Clinical trial NCT02522299
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: double-blind PI3Kdelta GSK2269557 exacerbation Chronic Obstructive Pulmonary Disease randomised placebo-controlled
Sponsor: GlaxoSmithKline
Start date: 2015-11-04; Completion date: 2018-06-22
Enrollment: 44 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate specific alterations in immune cell mechanisms related to neutrophil function as detected by PI3Kdelta-dependent changes in messenger ribonucleic acid (mRNA) extracted from induced sputum in patients experiencing an exacerbation of COPD, with or without treatment with GSK2269557. The efficacy of treatment with GSK2269557 will also be measured using functional respiratory imaging (FRI) and spirometry. This is a randomised, double-blind, placebo-controlled, parallel-group study. The study consisted of Screening Phase (up to 3 days prior to Day 1), Treatment Phase (Days 1 to 84) and Follow phase (7 to 14 days after last dose). The total duration of the study is 13-14 weeks including the screening visit. DISKUS TM and ELLIPTA TM are registered trademark of GSK group of companies.

Detailed description:

Arms: arm 1: Subjects will receive 2 inhalations of GSK2269557 (30 seconds apart, 2 x 500 mcg, total dose of 1000 mcg) once daily for 84 consecutive days via DISKUS™ device. arm 2: Subjects will receive 2 inhalations of placebo once daily for 84 days via DISKUS device. arm 3: Subjects will receive 2 inhalations of GSK2269557 700 mcg once daily for 84 consecutive days via ELLIPTA. arm 4: Subjects will receive Placebo once daily for 84 consecutive days via ELLIPTA.
Interventions: intervention 1: GSK2269557 intervention 2: Placebo intervention 3: DISKUS intervention 4: ELLIPTA
Intervention descriptions: intervention 1: GSK2269557 500 mcg blended with lactose per blister and will be administered using a DISKUS dry powder inhaler device. Since GSK2269557 will no longer be manufactured for use with the DISKUS device, it will be replaced with ELLIPTA Device. Subjects will receive GSK2269557 700 mcg once daily for 84 consecutive days via ELLIPTA. intervention 2: Lactose will be administered using a DISKUS and ELLIPTA dry powder inhaler device intervention 3: It is multi-dose dry powder inhaler containing one foil strip of drug with 60 blisters intervention 4: It is multi-dose dry powder inhaler containing one foil strip of drug with 30 blisters

Protocol documents:
Prot_000.pdf: 
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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 
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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 
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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 
visit.
 
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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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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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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
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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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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_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.
 
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PPD
PPD
PPD
PPD
PPD
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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PPD


2014N218070_00
CONFIDENTIAL
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4
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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SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
201928
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for Study 201928: 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
Effective Date 
:
09-JAN-2019
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 201928.

This RAP is intended to describe the pharmacodynamic/biomarker, safety, 
pharmacokinetic and efficacy analyses required for the study. 

This version of the RAP includes amendments to the originally approved RAP.

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
Approver
Statistician (Clinical Statistics)
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.
Unauthorised copying or use of this information is prohibited.
 
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RAP Team Review Confirmation:
Approver
Date
Approval Method
09-Jan-2019
Email
Study Accountable Person (Clinical 
Development)
09-Jan-2019
Email
Principal Programmer (Clinical Programming)
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
09-Jan-2019
eSignature
Director (Clinical Statistics)
09-Jan-2019
eSignature
Manager (Clinical Programming)
 
