and 84 days of treatment.

To evaluate the effect of once daily 
repeat inhaled doses of GSK2269557 on 
lung function parameters in subjects with 
acute exacerbation of COPD compared 
to placebo.

PEF

Reliever usage

FEV1 and  FVC at clinic prior to sputum 
induction
Exploratory

To establish any other PI3K-dependent 
changes in mRNA in sputum or blood 
from patients with an exacerbation of 
COPD, with or without treatment with 
GSK2269557.

To explore the pharmacodynamic effects 
in induced sputum of once daily repeat 
inhaled doses of GSK2269557 

Alterations in immune cell mechanisms 
as determined by changes in mRNA 
transcriptomics in induced sputum or 
blood after 12, 28 and 84 days of 
treatment.

Endpoints may include, but not limited to 
cytokines (IL-6, IL-8, TNF), microbiome 
(by 16SrRNA), bacterial qPCR, viral 
 
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Objectives
Endpoints
administered to subjects with acute 
exacerbation of COPD, compared to 
placebo.
qPCR.

To assess the changes in other CT 
parameters such as low attenuation 
score after once daily repeat inhaled 
doses of GSK2269557 administered to 
subjects with acute exacerbation of 
COPD, compared to placebo.

Change from baseline for other CT 
parameters including low attenuation 
score after 12 days of treatment and 
after 28 days of treatment
Overall Design
This is a randomised, double-blind, placebo-controlled, parallel-group study.  All subjects 
will continue on their usual Chronic Obstructive Pulmonary Disease (COPD) medications 
throughout the entire duration of the study regardless of treatment arm assignment.  
Subjects will be on standard of care treatment (antibiotic and corticosteroids) upon 
diagnosis of a COPD exacerbation.
SCR
Signature 
ICF
Day 1
Randomisation / 
First dose GSK2269557
Day 12
(+/- 2 days) 
HRCT
Day 28
(+/- 2 days)
HRCT
Day 56
(-4 / + 2 days)
Safety visit
Day 84
(-4 / + 2 days)
End treatment
FU
Baseline
HRCT
Within 48h / discharge
Baseline lung function
Treatment Arms and Duration
Subjects will be required to participate in the following:
Screening: Following diagnosis during outpatient assessment by a Respirologist, 
Emergency Department visit or acute admission to hospital, and up to 3 days before start 
of study treatment. During this time:

The start of the standard of care (to include both antibiotics and corticosteroids) is 
expected to start shortly after diagnosis, though it is allowed to have already been 
started before the formal diagnosis of COPD exacerbation is made. 
 
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
The High-Resolution Computed Tomography (HRCT) scan should be conducted at 
the earliest opportunity after obtaining Informed Consent from the subject and within 
48 h of diagnosis by a Respirologist or physician with respiratory experience.  

Randomisation and first dose administration should take place as soon as possible 
following HRCT scan assessment has been performed and no later than 24h after 
completing the HRCT scan.
Treatment period:  Once daily study treatment administration will start on Day 1 (visit 1). 

For subjects who were hospitalized: 
o
If discharge takes place before Day 10, the subject must complete the 
assessments planned for visit 2 on discharge and must then visit the unit 
on Day 12 (2 days) (visit 3).
o
If discharge takes place between Day 10 and Day 14 (inclusive), the 
assessments planned for visit 2 and visit 3 may be completed on the day of 
discharge.
o
If discharge takes place from Day 15 (inclusive), the assessments planned 
for visit 2 and visit 3 should be completed as soon as it is safe for the 
patient to do so.

For subjects who were not hospitalized: the subject must complete the 
assessments planned for visit 2 within 48 hours of start of treatment, and must 
then visit the unit on Day 12 (2 days) to complete the assessments planned for 
visit 3.
Subjects will then dose at home until Day 84 (– 4 / + 2 days), with the exception of the 
days when subjects come to the clinic. On those days, they will dose at the clinic. On Day 
12 (± 2 days) (unless visit completed on discharge), Day 28 (± 2 days), Day 56 (– 4 / + 2 
days) and Day 84 (– 4 / + 2 days) subjects will return on an outpatient basis to complete 
the assessments described in the Time & Event table. Subjects will be discharged once all 
assessments have been performed and there are no safety concerns.
Follow up: 7-14 days after last dose.
The total duration of the study is 13-14 weeks including the screening visit.
Type and Number of Subjects
Approximately 35 subjects with an acute exacerbation of COPD will be randomized such 
that approximately 15 subjects on active and 15 subjects on placebo provide sputum at all 
the scheduled time points and complete the study.  If a higher than expected numbers of 
subjects prematurely discontinue the study, or fail to produce sufficient sputum post 
randomisation additional subjects may be randomised at the discretion of the sponsor.
 
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Analysis
To estimate differences in mRNA intensities within and between treatment groups, a 
repeated measures model will be fitted to the results of the analysis of each probe set at 
Day 12, Day 28 and Day 84 following a loge transformation of the data. The Day 1 
response will be fitted as a baseline covariate. A separate model will be fitted for each of 
the approximate 54000 probe sets.
Back transformed ratios versus screening along with 95% confidence intervals will be 
calculated for each treatment group and timepoint.  Additionally, baseline adjusted ratios 
of the change between active treatment and placebo will be calculated along with 95% 
confidence intervals.
2.
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.
2.1.
Study Rationale
The purpose of this study is to evaluate specific alterations in immune cell mechanisms
related to neutrophil function as detected by PI3K-dependent changes in mRNA 
extracted from induced sputum in patients experiencing an exacerbation of COPD. In 
addition this study will also further evaluate the plasma PK and assess the safety of 
GSK2269557 administered to patients diagnosed with an acute exacerbation of Chronic 
Obstructive Pulmonary Disease (COPD). The efficacy of treatment with GSK2269557 
will also be measured using functional respiratory imaging (FRI) and spirometry. 
This study will also explore the pharmacodynamic effects of once daily repeat doses of 
inhaled GSK2269557 on cytokines, mediators and microbiome in induced sputum 
samples. These will be obtained from subjects at entry, during their exacerbation, and at 
additional time points over the 12 week treatment period.  To understand patient efficacy, 
at entry, Day 12 and Day28 the sputum biomarker data will be correlated with computed 
tomography (CT).   
2.2.
Brief Background
PI3Kis a member of the Class IA family of phosphoinositides 3-kinases (PI3Ks) that 
convert the membrane phospholipid phosphatidylinositol 4,5-biphosphate (PIP2) into 
phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 is a second messenger in many 
cellular processes including cell growth, differentiation and migration. PI3Khas 
specific roles in mediating antigen receptor and cytokine signalling in T-cells, mast cells 
and B-cells [Okkenhaug, 2007] and roles in neutrophil chemotaxis and activation [Sadhu, 
2003].  A PI3Kinhibitor has the potential to inhibit major cell types responsible for the
inflammation associated with both COPD and asthma.
 
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In COPD, tobacco smoke or other irritants activate epithelial cells and macrophages to 
release inflammatory mediators such as chemokines that attract neutrophils and T cells to 
the lungs. PI3Kis thought to play a role in a number of epithelial responses relevant for 
the development of COPD.  Therefore a PI3Kinhibitor may be able to suppress a 
number of these processes [Kim, 2010].  A greater proportion of macrophages appear to
be alternatively activated in COPD and their ability to phagocytose infective pathogens is 
reduced as a result of this alternative activation.  PI3Kis one of the mediators involved 
in determining this alternative phenotype in macrophages and therefore it is proposed that 
inhibition of PI3Kmight rebalance macrophage activation towards a classic phagocytic
phenotype [Weisser, 2011] facilitating clearance of bacteria, a major cause of
exacerbation in COPD.  The neutrophil and T cell are the two major inflammatory cell 
types involved in the pathogenesis of COPD and both are targeted by PI3Kinhibitors. 
GSK2269557 has demonstrated the ability to protect against and control bacterial 
infections in preclinical rodent models. This is coupled with recent observations that 
PI3Kinhibition leads to a correction in vitro of aberrant neutrophil chemotaxis 
directionality in the blood of COPD patients. Furthermore, a human point mutation which 
results in a constitutively activated version of PI3Khas recently been characterised 
where the majority of affected patients have recurrent lung infections with the same 
bacterial species which are seen in COPD patients and are known to drive exacerbations. 
Collectively these data suggest that repeat dosing with GSK2269557 could potentially
reduce the impact of an acute exacerbation, or prevent the onset of a secondary bacterial 
exacerbation or recurrent exacerbation.
Proinflammatory cytokines were reduced by GSK2269557, both in preclinical rodent 
bacterial models, and COPD patient samples treated in vitro and in the study setting 
(PII115119).
GSK2269557 has been administered as single and repeat doses to healthy subjects as 
nebulized solution in the FTIH study PII115117 up to a dose of 6400 μg per day for 7 
days. GSK2269557 has also been administered as single and repeat doses to healthy 
smokers as a dry powder formulation in study PII116617 up to a dose of 3000 μg as 
single dose and 2000 μg per day for 14 days.  GSK2269557 has been well tolerated 
across the range of doses used.  There is also an ongoing study (Study PII115119, non-
reported) where a total daily dose of up to 2000 µg of GSK2269557 is being administered 
to stable COPD patients via a dry powder inhaler for 14 days in a two part study.  Part A 
of this study has completed and Part B will characterise the steady-state (exposure) dose 
response following repeat inhaled doses of up to 2000µg for the same treatment duration.  
There is also an on-going larger clinical study PII116678 which is almost identical in 
design to 201928 using 1000 µg of GSK2269557 per day administered via a Diskus dry 
powder inhaler to patients diagnosed with an acute exacerbation of COPD.  For 
simplicity study PII116678 does not capture induced sputum hence cannot analyse any 
changes in mRNA. The primary objective of the current study is to capture induced 
sputum to enable the mRNA analysis on a smaller cohort.   
More information about the non-clinical and clinical studies is available in the 
GSK2269557 Investigator’s Brochure (IB) GlaxoSmithKline Document Number
2012N141231_04.
 
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2.2.1.
Use of mRNA transcriptomics by Affymetrix
Analysis of changes in mRNA can be used to demonstrate alterations in biochemical 
pathways at the gene transcription level. This can be used to better understand the 
consequences of drug intervention on disease pathophysiology, and ultimately predict 
alterations which could translate to a positive clinical benefit for patients.  Messenger 
RNA can be extracted from a variety of biological samples (including induced sputum 
and blood) taken from patients before and after drug dosing to show the impact a drug is 
having. 
The advantage of using Affymetrix is the broad (~50k) gene set covered using this 
technology enabling great depth in exploring the biological consequences of drug 
intervention. This technology has been used in previous preclinical and clinical studies 
using GSK2269557 generating a fingerprint of PI3Kinhibition in disease.  Importantly 
these approaches allow areas of complex PI3K-dependent immune cell mechanisms and 
pathophysiology, specifically related to neutrophil function to be explored which are not 
easily quantified using other techniques.
2.2.2.
Use of HRCT Endpoints to characterise Lung Function
High-resolution computed tomography (HRCT) scans provide a highly detailed insight 
into the structure and architecture of the respiratory system. A clear distinction can be 
made between the lung parenchyma, the intraluminal air and alveolar spaces up to the 
level of the smaller airways with a diameter of 1-2mm. To model dynamic information, 
low dose HRCT scans can be taken at two lung volumes: after deep inhalation (total lung 
capacity or TLC) and after normal expiration (functional residual capacity or FRC). The 
patient’s breathing is monitored in real time during the scans to ensure the correct lung 
levels are scanned.  Due to the natural contrast between the intraluminal air and the 
surrounding tissue, it is possible to attain a significant reduction in radiation dose (1-2 
mSv per scan) compared to standard CT protocols (>4 mSv per scan) by reducing the 
tube current and the voltage.  Depending on the patient’s weight, a 6- to 10-fold reduction 
can be obtained per scan without losing image quality. As a comparison, in the USA, the 
average annual background radiation exposure is 6.2 mSv and a transatlantic flight results 
in 0.07 mSv exposure.
The high resolution images allow for a three dimensional reconstruction of the airway 
tree and vasculature by applying segmentation principles.  These three dimensional 
models can be used to measure airway dimensions as well as potentially allowing the 
phenotyping of patients by disease severity.  The three dimensional computer 
reconstructions can be used for fluid dynamic modelling.  This method is used to 
simulate flow through these airway models and determine the typical flow characteristics 
such as local pressure drops, velocities and resistance.  It can also be used to predict 
particle deposition in the airways of these patients when using inhaled drug products.
This method consisting of 2 low dose HRCT scans at several time points has previously 
been used successfully in clinical trials involving COPD patients [De Backer, 2011; De 
Backer, 2012; De Backer, 2014; Goldin, 1999]. 
 
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3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To establish the PI3K-dependent 
changes in previously identified immune 
cell mechanisms specifically related to 
neutrophil function using mRNA in 
sputum from patients with an 
exacerbation of COPD, with or without 
treatment with GSK2269557.

Alterations in previously identified
immune cell mechanisms specifically 
related to neutrophil function as 
determined by changes in mRNA
transcriptomics in induced sputum after 
12, 28 and 84 days of treatment.
Secondary

To evaluate the effect of once daily 
repeat inhaled doses of GSK2269557 on 
lung parameters derived from HRCT 
scans in subjects with acute 
exacerbation of COPD, compared to 
placebo

Change from baseline in siVaw, iVaw, 
iRaw, siRAW, total lung capacity, lung 
lobar volumes, trachea length and 
diameter at FRC and TLC after 12 days 
of treatment and after 28 days of 
treatment.

To assess the safety and tolerability of 
once daily repeat inhaled doses of 
GSK2269557 administered to subjects 
with acute exacerbation of COPD, 
compared to placebo.

Adverse events 

Hematology, clinical chemistry 

Vital signs

12-lead ECG

To evaluate the plasma PK of once daily 
repeat inhaled doses of GSK2269557 
administered to subjects with acute 
exacerbation of COPD

Day 1 plasma Cmax and trough (24 
hours) post dose for inpatients

Trough concentration after 12 days, 28 
days, 56 days and 84 days of treatment.

To evaluate the effect of once daily 
repeat inhaled doses of GSK2269557 on 
lung function parameters in subjects with 
acute exacerbation of COPD, compared 
to placebo

PEF, Reliever usage.

FEV1 and FVC at clinic prior to sputum 
induction.
Exploratory 

To establish any other PI3K-dependent 
changes in mRNA in sputum or blood 
from patients with an exacerbation of 
COPD, with or without treatment with 
GSK2269557.

To explore the pharmacodynamic effects 
in induced sputum of once daily repeat 
inhaled doses of GSK2269557 
administered to subjects with acute 
exacerbation of COPD, compared to 

Alterations in immune cell mechanisms 
as determined by changes in mRNA 
transcriptomics in induced sputum or 
blood after 12, 28 and 84 days of 
treatment.

Endpoints may include, but not limited to 
cytokines (IL-6, IL-8, TNF), microbiome 
(by 16SrRNA), bacterial qPCR, viral 
qPCR.
 
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Objectives
Endpoints
placebo.

To assess the changes in other CT 
parameters such as low attenuation 
score after once daily repeat inhaled 
doses of GSK2269557 administered to 
subjects with acute exacerbation of 
COPD, compared to placebo.

Change from baseline for other CT 
parameters including low attenuation 
score after 12 days of treatment and 
after 28 days of treatment.
4.
STUDY DESIGN
4.1.
Overall Design
This is a randomised, double-blind, placebo-controlled, parallel-group study.  All subjects
will continue on their usual COPD medications throughout the entire duration of the 
study regardless of treatment arm assignment.  Subjects will be on standard of care 
treatment (antibiotic and corticosteroids) upon diagnosis of a COPD exacerbation.
SCR
Signature 
ICF
Day 1
Randomisation / 
First dose GSK2269557
Day 12
(+/- 2 days) 
HRCT
Day 28
(+/- 2 days)
HRCT
Day 56
(-4 / + 2 days)
Safety visit
Day 84
(-4 / + 2 days)
End treatment
FU
Baseline
HRCT
Within 48h / discharge
Baseline lung function
4.2.
Treatment Arms and Duration
Subjects will be required to participate in the following:
Screening: Following diagnosis during outpatient assessment by a Respirologist, 
Emergency Department visit or acute admission to hospital, and up to 3 days before start 
of study treatment. During this time:

The start of the standard of care (to include both antibiotics and corticosteroids) is 
expected to start shortly after diagnosis, though it is allowed to have already been 
started before the formal diagnosis of COPD exacerbation is made. 

The HRCT scan should be conducted at the earliest opportunity after obtaining 
Informed Consent from the subject and within 48 h of diagnosis by a Respirologist or 
physician with respiratory experience. 
 
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
Randomisation and first dose administration should take place as soon as possible 
following HRCT scan assessment has been performed and no later than 24h after 
completing the HRCT scan.
Treatment period:  Once daily study treatment administration will start on Day 1 (visit 1). 

For subjects who were hospitalized: 
o
If discharge takes place before Day 10, the subject must complete the 
assessments planned for visit 2 on discharge and must then visit the unit 
on Day 12 (2 days) (visit 3).
o
If discharge takes place between Day 10 and Day 14 (inclusive), the 
assessments planned for visit 2 and visit 3 may be completed on the day of 
discharge.
o
If discharge takes place from Day 15 (inclusive), the assessments planned 
for visit 2 and visit 3 should be completed as soon as it is safe for the 
patient to do so.

For subjects who were not hospitalized: the subject must complete the 
assessments planned for visit 2 within 48 hours of start of treatment, and must 
then visit the unit on Day 12 (2 days) to complete the assessments planned for 
visit 3.
Subjects will then dose at home until Day 84 (– 4 / + 2 days), with the exception of the 
days when subjects come to the clinic. On those days, they will dose at the clinic. On Day 
12 (± 2 days) (unless visit completed on discharge), Day 28 (± 2 days), Day 56 (– 4 / + 2 
days) and Day 84 (– 4 / + 2 days) subjects will return on an outpatient basis to complete 
the assessments described in the Time & Event table (Section 7.1). Subjects will be 
discharged once all assessments have been performed and there are no safety concerns.
Follow up: 7 to 14 days after last dose.
The total duration of the study is 13-14 weeks including the screening visit.
4.3.
Type and Number of Subjects
Approximately 35 subjects with an acute exacerbation of COPD will be randomized such 
that approximately 15 subjects on active and 15 subjects on placebo provide sputum at all 
the scheduled time points and complete the study.   If a higher than expected number of 
subjects prematurely discontinue the study, or fail to produce sufficient sputum post 
randomisation additional subjects may be randomised at the discretion of the sponsor.
4.4.
Design Justification
This study will include a placebo control to allow for a valid evaluation of the 
pharmacodynamic endpoints and adverse events attributable to treatment versus those 
 
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independent of treatment. Subjects will also receive standard of care for their 
exacerbation and throughout the study.
4.5.
Dose Justification
The dose chosen for this study is 1000 µg of GSK2269557 per day administered via a dry 
powder inhaler for a duration of 84 days (– 4 / + 2 days). This dose has been selected 
based on previous safety and tolerability data in man (healthy subjects and COPD 
subjects) as well as demonstration of target (PI3K) inhibition by observed changes in 
biomarkers. Together with an additional study to be run in parallel (PII116678), this dose 
of GSK2269557 is being dosed to subjects in PII116678 with an exacerbation of COPD,
so it will be assumed for exposure predictions, unless otherwise stated, that these subjects 
will have a similar lung deposition, distribution and plasma exposure to that of the 
healthy volunteers. However it is accepted that these types of subjects may have reduced 
airway conductance and hence likely reduced deposition. This can be appropriately 
defined in this study based on the actual plasma exposures achieved. 
Twice this dose level (2000 µg) using the same formulation has previously been given 
once daily to healthy male smokers for 14 days (study PII116617). There is also an 
ongoing study where a total daily dose of 1000 µg of GSK2269557 is administered to 
stable COPD subjects via a dry powder inhaler for 14 days (study PII115119) which at 
the time of writing of this protocol had successfully dosed 21 subjects on active treatment 
and collected pharmacokinetics (PK) samples for analysis out to 14 days.
The target effect compartment for PI3Kinhibition is the intracellular compartment of 
the immune cells resident in the lung tissue and lumen.  GSK2269557 has a high potency 
and selectivity at the PI3Kenzyme (Ki value 0.1 ng/mL) which translates into an IC50 in 
a more complex system (PHA stimulated lung tissue) of approximately 120 ng/mL (or 
2.5 ng/mL free unbound drug).  Based on the measured steady-state cellular 
concentration of GSK2269557 collected at trough (24 h) from the lungs of healthy 
smokers at 2000 µg DPI (450 ng/mL) in the clinical study it is expected that at 1000 µg 
(225 ng/mL), concentrations will be sufficient and PI3Kinhibition maintained in the 
lung at 90% inhibition for 24 h. 
Target PI3Kinhibition is based on a wide range of pharmacology experiments.  Details 
of these as well as the pharmacokinetics and safety data can be found in the IB, 
[GlaxoSmithKline Document Number: 2012N141231_04].
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK2269557 can be found in the IB [GlaxoSmithKline Document Number 
2012N141231_04]. The following section outlines the risk assessment and mitigation 
strategy for this protocol:  
 
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4.6.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Investigational Product (IP) [e.g., GSK2269557]
Bronchospasm
Mucosal irritancy
A general risk with Inhaled 
treatment
Detected in 13 week toxicology 
study in the dog
Subjects will be allowed to 
continue regular COPD 
treatments and have standard 
of care for treatment of their 
exacerbation. More severe 
patients will have their 
treatment started in hospital. 
Patients will be regularly 
monitored for AEs and a 
patient diary kept. Thus far this 
has not been seen in clinical 
studies.
Potential photosensitivity  
In the absorption spectrum for 
GSK2269557 there are peaks 
at the boundary of the 
ultraviolet (UV) light 
[UVA/UVB] region with a 
lambda max at 320 nm (molar 
extinction coefficient 
43800 L/Mol/cm), with smaller 
peaks at 305 nm and 332 nm.
Subjects will be advised to 
take UV protection measures 
(see Section 6.11).
Study Procedures
Radiation risk as part of HRCT 
scans
The maximum amount of 
radiation dose a patient 
undergoing all six scans will 
receive is approximately 
12mSv. Six low dose HRCT 
scans (one at TLC and FRC on 
screening, Day 12 and Day 28 
visits) at are required 
throughout the study for the 
functional imaging protocol
Reduced tube voltage (100 
kV), and tube current are used.
Scanning time less than 5 s 
per scan.
Total radiation dose for a total 
of six CT scans will be 
approximately 12mSv.
Final radiation dose will be 
dependent on the patient 
weight, with a range of 
between 1-2mSv per scan per 
patient. This radiation dose 
falls into the International 
Commission on Radiological 
Protections [ICRP, 2007]
category IIb (minor to 
intermediate risk).
 
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
The outcomes of this study will 
provide information which 
would produce advances in 
knowledge, leading to a 
potential health benefit in the 
future for patients in this target 
population. The CT may also 
provide information for the 
patients general clinical 
management
Sputum induction
Standard sputum induction 
techniques using hypertonic 
saline can result in 
bronchospasm and therefore 
could potentially induce 
bronchospasm in a patient or 
impact a pre-existing 
exacerbation..
For patients during an 
exacerbation and for sputum 
induction during the recovery 
period, including the day 28 
visit, patients will be pre-dosed 
with nebulised or inhaled beta-
2-agonist (or ipratropium 
bromide if beta-2-agonist 
intolerant). Sputum induction 
will only be carried out using 
Normal (0.9%) saline, which is 
also often used in patients 
clinically to facilitate sputum 
clearance.  
For the final sputum induction 
patients will be pre-dosed with 
nebulised or inhaled beta-2-
agonist (or ipratropium bromide 
if beta-2-agonist intolerant) and 
the induction carried out with 
0.9% saline initially and only 
then followed by hypertonic (3-
5%) if required, and, in the 
opinion of the Investigator,  it is 
considered safe to do so.
4.6.2.
Benefit Assessment
The outcomes of this study will provide information which will produce advances in 
knowledge of the pathophysiology of COPD exacerbations, leading to a potential health 
benefit in the future for patients in this target population. The CT scan may also provide 
information for the patient’s general clinical management.
 
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4.6.3.
Overall Benefit:Risk Conclusion
The overall benefit:risk is considered to be positive. There is an opportunity to determine 
if there may be a new drug developable for the treatment of acute exacerbations of COPD 
which has not seen any new treatments recently. The scientific value in obtaining 
functional CT information on the anatomy and pathophysiology of COPD exacerbations 
and how the lung responds to therapy will be extremely valuable to the wider clinical 
community and justifies the limited radiation exposure (maximum 12 mSv in total) from 
the CT scan procedures. The CT will also be useful to provide clinical information about 
the patient for the patient’s physician and contribute to clinical management.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB [GlaxoSmithKline 
Document Number: 2012N141231_04] 
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
[1] AGE

Between 40 and 80 years of age inclusive, at the time of signing the informed 
consent.
[2] TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY

The subject has a confirmed and established diagnosis of COPD, as defined by the 
GOLD guidelines for at least 6 months prior to entry.

The subject is able to produce >100 mg of sputum at screening for processing, (ie, 
total weight of sputum plugs.).

The subject has a post-bronchodilator FEV1/FVC < 0.7 and FEV1 80 % of predicted 
documented in the last 5 years.

Disease severity: Acute exacerbation of COPD requiring an escalation in therapy to 
include both corticosteroid and antibiotics. Acute exacerbation to be confirmed by an 
experienced physician and represent a recent change in at least two major and one 
minor symptoms, one major and two minor symptoms, or all 3 major symptoms.
 
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1. Major symptoms:

Subjective increase in dyspnea

Increase in sputum volume

Change in sputum colour
2.
Minor symptoms:

Cough

Wheeze

Sore throat

The subject is a smoker or an ex-smoker with a smoking history of at least 10 pack 
years (pack years = (cigarettes per day smoked/20 x number of years smoked)).
[3] WEIGHT

Body weight 45 kg and body mass index (BMI) within the range 18 – 32 kg/m2
(inclusive).
[4] SEX

Male

Female subject : is eligible to participate if she is not pregnant (as confirmed by a 
negative urine human chorionic gonadotrophin (hCG) test), not lactating, and at least 
one of the following conditions applies:
1. Non-reproductive potential defined as:
Pre-menopausal females with one of the following:
Documented tubal ligation
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 
Hysterectomy
Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea.  Females whose 
menopausal status is in doubt will be required to use, or have been using, one of the 
highly effective contraception methods as specified below from 30 days prior to the first 
dose of study medication and until completion of the follow-up visit.
2. Reproductive potential and agrees to follow one of the options listed 
below in the GSK Modified List of Highly Effective Methods for 
Avoiding Pregnancy in Females of Reproductive Potential (FRP) 
requirements from 30 days prior to the first dose of study medication 
and until completion of the follow-up visit.
 
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GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females 
of Reproductive Potential (FRP)
This list does not apply to FRP with same sex partners, when this is their preferred and 
usual lifestyle or for subjects who are and will continue to be abstinent from penile-
vaginal intercourse on a long term and persistent basis.
1. Contraceptive subdermal implant that meets GSK standard criteria including a 
<1% rate of failure per year, as stated in the product label
2. Intrauterine device or intrauterine system that meets GSK standard criteria 
including a <1% rate of failure per year, as stated in the product label [Hatcher, 
2007a]
3. Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007a] 
4. Injectable progestogen [Hatcher, 2007a]
5. Contraceptive vaginal ring [Hatcher, 2007a]
6. Percutaneous contraceptive patches [Hatcher, 2007a]
7. Male partner sterilization with documentation of azoospermia prior to the female 
subject’s entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2007a].  
8. Male condom combined with a vaginal spermicide (foam, gel, film, cream, or 
suppository) [Hatcher, 2007b]
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
Specific inclusion criteria for Male subjects with female partners of reproductive 
potential is outlined below:
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until after the completion of the follow up visit.
3. Vasectomy with documentation of azoospermia.  
4. Male condom plus partner use of one of the contraceptive options below:
Contraceptive subdermal implant that meets GSK standard criteria including a 
<1% rate of failure per year, as stated in the product label
Intrauterine device or intrauterine system that meets GSK standard criteria 
including a <1% rate of failure per year, as stated in the product label [Hatcher, 
2007a]
 
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Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007a] 
Injectable progestogen [Hatcher, 2007a]
Contraceptive vaginal ring [Hatcher, 2007a]
Percutaneous contraceptive patches [Hatcher, 2007a]
5.
These allowed methods of contraception are only effective when used 
consistently, correctly and in accordance with the product label.  The 
investigator is responsible for ensuring that subjects understand how to properly 
use these methods of contraception.
[5] INFORMED CONSENT

Capable of giving signed informed consent as described in Section 10.2 which
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
[1]  CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL)

To avoid recruitment of subjects with a severe COPD exacerbation, the presence of 
any one of the following severity criteria will render the subject ineligible for 
inclusion in the study:

Need for invasive mechanical ventilation (short term (< 48h) NIV or CPAP is 
acceptable)

Haemodynamic instability or clinically significant heart failure

Confusion

Clinically significant pneumonia, identified by chest X-ray at screening, and as 
judged by the Investigator. 

Subjects who have current medical conditions or diseases that are not well controlled 
and, which as judged by the Investigator, may affect subject safety or influence the 
outcome of the study. (Note: Patients with adequately treated and well controlled 
concurrent medical conditions (e.g. hypertension or NIDDM) are permitted to be 
entered into the study).

Subject has a diagnosis of active tuberculosis, lung cancer, clinically overt 
bronchiectasis, pulmonary fibrosis, asthma or any other respiratory condition that 
might, in the opinion of the investigator, compromise the safety of the subject or 
affect the interpretation of the results.

ALT >2xULN and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if 
 
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bilirubin is fractionated and direct bilirubin <35%). 

A subject with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the exclusion criteria, outside of the reference range for the 
population being studied may be included if the Investigator [in consultation with the 
GSK Medical Monitor if required] documents that the finding is unlikely to 
introduce additional risk factors and will not interfere with the study procedures.

Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert’s syndrome or asymptomatic gallstones)

ECG indicative of an acute cardiac event (e.g. Myocardial Infarction) or 
demonstrating a clinically significant arrhythmia requiring treatment.

QTcF > 450 msec or QTcF > 480 msec in subjects with Bundle Branch Block, based 
on single QTcF value.

Subjects who have undergone lung volume reduction surgery.
[2] CONCOMITANT MEDICATIONS

Subject is currently on chronic treatment with macrolides or long term antibiotics.

Subject is being treated with long term oxygen therapy - LTOT (> 15 hours/day).

The subject has been on chronic treatment with anti-Tumour Necrosis Factor (anti-
TNF), or any other immunosuppressive therapy (except corticosteroid) within 60 days 
prior to dosing.
[3] RELEVANT HABITS

History of regular alcohol consumption within 6 months of the study defined as an 
average weekly intake of >28 units for males or >21 units for 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.
[4]  CONTRAINDICATIONS 

History of sensitivity to any of the study medications, or components thereof (such as 
lactose) or a history of drug or other allergy that, in the opinion of the investigator or 
Medical Monitor, contraindicates their participation.
[5] DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA

A known (historical) positive test for HIV antibody.

Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test 
result at screening or within 3 months prior to first dose of study treatment.
NOTE: Because of the short window for screening, treatment with GSK2269557 
may start before receiving the result of the hepatitis tests. If subsequently the test is 
found to be positive, the subject may be withdrawn, as judged by the Principal 
 
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Investigator in consultation with the Medical Monitor.

Where participation in the study would result in donation of blood or blood 
products in excess of 500 mL within 56 days.

The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the 
current study: 30 days, 5 half-lives or twice the duration of the biological effect of 
the investigational product (whichever is longer).

Exposure to more than 4 investigational medicinal products within 12 months 
prior to the first dosing day.
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized.  In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria Protocol Deviations, and any Serious Adverse Events.
5.4.
Withdrawal/Stopping Criteria
Subjects who are withdrawn from treatment will also be withdrawn from the study. 
If a higher than expected number of subjects prematurely discontinues the study, 
additional subjects may be randomised and assigned to the same treatment sequence, at 
the discretion of the Sponsor.  
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as soon 
as possible. 

The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 
telephone calls and if necessary a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
 
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A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
Subjects who are withdrawn should complete the assessments planned for the follow up 
visit.
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase II Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5, if 
measured*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
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 2.
 
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5.4.1.1.
Study Treatment Restart or Re-challenge
Study treatment restart or re-challenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.4.2.
QTc Stopping Criteria

QTcF should be based on averaged QTcF values of triplicate electrocardiograms 
obtained over a brief (e.g., 5-10 minute) recording period. For example, if an ECG 
(Electrocardiogram) demonstrates a prolonged QTcF interval, obtain two more 
ECGs and use the averaged QTcF values of the three ECGs to determine whether the 
patient should be discontinued from the study.
A subject who meets either of the bulleted criteria below will be withdrawn from the 
study:

QTcF >500 msec OR Uncorrected QT >600 msec

Change from baseline of QTcF > 60 msec
For patients with underlying bundle branch block, follow the discontinuation criteria 
listed below:
Baseline QTcF with Bundle 
Branch Block
Discontinuation QTcF with 
Bundle Branch Block
<450 msec
>500 msec
450 – 480 msec
≥530 msec
5.4.3.
Other Stopping Safety Criteria
For an individual study participant, stopping criteria include, but are not limited to:
Severe signs or symptoms, or significant changes in any of the safety assessments, that 
put the safety of the individual at risk (e.g. ECG, vital signs, laboratory tests, spirometry 
assessments, etc), as judged by the Principal Investigator in consultation with the Medical 
Monitor if necessary.
Treatment failure or recurrent exacerbation does not mandate withdrawal from the study, 
unless there is a safety concern as judged by the Investigator, in consultation with the 
Medical Monitor if necessary.
Subjects should be withdrawn from the study if confusion, acute respiratory acidosis (pH 
< 7.30), or need for invasive mechanical ventilation occurs.
5.5.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit.
The end of the study is defined as the last subject’s last visit.
 
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6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
Study Treatment
Product name:
GSK2269557
Placebo
Formulation description:
Lactose blend containing 
GSK2269557 in Diskus™device
Lactose in Diskus device
Dosage form:
Dry powder for inhalation
Dry powder for inhalation
Unit dose 
strength(s)/Dosage 
level(s):
500 µg / blister
N/A
Route of Administration
Inhalation
Inhalation
Dosing instructions:
2 inhalations to be taken every 
day before breakfast (with the 
exception of days when the 
subjects have a planned visit to 
the clinic. On those days, they 
will be dosed at the clinic). The 
subject should hold their breath 
for approximately 10 seconds 
before exhaling. Inhalations 
should be taken approximately 
30 seconds apart. 
2 inhalations to be taken every 
day before breakfast (with the 
exception of days when the 
subjects have a planned visit to 
the clinic. On those days, they 
will be dosed at the clinic). The 
subject should hold their breath 
for approximately 10 seconds 
before exhaling. Inhalations 
should be taken approximately 
30 seconds apart.
6.2.
Treatment Assignment
Subjects will be assigned to treatments in accordance with the randomization schedule
generated by Clinical Statistics, prior to the start of the study, using validated internal 
software. Central based randomisation will be used.
Subjects will be randomised to treatments A or B where:
A = Placebo 
B = GSK2269557 1000 µg 
A web based interactive response system will be used to assign subjects to treatment.
 
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6.3.
Planned Dose Adjustments
If adverse events, unrelated to COPD exacerbation, which are of moderate or severe 
intensity and are consistent across subjects in the group, or if unacceptable 
pharmacological effects, reasonably attributable in the opinion of the investigator to 
dosing with GSK2269557, are observed in more than 30% of the subjects then the study
will be halted and no further subject will be dosed until a full safety review of the study 
has taken place. Relevant reporting and discussion with the Medical Monitor, relevant 
GSK personnel, and with the Ethics Committees will then take place prior to any 
resumption of dosing. If the above is observed consideration may be given to reducing 
the dose of GSK2269557 to 500 µg O.D.
6.4.
Subject Specific Dose Adjustment Criteria
There are no subject specific dose adjustment criteria.
6.5.
Blinding
This will be a double blind study and the following will apply. 

The investigator or treating physician may un-blind a subject’s treatment assignment 
only in the case of an emergency OR in the event of a serious medical condition 
when knowledge of the study treatment is essential for the appropriate clinical 
management or welfare of the subject as judged by the investigator. 

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before un-blinding 
the subject’s treatment assignment. 