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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Objective(s) and Endpoint(s)...............................................................8
2.3.
Study Design ................................................................................................9
2.4.
Statistical Analyses.....................................................................................10
2.4.1.
Primary Analyses.........................................................................10
3.
PLANNED ANALYSES ..........................................................................................10
3.1.
Final Analyses ............................................................................................10
4.
ANALYSIS POPULATIONS ...................................................................................10
4.1.
Protocol Deviations.....................................................................................11
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................12
5.1.
Study Treatment & Sub-group Display Descriptors.....................................12
5.2.
Baseline Definitions ....................................................................................13
5.3.
Examination of Covariates and Subgroups .................................................14
5.3.1.
Covariates and Other Strata ........................................................14
5.3.2.
Examination of Subgroups...........................................................14
5.4.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................14
6.
STUDY POPULATION ANALYSES .......................................................................15
6.1.
Overview of Planned Study Population Analyses........................................15
7.
PHARMACODYNAMIC AND BIOMARKER ANALYSES........................................15
7.1.
Primary Pharmacodynamic and Biomarker Analyses..................................15
7.1.1.
Endpoint / Variables.....................................................................15
7.1.2.
Summary Measure ......................................................................16
7.1.3.
Population of Interest...................................................................16
7.1.4.
Statistical Analyses / Methods .....................................................16
7.1.4.1.
Statistical Methodology Specification..........................16
7.2.
Exploratory Pharmacodynamic and Biomarker Analyses............................17
7.2.1.
Endpoint / Variables.....................................................................17
7.2.2.
Summary Measure ......................................................................18
7.2.3.
Population of Interest...................................................................18
7.2.4.
Statistical Analyses / Methods .....................................................19
8.
EFFICACY ANALYSES..........................................................................................19
8.1.
Secondary Efficacy Analyses (Not From HRCT Analyses)..........................19
8.1.1.
Endpoint / Variables.....................................................................19
8.1.2.
Summary Measure ......................................................................19
8.1.3.
Population of Interest...................................................................20
8.1.4.
Statistical Analyses / Methods .....................................................20
8.1.4.1.
Statistical Methodology Specification..........................20
 
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8.2.
Secondary Efficacy Analyses (From HRCT Analyses) ................................21
8.2.1.
Endpoint / Variables.....................................................................21
8.2.2.
Summary Measure ......................................................................21
8.2.3.
Population of Interest...................................................................25
8.2.4.
Statistical Analyses / Methods .....................................................26
8.2.4.1.
Statistical Methodology Specification..........................26
8.3.
Exploratory Efficacy Analyses (From HRCT Analyses) ...............................30
8.3.1.
Endpoint / Variables.....................................................................30
8.3.2.
Summary Measure ......................................................................30
8.3.3.
Population of Interest...................................................................31
8.3.4.
Statistical Analyses / Methods .....................................................31
8.3.4.1.
Statistical Methodology Specification..........................31
8.4.
Exploratory Efficacy Analyses (Not from HRCT Analyses)..........................32
8.4.1.
Endpoint / Variables.....................................................................32
8.4.2.
Summary Measure ......................................................................32
8.4.3.
Population of Interest...................................................................32
8.4.4.
Statistical Analyses / Methods .....................................................33
9.
RELATIONSHIP BETWEEN THE PHARMACODYNAMIC AND 
BIOMARKER DATA AND THE HRCT DATA..........................................................33
9.1.
Relationship between the mRNA data and the HRCT data.........................33
10. SAFETY ANALYSES .............................................................................................33
10.1.
Adverse Events Analyses ...........................................................................33
10.2.
Clinical Laboratory Analyses.......................................................................33
10.3.
Other Safety Analyses ................................................................................33
11. PHARMACOKINETIC ANALYSES.........................................................................34
11.1.
Secondary Pharmacokinetic Analyses........................................................34
11.1.1.
Endpoint / Variables.....................................................................34
11.1.1.1.
Drug Concentration Measures....................................34
11.1.1.2.
Derived Pharmacokinetic Parameters.........................34
11.1.2.
Summary Measure ......................................................................34
11.1.3.
Population of Interest...................................................................34
12. REFERENCES.......................................................................................................35
13. APPENDICES........................................................................................................36
13.1.
Appendix 1: Protocol Deviation Management .............................................36
13.1.1.
Important Protocol Deviations......................................................36
13.2.
Appendix 2: Schedule of Activities ..............................................................37
13.2.1.
Protocol Defined Schedule of Events...........................................37
13.3.
Appendix 3: Assessment Windows .............................................................41
13.3.1.
Definitions of Assessment Windows for Analyses........................41
13.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................42
13.4.1.
Study Phases ..............................................................................42
13.4.1.1.
Study Phases for Concomitant Medication .................42
13.4.2.
Treatment States for Adverse Events ..........................................42
13.5.
Appendix 5: Data Display Standards & Handling Conventions....................43
13.5.1.
Reporting Process .......................................................................43
13.5.2.
Reporting Standards....................................................................43
 