If GSK personnel are not contacted before the un-blinding, the investigator must 
notify GSK as soon as possible after un-blinding. 

The date and reason for the un-blinding must be fully documented in the Case Report 
Form (CRF)

A subject will be withdrawn if the subject’s treatment code is un-blinded by the 
investigator or treating physician. The primary reason for discontinuation (the event 
or condition which led to the un-blinding) will be recorded in the CRF.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may un-blind the 
treatment assignment for any subject with a Serious Adverse Event (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 subject’s treatment assignment, may be 
sent to investigators in accordance with local regulations and/or GSK policy.
6.6.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
 
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6.7.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

Only subjects 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 labelled storage conditions with access limited to the 
investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e. receipt, reconciliation and final disposition records).  

Further guidance and information for final disposition of unused study treatment are 
provided in the Study Reference Manual (SRM).

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, Medical Monitor and/or 
GSK study contact.

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
6.8.
Compliance with Study Treatment Administration
When subjects 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 subjects will be asked to complete a diary when dose administration takes place at 
home. The date, time and number of inhalations will be recorded. The compliance will be 
checked by the site staff at each planned visit. 
A record of the number of Diskus inhalers dispensed to each subject and the number of 
actuation administered, read from the dose counter for each Diskus inhaler, must be 
maintained and reconciled with study treatment and compliance records.  Treatment start 
and stop dates, including dates for treatment delays and/or dose reductions will also be
recorded in the CRF.
 
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6.9.
Treatment of Study Treatment Overdose
For this study, any dose of GSK2269557 >2000 µg within a 22 hour time period will be 
considered an overdose.
GSK does not recommend specific treatment for an overdose
In the event of an overdose the investigator should:
1) contact the Medical Monitor immediately
2) closely monitor the subject for adverse events (AEs)/serious adverse events 
(SAEs) and laboratory abnormalities until GSK2269557 can no longer be detected 
systemically (at least 14 days for GSK2269557)
3) obtain a plasma sample for pharmacokinetic (PK) analysis within 7 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 subject.
6.10.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because the indication being studied is not life threatening or seriously debilitating 
and/or other treatment options are available.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
Any clinical abnormalities identified during the conduct of the study will be locally 
managed by the Investigator.
6.11.
Lifestyle and/or Dietary Restrictions

Subjects must not sunbathe or use a tanning device (e.g. sunbed or solarium) whilst 
taking the study medication and until at least 2 weeks after their last dose. Subjects 
are to be advised that they should cover exposed areas of skin (e.g. use sun hat, long 
sleeves) and use a broad spectrum UVA/UVB sunscreen (SPF ≥30) on exposed areas 
of skin when outdoors.

Subjects should refrain from consumption of Seville oranges, grapefruit or grapefruit 
juice, exotic citrus fruits or grapefruit hybrids from first dose till the end of the study.

Subjects should abstain from alcohol on the day when they visit the clinical unit and 
until their discharge on that day.
 
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
Subjects should refrain from smoking for at least 2 hours prior to each pulmonary 
function test conducted at the clinical unit/site.
6.12.
Concomitant Medications and Non-Drug Therapies
6.12.1.
Permitted Medications and Non-Drug Therapies
On entry to the study all treatment required for standard of care and additional medical 
problems is permitted to start and continue.
The subjects are allowed to continue their regular COPD treatments for the duration of 
the study. However, the subjects should refrain, if possible, from using relief 
bronchodilators for at least 4 hours prior to each spirometry conducted at the clinical unit, 
and HRCT scan assessment unless essential for clinical symptom relief. Otherwise free 
use of reliever/rescue medication is allowed.  Rescue ventolin and aerochambers may be 
provided by GSK for this study.
All prior (up to 2 months prior to screening) and concomitant medications should be 
recorded in the subject’s CRF.
6.12.2.
Prohibited Medications and Non-Drug Therapies
Regular or chronic treatment with medications that are considered strong inhibitors of 
CYP3A4 or CYP2D6 are not permitted. This includes anti-epileptic treatments, 
macrolide antibiotics, oral antifungal treatments (single doses and courses up to 7 days 
are allowed) and anti-tuberculous therapy. These medications must all have been stopped 
at least 14 days prior to first dose.
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1
 
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7.1.
Time and Events Table (Screening and Follow Up Visits)
Procedure
Screening 
(up to 3 days prior to Visit 1)
Follow-up
(7-14 days post-last dose)
Notes
Informed consent
X
Demography
X
Inclusion and exclusion criteria
X
Full physical exam, including height and 
weight
X
Brief physical examination, including weight
X
Chest X-Ray
X
To be done before baseline HRCT to exclude significant 
pneumonia and other incidental serious underlying 
pathology.
Medical history (includes substance usage
and Family history of premature CV disease)
X
Substances: Drugs, Alcohol, tobacco via history.  No drug, 
alcohol screening is required.
Past and current medical conditions  
(including cardiovascular medical history and 
therapy history)
X
Laboratory assessments (include Hematology 
and biochemistry)1
X
X
Historical values analysed by local lab to be used for 
eligibility assessment. Another sample must be collected 
and sent to central lab as soon as informed consent is 
obtained. 
Hep B and Hep C screen2
X
Urine pregnancy test (only WCBP)
X
Before conducting the HRCT.  Done locally at the site.
12-lead ECG
X
X
Single assessment
Vital signs
X
X
Single assessment
HRCT (at TLC and FRC)
X
Within 48 h of diagnosis, if subject otherwise eligible. 
Includes electronic monitoring of breathing (if applicable).  
Baseline HRCT will be reviewed by the local site’s 
radiologist to identify any significant occurring underlying 
medical conditions that require further clinical management 
or monitoring.
Induced Sputum3
X4
To include sputum culture pre-first dose. Culture to be done 
by the local site laboratory.
 
 
 
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Procedure
Screening 
(up to 3 days prior to Visit 1)
Follow-up
(7-14 days post-last dose)
Notes
Blood sample for mRNA Analysis
X4
Collected at any time on specified days
AE/SAE collection and review
X
Concomitant medication review
X
X
1.
Due to the short screening window, central laboratory analysis results will not be available on time. Therefore the local laboratory results should be used for eligibility assessment 
(to exclude severe subjects and underlying medical conditions). If local laboratory results are already available from diagnosis of current exacerbation, there is no need to take 
another sample for local analysis. A sample for central laboratory analysis should also be obtained. See Section 7.8.6 for further details.
2.
If test otherwise performed within 3 months prior to first dose of study treatment, testing at screening is not required. Because of the short window for screening, treatment with 
GSK2269557 may start before receiving the result of the hepatitis tests. If subsequently the test is found to be positive, the subject may be withdrawn, as judged by the Principal 
Investigator in consultation with the Medical Monitor.
3.
Induced sputum collection may be attempted on several occasions if an adequate sample is not produced at the first attempt.
4.
To be collected at any time point before randomisation.
 
 
 
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7.2.
Time and Events Table (Treatment Period)
Procedure
Treatment Period 
Notes
Visit
1
21
3
4
5
6
Day
1
Within 48h 
/ discharge
12
28
56
84
Visit window
N/A
1 days
2 days
2 days
- 4 / +2 days
- 4 / +2 days
SAFETY ASSESSMENTS
AE/SAE collection and review
=========================================================
Concomitant medication review
=========================================================
Reliever usage
=========================================================
Brief physical exam, including weight
X2
X
X
X
X
Pre-dose
Laboratory assessments (include 
haematology and biochemistry)
X2
X
X
X
X
Pre-dose
12-lead ECG
X2
X
X
X
X
Pre-dose. Single assessment
Vital signs
X2
X
X
X
X
Pre-dose. Single assessment
Urine pregnancy test (only WCBP)
X
X
Before conducting the HRCT
STUDY TREATMENT
Randomisation
X
Study drug administration
=========================================================
Daily in the morning before breakfast, 
(with the exception of days when the 
subjects have a planned visit to the 
clinic. On those days, they will be 
dosed at the clinic).
Assessment of study treatment compliance
X
X
X
X
 
 
 
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Procedure
Treatment Period 
Notes
Visit
1
21
3
4
5
6
Day
1
Within 48h 
/ discharge
12
28
56
84
Visit window
N/A
1 days
2 days
2 days
- 4 / +2 days
- 4 / +2 days
EFFICACY ASSESSMENTS
HRCT (at TLC and FRC)
X
X
At any time on specified days. Includes 
electronic monitoring of breathing (if 
applicable).  The radiologist may review 
any of the scan(s) if they wish, but this 
is NOT required for the study.  A formal 
review is required at screening only by 
the radiologist.
FEV1  and FVC
X
X
X
X
X
X
In clinic only for all visits where 
possible.
PEF 
=========================================================
Daily before drug administration at 
home.  If subject in hospital, this may 
be collected using the handheld device 
provided prior to drug administration.
OTHER ASSESSMENTS
Blood sample for PK
X
X
X
X
X
Day 1:  5 min and 24 h post-dose. The 
24 h post-dose time-point is optional for 
subjects not hospitalised. Pre-dose at 
all other time-points.
Sputum induction3
X
X
X
Blood sample for mRNA analysis
X
X
X
Genetic sample (PGx)4
X
Collected at any time after 
randomisation
1.
On discharge if the subject was hospitalized. Within 48 hours of first dose administration if the subject was not hospitalised. See Section 4.2
2.
Assessments do not need to be completed if screening assessments conducted within 48 hours 
3.
Induced sputum collection may be repeated on several occasions if an adequate sample is not produced at the first attempt 
4.
Informed consent for optional sub-studies (e.g. ,genetics research) must be obtained before collecting a sample.  May be obtained at any visits.
 
 
 
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7.3.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.  
Procedures conducted as part of the subject’s routine clinical management and obtained 
prior to signing of informed consent may be utilized for Screening or baseline purposes 
provided the procedure meets the protocol-defined criteria and has been performed in the 
timeframe of the study.
If they are being utilised in the study, Patient Reported Outcomes questionnaires should 
be completed by subjects before any other assessment at a clinic visit, in the order 
specified.
7.4.
Biomarker(s)/Pharmacodynamic Markers
7.4.1.
Pharmacodynamic Biomarkers in Sputum

Collect sputum induction samples at the time-points shown in the time and events 
table (Section 7.1).

The sputum induction collection process will follow local standard procedures and
guidelines outlined in the SRM.

The collection of induced sputum may be attempted on several occasions if an 
adequate sample is not produced at the first attempt.

Further information on collection, processing, storage and shipping procedures are 
provided in the SRM.
7.4.2.
mRNA in blood

Collect 2.5 mL of blood into a PAXgene mRNA tube.
Details of blood sample collection, processing, storage and shipping procedures are 
provided in the SRM.
7.5.
Patient diary
The subjects will be provided with a diary to record the following data when at home: 

Time and date of each dose administration and number of inhalations.
 
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
Adverse Events and concomitant medications taken (including daily rescue 
medication – if used and how many times used).

PEF from a handheld device.  The best/highest result is recorded.
Changes in Health and details of any concomitant medications as well as PEF assessment 
details will be collected in the paper diaries and later transcribed into the CRF. 
7.6.
Genetics
Information regarding genetic research is included in Appendix 3.
7.7.
Efficacy
7.7.1.
Functional Respiratory Imaging

A CT scan with a low radiation protocol at FRC and TLC will be conducted as listed 
in the Time and Events Table (Section 7.1). The same scanner should be used for 
baseline and post-treatment scans for an individual subject.

A urine pregnancy test should be performed before the CT scan in female subjects of 
childbearing potential.

Further information is provided in the SRM.
7.7.2.
FEV1  and FVC
A triplicate FEV1 and FVC measurement will be taken at the clinic before dosing using 
the site’s spirometer as soon as it is safe to do so. These will be recorded as absolute 
values.  The best/highest result is recorded.

Further details are provided in the SRM.
7.7.3.
Peak Expiratory Flow PEF

PEF measurements will be taken (in triplicate) daily in the morning before dose 
administration, as soon as it is safe for the subject to do so. The best/highest result is 
recorded.

Subjects will be provided with a handheld device.

Further details are provided in the SRM.
7.8.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests (such as vital signs, physical exams
and laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
 
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7.8.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.
7.8.1.1.
Time period and Frequency for collecting AE and SAE information

AEs and SAEs will be collected from the start of Study Treatment until the follow-
up contact (see Section 7.8.1.3), at the time-points specified in the Time and Events 
Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product 
will be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact. 

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 4.

Investigators are not obligated to actively seek AEs or SAEs in former study
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the investigator 
must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 4.
7.8.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
 
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7.8.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in
Appendix 4.
7.8.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
7.8.1.5.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
COPD exacerbations are associated with the disease to be studied and will not be 
recorded as AEs unless they meet the definition of an SAE as defined in Appendix 4
Exacerbations that meet the definition of an SAE will be recorded on the appropriate 
eCRF section and should be reported to GSK.
Medications used to treat a COPD exacerbation will be recorded in the exacerbation 
eCRF
7.8.1.6.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs and non-serious AEs related to 
study treatment (even for non- interventional post-marketing studies) is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and the safety 
of a product under clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
 
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Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.8.2.
Pregnancy

Details of all pregnancies in female subjects and female partners of male subjects 
will be collected after the start of dosing and until the follow-up visit

If a pregnancy is reported then the investigator should inform GSK within 2 weeks 
of learning of the pregnancy and should follow the procedures outlined in Appendix 
5. 
7.8.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems.  Height and 
weight will also be measured and recorded.

A brief physical examination will include, at a minimum assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
7.8.4.
Vital Signs

Vital signs will be measured in semi-supine position after 5 minutes rest and will
include temperature, systolic and diastolic blood pressure and pulse rate and 
respiratory rate.

Three readings of blood pressure and pulse rate will be taken

First reading should be rejected

Second and third readings should be averaged to give the measurement to be 
recorded in the CRF. 
7.8.5.
Electrocardiogram (ECG)

Single 12-lead ECGs will be obtained at screening and at each other timepoint during 
the study using an ECG machine that automatically calculates the heart rate and 
measures PR, QRS, QT, and QTcF intervals.  Refer to Section 5.4.2 for QTcF
withdrawal criteria and additional QTcF readings that may be necessary.
 
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7.8.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 1, must be conducted in
accordance with the Laboratory Manual, and Protocol Time and Events Schedule.
Laboratory requisition forms must be completed and samples must be clearly labelled 
with the subject number, protocol number, site/centre number, and visit date. Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the laboratory manual. Reference ranges for all safety parameters will be
provided to the site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Historical values (if the assessment was conducted as part of the standard of care) for 
blood gases, blood culture and sputum culture may also be collected if available.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
Table 1
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 1
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose (non 
fasted)
Calcium
Alkaline 
phosphatise
Albumin
CRP
Other 
Screening 
Tests

Urine hCG Pregnancy test (as needed for women of child bearing 
potential) 2

Hepatitis B (HBsAg)

Hepatitis C (Hep C antibody)
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 5.4.1 and Appendix 2
2. Local urine testing will be standard for the protocol unless serum testing is required by local regulation or ethics 
committee.
 
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All study-required laboratory assessments will be performed by a central laboratory, apart 
from:

Hematology and clinical chemistry at screening for excluding subjects with severe 
disease and uncontrolled medical conditions. The results of each test must be entered 
into the CRF.
NOTE:  Local laboratory results are only required in the event that the central laboratory
results are not available in time for either a treatment and/or response evaluation to be 
performed. If a local sample is required it is important that the sample for central 
analysis is obtained at the same time. Additionally if the local laboratory results are used 
to make either a treatment or response evaluation, the results must be entered into the 
CRF.
Hematology, clinical chemistry and additional parameters to be tested are listed in Table 
1. 
7.9.
Pharmacokinetics
7.9.1.
Blood Sample Collection
A 2 mL blood samples for pharmacokinetic (PK) analysis of GSK2269557 will be
collected at the time points indicated in Section 7.1, Time and Events Table.  The actual
date and time of each blood sample collection will be recorded.  The timing of PK 
samples may be altered and/or PK samples may be obtained at additional time points to 
ensure thorough PK monitoring.  
Processing, storage and shipping procedures are provided in the Study Reference Manual
(SRM). 
7.9.2.
Sample Analysis
Plasma analysis will be performed under the control of PTS-DMPK/Scinovo, 
GlaxoSmithKline, the details of which will be included in the SRM. Concentrations of 
GSK2269557 will be determined in plasma samples using the currently approved 
bioanalytical methodology. Raw data will be archived at the bioanalytical site (detailed 
in the SRM).
Once the plasma has been analyzed for GSK2269557 any remaining plasma may be
analyzed for other compound-related metabolites and the results reported under a 
separate PTS-DMPK/Scinovo, GlaxoSmithKline protocol.
 
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8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.

Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSK Drug.  

CRFs (including queries and audit trails) will be retained by GSK, and copies will be 
sent to the investigator to maintain as the investigator copy.  Subject initials will not 
be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
This study is designed to establish the PI3K-dependent alterations in immune cell 
mechanisms related to neutrophil function as detected by changes in mRNA 
transcriptomics in samples of induced sputum from patients admitted with an 
exacerbation of COPD. The primary comparison will be between  subjects treated with 
GSK2269557 in addition to standard of care, and subjects treated with placebo in 
addition to standard of care. In addition, treatment comparisons between subjects at 
baseline and subsequent time points will also be produced.
9.1.
Sample Size Considerations
The sample size for this study has been based on feasibility. The sample size of 30 
subjects completing the trial, with approximately 15 of which will receive GSK2269557 
and 15 will receive placebo, is expected to be sufficient to provide a meaningful estimate 
of the mRNA alterations within the lungs.
Previous studies with similar sample size populations have yielded significant fold-
changes (fold-change>1.5 and p<0.05) in immune cell mechanisms using the changes in 
mRNA transcriptomics.
 
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Study Name
Sample
Study Design
Number of Subjects
Number of Differential 
probesets FC = >= 1.5, 
Pval <= 0.05
Notes
PII115117 FTIH 
Healthy Smoker 
nebulised 
GSK2269557
Sputum
Sputum N=12 3-
way x-over 
placebo 400ug, 
6400ug 
12 (9 with all data 
points)
57 probesets change with 
both doses = 44 Genes
Gene changes relate predominantly 
to a down regulation of infection and 
inflammation responses.
Link to Haemophilus influenzae and 
Moraxella catarrhalis infection 
biology – Identified prior to 
knowledge of Activated PI3Kδ 
Syndrome phenotype
200114 Enabler 
GSK2269557 on ex-
vivo COPD Sputum 
and Blood
Sputum
Ex vivo Sputum 
incubated with 
GSK2269557 
sampled at 
6hrs (Sputum 
producers)
15 Subjects
490 probesets change vs 
vehicle control = 295 
genes (of which 43 are 
dysregulated in COPD 
disease vs Healthy 
comparison)
43 genes altered in COPD and 
positively modulated by PI3Kδi 
GSK2269557. Biological themes in 
signature: Pro-cell 
movement/migration  and cell 
viability, anti-apoptotic. Additionally 
link to B/T cell function. Signature 
supports GSK2269557 correction of 
neutrophil migration 
200114 Enabler 
GSK2269557 on ex-
vivo COPD Sputum 
and Blood
Blood
Ex vivo blood 
incubated with 
GSK2269557 
sampled at 
6hrs (Sputum 
15 Subjects
19 probesets change vs 
vehicle control = 15 genes 
Infection and inflammation 
associated genes
200114 Enabler 
GSK2269557 on ex-
vivo COPD Sputum 
and Blood
Blood
Ex vivo blood 
incubated with 
GSK2269557 
sampled at 
6h
(N
15 Subjects
30 probesets change vs 
vehicle control = 25 genes 
Infection and inflammation 
associated genes
9.1.1.
Sample Size Re-estimation or Adjustment
No sample size re-estimation will be performed in this study. 
9.2.
Data Analysis Considerations
9.2.1.
Analysis Populations
Population
Definition / Criteria
Analyses Evaluated
Screened
All subjects who were screened.

Study Population
All subject
All randomised subjects who receive at least 
one dose of the study treatment.
This population will be based on the 
treatment the subject actually received.

Study Population

Pharmacodynamics

Safety

Efficacy
Pharmacokinetic
Subjects in the ‘All subject’ population for 
whom a pharmacokinetic sample was 
obtained and analysed.

PK
9.2.2.
Interim Analysis
No interim analyses will be performed.
 
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9.3.
Key Elements of Analysis Plan
9.3.1.
Primary Analyses
To estimate differences in mRNA intensities within and between treatment groups, a 
repeated measures model will be fitted to the results of the analysis of each probe set at 
Day 12, Day 28 and Day 84 following a loge transformation of the data. The Day 1 
response will be fitted as a baseline covariate. A separate model will be fitted for each of 
the approximate 54000 probe sets.
Back transformed ratios versus screening along with 95% confidence intervals will be 
calculated for each treatment group and timepoint.  Additionally, baseline adjusted ratios 
of the change between active treatment and placebo will be calculated along with 95% 
confidence intervals.
Further details around the analysis of the mRNA data will be provided in the RAP.
9.3.2.
Secondary Analyses
All secondary analyses will be described in full prior to unblinding in the RAP.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Signed informed consent  to be obtained for each subject before participation in the 
study (and for amendments as applicable)
 
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
Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, or 
both.

Signed informed consent must be obtained for each subject prior to participation in 
the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, written 
approval of the clinical protocol should state that approval of optional assessments is 
being deferred and the study, with the exception of the optional assessments, can be 
initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will
serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and the 
regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study. 
 
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
In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective 
and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard Operating 
Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this study 
at any time for reasons including, but not limited to, safety or ethical issues or severe 
non-compliance. For multicenter studies, this can occur at one or more or at all sites.  

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by 
local regulations to be maintained elsewhere), in a safe and secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review in 
conjunction with assessment of the facility, supporting systems, and relevant site 
staff.  

Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, including 
re-generating a hard copy, if required.  Furthermore, the investigator must ensure 
 
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there is an acceptable back-up of these reproductions and that an acceptable quality 
control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by any 
institutional requirements or local laws or regulations, GSK standards/procedures, 
and/or institutional requirements. 

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of ownership 
of the records in the event the investigator is no longer associated with the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
The procedures and timing for public disclosure of the 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.
 
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11.
REFERENCES
De Backer J, Vos W, Vinchurkar S, Van Holsbeke C, Poli, G, Claes R et al. The Effect of 
Extrafine Beclometasone/Formoterol (BDP/F) on Lung Function, Dyspnea, 
Hyperinflation, and Airway Geometry in COPD Patients:  Novel Insight Using 
Fundtional Respiratory Imaging. Journal of Aerosol Medicine and Pulmonary Drug 
Delivery. 2014;27:1-12. 
De Backer LA, Vos WG, Salgado R, De Backer JW, Devoldr A, Verhulst SL et al. 
Functional imaging using computer methods to compare the effect of salbutamol and 
ipratropium bromide in patient-specific airway models of COPD. International Journal 
of COPD. 2011;6:637-646. 
De Backer Lieve A, Vos Wim, Van Holsbeke C, Vinchurkar S, De Backer W. The acute 
effect of budesonide/formoterol in COPD:  a multi-slice computed tomography and lung 
function study. Eur Respir J. 2012;40:298-305. 
GlaxoSmithKline Document Number 2012N141231_04: GSK2269557 Investigator's 
Brochure. Report Date 12-FEB-2015. 
Goldin J, Tashkin D, Kleerup E, Greaser MS, Haywood U, Sayre J et al. Comparative 
effects of hydrofluoroalkane and chloroflurocarbon beclomethasone dipropionate 
inhalation on small airways: Assessment with functional helical thin-section computed 
tomography. J Allergy Clin Immunol. 1999;104 #6:S258-S267. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D et al. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007(a):24. Table 3-2. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D et al. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007(b): 28. 
ICRP. 2007 Recommendation of the International Commission on Radiological 
Protection. ICRP Publication 103. 2007;37:2-4. 
Kim SR, Lee KS, Park HS, et al. HIF -1 alpha inhibition ameliorates an allergic airway
disease via VEGF suppression in bronchial epithelium. Eur J Immunol. 2010;40 
(10):2858-69. 
Okkenhaug K, Aki K, Vanhaesebroeck B. Antigen receptor signalling:  A distincive role 
for the p110 isoform of PI3K. Trends in Immunuology. 2007;28:80-7. 
Sadhu C, Dick K, Tino WT, Staunton DE. Selective role of PI13K delta in neutrophil 
inflammatory responses. Biochem Biophys Res Commun. 2003 Sep 5;308 (4):764-9. 
Weisser SB, McLarren KW, Voglmaier B, et al. Alternative activation of macrophages 
by IL-4 requires SHIP degradation. Eur J Immunol. 2011;41(6):1742-53. 
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
AE
Adverse Event
ALT
Alanine aminotransferase
COPD
Chronic Obstructive Pulmonary Disease
CRF
Case Report Form
CT
Computed Tomography
CV
Cardiovascular
ECG
Electrocardiogram
FEV1
Forced Expiratory Volume in One Second
FRC
Functional Residual Capacity
FRI
Functional Respiratory Imaging
GCP
ICH Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GSK
GlaxoSmithKline
HRCT
High-Resolution Computed Tomography
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
PEF
Peak Expiratory Flow
PI3K
Phosphoinositide 3-Kinase Delta
PK
Pharmacokinetic
QTcF
QT interval corrected using the Fridericia's formula
RAP
Reporting and Analysis Plan
SAE
Serious Adverse Event
SRM
Study Reference Manual
TLC
Total Lung Capacity
ULN
Upper Limit of Normal
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
DISKUS
None
 
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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Phase II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase II liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete an
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with study 
treatment unless allowed per protocol and GSK 
Medical Governance approval is granted (refer 
to Appendix 2).

If restart/rechallenge not allowed per protocol 
or not granted, permanently discontinue study 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained 7 days after last 
dose5

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 
 
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treatment and may continue subject in the study 
for any protocol specified follow up assessments 
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-72 
hrs 

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline
form including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in subjects with definite or likely 
acetaminophen use in the preceding 
week [James, 2009]). NOTE: not 
required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN.. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, 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 subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
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 
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.)  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.
 
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Phase II liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject safety. 

Subject can continue study treatment 

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
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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12.3.
Appendix 3: Genetic Research
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and:

Response to medicine, including any treatment regimens under investigation in this 
study or any concomitant medicines;

COPD susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.

A 6 mL blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. A 
Blood sample is collected at the baseline visit, after the subject has been randomized 
and provided informed consent for genetic research. Instructions for collection and 
shipping of the genetic sample are described in the laboratory manual. The DNA 
from the blood sample may undergo quality control analyses to confirm the integrity 
of the sample. If there are concerns regarding the quality of the sample, then the 
sample may be destroyed. The blood sample is taken on a single occasion unless a
duplicate sample is required due to an inability to utilize the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
 
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the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA sample 
is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will continue 
to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
 
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reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
 
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12.4.
Appendix 4: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.4.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

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 medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

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 prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected 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 this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).
Events NOT meeting definition of an AE include:

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 subject’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 
subject’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
 
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convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
12.4.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject 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 hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject 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 out-patient setting.  Complications that occur during 
hospitalization are AEs.  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 disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g. sprained ankle) which may interfere or 
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e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether 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 subject or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition.  These should also be 
considered serious.

Examples of such events are 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
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.4.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
 
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12.4.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’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 instance, all subject identifiers, with the exception of 
the subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
12.4.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
 
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Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence 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 natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of 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 when 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 prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject 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 the designated 
reporting time frames.
 
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12.4.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data 
collection tool

If the electronic system is unavailable for greater than 24 hours, the site will use 
the paper SAE data collection tool and fax it to the Medical Monitor.

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission 
of the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes 
to existing data

If a site receives a report of a new SAE from a study subject or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, the site can report this information on a paper SAE form or to the 
Medical Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
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12.5.
Appendix 5: Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who 
becomes pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 
2 weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, 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. 

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 4. 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 subject who becomes pregnant while participating will discontinue 
study medication
Pregnancy information on female partner of male study subjects

Investigator will attempt to collect pregnancy information on any female partner of 
a male study subject who becomes pregnant while participating in this study.  This 
applies only to subjects who are randomized to receive study medication. 

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate 
form and submit it to GSK within 2 weeks of learning of the partner’s pregnancy

Partner will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded to GSK. 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date.  Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for procedure.
 
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12.6.
Appendix 6: Country Specific Requirements
No country-specific requirements exist.
 
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12.7.
Appendix 7: Protocol Amendment Changes
The amendment was created to remove the specific equations for the prediction of 
percent predicted from spirometry from the inclusion criteria (European Community of 
Coal and Steel and European Respiratory Society Global Lung Function Initiative 
reference equations (Quanjer 2012) in Section 7.7.2.  At screening it may not be possible
to identify which correction method was used, or modify the correction method used, at 
the time.  As a result it may not be valid to stipulate that lung function values be 
corrected using any particular method.  Both FEV1 and FVC measurements (which are 
not entry criteria for the study) collected during the study will be collected as absolute 
values (uncorrected), so that consistency will be obtained across all sites in the study, and 
percent predicted will be calculated using a standard approach in house at the end of the 
study.
List of specific changes:
Page 22, Inclusion Criteria (#2 – Type of Subject and Diagnosis Including Disease 
Severity) - Third Bullet.
PREVIOUS TEXT

The subject has a post-bronchodilator FEV1/FVC < 0.7 and FEV1 80 % of 
predicted. Predictions should be according to the European Community of Coal and 
Steel (ECCS) equations OR the European Respiratory Society Global Lung Function 
Initiative reference equations [Quanjer, 2012] and documented in the last 5 years.
REVISED TEXT

The subject has a post-bronchodilator FEV1/FVC < 0.7 and FEV1 80 % of
predicted documented in the last 5 years.
Page 40, Section 7.7.2 (FEV1 and FVC)
PREVIOUS TEXT
A triplicate FEV1 and FVC measurement will be taken at the clinic before dosing using 
the site’s spirometer as soon as it is safe to do so.  Predicted values will be based upon the 
European Respiratory Society Global Lung Function Initiative reference equations
[Quanjer, 2012].
 
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REVISED TEXT
A triplicate FEV1 and FVC measurement will be taken at the clinic before dosing using 
the site’s spirometer as soon as it is safe to do so.  These will be recorded as absolute 
values.  The best/highest result is recorded.
Page 54 – References
PREVIOUS TEXT
De Backer J, Vos W, Vinchurkar S, Van Holsbeke C, Poli, G, Claes R et al. The Effect of 
Extrafine Beclometasone/Formoterol (BDP/F) on Lung Function, Dyspnea, 
Hyperinflation, and Airway Geometry in COPD Patients:  Novel Insight Using 
Fundtional Respiratory Imaging. Journal of Aerosol Medicine and Pulmonary Drug 
Delivery. 2014;27:1-12. 
De Backer LA, Vos WG, Salgado R, De Backer JW, Devoldr A, Verhulst SL et al. 
Functional imaging using computer methods to compare the effect of salbutamol and 
ipratropium bromide in patient-specific airway models of COPD. International Journal 
of COPD. 2011;6:637-646. 
De Backer Lieve A, Vos Wim, Van Holsbeke C, Vinchurkar S, De Backer W. The acute 
effect of budesonide/formoterol in COPD:  a multi-slice computed tomography and lung 
function study. Eur Respir J. 2012;40:298-305. 
GlaxoSmithKline Document Number 2012N141231_04: GSK2269557 Investigator's 
Brochure. Report Date 12-FEB-2015. 
Goldin J, Tashkin D, Kleerup E, Greaser MS, Haywood U, Sayre J et al. Comparative 
effects of hydrofluoroalkane and chloroflurocarbon beclomethasone dipropionate 
inhalation on small airways: Assessment with functional helical thin-section computed 
tomography. J Allergy Clin Immunol. 1999;104 #6:S258-S267. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D et al. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007(a):24. Table 3-2. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D et al. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007(b): 28. 
ICRP. 2007 Recommendation of the International Commission on Radiological 
Protection. ICRP Publication 103. 2007;37:2-4. 
Kim SR, Lee KS, Park HS, et al. HIF -1 alpha inhibition ameliorates an allergic airway 
disease via VEGF suppression in bronchial epithelium. Eur J Immunol. 2010;40 
(10):2858-69. 
Okkenhaug K, Aki K, Vanhaesebroeck B. Antigen receptor signalling:  A distincive role 
for the p110 isoform of PI3K. Trends in Immunuology. 2007;28:80-7. 
 
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Quanjer P, Stanojevic S, Cole T, Baur X, Hall G, et al. Multi-ethnic reference values for 
spirometry for the 3-95-yr age range:  The global lung function 2012 equations. 
European Respiratory Journal. 2012;40(6):1324-1343. 
Sadhu C, Dick K, Tino WT, Staunton DE. Selective role of PI13K delta in neutrophil 
inflammatory responses. Biochem Biophys Res Commun. 2003 Sep 5;308 (4):764-9. 
Weisser SB, McLarren KW, Voglmaier B, et al. Alternative activation of macrophages 
by IL-4 requires SHIP degradation. Eur J Immunol. 2011;41(6):1742-53. 
REVISED TEXT
De Backer J, Vos W, Vinchurkar S, Van Holsbeke C, Poli, G, Claes R et al. The Effect of 
Extrafine Beclometasone/Formoterol (BDP/F) on Lung Function, Dyspnea, 
Hyperinflation, and Airway Geometry in COPD Patients:  Novel Insight Using 
Fundtional Respiratory Imaging. Journal of Aerosol Medicine and Pulmonary Drug 
Delivery. 2014;27:1-12. 
De Backer LA, Vos WG, Salgado R, De Backer JW, Devoldr A, Verhulst SL et al. 
Functional imaging using computer methods to compare the effect of salbutamol and 
ipratropium bromide in patient-specific airway models of COPD. International Journal 
of COPD. 2011;6:637-646. 
De Backer Lieve A, Vos Wim, Van Holsbeke C, Vinchurkar S, De Backer W. The acute 
effect of budesonide/formoterol in COPD:  a multi-slice computed tomography and lung 
function study. Eur Respir J. 2012;40:298-305. 
GlaxoSmithKline Document Number 2012N141231_04: GSK2269557 Investigator's 
Brochure. Report Date 12-FEB-2015. 
Goldin J, Tashkin D, Kleerup E, Greaser MS, Haywood U, Sayre J et al. Comparative 
effects of hydrofluoroalkane and chloroflurocarbon beclomethasone dipropionate 
inhalation on small airways: Assessment with functional helical thin-section computed 
tomography. J Allergy Clin Immunol. 1999;104 #6:S258-S267. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D et al. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007(a):24. Table 3-2. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D et al. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007(b): 28. 
ICRP. 2007 Recommendation of the International Commission on Radiological 
Protection. ICRP Publication 103. 2007;37:2-4. 
Kim SR, Lee KS, Park HS, et al. HIF -1 alpha inhibition ameliorates an allergic airway 
disease via VEGF suppression in bronchial epithelium. Eur J Immunol. 2010;40 
(10):2858-69. 
 
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Okkenhaug K, Aki K, Vanhaesebroeck B. Antigen receptor signalling:  A distincive role 
for the p110 isoform of PI3K. Trends in Immunuology. 2007;28:80-7. 
Sadhu C, Dick K, Tino WT, Staunton DE. Selective role of PI13K delta in neutrophil 
inflammatory responses. Biochem Biophys Res Commun. 2003 Sep 5;308 (4):764-9. 
Weisser SB, McLarren KW, Voglmaier B, et al. Alternative activation of macrophages 
by IL-4 requires SHIP degradation. Eur J Immunol. 2011;41(6):1742-53. 
 
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TITLE PAGE
Division:  Worldwide Development
Information Type: Clinical Protocol
Title:
A randomised, double-blind, placebo-controlled study to 
evaluate the safety, efficacy and changes in induced sputum and 
blood biomarkers following daily repeat doses of inhaled 
GSK2269557 for 12 weeks in adult subjects diagnosed with an 
acute exacerbation of Chronic Obstructive Pulmonary Disease 
(COPD)
Compound Number:
GSK2269557
Development Phase
IIA
Effective Date:
04-JUN-2015
Author(s):  
 (CCSE); 
 (CPSSO); 
 
(Respiratory CEDD); 
 (Exp Biology); 
 (Clinical Statistics); 
 (CPMS); 
 (GCSP).
Copyright 2015 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information:
Role
Name
Day Time Phone 
Number and email 
address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site Address
Primary 
Medical 
Monitor
Discovery 
Medicine 
Respiratory 
CEDD 
GlaxoSmithKline 
Gumnnels Wood 
Rd. 
Stevenage, 
Herts, 
SG1 2NY
Secondary 
Medical 
Monitor
Discovery 
Medicine 
Respiratory 
CEDD 
GlaxoSmithKline 
Gumnnels Wood
Rd. 
Stevenage, 
Herts, 
SG1 2NY
SAE contact  
information 
Medical 
monitor as 
above
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol.