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13.5.3.
Reporting Standards for Pharmacokinetic....................................44
13.6.
Appendix 6: Derived and Transformed Data ...............................................45
13.6.1.
General........................................................................................45
13.6.2.
Study Population..........................................................................45
13.6.3.
Efficacy........................................................................................46
13.6.4.
Safety ..........................................................................................48
13.6.5.
Pharmacodynamic and Biomarker ...............................................49
13.7.
Appendix 7: Reporting Standards for Missing Data.....................................60
13.7.1.
Premature Withdrawals................................................................60
13.7.2.
Handling of Missing Data.............................................................60
13.7.2.1.
Handling of Missing and Partial Dates ........................61
13.8.
Appendix 8: Values of Potential Clinical Importance ...................................62
13.8.1.
Laboratory Values........................................................................62
13.8.2.
ECG.............................................................................................63
13.8.3.
Vital Signs....................................................................................63
13.9.
Appendix 9: Abbreviations & Trade Marks ..................................................64
13.9.1.
Abbreviations...............................................................................64
13.9.2.
Trademarks .................................................................................66
13.10. Appendix 10: List of Data Displays..............................................................67
13.10.1. Data Display Numbering..............................................................67
13.10.2. Deliverables.................................................................................67
13.10.3. Study Population Tables..............................................................68
13.10.4. Efficacy Tables ............................................................................70
13.10.5. Efficacy Figures ...........................................................................88
13.10.6. Safety Tables...............................................................................89
13.10.7. Pharmacokinetic Tables...............................................................92
13.10.8. Pharmacokinetic Figures .............................................................95
13.10.9. Pharmacodynamic and Biomarker Tables....................................96
13.10.10.ICH Listings ...............................................................................102
13.10.11.Non-ICH Listings........................................................................105
13.11. Appendix 11: Example Mock Shells for Data Displays ..............................108
 
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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol:
Revision Chronology:
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-2
Amendment No. 4
Replace the administration of GSK2269557 via the DISKUSTM device (1000 µg) by a
comparable dose administered via the ELLIPTATM device (700 µg). 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.
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1.
 
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Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes

Total lung capacity and lung lobar 
volumes included in HRCT 
secondary endpoint parameters

Total lung capacity and lung lobar 
volumes dropped from HRCT 
secondary endpoint parameters 
included as an exploratory 
endpoint parameter instead

The clinically relevant 
HRCT parameters are still 
to be decided. However, 
there was no clinical benefit 
seen in the comparison 
between GSK2269557 
1000 mcg and Placebo in 
these parameters.

Analysis 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.

Pharmacokinetic
Subjects in the ‘All subject’ 
population for whom a 
pharmacokinetic sample was 
obtained and analysed.

Analysis 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.

Pharmacokinetic
Subjects in the ‘All subject’ 
population for whom a 
pharmacokinetic sample was 
obtained and analysed.
Note: The two subjects who were 
not compliant with inhaler 
instructions will be excluded from 
the outcome summaries if they 
received active treatment but will 
be included if they received 
placebo

2 subjects were not 
compliant with inhaler 
instructions and may not 
have received the full dose 
in amendment 4. Therefore,
these subjects will be 
excluded from the outcome 
summaries if they received 
active treatment but will be 
included if they received 
placebo. Sensitivity 
analyses may be conducted 
including these subjects.
 