I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.

I agree to ensure that all associates, colleagues and employees assisting in the 
conduct of the study are informed about their obligations. Mechanisms are in place 
to ensure that site staff receives the appropriate information throughout the study.
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
 
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 201928........................................................8
2.
INTRODUCTION....................................................................................................12
2.1.
Study Rationale ..........................................................................................12
2.2.
Brief Background ........................................................................................12
2.2.1.
Use of mRNA transcriptomics by Affymetrix.................................13
2.2.2.
Use of HRCT Endpoints to characterise Lung Function ...............14
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................15
4.
STUDY DESIGN ....................................................................................................16
4.1.
Overall Design ............................................................................................16
4.2.
Treatment Arms and Duration.....................................................................16
4.3.
Type and Number of Subjects.....................................................................17
4.4.
Design Justification.....................................................................................17
4.5.
Dose Justification........................................................................................18
4.6.
Benefit:Risk Assessment ............................................................................18
4.6.1.
Risk Assessment .........................................................................19
4.6.2.
Benefit Assessment.....................................................................20
4.6.3.
Overall Benefit:Risk Conclusion...................................................21
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............21
5.1.
Inclusion Criteria.........................................................................................22
5.2.
Exclusion Criteria........................................................................................25
5.3.
Screening/Baseline/Run-in Failures............................................................27
5.4.
Withdrawal/Stopping Criteria.......................................................................27
5.4.1.
Liver Chemistry Stopping Criteria ................................................27
5.4.1.1.
Study Treatment Restart or Re-challenge...................28
5.4.2.
QTc Stopping Criteria ..................................................................28
5.4.3.
Other Stopping Safety Criteria .....................................................29
5.5.
Subject and Study Completion....................................................................29
6.
STUDY TREATMENT ............................................................................................29
6.1.
Investigational Product and Other Study Treatment....................................29
6.2.
Treatment Assignment................................................................................30
6.3.
Planned Dose Adjustments.........................................................................30
6.4.
Subject Specific Dose Adjustment Criteria..................................................31
6.5.
Blinding.......................................................................................................31
6.6.
Packaging and Labeling..............................................................................31
6.7.
Preparation/Handling/Storage/Accountability..............................................31
6.8.
Compliance with Study Treatment Administration.......................................32
6.9.
Treatment of Study Treatment Overdose....................................................32
6.10.
Treatment after the End of the Study ..........................................................33
6.11.
Lifestyle and/or Dietary Restrictions............................................................33
6.12.
Concomitant Medications and Non-Drug Therapies....................................33
6.12.1.
Permitted Medications and Non-Drug Therapies..........................33
6.12.2.
Prohibited Medications and Non-Drug Therapies.........................34
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................34
 
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7.1.
Time and Events Table (Screening and Follow Up Visits)...........................35
7.2.
Time and Events Table (Treatment Period) ................................................37
7.3.
Screening and Critical Baseline Assessments ............................................39
7.4.
Biomarker(s)/Pharmacodynamic Markers ...................................................39
7.4.1.
Pharmacodynamic Biomarkers in Sputum ...................................39
7.4.2.
mRNA in blood ............................................................................39
7.5.
Patient diary................................................................................................39
7.6.
Genetics .....................................................................................................40
7.7.
Efficacy.......................................................................................................40
7.7.1.
Functional Respiratory Imaging ...................................................40
7.7.2.
FEV1  and FVC.............................................................................40
7.7.3.
Peak Expiratory Flow PEF ...........................................................40
7.8.
Safety .........................................................................................................41
7.8.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........41
7.8.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................41
7.8.1.2.
Method of Detecting AEs and SAEs ...........................41
7.8.1.3.
Follow-up of AEs and SAEs........................................42
7.8.1.4.
Cardiovascular and Death Events ..............................42
7.8.1.5.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................42
7.8.1.6.
Regulatory Reporting Requirements for SAEs............42
7.8.2.
Pregnancy ...................................................................................43
7.8.3.
Physical Exams ...........................................................................43
7.8.4.
Vital Signs....................................................................................43
7.8.5.
Electrocardiogram (ECG).............................................................43
7.8.6.
Clinical Safety Laboratory Assessments ......................................44
7.9.
Pharmacokinetics .......................................................................................45
7.9.1.
Blood Sample Collection..............................................................45
7.9.2.
Sample Analysis ..........................................................................45
8.
DATA MANAGEMENT ...........................................................................................46
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................46
9.1.
Sample Size Considerations.......................................................................46
9.1.1.
Sample Size Re-estimation or Adjustment...................................47
9.2.
Data Analysis Considerations .....................................................................47
9.2.1.
Analysis Populations....................................................................47
9.2.2.
Interim Analysis ...........................................................................47
9.3.
Key Elements of Analysis Plan ...................................................................48
9.3.1.
Primary Analyses.........................................................................48
9.3.2.
Secondary Analyses ....................................................................48
10. STUDY GOVERNANCE CONSIDERATIONS........................................................48
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............48
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................48
10.3.
Quality Control (Study Monitoring) ..............................................................49
10.4.
Quality Assurance.......................................................................................50
10.5.
Study and Site Closure ...............................................................................50
10.6.
Records Retention......................................................................................50
 
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10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................51
11. REFERENCES.......................................................................................................52
12. APPENDICES........................................................................................................54
12.1.
Appendix 1: Abbreviations and Trademarks................................................54
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................55
12.3.
Appendix 3: Genetic Research ...................................................................58
12.4.
Appendix 4: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................61
12.4.1.
Definition of Adverse Events........................................................61
12.4.2.
Definition of Serious Adverse Events...........................................62
12.4.3.
Definition of Cardiovascular Events .............................................63
12.4.4.
Recording of AEs and SAEs ........................................................64
12.4.5.
Evaluating AEs and SAEs............................................................64
12.4.6.
Reporting of SAEs to GSK...........................................................66
12.5.
Appendix 5: Collection of Pregnancy Information........................................67
12.6.
Appendix 6: Country Specific Requirements...............................................68
 
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1.
PROTOCOL SYNOPSIS FOR STUDY 201928
Rationale
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To establish the PI3K-dependent 
changes in previously identified immune 
cell mechanisms specifically related to 
neutrophil function using mRNA in 
sputum from patients with an 
exacerbation of COPD, with or without 
treatment with GSK2269557.

Alterations in previously identified
immune cell mechanisms specifically 
related to neutrophil function as 
determined by changes in mRNA
transcriptomics in induced sputum after 
12, 28 and 84 days of treatment.
Secondary

To evaluate the effect of once daily 
repeat inhaled doses of GSK2269557 on 
lung parameters derived from HRCT 
scans in subjects with acute 
exacerbation of COPD, compared to 
placebo.

Change from baseline in siVaw, iVaw, 
iRaw, siRAW, total lung capacity, lung 
lobar volumes, trachea length and 
diameter at FRC and TLC after 12 days 
of treatment and after 28 days of 
treatment.

To assess the safety and tolerability of 
once daily repeat inhaled doses of 
GSK2269557 administered to subjects 
with acute exacerbation of COPD, 
compared to placebo.

Adverse events 

Haematology, clinical chemistry 

Vital signs

12-lead ECG

To evaluate the plasma PK of once daily 
repeat inhaled doses of GSK2269557 
administered to subjects with acute 
exacerbation of COPD.

Day 1 plasma Cmax and trough (24 
hours) post dose for inpatients

Trough concentration after 12 days, 28 
days, 56 days and 84 days of treatment.

To evaluate the effect of once daily 
repeat inhaled doses of GSK2269557 on 
lung function parameters in subjects with 
acute exacerbation of COPD compared 
to placebo.

PEF

Reliever usage

FEV1 and FVC at clinic prior to sputum 
induction
Exploratory

To establish any other PI3K-dependent 
changes in mRNA in sputum or blood 
from patients with an exacerbation of 
COPD, with or without treatment with 
GSK2269557.

To explore the pharmacodynamic effects 
in induced sputum of once daily repeat 
inhaled doses of GSK2269557

Alterations in immune cell mechanisms 
as determined by changes in mRNA 
transcriptomics in induced sputum or 
blood after 12, 28 and 84 days of 
treatment.

Endpoints may include, but not limited to 
cytokines (IL-6, IL-8, TNF), microbiome 
(by 16SrRNA), bacterial qPCR, viral 
 
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Objectives
Endpoints
administered to subjects with acute 
exacerbation of COPD, compared to 
placebo.
qPCR.

To assess the changes in other CT 
parameters such as low attenuation 
score after once daily repeat inhaled 
doses of GSK2269557 administered to 
subjects with acute exacerbation of 
COPD, compared to placebo.

Change from baseline for other CT 
parameters including low attenuation 
score after 12 days of treatment and 
after 28 days of treatment
Overall Design
This is a randomised, double-blind, placebo-controlled, parallel-group study.  All subjects 
will continue on their usual Chronic Obstructive Pulmonary Disease (COPD) medications 
throughout the entire duration of the study regardless of treatment arm assignment.  
Subjects will be on standard of care treatment (antibiotic and corticosteroids) upon 
diagnosis of a COPD exacerbation.
SCR
Signature 
ICF
Day 1
Randomisation / 
First dose GSK2269557
Day 12
(+/- 2 days) 
HRCT
Day 28
(+/- 2 days)
HRCT
Day 56
(-4 / + 2 days)
Safety visit
Day 84
(-4 / + 2 days)
End treatment
FU
Baseline
HRCT
Within 48h / discharge
Baseline lung function
Treatment Arms and Duration
Subjects will be required to participate in the following:
Screening: Following diagnosis during outpatient assessment by a Respirologist, 
Emergency Department visit or acute admission to hospital, and up to 3 days before start 
of study treatment. During this time:

The start of the standard of care (to include both antibiotics and corticosteroids) is 
expected to start shortly after diagnosis, though it is allowed to have already been 
started before the formal diagnosis of COPD exacerbation is made. 
 
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
The High-Resolution Computed Tomography (HRCT) scan should be conducted at 
the earliest opportunity after obtaining Informed Consent from the subject and within 
48 h of diagnosis by a Respirologist or physician with respiratory experience. 

Randomisation and first dose administration should take place as soon as possible 
following HRCT scan assessment has been performed and no later than 24h after 
completing the HRCT scan.
Treatment period:  Once daily study treatment administration will start on Day 1 (visit 1). 

For subjects who were hospitalized: 
o
If discharge takes place before Day 10, the subject must complete the 
assessments planned for visit 2 on discharge and must then visit the unit 
on Day 12 (2 days) (visit 3).
o
If discharge takes place between Day 10 and Day 14 (inclusive), the 
assessments planned for visit 2 and visit 3 may be completed on the day of 
discharge.
o
If discharge takes place from Day 15 (inclusive), the assessments planned 
for visit 2 and visit 3 should be completed as soon as it is safe for the 
patient to do so.

For subjects who were not hospitalized: the subject must complete the 
assessments planned for visit 2 within 48 hours of start of treatment, and must 
then visit the unit on Day 12 (2 days) to complete the assessments planned for 
visit 3.
Subjects will then dose at home until Day 84 (– 4 / + 2 days), with the exception of the 
days when subjects come to the clinic. On those days, they will dose at the clinic. On Day 
12 (± 2 days) (unless visit completed on discharge), Day 28 (± 2 days), Day 56 (– 4 / + 2 
days) and Day 84 (– 4 / + 2 days) subjects will return on an outpatient basis to complete 
the assessments described in the Time & Event table. Subjects will be discharged once all 
assessments have been performed and there are no safety concerns.
Follow up: 7-14 days after last dose.
The total duration of the study is 13-14 weeks including the screening visit.
Type and Number of Subjects
Approximately 35 subjects with an acute exacerbation of COPD will be randomized such 
that approximately 15 subjects on active and 15 subjects on placebo provide sputum at all 
the scheduled time points and complete the study.  If a higher than expected numbers of 
subjects prematurely discontinue the study, or fail to produce sufficient sputum post 
randomisation additional subjects may be randomised at the discretion of the sponsor.
 
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Analysis
To estimate differences in mRNA intensities within and between treatment groups, a 
repeated measures model will be fitted to the results of the analysis of each probe set at 
Day 12, Day 28 and Day 84 following a loge transformation of the data. The Day 1 
response will be fitted as a baseline covariate. A separate model will be fitted for each of 
the approximate 54000 probe sets.
Back transformed ratios versus screening along with 95% confidence intervals will be 
calculated for each treatment group and timepoint.  Additionally, baseline adjusted ratios 
of the change between active treatment and placebo will be calculated along with 95% 
confidence intervals.
 
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2.
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.
2.1.
Study Rationale
The purpose of this study is to evaluate specific alterations in immune cell mechanisms
related to neutrophil function as detected by PI3K-dependent changes in mRNA 
extracted from induced sputum in patients experiencing an exacerbation of COPD. In 
addition this study will also further evaluate the plasma PK and assess the safety of 
GSK2269557 administered to patients diagnosed with an acute exacerbation of Chronic 
Obstructive Pulmonary Disease (COPD). The efficacy of treatment with GSK2269557 
will also be measured using functional respiratory imaging (FRI) and spirometry. 
This study will also explore the pharmacodynamic effects of once daily repeat doses of 
inhaled GSK2269557 on cytokines, mediators and microbiome in induced sputum 
samples. These will be obtained from subjects at entry, during their exacerbation, and at 
additional time points over the 12 week treatment period.  To understand patient efficacy, 
at entry, Day 12 and Day28 the sputum biomarker data will be correlated with computed 
tomography (CT).  
2.2.
Brief Background
PI3Kis a member of the Class IA family of phosphoinositides 3-kinases (PI3Ks) that 
convert the membrane phospholipid phosphatidylinositol 4,5-biphosphate (PIP2) into 
phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 is a second messenger in many 
cellular processes including cell growth, differentiation and migration. PI3Khas 
specific roles in mediating antigen receptor and cytokine signalling in T-cells, mast cells 
and B-cells [Okkenhaug, 2007] and roles in neutrophil chemotaxis and activation [Sadhu, 
2003].  A PI3Kinhibitor has the potential to inhibit major cell types responsible for the
inflammation associated with both COPD and asthma.
In COPD, tobacco smoke or other irritants activate epithelial cells and macrophages to 
release inflammatory mediators such as chemokines that attract neutrophils and T cells to 
the lungs. PI3Kis thought to play a role in a number of epithelial responses relevant for 
the development of COPD.  Therefore a PI3Kinhibitor may be able to suppress a 
number of these processes [Kim, 2010].  A greater proportion of macrophages appear to
be alternatively activated in COPD and their ability to phagocytose infective pathogens is 
reduced as a result of this alternative activation.  PI3Kis one of the mediators involved 
in determining this alternative phenotype in macrophages and therefore it is proposed that 
inhibition of PI3Kmight rebalance macrophage activation towards a classic phagocytic
phenotype [Weisser, 2011] facilitating clearance of bacteria, a major cause of
exacerbation in COPD.  The neutrophil and T cell are the two major inflammatory cell 
types involved in the pathogenesis of COPD and both are targeted by PI3Kinhibitors. 
 
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GSK2269557 has demonstrated the ability to protect against and control bacterial 
infections in preclinical rodent models. This is coupled with recent observations that 
PI3Kinhibition leads to a correction in vitro of aberrant neutrophil chemotaxis 
directionality in the blood of COPD patients. Furthermore, a human point mutation which 
results in a constitutively activated version of PI3Khas recently been characterised 
where the majority of affected patients have recurrent lung infections with the same 
bacterial species which are seen in COPD patients and are known to drive exacerbations. 
Collectively these data suggest that repeat dosing with GSK2269557 could potentially
reduce the impact of an acute exacerbation, or prevent the onset of a secondary bacterial
exacerbation or recurrent exacerbation.
Proinflammatory cytokines were reduced by GSK2269557, both in preclinical rodent 
bacterial models, and COPD patient samples treated in vitro and in the study setting 
(PII115119).
GSK2269557 has been administered as single and repeat doses to healthy subjects as 
nebulized solution in the FTIH study PII115117 up to a dose of 6400 μg per day for 7 
days. GSK2269557 has also been administered as single and repeat doses to healthy 
smokers as a dry powder formulation in study PII116617 up to a dose of 3000 μg as 
single dose and 2000 μg per day for 14 days.  GSK2269557 has been well tolerated 
across the range of doses used.  There is also an ongoing study (Study PII115119, non-
reported) where a total daily dose of up to 2000 µg of GSK2269557 is being administered 
to stable COPD patients via a dry powder inhaler for 14 days in a two part study.  Part A 
of this study has completed and Part B will characterise the steady-state (exposure) dose 
response following repeat inhaled doses of up to 2000µg for the same treatment duration.  
There is also an on-going larger clinical study PII116678 which is almost identical in 
design to 201928 using 1000 µg of GSK2269557 per day administered via a Diskus dry 
powder inhaler to patients diagnosed with an acute exacerbation of COPD.  For 
simplicity study PII116678 does not capture induced sputum hence cannot analyse any 
changes in mRNA. The primary objective of the current study is to capture induced
sputum to enable the mRNA analysis on a smaller cohort.   
More information about the non-clinical and clinical studies is available in the 
GSK2269557 Investigator’s Brochure (IB) GlaxoSmithKline Document Number
2012N141231_04.
2.2.1.
Use of mRNA transcriptomics by Affymetrix
Analysis of changes in mRNA can be used to demonstrate alterations in biochemical 
pathways at the gene transcription level. This can be used to better understand the 
consequences of drug intervention on disease pathophysiology, and ultimately predict 
alterations which could translate to a positive clinical benefit for patients. Messenger 
RNA can be extracted from a variety of biological samples (including induced sputum 
and blood) taken from patients before and after drug dosing to show the impact a drug is 
having. 
The advantage of using Affymetrix is the broad (~50k) gene set covered using this 
technology enabling great depth in exploring the biological consequences of drug 
 
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intervention. This technology has been used in previous preclinical and clinical studies 
using GSK2269557 generating a fingerprint of PI3Kinhibition in disease.  Importantly 
these approaches allow areas of complex PI3K-dependent immune cell mechanisms and 
pathophysiology, specifically related to neutrophil function to be explored which are not 
easily quantified using other techniques.
2.2.2.
Use of HRCT Endpoints to characterise Lung Function
High-resolution computed tomography (HRCT) scans provide a highly detailed insight 
into the structure and architecture of the respiratory system. A clear distinction can be 
made between the lung parenchyma, the intraluminal air and alveolar spaces up to the 
level of the smaller airways with a diameter of 1-2mm. To model dynamic information, 
low dose HRCT scans can be taken at two lung volumes: after deep inhalation (total lung 
capacity or TLC) and after normal expiration (functional residual capacity or FRC). The 
patient’s breathing is monitored in real time during the scans to ensure the correct lung 
levels are scanned.  Due to the natural contrast between the intraluminal air and the 
surrounding tissue, it is possible to attain a significant reduction in radiation dose (1-2 
mSv per scan) compared to standard CT protocols (>4 mSv per scan) by reducing the 
tube current and the voltage.  Depending on the patient’s weight, a 6- to 10-fold reduction 
can be obtained per scan without losing image quality. As a comparison, in the USA, the 
average annual background radiation exposure is 6.2 mSv and a transatlantic flight results 
in 0.07 mSv exposure.
The high resolution images allow for a three dimensional reconstruction of the airway 
tree and vasculature by applying segmentation principles.  These three dimensional 
models can be used to measure airway dimensions as well as potentially allowing the 
phenotyping of patients by disease severity.  The three dimensional computer 
reconstructions can be used for fluid dynamic modelling.  This method is used to 
simulate flow through these airway models and determine the typical flow characteristics 
such as local pressure drops, velocities and resistance.  It can also be used to predict 
particle deposition in the airways of these patients when using inhaled drug products.
This method consisting of 2 low dose HRCT scans at several time points has previously 
been used successfully in clinical trials involving COPD patients [De Backer, 2011; De 
Backer, 2012; De Backer, 2014; Goldin, 1999]. 
 