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2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

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 Objectives
Secondary Endpoints

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.

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.
Exploratory Objectives
Exploratory Endpoints

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.

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 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
 
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2.3.
Study Design
Overview of Study Design and Key Features
Design
Features

Multi-centre and Multi-Country

Randomised

Double-blind

Placebo-controlled

Parallel group
Dosing

Once daily, in the morning for 84 days

Administered through the Diskus dry powder Inhaler
Time & 
Events

Refer to Appendix 2: Schedule of Activities
Treatment 
Assignment

Initially planned for approximately 30 subjects randomised to receive either 1000 g 
GSK2269557 (Diskus) or matching Placebo in a 1:1 ratio as it was anticipated that 10 
patients would drop-out. Twenty-eight subjects were randomised to this schedule,
however, due to expiration date there was a protocol amendment following which
additional subjects were subsequently randomised to receive either 700 g 
GSK2269557 (Ellipta) or matching Placebo (Ellipta) in a 1:1 ratio. The protocol was 
updated such that approximately 45 subjects with an acute exacerbation of COPD 
would 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.

Subjects are assigned to treatment in accordance with the randomisation schedule 
generated by Clinical Statistics, using validated software.
Interim 
Analysis

No formal interim analysis will be conducted
 
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2.4.
Statistical Analyses
2.4.1.
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.
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 are provided in Section 7.1.
3.
PLANNED ANALYSES
3.1.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All participants have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management.
3.
All criteria for unblinding the randomisation codes have been met. 
4.
Randomisation codes have been distributed according to RandAll NG procedures.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Participants 
Enrolled (APE)

All subjects who were screened for eligibility

Study Population
All Subjects

Comprised of all subjects who were randomised.

This population will be based on the treatment the 
subject actually received.
o
If participants receive >1 treatment, then they 
will be summarised according to the most 
frequently dosed treatment. In cases where 
the frequency is equal, the participant will be 
assigned the lowest dose strength of 
nemiralisib. 
o
If participants receive no treatment, then they 
will be summarised according to “No 
Treatment”

Study Population

Pharmacodynamics
and Biomarker

Safety

Efficacy
Pharmacokinetic 
(PK)

Subjects in the ‘All Subjects’ population for whom a 
pharmacokinetic sample was obtained and analysed.

PK
 
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Refer to Appendix 10: List of Data Displays which details the population used for each display.
Note: The two subjects who were not compliant with inhaler instructions will be excluded from the outcome summaries 
if they received active treatment but will be included if they received placebo
4.1.
Protocol Deviations
During the course of the study it was noted that two subjects did not complete dosing 
instructions as required. The primary plan is if the subjects received active treatment they 
will be excluded from the study outcome summaries; if the subject received placebo 
treatment, they will be included in the study outcome summaries. It has not yet been 
identified if they received placebo or active treatment. A footnote will be applied to all 
relevant displays stating the rationale, subject number, treatment and if they were 
excluded, e.g. “Subjects X & Y did not complete dosing instructions as required; subject 
X received nemiralisib and was therefore excluded, subject Y received placebo and was 
therefore included.” The footnote may be tweaked for aesthetic purposes.
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan, refer to Appendix 1.
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations are captured and categorised on the protocol deviations
dataset. 
o This dataset will be the basis for the summaries and listings of protocol 
deviations.
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF.
 
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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order in TLF 
This will be derived as subjects who did not 
receive any treatment
No Treatment
1
This will be derived as subjects in RandALL 
codes A or C
All Placebo
2
This will be derived as subjects in RandALL 
codes B or D
All NEMI
3
A
Placebo
Placebo Diskus
4
B
GSK2269557 1000 mcg
NEMI Diskus
5
C
Placebo via Ellipta
Placebo Ellipta
6
D
GSK2269557 700 mcg
NEMI Ellipta
7
NOTES:
1.
The following footnote will be presented on displays which use the “Placebo Diskus”, “NEMI Diskus”, “Placebo 
Ellipta” or “NEMI Ellipta” treatment groups:
NEMI Diskus =1000 mcg Nemiralisib administered via the Diskus device; NEMI Ellipta =700 mcg Nemiralisib 
administered via the Ellipta device
2.
Order represents treatments being presented in TFL, as appropriate
Treatment groups “Placebo” and “Placebo via Ellipta” (RandAll NG codes A and C) will 
be combined into “All Placebo” treatment group. Similarly, treatment groups 
“GSK2269557 700 mcg” and “GSK2269557 1000 mcg” (RandAll NG codes B and D) 
will be combined into “All NEMI” treatment group. 
Treatment comparisons will be displayed as follows using the descriptors as specified:
1.
All NEMI vs All Placebo
Notes: 

The “All Placebo” and “All NEMI” groups and “All NEMI vs All Placebo” 
treatment comparison will be presented for Pharmacodynamic and biomarker, 
efficacy and study population summaries unless otherwise specified.

The “Placebo Diskus”, “NEMI Diskus”, “Placebo Ellipta” or “NEMI Ellipta” 
treatment groups will be presented for Pharmacokinetic and safety summaries 
unless otherwise specified.

The “Placebo Diskus”, “NEMI Diskus”, “Placebo Ellipta” or “NEMI Ellipta” 
treatment groups will be presented for all listings
 
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5.2.
Baseline Definitions
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment with a non-missing value, including those from unscheduled 
visits. If time is not collected, Day 1 assessments are assumed to be taken prior to first 
dose and used as baseline.
Parameter
Study Assessments Considered as Baseline
Baseline 
Used in Data 
Display
Screening
Day 1 
(Pre-
Treatment)
Day 2 
Within 
48H/discharge
(On Treatment)
Day 12 
(On 
Treatment)
Safety
Labs including 
Haematology
X
X
Day 1
ECG
X
X
Day 1
Vitals
X
X
Day 1
Efficacy
HRCT Untrimmed
X
Screening
HRCT Scan 
Trimmed
     
Screening&Day12
X
Screening
     
Screening&Day28
X
Screening
     Day12&Day28
X
Day 12
FEV1 and FVC
X
X
Day 1[1]
Daily PEF [2]
X
Day 1
Mean of Days 
1 to 3
Maximum of 
Days 1 to 3
Pharmacodynamic
Sputum and Blood
X
Screening
Genetic sample 
(PGx) [3]
X
NOTES:

Unless otherwise stated, the mean of replicate assessments at any given time point will be used as the value for 
that time point.

[1] Baseline will be investigated to ensure there is sufficient data and will be footnoted as appropriate

[2] For PEF 3 different baselines will be calculated: Day 1, mean of Days 1 to 3 and Maximum of Days 1 to 3.
TFLs will be footnoted with the relevant baseline.

[3] Collected at any time after randomisation
 
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Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing.
5.3.
Examination of Covariates and Subgroups
5.3.1.
Covariates and Other Strata
The list of covariates may be used in descriptive summaries and statistical analyses, some 
of which may also be used for subgroup analyses. Additional covariates of clinical 
interest may also be considered.
Category
Details
Covariates
Age, Sex, BMI, Country, Primary exacerbation severity
5.3.2.
Examination of Subgroups
The list of subgroups may be used in descriptive summaries and statistical analyses.
Additional subgroups of clinical interest may also be considered.

If the percentage of subjects is small within a particular subgroup, then the subgroup 
categories may be refined prior to unblinding the trial.