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3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To establish the PI3K-dependent 
changes in previously identified immune 
cell mechanisms specifically related to 
neutrophil function using mRNA in 
sputum from patients with an 
exacerbation of COPD, with or without 
treatment with GSK2269557.

Alterations in previously identified
immune cell mechanisms specifically 
related to neutrophil function as 
determined by changes in mRNA
transcriptomics in induced sputum after 
12, 28 and 84 days of treatment.
Secondary

To evaluate the effect of once daily 
repeat inhaled doses of GSK2269557 on 
lung parameters derived from HRCT 
scans in subjects with acute 
exacerbation of COPD, compared to 
placebo

Change from baseline in siVaw, iVaw, 
iRaw, siRAW, total lung capacity, lung 
lobar volumes, trachea length and 
diameter at FRC and TLC after 12 days 
of treatment and after 28 days of 
treatment.

To assess the safety and tolerability of 
once daily repeat inhaled doses of 
GSK2269557 administered to subjects 
with acute exacerbation of COPD, 
compared to placebo.

Adverse events 

Hematology, clinical chemistry 

Vital signs

12-lead ECG

To evaluate the plasma PK of once daily 
repeat inhaled doses of GSK2269557 
administered to subjects with acute 
exacerbation of COPD

Day 1 plasma Cmax and trough (24 
hours) post dose for inpatients

Trough concentration after 12 days, 28 
days, 56 days and 84 days of treatment.

To evaluate the effect of once daily 
repeat inhaled doses of GSK2269557 on 
lung function parameters in subjects with 
acute exacerbation of COPD, compared 
to placebo

PEF, Reliever usage.

FEV1 and FVC at clinic prior to sputum
induction.
Exploratory 

To establish any other PI3K-dependent 
changes in mRNA in sputum or blood 
from patients with an exacerbation of 
COPD, with or without treatment with 
GSK2269557.

To explore the pharmacodynamic effects 
in induced sputum of once daily repeat 
inhaled doses of GSK2269557 
administered to subjects with acute 
exacerbation of COPD, compared to 

Alterations in immune cell mechanisms 
as determined by changes in mRNA 
transcriptomics in induced sputum or 
blood after 12, 28 and 84 days of 
treatment.

Endpoints may include, but not limited to 
cytokines (IL-6, IL-8, TNF), microbiome 
(by 16SrRNA), bacterial qPCR, viral 
qPCR.
 
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Objectives
Endpoints
placebo.

To assess the changes in other CT 
parameters such as low attenuation 
score after once daily repeat inhaled 
doses of GSK2269557 administered to 
subjects with acute exacerbation of 
COPD, compared to placebo.

Change from baseline for other CT 
parameters including low attenuation 
score after 12 days of treatment and 
after 28 days of treatment.
4.
STUDY DESIGN
4.1.
Overall Design
This is a randomised, double-blind, placebo-controlled, parallel-group study.  All subjects 
will continue on their usual COPD medications throughout the entire duration of the 
study regardless of treatment arm assignment.  Subjects will be on standard of care 
treatment (antibiotic and corticosteroids) upon diagnosis of a COPD exacerbation.
SCR
Signature 
ICF
Day 1
Randomisation / 
First dose GSK2269557
Day 12
(+/- 2 days) 
HRCT
Day 28
(+/- 2 days)
HRCT
Day 56
(-4 / + 2 days)
Safety visit
Day 84
(-4 / + 2 days)
End treatment
FU
Baseline
HRCT
Within 48h / discharge
Baseline lung function
4.2.
Treatment Arms and Duration
Subjects will be required to participate in the following:
Screening: Following diagnosis during outpatient assessment by a Respirologist, 
Emergency Department visit or acute admission to hospital, and up to 3 days before start 
of study treatment. During this time:

The start of the standard of care (to include both antibiotics and corticosteroids) is 
expected to start shortly after diagnosis, though it is allowed to have already been 
started before the formal diagnosis of COPD exacerbation is made. 

The HRCT scan should be conducted at the earliest opportunity after obtaining 
Informed Consent from the subject and within 48 h of diagnosis by a Respirologist or 
physician with respiratory experience. 
 
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
Randomisation and first dose administration should take place as soon as possible 
following HRCT scan assessment has been performed and no later than 24h after 
completing the HRCT scan.
Treatment period:  Once daily study treatment administration will start on Day 1 (visit 1). 

For subjects who were hospitalized: 
o
If discharge takes place before Day 10, the subject must complete the 
assessments planned for visit 2 on discharge and must then visit the unit 
on Day 12 (2 days) (visit 3).
o
If discharge takes place between Day 10 and Day 14 (inclusive), the 
assessments planned for visit 2 and visit 3 may be completed on the day of 
discharge.
o
If discharge takes place from Day 15 (inclusive), the assessments planned 
for visit 2 and visit 3 should be completed as soon as it is safe for the 
patient to do so.

For subjects who were not hospitalized: the subject must complete the 
assessments planned for visit 2 within 48 hours of start of treatment, and must 
then visit the unit on Day 12 (2 days) to complete the assessments planned for
visit 3.
Subjects will then dose at home until Day 84 (– 4 / + 2 days), with the exception of the 
days when subjects come to the clinic. On those days, they will dose at the clinic. On Day 
12 (± 2 days) (unless visit completed on discharge), Day 28 (± 2 days), Day 56 (– 4 / + 2 
days) and Day 84 (– 4 / + 2 days) subjects will return on an outpatient basis to complete 
the assessments described in the Time & Event table (Section 7.1). Subjects will be 
discharged once all assessments have been performed and there are no safety concerns.
Follow up: 7 to 14 days after last dose.
The total duration of the study is 13-14 weeks including the screening visit.
4.3.
Type and Number of Subjects
Approximately 35 subjects with an acute exacerbation of COPD will be randomized such 
that approximately 15 subjects on active and 15 subjects on placebo provide sputum at all 
the scheduled time points and complete the study.   If a higher than expected number of 
subjects prematurely discontinue the study, or fail to produce sufficient sputum post 
randomisation additional subjects may be randomised at the discretion of the sponsor.
4.4.
Design Justification
This study will include a placebo control to allow for a valid evaluation of the 
pharmacodynamic endpoints and adverse events attributable to treatment versus those 
 
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independent of treatment. Subjects will also receive standard of care for their 
exacerbation and throughout the study.
4.5.
Dose Justification
The dose chosen for this study is 1000 µg of GSK2269557 per day administered via a dry 
powder inhaler for a duration of 84 days (– 4 / + 2 days). This dose has been selected 
based on previous safety and tolerability data in man (healthy subjects and COPD 
subjects) as well as demonstration of target (PI3K) inhibition by observed changes in 
biomarkers. Together with an additional study to be run in parallel (PII116678), this dose 
of GSK2269557 is being dosed to subjects in PII116678 with an exacerbation of COPD,
so it will be assumed for exposure predictions, unless otherwise stated, that these subjects 
will have a similar lung deposition, distribution and plasma exposure to that of the 
healthy volunteers. However it is accepted that these types of subjects may have reduced 
airway conductance and hence likely reduced deposition. This can be appropriately 
defined in this study based on the actual plasma exposures achieved. 
Twice this dose level (2000 µg) using the same formulation has previously been given 
once daily to healthy male smokers for 14 days (study PII116617). There is also an 
ongoing study where a total daily dose of 1000 µg of GSK2269557 is administered to 
stable COPD subjects via a dry powder inhaler for 14 days (study PII115119) which at 
the time of writing of this protocol had successfully dosed 21 subjects on active treatment 
and collected pharmacokinetics (PK) samples for analysis out to 14 days.
The target effect compartment for PI3Kinhibition is the intracellular compartment of 
the immune cells resident in the lung tissue and lumen.  GSK2269557 has a high potency 
and selectivity at the PI3Kenzyme (Ki value 0.1 ng/mL) which translates into an IC50 in 
a more complex system (PHA stimulated lung tissue) of approximately 120 ng/mL (or 
2.5 ng/mL free unbound drug).  Based on the measured steady-state cellular 
concentration of GSK2269557 collected at trough (24 h) from the lungs of healthy 
smokers at 2000 µg DPI (450 ng/mL) in the clinical study it is expected that at 1000 µg 
(225 ng/mL), concentrations will be sufficient and PI3Kinhibition maintained in the 
lung at 90% inhibition for 24 h. 
Target PI3Kinhibition is based on a wide range of pharmacology experiments. Details 
of these as well as the pharmacokinetics and safety data can be found in the IB, 
[GlaxoSmithKline Document Number: 2012N141231_04].
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK2269557 can be found in the IB [GlaxoSmithKline Document Number 
2012N141231_04]. The following section outlines the risk assessment and mitigation 
strategy for this protocol:  
 
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4.6.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Investigational Product (IP) [e.g., GSK2269557]
Bronchospasm
Mucosal irritancy
A general risk with Inhaled 
treatment
Detected in 13 week toxicology 
study in the dog
Subjects will be allowed to 
continue regular COPD 
treatments and have standard 
of care for treatment of their 
exacerbation. More severe 
patients will have their 
treatment started in hospital. 
Patients will be regularly 
monitored for AEs and a 
patient diary kept. Thus far this 
has not been seen in clinical 
studies.
Potential photosensitivity  
In the absorption spectrum for 
GSK2269557 there are peaks 
at the boundary of the 
ultraviolet (UV) light 
[UVA/UVB] region with a 
lambda max at 320 nm (molar 
extinction coefficient 
43800 L/Mol/cm), with smaller 
peaks at 305 nm and 332 nm.
Subjects will be advised to 
take UV protection measures 
(see Section 6.11).
Study Procedures
Radiation risk as part of HRCT 
scans
The maximum amount of 
radiation dose a patient 
undergoing all six scans will 
receive is approximately 
12mSv. Six low dose HRCT 
scans (one at TLC and FRC on 
screening, Day 12 and Day 28 
visits) at are required 
throughout the study for the 
functional imaging protocol
Reduced tube voltage (100 
kV), and tube current are used.
Scanning time less than 5 s 
per scan.
Total radiation dose for a total 
of six CT scans will be 
approximately 12mSv.
Final radiation dose will be 
dependent on the patient 
weight, with a range of 
between 1-2mSv per scan per 
patient. This radiation dose 
falls into the International 
Commission on Radiological 
Protections [ICRP, 2007]
category IIb (minor to 
intermediate risk).
 
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
The outcomes of this study will 
provide information which 
would produce advances in 
knowledge, leading to a 
potential health benefit in the 
future for patients in this target 
population. The CT may also 
provide information for the 
patients general clinical 
management
Sputum induction
Standard sputum induction
techniques using hypertonic 
saline can result in 
bronchospasm and therefore 
could potentially induce 
bronchospasm in a patient or 
impact a pre-existing 
exacerbation..
For patients during an 
exacerbation and for sputum 
induction during the recovery
period, including the day 28 
visit, patients will be pre-dosed 
with nebulised or inhaled beta-
2-agonist (or ipratropium
bromide if beta-2-agonist 
intolerant). Sputum induction 
will only be carried out using 
Normal (0.9%) saline, which is 
also often used in patients 
clinically to facilitate sputum 
clearance.  
For the final sputum induction 
patients will be pre-dosed with 
nebulised or inhaled beta-2-
agonist (or ipratropium bromide
if beta-2-agonist intolerant) and 
the induction carried out with 
0.9% saline initially and only 
then followed by hypertonic (3-
5%) if required, and, in the 
opinion of the Investigator, it is 
considered safe to do so.
4.6.2.
Benefit Assessment
The outcomes of this study will provide information which will produce advances in 
knowledge of the pathophysiology of COPD exacerbations, leading to a potential health 
benefit in the future for patients in this target population. The CT scan may also provide 
information for the patient’s general clinical management.
 
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4.6.3.
Overall Benefit:Risk Conclusion
The overall benefit:risk is considered to be positive. There is an opportunity to determine 
if there may be a new drug developable for the treatment of acute exacerbations of COPD 
which has not seen any new treatments recently. The scientific value in obtaining 
functional CT information on the anatomy and pathophysiology of COPD exacerbations 
and how the lung responds to therapy will be extremely valuable to the wider clinical 
community and justifies the limited radiation exposure (maximum 12 mSv in total) from 
the CT scan procedures. The CT will also be useful to provide clinical information about 
the patient for the patient’s physician and contribute to clinical management.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB [GlaxoSmithKline 
Document Number: 2012N141231_04] 
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
 
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5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
[1] AGE

Between 40 and 80 years of age inclusive, at the time of signing the informed 
consent.
[2] TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY

The subject has a confirmed and established diagnosis of COPD, as defined by the 
GOLD guidelines for at least 6 months prior to entry.

The subject is able to produce >100 mg of sputum at screening for processing, (ie, 
total weight of sputum plugs.).

The subject has a post-bronchodilator FEV1/FVC < 0.7 and FEV1 80 % of 
predicted. Predictions should be according to the European Community of Coal and 
Steel (ECCS) equations OR the European Respiratory Society Global Lung Function 
Initiative reference equations [Quanjer, 2012] and documented in the last 5 years.

Disease severity: Acute exacerbation of COPD requiring an escalation in therapy to 
include both corticosteroid and antibiotics. Acute exacerbation to be confirmed by an 
experienced physician and represent a recent change in at least two major and one 
minor symptoms, one major and two minor symptoms, or all 3 major symptoms.
Major symptoms:

Subjective increase in dyspnea

Increase in sputum volume

Change in sputum colour
Minor symptoms:

Cough

Wheeze

Sore throat

The subject is a smoker or an ex-smoker with a smoking history of at least 10 pack 
years (pack years = (cigarettes per day smoked/20 x number of years smoked)).
[3] WEIGHT

Body weight 45 kg and body mass index (BMI) within the range 18 – 32 kg/m2
(inclusive).
 
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[4] SEX

Male

Female subject : is eligible to participate if she is not pregnant (as confirmed by a 
negative urine human chorionic gonadotrophin (hCG) test), not lactating, and at least 
one of the following conditions applies:
1. Non-reproductive potential defined as:
Pre-menopausal females with one of the following:
Documented tubal ligation
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 
Hysterectomy
Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea.  Females whose 
menopausal status is in doubt will be required to use, or have been using, one of the 
highly effective contraception methods as specified below from 30 days prior to the first 
dose of study medication and until completion of the follow-up visit.
2. Reproductive potential and agrees to follow one of the options listed 
below in the GSK Modified List of Highly Effective Methods for 
Avoiding Pregnancy in Females of Reproductive Potential (FRP) 
requirements from 30 days prior to the first dose of study medication 
and until completion of the follow-up visit.
GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females 
of Reproductive Potential (FRP)
This list does not apply to FRP with same sex partners, when this is their preferred and 
usual lifestyle or for subjects who are and will continue to be abstinent from penile-
vaginal intercourse on a long term and persistent basis.
1. Contraceptive subdermal implant that meets GSK standard criteria including a 
<1% rate of failure per year, as stated in the product label
2. Intrauterine device or intrauterine system that meets GSK standard criteria 
including a <1% rate of failure per year, as stated in the product label [Hatcher, 
2007a]
3. Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007a] 
4. Injectable progestogen [Hatcher, 2007a]
5. Contraceptive vaginal ring [Hatcher, 2007a]
6. Percutaneous contraceptive patches [Hatcher, 2007a]
7. Male partner sterilization with documentation of azoospermia prior to the female 
subject’s entry into the study, and this male is the sole partner for that subject 
 
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[Hatcher, 2007a].  
8. Male condom combined with a vaginal spermicide (foam, gel, film, cream, or 
suppository) [Hatcher, 2007b]
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
Specific inclusion criteria for Male subjects with female partners of reproductive 
potential is outlined below:
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until after the completion of the follow up visit.
1. Vasectomy with documentation of azoospermia.  
2. Male condom plus partner use of one of the contraceptive options below:
Contraceptive subdermal implant that meets GSK standard criteria including a 
<1% rate of failure per year, as stated in the product label
Intrauterine device or intrauterine system that meets GSK standard criteria 
including a <1% rate of failure per year, as stated in the product label [Hatcher, 
2007a]
Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007a] 
Injectable progestogen [Hatcher, 2007a]
Contraceptive vaginal ring [Hatcher, 2007a]
Percutaneous contraceptive patches [Hatcher, 2007a]
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
[5] INFORMED CONSENT

Capable of giving signed informed consent as described in Section 10.2 which
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
 
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5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
[1]  CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL)

To avoid recruitment of subjects with a severe COPD exacerbation, the presence of 
any one of the following severity criteria will render the subject ineligible for 
inclusion in the study:

Need for invasive mechanical ventilation (short term (< 48h) NIV or CPAP is 
acceptable)

Haemodynamic instability or clinically significant heart failure

Confusion

Clinically significant pneumonia, identified by chest X-ray at screening, and as 
judged by the Investigator.