If the category cannot be refined further, then descriptive rather than statistical 
comparisons may be performed for the particular subgroup.
Subgroup
Categories 
Primary exacerbation severity
Moderate or Severe [1]
Country
Country
NOTES:
[1] Exacerbations are defined as severe if they require hospitalisation, otherwise they are defined 
as moderate
5.4.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
13.3
Appendix 3: Assessment Windows
13.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
13.5
Appendix 5: Data Display Standards & Handling Conventions
13.6
Appendix 6: Derived and Transformed Data
13.7
Appendix 7: Reporting Standards for Missing Data
13.8
Appendix 8: Values of Potential Clinical Importance
 
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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the “All Subjects” population, unless 
otherwise specified.
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.
Details of the planned displays are presented in Appendix 10: List of Data Displays.
7.
PHARMACODYNAMIC AND BIOMARKER ANALYSES
7.1.
Primary Pharmacodynamic and Biomarker Analyses
7.1.1.
Endpoint / Variables
Sputum RNA will be extracted and hybridised using a balanced batch design. An 
appropriate microarray platform will be determined at the time of hybridisation, to allow 
for improvements in technology. The quality of the data will be assessed and then 
normalised using appropriate methodologies and software.
Microarray mRNA data will be normalised using gcRMA or RMA in Array Studio v5.0 
or later. After normalisation, the data will be quality assessed and any samples deemed as 
QC fails will be excluded from any further analysis. This quality assessment will involve 
looking for outlying signals in both the normalised expression data and the MAS5 QC 
metrics generated from each sample. If any samples are excluded, the remaining data will 
be re-normalised. The output from the normalisation will be log2 transformed mRNA 
intensity data (measured in arbitrary units).
Since the data will be log2 transformed prior to the analysis the treatment effects will be 
expressed as ratios after back transformation (2^). These ratios can be converted to fold 
change values as follows:

If ratio ≥ 1 then fold change = ratio

If ratio <1 then fold change = -1/ratio
Microarray data consists of expression values (log2-transformed) derived from individual 
probe sets designed against coding regions of individual genes. More than one probe set
can exist per gene. This analysis will be conducted at the probe set level.
The mRNA data gives results from ~14000 genes encoded by ~54000 probe sets. To 
establish the PI3Kδ-dependent changes in previously identified immune cell mechanisms 
specifically related to neutrophil function using mRNA, we identified 258 gene to subset 
our data on, refer to Section 13.6.5. The gene names were converted to Affymetrix probe 
IDs, this resulted in 638 probes refer to Section 13.6.5.
 
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To compare the expression value between treatments for each probe set, linear repeated 
measures mixed effects model will be fitted to each probe set, with log2 (intensity) as the 
response variable. Note: log2 (intensity) may also be referred to as mRNA intensities 
(logarithm base 2 scale). Alteration in previously identified immune cell mechanisms 
specifically related to neutrophil function will be determined by changes in mRNA 
transcriptomics in induced sputum after 12, 28 and 84 days of treatment by the analysis 
of mRNA intensities (logarithm base 2 scale) subset by the 638 probes identified in 
Section 13.6.5.
7.1.2.
Summary Measure
A repeated measures modelling analysis will be performed on the subset of 638 probes 
which have previously identified immune cell mechanisms specifically related to 
neutrophil function. 
The model will be used to estimate the baseline adjusted fold changes for active treatment 
and placebo calculated for Day 12, Day 28 and Day 84 along with the corresponding 95% 
confidence intervals and unadjusted P-values. Additionally, baseline adjusted ratios of the 
change between active treatment and placebo will be calculated along with 95% 
confidence intervals and unadjusted P-values.
7.1.3.
Population of Interest 
The primary pharmacodynamic analyses will be based on the “All Subjects” population, 
unless otherwise specified.
7.1.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and
listed.
7.1.4.1.
Statistical Methodology Specification
Endpoint / Variables

Alterations in the 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. The response variable will be mRNA intensities 
(logarithm base 2 scale).
Model Specification
The mRNA data gives results from ~14000 genes encoded by ~54000 probe sets. A subset of 638 
probe sets specifically relating to the cell mechanisms of neutrophil function is specified in Section 
13.6.5 This subset will comprise the primary statistical analysis dataset.
 