Subjects who have current medical conditions or diseases that are not well controlled 
and, which as judged by the Investigator, may affect subject safety or influence the
outcome of the study. (Note: Patients with adequately treated and well controlled 
concurrent medical conditions (e.g. hypertension or NIDDM) are permitted to be 
entered into the study).

Subject has a diagnosis of active tuberculosis, lung cancer, clinically overt 
bronchiectasis, pulmonary fibrosis, asthma or any other respiratory condition that 
might, in the opinion of the investigator, compromise the safety of the subject or 
affect the interpretation of the results.

ALT >2xULN and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if 
bilirubin is fractionated and direct bilirubin <35%). 

A subject with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the exclusion criteria, outside of the reference range for the 
population being studied may be included if the Investigator [in consultation with the 
GSK Medical Monitor if required] documents that the finding is unlikely to 
introduce additional risk factors and will not interfere with the study procedures.

Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert’s syndrome or asymptomatic gallstones)

ECG indicative of an acute cardiac event (e.g. Myocardial Infarction) or 
demonstrating a clinically significant arrhythmia requiring treatment.

QTcF > 450 msec or QTcF > 480 msec in subjects with Bundle Branch Block, based 
on single QTcF value.

Subjects who have undergone lung volume reduction surgery.
 
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[2] CONCOMITANT MEDICATIONS 
• Subject is currently on chronic treatment with macrolides or long term antibiotics. 
• Subject is being treated with long term oxygen therapy - LTOT (> 15 hours/day). 
• The subject has been on chronic treatment with anti-Tumour Necrosis Factor (anti-
TNF), or any other immunosuppressive therapy (except corticosteroid) within 60 days 
prior to dosing. 
 
[3] RELEVANT HABITS 
• History of regular alcohol consumption within 6 months of the study defined as an 
average weekly intake of >28 units for males or >21 units for 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. 
 
[4]  CONTRAINDICATIONS  
• History of sensitivity to any of the study medications, or components thereof (such as 
lactose) or a history of drug or other allergy that, in the opinion of the investigator or 
Medical Monitor, contraindicates their participation. 
 
[5] DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA 
• A known (historical) positive test for HIV antibody. 
• Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test 
result at screening or within 3 months prior to first dose of study treatment. 
NOTE: Because of the short window for screening, treatment with GSK2269557 
may start before receiving the result of the hepatitis tests. If subsequently the test is 
found to be positive, the subject may be withdrawn, as judged by the Principal 
Investigator in consultation with the Medical Monitor. 
• Where participation in the study would result in donation of blood or blood 
products in excess of 500 mL within 56 days. 
• The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the 
current study: 30 days, 5 half-lives or twice the duration of the biological effect of 
the investigational product (whichever is longer). 
• Exposure to more than 4 investigational medicinal products within 12 months 
prior to the first dosing day. 
 
 
 
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5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized.  In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria Protocol Deviations, and any Serious Adverse Events.
5.4.
Withdrawal/Stopping Criteria
Subjects who are withdrawn from treatment will also be withdrawn from the study. 
If a higher than expected number of subjects prematurely discontinues the study, 
additional subjects may be randomised and assigned to the same treatment sequence, at 
the discretion of the Sponsor.  
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as soon 
as possible. 

The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 
telephone calls and if necessary a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
Subjects who are withdrawn should complete the assessments planned for the follow up 
visit.
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
 
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http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase II Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5, if 
measured*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
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 2.
5.4.1.1.
Study Treatment Restart or Re-challenge
Study treatment restart or re-challenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.4.2.
QTc Stopping Criteria

QTcF should be based on averaged QTcF values of triplicate electrocardiograms 
obtained over a brief (e.g., 5-10 minute) recording period. For example, if an ECG 
(Electrocardiogram) demonstrates a prolonged QTcF interval, obtain two more 
ECGs and use the averaged QTcF values of the three ECGs to determine whether the 
patient should be discontinued from the study.
A subject who meets either of the bulleted criteria below will be withdrawn from the 
study:

QTcF >500 msec OR Uncorrected QT >600 msec
 
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
Change from baseline of QTcF > 60 msec
For patients with underlying bundle branch block, follow the discontinuation criteria 
listed below:
Baseline QTcF with Bundle 
Branch Block
Discontinuation QTcF with 
Bundle Branch Block
<450 msec
>500 msec
450 – 480 msec
≥530 msec
5.4.3.
Other Stopping Safety Criteria
For an individual study participant, stopping criteria include, but are not limited to:
Severe signs or symptoms, or significant changes in any of the safety assessments, that 
put the safety of the individual at risk (e.g. ECG, vital signs, laboratory tests, spirometry 
assessments, etc), as judged by the Principal Investigator in consultation with the Medical 
Monitor if necessary.
Treatment failure or recurrent exacerbation does not mandate withdrawal from the study, 
unless there is a safety concern as judged by the Investigator, in consultation with the 
Medical Monitor if necessary.
Subjects should be withdrawn from the study if confusion, acute respiratory acidosis (pH 
< 7.30), or need for invasive mechanical ventilation occurs.
5.5.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit.
The end of the study is defined as the last subject’s last visit.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
 
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Study Treatment
Product name:
GSK2269557
Placebo
Formulation description:
Lactose blend containing 
GSK2269557 in Diskus™device
Lactose in Diskus™device
Dosage form:
Dry powder for inhalation
Dry powder for inhalation
Unit dose 
strength(s)/Dosage 
level(s):
500 µg / blister
N/A
Route of Administration
Inhalation
Inhalation
Dosing instructions:
2 inhalations to be taken every 
day before breakfast (with the 
exception of days when the 
subjects have a planned visit to 
the clinic. On those days, they 
will be dosed at the clinic). The 
subject should hold their breath 
for approximately 10 seconds 
before exhaling. Inhalations 
should be taken approximately 
30 seconds apart. 
2 inhalations to be taken every 
day before breakfast (with the 
exception of days when the 
subjects have a planned visit to 
the clinic. On those days, they 
will be dosed at the clinic). The 
subject should hold their breath 
for approximately 10 seconds 
before exhaling. Inhalations 
should be taken approximately 
30 seconds apart.
6.2.
Treatment Assignment
Subjects will be assigned to treatments in accordance with the randomization schedule
generated by Clinical Statistics, prior to the start of the study, using validated internal 
software. Central based randomisation will be used.
Subjects will be randomised to treatments A or B where:
A = Placebo 
B = GSK2269557 1000 µg 
A web based interactive response system will be used to assign subjects to treatment.
6.3.
Planned Dose Adjustments
If adverse events, unrelated to COPD exacerbation, which are of moderate or severe 
intensity and are consistent across subjects in the group, or if unacceptable 
pharmacological effects, reasonably attributable in the opinion of the investigator to 
dosing with GSK2269557, are observed in more than 30% of the subjects then the study
will be halted and no further subject will be dosed until a full safety review of the study 
has taken place. Relevant reporting and discussion with the Medical Monitor, relevant 
GSK personnel, and with the Ethics Committees will then take place prior to any 
resumption of dosing. If the above is observed consideration may be given to reducing 
the dose of GSK2269557 to 500 µg O.D.
 
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6.4.
Subject Specific Dose Adjustment Criteria
There are no subject specific dose adjustment criteria.
6.5.
Blinding
This will be a double blind study and the following will apply. 

The investigator or treating physician may un-blind a subject’s treatment assignment 
only in the case of an emergency OR in the event of a serious medical condition 
when knowledge of the study treatment is essential for the appropriate clinical 
management or welfare of the subject as judged by the investigator. 

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before un-blinding 
the subject’s treatment assignment. 

If GSK personnel are not contacted before the un-blinding, the investigator must 
notify GSK as soon as possible after un-blinding. 

The date and reason for the un-blinding must be fully documented in the Case Report 
Form (CRF)

A subject will be withdrawn if the subject’s treatment code is un-blinded by the 
investigator or treating physician. The primary reason for discontinuation (the event 
or condition which led to the un-blinding) will be recorded in the CRF.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may un-blind the 
treatment assignment for any subject with a Serious Adverse Event (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 subject’s treatment assignment, may be 
sent to investigators in accordance with local regulations and/or GSK policy.
6.6.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.7.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

Only subjects 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 labelled storage conditions with access limited to the 
investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e. receipt, reconciliation and final disposition records).  
 
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
Further guidance and information for final disposition of unused study treatment are 
provided in the Study Reference Manual (SRM).

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, Medical Monitor and/or 
GSK study contact.

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
6.8.
Compliance with Study Treatment Administration
When subjects 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 subjects will be asked to complete a diary when dose administration takes place at 
home. The date, time and number of inhalations will be recorded. The compliance will be 
checked by the site staff at each planned visit. 
A record of the number of Diskus inhalers dispensed to each subject and the number of 
actuation administered, read from the dose counter for each Diskus inhaler, must be 
maintained and reconciled with study treatment and compliance records.  Treatment start 
and stop dates, including dates for treatment delays and/or dose reductions will also be
recorded in the CRF.
6.9.
Treatment of Study Treatment Overdose
For this study, any dose of GSK2269557 >2000 µg within a 22 hour time period will be 
considered an overdose.
GSK does not recommend specific treatment for an overdose
In the event of an overdose the investigator should:
1) contact the Medical Monitor immediately
2) closely monitor the subject for adverse events (AEs)/serious adverse events 
(SAEs) and laboratory abnormalities until GSK2269557 can no longer be detected 
systemically (at least 14 days for GSK2269557)
3) obtain a plasma sample for pharmacokinetic (PK) analysis within 7 days from the 
date of the last dose of study treatment if requested by the Medical Monitor 
(determined on a case-by-case basis)
 
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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 subject.
6.10.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because the indication being studied is not life threatening or seriously debilitating 
and/or other treatment options are available.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
Any clinical abnormalities identified during the conduct of the study will be locally 
managed by the Investigator.
6.11.
Lifestyle and/or Dietary Restrictions

Subjects must not sunbathe or use a tanning device (e.g. sunbed or solarium) whilst 
taking the study medication and until at least 2 weeks after their last dose. Subjects 
are to be advised that they should cover exposed areas of skin (e.g. use sun hat, long 
sleeves) and use a broad spectrum UVA/UVB sunscreen (SPF ≥30) on exposed areas 
of skin when outdoors.

Subjects should refrain from consumption of Seville oranges, grapefruit or grapefruit 
juice, exotic citrus fruits or grapefruit hybrids from first dose till the end of the study.

Subjects should abstain from alcohol on the day when they visit the clinical unit and 
until their discharge on that day.

Subjects should refrain from smoking for at least 2 hours prior to each pulmonary 
function test conducted at the clinical unit/site.
6.12.
Concomitant Medications and Non-Drug Therapies
6.12.1.
Permitted Medications and Non-Drug Therapies
On entry to the study all treatment required for standard of care and additional medical 
problems is permitted to start and continue.
The subjects are allowed to continue their regular COPD treatments for the duration of 
the study. However, the subjects should refrain, if possible, from using relief 
bronchodilators for at least 4 hours prior to each spirometry conducted at the clinical unit, 
 
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and HRCT scan assessment unless essential for clinical symptom relief. Otherwise free 
use of reliever/rescue medication is allowed.  Rescue ventolin and aerochambers may be
provided by GSK for this study.
All prior (up to 2 months prior to screening) and concomitant medications should be 
recorded in the subject’s CRF.
6.12.2.
Prohibited Medications and Non-Drug Therapies
Regular or chronic treatment with medications that are considered strong inhibitors of 
CYP3A4 or CYP2D6 are not permitted. This includes anti-epileptic treatments, 
macrolide antibiotics, oral antifungal treatments (single doses and courses up to 7 days 
are allowed) and anti-tuberculous therapy. These medications must all have been stopped 
at least 14 days prior to first dose.
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1
 
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7.1.
Time and Events Table (Screening and Follow Up Visits)
Procedure
Screening 
(up to 3 days prior to Visit 1)
Follow-up
(7-14 days post-last dose)
Notes
Informed consent
X
Demography
X
Inclusion and exclusion criteria
X
Full physical exam, including height and 
weight
X
Brief physical examination, including weight
X
Chest X-Ray
X
To be done before baseline HRCT to exclude significant 
pneumonia and other incidental serious underlying 
pathology.
Medical history (includes substance usage
and Family history of premature CV disease)
X
Substances: Drugs, Alcohol, tobacco via history.  No drug, 
alcohol screening is required.
Past and current medical conditions  
(including cardiovascular medical history and 
therapy history)
X
Laboratory assessments (include Hematology 
and biochemistry)1
X
X
Historical values analysed by local lab to be used for 
eligibility assessment. Another sample must be collected 
and sent to central lab as soon as informed consent is 
obtained. 
Hep B and Hep C screen2
X
Urine pregnancy test (only WCBP)
X
Before conducting the HRCT.  Done locally at the site.
12-lead ECG
X
X
Single assessment
Vital signs
X
X
Single assessment
HRCT (at TLC and FRC)
X
Within 48 h of diagnosis, if subject otherwise eligible. 
Includes electronic monitoring of breathing (if applicable).  
Baseline HRCT will be reviewed by the local site’s 
radiologist to identify any significant occurring underlying 
medical conditions that require further clinical management 
or monitoring.
Induced Sputum3
X4
To include sputum culture pre-first dose. Culture to be done 
by the local site laboratory.
 
 
 
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Procedure
Screening 
(up to 3 days prior to Visit 1)
Follow-up
(7-14 days post-last dose)
Notes
Blood sample for mRNA Analysis
X4
Collected at any time on specified days
AE/SAE collection and review
X
Concomitant medication review
X
X
1.
Due to the short screening window, central laboratory analysis results will not be available on time. Therefore the local laboratory results should be used for eligibility assessment
(to exclude severe subjects and underlying medical conditions). If local laboratory results are already available from diagnosis of current exacerbation, there is no need to take 
another sample for local analysis. A sample for central laboratory analysis should also be obtained. See Section 7.8.6 for further details.
2.
If test otherwise performed within 3 months prior to first dose of study treatment, testing at screening is not required. Because of the short window for screening, treatment with 
GSK2269557 may start before receiving the result of the hepatitis tests. If subsequently the test is found to be positive, the subject may be withdrawn, as judged by the Principal 
Investigator in consultation with the Medical Monitor.
3.
Induced sputum collection may be attempted on several occasions if an adequate sample is not produced at the first attempt.
4.
To be collected at any time point before randomisation.
 
 
 
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7.2.
Time and Events Table (Treatment Period)
Procedure
Treatment Period 
Notes
Visit
1
21
3
4
5
6
Day
1
Within 48h 
/ discharge
12
28
56
84
Visit window
N/A
1 days
2 days
2 days
- 4 / +2 days
- 4 / +2 days
SAFETY ASSESSMENTS
AE/SAE collection and review
=========================================================
Concomitant medication review
=========================================================
Reliever usage
=========================================================
Brief physical exam, including weight
X2
X
X
X
X
Pre-dose
Laboratory assessments (include 
haematology and biochemistry)
X2
X
X
X
X
Pre-dose
12-lead ECG
X2
X
X
X
X
Pre-dose. Single assessment
Vital signs
X2
X
X
X
X
Pre-dose. Single assessment
Urine pregnancy test (only WCBP)
X
X
Before conducting the HRCT
STUDY TREATMENT
Randomisation
X
Study drug administration
=========================================================
Daily in the morning before breakfast, 
(with the exception of days when the 
subjects have a planned visit to the 
clinic. On those days, they will be 
dosed at the clinic).
Assessment of study treatment compliance
X
X
X
X
EFFICACY ASSESSMENTS
 
 
 
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Procedure
Treatment Period 
Notes
Visit
1
21
3
4
5
6
Day
1
Within 48h 
/ discharge
12
28
56
84
Visit window
N/A
1 days
2 days
2 days
- 4 / +2 days
- 4 / +2 days
HRCT (at TLC and FRC)
X
X
At any time on specified days. Includes 
electronic monitoring of breathing (if 
applicable).  The radiologist may review 
any of the scan(s) if they wish, but this
is NOT required for the study.  A formal 
review is required at screening only by 
the radiologist.
FEV1 and FVC
       X                        X                      X                      X                     X                         X
In clinic only for all visits where 
possible.
PEF
=========================================================
Daily before drug administration at 
home.  If subject in hospital, this may 
be collected using the handheld device 
provided prior to drug administration.
OTHER ASSESSMENTS
Blood sample for PK
X
X
X
X
X
Day 1:  5 min and 24 h post-dose. The 
24 h post-dose time-point is optional for 
subjects not hospitalised. Pre-dose at 
all other time-points.
Sputum induction3
X
X
X
Blood sample for mRNA analysis
X
X
X
Genetic sample (PGx)4
X
Collected at any time after 
randomisation
1.
On discharge if the subject was hospitalized. Within 48 hours of first dose administration if the subject was not hospitalised. See Section 4.2
2.
Assessments do not need to be completed if screening assessments conducted within 48 hours 
3.
Induced sputum collection may be repeated on several occasions if an adequate sample is not produced at the first attempt 
4.
Informed consent for optional sub-studies (e.g. ,genetics research) must be obtained before collecting a sample.  May be obtained at any visits.
 
 
 
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7.3.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.  
Procedures conducted as part of the subject’s routine clinical management and obtained 
prior to signing of informed consent may be utilized for Screening or baseline purposes 
provided the procedure meets the protocol-defined criteria and has been performed in the 
timeframe of the study.
If they are being utilised in the study, Patient Reported Outcomes questionnaires should 
be completed by subjects before any other assessment at a clinic visit, in the order 
specified.
7.4.
Biomarker(s)/Pharmacodynamic Markers
7.4.1.
Pharmacodynamic Biomarkers in Sputum

Collect sputum induction samples at the time-points shown in the time and events 
table (Section 7.1).

The sputum induction collection process will follow local standard procedures and
guidelines outlined in the SRM.

The collection of induced sputum may be attempted on several occasions if an 
adequate sample is not produced at the first attempt.

Further information on collection, processing, storage and shipping procedures are 
provided in the SRM.
7.4.2.
mRNA in blood

Collect 2.5 mL of blood into a PAXgene mRNA tube.
Details of blood sample collection, processing, storage and shipping procedures are 
provided in the SRM.
7.5.
Patient diary
The subjects will be provided with a diary to record the following data when at home: 

Time and date of each dose administration and number of inhalations.
 