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Each probe set will be analysed separately. 
The log2 transformed mRNA intensities will be analysed in a repeated measures model under a 
Frequentist framework. The model will include a Treatment, Visit and Treatment*Visit term. The 
Visit will consist of 4 levels: Screening (Baseline), Day 12, Day 28 and Day 84, and the Treatment 
will consist of three levels: Null (when Visit = Screening), All Placebo and All NEMI. An 
unstructured (UN) covariance structure will be fitted. The denominator degrees of freedom for use 
in significance testing will be computed using the Kenward Rogers approximation.
Back transformed baseline-adjusted ratios along with 95% CIs and two-sided unadjusted p-values 
will be calculated for each Visit for the All NEMI and All Placebo Treatments, i.e. Day 84, Day 28 
and Day 12 in the All NEMI Treatment group vs Screening and Day 84, Day 28 and Day 12 in the 
All Placebo Treatment group vs Screening. Additionally, baseline adjusted ratios between All NEMI
vs All Placebo will be calculated for Day 12, Day 28 and Day 84 along with 95% CI and two-sided
unadjusted p-values, i.e. Day 84 in the All NEMI Treatment group vs Day 84 in the All Placebo 
Treatment group, similarly for Day 28 and Day 12. Other comparisons of interest may also be 
calculated such as means for each Visit and Treatment, i.e. Screening (Null Treatment), Day 12, 
28 and 84 (All NEMI Treatment) Day 12, 28 and 84 (All Placebo Treatment).
To enable review by the study team, csv files will be created containing the output for all probe sets 
in scope for the primary statistical analysis will be generated sorted alphabetically by probe set ID. 
Separate csv files may be created containing only probe sets where the p-value for the 
comparisons is <0.05. Such probe sets will be ranked by fold change, with the expectation that, in 
general, a greater than a 1.5-fold change is scientifically meaningful. To comply with guidance 
regarding QC, csv files will be stored as a SAS dataset to ensure QC can be audited.
Following review by the study team of the results, a subset of probe sets may be identified and 
may be used for further reporting.
Model Checking & Diagnostics

The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used.

An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ on 
the REPEATED line.

In the event that this model fails to converge, alternative correlation structures may be 
considered
Model Results Presentation
Output from the repeated measures modelling detailed above will be tabulated.
In particular, the estimated baseline adjusted fold changes, 95% CI, standard error (on the 
logarithm base 2 scale), unadjusted p-values at each time point and for the active treatment 
comparison with placebo. The probe set, gene/gene description will be included in the outputs.
7.2.
Exploratory Pharmacodynamic and Biomarker Analyses
7.2.1.
Endpoint / Variables
In addition to the primary analysis, there is an exploratory objective to establish any other 
PI3Kδ-dependent changes in mRNA in sputum or blood from patients with an 
exacerbation of COPD, with or without treatment with GSK2269557. To address this 
 