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
Adverse Events and concomitant medications taken (including daily rescue 
medication – if used and how many times used).

PEF from a handheld device.  The best/highest result is recorded.
Changes in Health and details of any concomitant medications as well as PEF 
assessment details will be collected in the paper diaries and later transcribed into the 
CRF. 
7.6.
Genetics
Information regarding genetic research is included in Appendix 3.
7.7.
Efficacy
7.7.1.
Functional Respiratory Imaging

A CT scan with a low radiation protocol at FRC and TLC will be conducted as listed 
in the Time and Events Table (Section 7.1). The same scanner should be used for 
baseline and post-treatment scans for an individual subject.

A urine pregnancy test should be performed before the CT scan in female subjects of 
childbearing potential.

Further information is provided in the SRM.
7.7.2.
FEV1  and FVC
A triplicate FEV1 and FVC measurement will be taken at the clinic before dosing using 
the site’s spirometer as soon as it is safe to do so.  Predicted values will be based upon the 
European Respiratory Society Global Lung Function Initiative reference equations
[Quanjer, 2012].

Further details are provided in the SRM.
7.7.3.
Peak Expiratory Flow PEF

PEF measurements will be taken (in triplicate) daily in the morning before dose 
administration, as soon as it is safe for the subject to do so. The best/highest result is 
recorded.

Subjects will be provided with a handheld device.

Further details are provided in the SRM.
 
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7.8.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests (such as vital signs, physical exams
and laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
7.8.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.
7.8.1.1.
Time period and Frequency for collecting AE and SAE information

AEs and SAEs will be collected from the start of Study Treatment until the follow-
up contact (see Section 7.8.1.3), at the time-points specified in the Time and Events 
Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product 
will be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact. 

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 4.

Investigators are not obligated to actively seek AEs or SAEs in former study
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the investigator 
must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 4.
7.8.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 
 
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
“Have you had any (other) medical problems since your last visit/contact

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
7.8.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in
Appendix 4.
7.8.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
7.8.1.5.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
COPD exacerbations are associated with the disease to be studied and will not be
recorded as AEs unless they meet the definition of an SAE as defined in Appendix 4
Exacerbations that meet the definition of an SAE will be recorded on the appropriate 
eCRF section and should be reported to GSK.
Medications used to treat a COPD exacerbation will be recorded in the exacerbation 
eCRF
7.8.1.6.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs and non-serious AEs related to 
study treatment (even for non- interventional post-marketing studies) is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and the safety 
of a product under clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
 
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regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.8.2.
Pregnancy

Details of all pregnancies in female subjects and female partners of male subjects 
will be collected after the start of dosing and until the follow-up visit

If a pregnancy is reported then the investigator should inform GSK within 2 weeks 
of learning of the pregnancy and should follow the procedures outlined in Appendix 
5. 
7.8.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height and 
weight will also be measured and recorded.

A brief physical examination will include, at a minimum assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
7.8.4.
Vital Signs

Vital signs will be measured in semi-supine position after 5 minutes rest and will
include temperature, systolic and diastolic blood pressure and pulse rate and 
respiratory rate.

Three readings of blood pressure and pulse rate will be taken

First reading should be rejected

Second and third readings should be averaged to give the measurement to be 
recorded in the CRF. 
7.8.5.
Electrocardiogram (ECG)

Single 12-lead ECGs will be obtained at screening and at each other timepoint during 
the study using an ECG machine that automatically calculates the heart rate and 
measures PR, QRS, QT, and QTcF intervals.  Refer to Section 5.4.2 for QTcF
withdrawal criteria and additional QTcF readings that may be necessary.
 
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7.8.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 1, must be conducted in
accordance with the Laboratory Manual, and Protocol Time and Events Schedule.
Laboratory requisition forms must be completed and samples must be clearly labelled 
with the subject number, protocol number, site/centre number, and visit date. Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the laboratory manual. Reference ranges for all safety parameters will be
provided to the site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Historical values (if the assessment was conducted as part of the standard of care) for 
blood gases, blood culture and sputum culture may also be collected if available.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
Table 1
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 1
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose (non 
fasted)
Calcium
Alkaline 
phosphatise
Albumin
CRP
Other 
Screening 
Tests

Urine hCG Pregnancy test (as needed for women of child bearing 
potential) 2

Hepatitis B (HBsAg)

Hepatitis C (Hep C antibody)
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 5.4.1 and 
Appendix 2
 
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2. Local urine testing will be standard for the protocol unless serum testing is required 
by local regulation or ethics committee.
All study-required laboratory assessments will be performed by a central laboratory, apart 
from:

Hematology and clinical chemistry at screening for excluding subjects with severe 
disease and uncontrolled medical conditions. The results of each test must be entered 
into the CRF.
NOTE:  Local laboratory results are only required in the event that the central laboratory
results are not available in time for either a treatment and/or response evaluation to be 
performed. If a local sample is required it is important that the sample for central 
analysis is obtained at the same time. Additionally if the local laboratory results are used 
to make either a treatment or response evaluation, the results must be entered into the 
CRF.
Hematology, clinical chemistry and additional parameters to be tested are listed in Table 
1. 
7.9.
Pharmacokinetics
7.9.1.
Blood Sample Collection
A 2 mL blood samples for pharmacokinetic (PK) analysis of GSK2269557 will be
collected at the time points indicated in Section 7.1, Time and Events Table.  The actual
date and time of each blood sample collection will be recorded.  The timing of PK 
samples may be altered and/or PK samples may be obtained at additional time points to 
ensure thorough PK monitoring.  
Processing, storage and shipping procedures are provided in the Study Reference Manual
(SRM). 
7.9.2.
Sample Analysis
Plasma analysis will be performed under the control of PTS-DMPK/Scinovo, 
GlaxoSmithKline, the details of which will be included in the SRM. Concentrations of 
GSK2269557 will be determined in plasma samples using the currently approved 
bioanalytical methodology. Raw data will be archived at the bioanalytical site (detailed 
in the SRM).
Once the plasma has been analyzed for GSK2269557 any remaining plasma may be
analyzed for other compound-related metabolites and the results reported under a 
separate PTS-DMPK/Scinovo, GlaxoSmithKline protocol.
 
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8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.

Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSK Drug.  

CRFs (including queries and audit trails) will be retained by GSK, and copies will be 
sent to the investigator to maintain as the investigator copy.  Subject initials will not 
be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
This study is designed to establish the PI3K-dependent alterations in immune cell 
mechanisms related to neutrophil function as detected by changes in mRNA 
transcriptomics in samples of induced sputum from patients admitted with an 
exacerbation of COPD. The primary comparison will be between  subjects treated with 
GSK2269557 in addition to standard of care, and subjects treated with placebo in 
addition to standard of care. In addition, treatment comparisons between subjects at 
baseline and subsequent time points will also be produced.
9.1.
Sample Size Considerations
The sample size for this study has been based on feasibility. The sample size of 30 
subjects completing the trial, with approximately 15 of which will receive GSK2269557 
and 15 will receive placebo, is expected to be sufficient to provide a meaningful estimate 
of the mRNA alterations within the lungs.
Previous studies with similar sample size populations have yielded significant fold-
changes (fold-change>1.5 and p<0.05) in immune cell mechanisms using the changes in 
mRNA transcriptomics.
 
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Study Name
Sample
Study Design
Number of Subjects
Number of Differential 
probesets FC = >= 1.5, 
Pval <= 0.05
Notes
PII115117 FTIH 
Healthy Smoker 
nebulised 
GSK2269557
Sputum
Sputum N=12 3-
way x-over 
placebo 400ug, 
6400ug 
12 (9 with all data 
points)
57 probesets change with 
both doses = 44 Genes
Gene changes relate predominantly 
to a down regulation of infection and 
inflammation responses.
Link to Haemophilus influenzae and 
Moraxella catarrhalis infection 
biology – Identified prior to 
knowledge of Activated PI3Kδ 
Syndrome phenotype
200114 Enabler 
GSK2269557 on ex-
vivo COPD Sputum 
and Blood
Sputum
Ex vivo Sputum 
incubated with 
GSK2269557 
sampled at 
6hrs (Sputum 
producers)
15 Subjects
490 probesets change vs 
vehicle control = 295 
genes (of which 43 are 
dysregulated in COPD 
disease vs Healthy 
comparison)
43 genes altered in COPD and 
positively modulated by PI3Kδi 
GSK2269557. Biological themes in 
signature: Pro-cell 
movement/migration  and cell 
viability, anti-apoptotic. Additionally 
link to B/T cell function. Signature 
supports GSK2269557 correction of 
neutrophil migration 
200114 Enabler 
GSK2269557 on ex-
vivo COPD Sputum 
and Blood
Blood
Ex vivo blood 
incubated with 
GSK2269557 
sampled at 
6hrs (Sputum 
15 Subjects
19 probesets change vs 
vehicle control = 15 genes 
Infection and inflammation 
associated genes
200114 Enabler 
GSK2269557 on ex-
vivo COPD Sputum 
and Blood
Blood
Ex vivo blood 
incubated with 
GSK2269557 
sampled at 
6h
(N
15 Subjects
30 probesets change vs 
vehicle control = 25 genes 
Infection and inflammation 
associated genes
9.1.1.
Sample Size Re-estimation or Adjustment
No sample size re-estimation will be performed in this study. 
9.2.
Data Analysis Considerations
9.2.1.
Analysis Populations
Population
Definition / Criteria
Analyses Evaluated
Screened
All subjects who were screened.

Study Population
All subject
All randomised subjects who receive at least 
one dose of the study treatment.
This population will be based on the 
treatment the subject actually received.

Study Population

Pharmacodynamics

Safety

Efficacy
Pharmacokinetic
Subjects in the ‘All subject’ population for 
whom a pharmacokinetic sample was 
obtained and analysed.

PK
9.2.2.
Interim Analysis
No interim analyses will be performed.
 
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9.3.
Key Elements of Analysis Plan
9.3.1.
Primary Analyses
To estimate differences in mRNA intensities within and between treatment groups, a 
repeated measures model will be fitted to the results of the analysis of each probe set at 
Day 12, Day 28 and Day 84 following a loge transformation of the data. The Day 1 
response will be fitted as a baseline covariate. A separate model will be fitted for each of 
the approximate 54000 probe sets.
Back transformed ratios versus screening along with 95% confidence intervals will be 
calculated for each treatment group and timepoint.  Additionally, baseline adjusted ratios
of the change between active treatment and placebo will be calculated along with 95% 
confidence intervals.
Further details around the analysis of the mRNA data will be provided in the RAP.
9.3.2.
Secondary Analyses
All secondary analyses will be described in full prior to unblinding in the RAP.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable
 
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
Signed informed consent  to be obtained for each subject before participation in the 
study (and for amendments as applicable)

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, or 
both.

Signed informed consent must be obtained for each subject prior to participation in 
the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, written 
approval of the clinical protocol should state that approval of optional assessments is 
being deferred and the study, with the exception of the optional assessments, can be 
initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will
serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
 
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10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and the 
regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective 
and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard Operating 
Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this study 
at any time for reasons including, but not limited to, safety or ethical issues or severe 
non-compliance. For multicenter studies, this can occur at one or more or at all sites.  

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by 
local regulations to be maintained elsewhere), in a safe and secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review in 
conjunction with assessment of the facility, supporting systems, and relevant site 
staff.  
 
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
Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, including 
re-generating a hard copy, if required.  Furthermore, the investigator must ensure 
there is an acceptable back-up of these reproductions and that an acceptable quality 
control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by any 
institutional requirements or local laws or regulations, GSK standards/procedures, 
and/or institutional requirements. 

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of ownership 
of the records in the event the investigator is no longer associated with the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
The procedures and timing for public disclosure of the 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.
 
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11.
REFERENCES
De Backer J, Vos W, Vinchurkar S, Van Holsbeke C, Poli, G, Claes R et al. The Effect of 
Extrafine Beclometasone/Formoterol (BDP/F) on Lung Function, Dyspnea, 
Hyperinflation, and Airway Geometry in COPD Patients:  Novel Insight Using 
Fundtional Respiratory Imaging. Journal of Aerosol Medicine and Pulmonary Drug 
Delivery. 2014;27:1-12. 
De Backer LA, Vos WG, Salgado R, De Backer JW, Devoldr A, Verhulst SL et al. 
Functional imaging using computer methods to compare the effect of salbutamol and 
ipratropium bromide in patient-specific airway models of COPD. International Journal 
of COPD. 2011;6:637-646. 
De Backer Lieve A, Vos Wim, Van Holsbeke C, Vinchurkar S, De Backer W. The acute 
effect of budesonide/formoterol in COPD:  a multi-slice computed tomography and lung 
function study. Eur Respir J. 2012;40:298-305. 
GlaxoSmithKline Document Number 2012N141231_04: GSK2269557 Investigator's 
Brochure. Report Date 12-FEB-2015. 
Goldin J, Tashkin D, Kleerup E, Greaser MS, Haywood U, Sayre J et al. Comparative 
effects of hydrofluoroalkane and chloroflurocarbon beclomethasone dipropionate 
inhalation on small airways: Assessment with functional helical thin-section computed 
tomography. J Allergy Clin Immunol. 1999;104 #6:S258-S267. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D et al. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007(a):24. Table 3-2. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D et al. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007(b): 28. 
ICRP. 2007 Recommendation of the International Commission on Radiological 
Protection. ICRP Publication 103. 2007;37:2-4. 
Kim SR, Lee KS, Park HS, et al. HIF -1 alpha inhibition ameliorates an allergic airway 
disease via VEGF suppression in bronchial epithelium. Eur J Immunol. 2010;40 
(10):2858-69. 
Okkenhaug K, Aki K, Vanhaesebroeck B. Antigen receptor signalling:  A distincive role 
for the p110 isoform of PI3K. Trends in Immunuology. 2007;28:80-7. 
Quanjer P, Stanojevic S, Cole T, Baur X, Hall G, et al. Multi-ethnic reference values for 
spirometry for the 3-95-yr age range:  The global lung function 2012 equations. 
European Respiratory Journal. 2012;40(6):1324-1343. 
Sadhu C, Dick K, Tino WT, Staunton DE. Selective role of PI13K delta in neutrophil 
inflammatory responses. Biochem Biophys Res Commun. 2003 Sep 5;308 (4):764-9. 
 
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Weisser SB, McLarren KW, Voglmaier B, et al. Alternative activation of macrophages 
by IL-4 requires SHIP degradation. Eur J Immunol. 2011;41(6):1742-53. 
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
AE
Adverse Event
ALT
Alanine aminotransferase
COPD
Chronic Obstructive Pulmonary Disease
CRF
Case Report Form
CT
Computed Tomography
CV
Cardiovascular
ECG
Electrocardiogram
FEV1
Forced Expiratory Volume in One Second
FRC
Functional Residual Capacity
FRI
Functional Respiratory Imaging
GCP
ICH Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GSK
GlaxoSmithKline
HRCT
High-Resolution Computed Tomography
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
PEF
Peak Expiratory Flow
PI3K
Phosphoinositide 3-Kinase Delta
PK
Pharmacokinetic
QTcF
QT interval corrected using the Fridericia's formula
RAP
Reporting and Analysis Plan
SAE
Serious Adverse Event
SRM
Study Reference Manual
TLC
Total Lung Capacity
ULN
Upper Limit of Normal
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
DISKUS
None
 
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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Phase II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase II liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete an
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with study 
treatment unless allowed per protocol and GSK 
Medical Governance approval is granted (refer 
to Appendix 2).

If restart/rechallenge not allowed per protocol 
or not granted, permanently discontinue study 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained 7 days after last 
dose5

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 
 
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treatment and may continue subject in the study 
for any protocol specified follow up assessments 
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-72 
hrs 

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline
form including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in subjects with definite or likely 
acetaminophen use in the preceding 
week [James, 2009]). NOTE: not 
required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN.. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, 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 subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
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 
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.)  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.
 
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Phase II liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject safety. 

Subject can continue study treatment 

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
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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12.3.
Appendix 3: Genetic Research
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and:

Response to medicine, including any treatment regimens under investigation in this 
study or any concomitant medicines;

COPD susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.

A 6 mL blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. A 
Blood sample is collected at the baseline visit, after the subject has been randomized 
and provided informed consent for genetic research. Instructions for collection and 
shipping of the genetic sample are described in the laboratory manual. The DNA 
from the blood sample may undergo quality control analyses to confirm the integrity 
of the sample. If there are concerns regarding the quality of the sample, then the 
sample may be destroyed. The blood sample is taken on a single occasion unless a
duplicate sample is required due to an inability to utilize the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
 
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the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA sample 
is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will continue 
to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
 
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reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
 
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12.4.
Appendix 4: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.4.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

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 medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

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 prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected 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 this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).
Events NOT meeting definition of an AE include:

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 subject’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 
subject’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
 
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convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
12.4.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject 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 hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject 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 out-patient setting.  Complications that occur during 
hospitalization are AEs.  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 disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g. sprained ankle) which may interfere or 
prevent everyday life functions but do not constitute a substantial disruption
 
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e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether 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 subject or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition.  These should also be 
considered serious.

Examples of such events are 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
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.4.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
 
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12.4.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’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 instance, all subject identifiers, with the exception of 
the subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
12.4.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.
 
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
A "reasonable possibility" is meant to convey that there are facts/evidence 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 natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of 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 when 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 prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject 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 the designated 
reporting time frames.
 
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12.4.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data 
collection tool

If the electronic system is unavailable for greater than 24 hours, the site will use 
the paper SAE data collection tool and fax it to the Medical Monitor.

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission 
of the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes 
to existing data

If a site receives a report of a new SAE from a study subject or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, the site can report this information on a paper SAE form or to the 
Medical Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
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12.5.
Appendix 5: Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who 
becomes pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 
2 weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, 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. 

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 4. 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 subject who becomes pregnant while participating will discontinue 
study medication
Pregnancy information on female partner of male study subjects

Investigator will attempt to collect pregnancy information on any female partner of 
a male study subject who becomes pregnant while participating in this study.  This 
applies only to subjects who are randomized to receive study medication. 

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate 
form and submit it to GSK within 2 weeks of learning of the partner’s pregnancy

Partner will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded to GSK. 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date.  Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for procedure.
 
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12.6.
Appendix 6: Country Specific Requirements
No country-specific requirements exist.
 
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