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blood and sputum mRNA data, as described in Section 7.1,but analyses will be conducted 
on the complete mRNA data, i.e. the results from ~14000 genes encoded by ~54000 
probe sets.
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. Endpoints may include, but not limited to, cytokines (IL-6, IL-8, 
TNFα), microbiome (by 16SrRNA), bacterial qPCR, total cell counts and PMNs 
differentials.
To explore the pharmacodynamic effects in blood of once daily repeat inhaled doses of 
GSK2269557 administered to subjects with acute exacerbation of COPD, compared to 
placebo. Endpoints may include, but not limited to, total cell counts and PMNs 
differentials.
7.2.2.
Summary Measure
To establish any other PI3Kδ-dependent changes in mRNA in sputum or blood from 
patients with an exacerbation of COPD, with or without treatment with GSK2269557. A 
repeated measures modelling analysis will be performed on the complete probe set. The 
model will be used to estimate the baseline adjusted fold changes for active treatment and 
placebo calculated for Day 12, Day 28 and Day 84 along with the corresponding 95% 
confidence intervals and unadjusted P-values. Additionally, baseline adjusted ratios of the 
change between active treatment and placebo will be calculated along with 95% 
confidence intervals and unadjusted P-values.
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. Summary statistics of endpoints may include, but not limited to,
cytokines (IL-6, IL-8, TNFα), microbiome (by 16SrRNA), bacterial qPCR, total cell 
counts and PMNs differentials.
To explore the pharmacodynamic effects in blood of once daily repeat inhaled doses of 
GSK2269557 administered to subjects with acute exacerbation of COPD, compared to 
placebo. Summary statistics of endpoints may include, but not limited to, total cell counts
and PMNs differentials.
7.2.3.
Population of Interest 
The exploratory pharmacodynamic analyses will be based on the “All Subjects” 
population, unless otherwise specified.
As previously discussed for the two subjects that did not follow inhalation instructions, if 
the subjects received active treatment they will be excluded from the study outcome 
summaries; if the subject received placebo treatment, they will be included in the study 
outcome summaries. 
 
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7.2.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Refer to Section 7.1.4.1 for statistical methodology specification, however, for the 
exploratory analysis, the models will be fitted but on the complete dataset ~14000 genes 
encoded by ~54000 probe sets; sputum and blood data will be analysed separately. Note: 
only a subset of the results will be presented as it is not feasible to present all ~54,000 
probe sets for the sputum and blood data. Biostatistics will await guidance following 
unblinded regarding which, if any, probe sets should be presented for the exploratory 
analysis and confirmation if a cut off criteria other than p-value<0.05 AND (fold change> 
1.5 OR fold change< -1.5) should be used in determining which comparisons for the 
probe sets should be presented.
Unless otherwise specified, endpoints / variables defined in Section 7.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. For each endpoint, the values will be inspected to determine whether a data
transformation is required. It is expected that: cytokines may require a transformed on the 
natural logarithm scale
8.
EFFICACY ANALYSES
8.1.
Secondary Efficacy Analyses (Not From HRCT Analyses)
8.1.1.
Endpoint / Variables
To evaluate the effect of once daily repeat inhaled doses of nemiralisib on lung function 
parameters in subjects with acute exacerbation of COPD compared to placebo. Lung 
function parameters including: 

PEF

FEV1 and FVC at clinic prior to sputum induction 

reliever usage
8.1.2.
Summary Measure
For PEF, summary statistics for the change from baseline PEF will be presented in 
tabular form, mean and 95% CIs of AM PEF readings will be plotted by study treatment 
vs. Study Day. 
For FEV1 (L) and FVC (L), a change from baseline statistical analysis will be conducted 
and presented via tables of predicted adjusted medians for each Treatment arm at each 
visit, and the difference between treatment arms at each visit. 
For reliever use, bronchodilator use recorded in the diary will be summarised as the mean 
number of occasions of rescue use per day and the percentage of rescue-free days in four-
week interval periods as described in Section 13.6.3, where a rescue-free day is defined 
as a 24-hour period in which the number of occasions bronchodilator taken is zero.
Summary tables will display estimates for each 4-weekly period for mean number of 
occasions of rescue use per day and percentage of rescue-free days separately.
 
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8.1.3.
Population of Interest
The primary efficacy analyses will be based on the “All Subjects” population, unless 
otherwise specified. 
8.1.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 8.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
8.1.4.1.
Statistical Methodology Specification
NOTE: The description below describes the current thinking of how to analyse these 
endpoints. The proposed models will be assessed, and if not appropriate alternative 
models could be used.
Endpoint / Variables

FEV1 (L), FVC(L)
Model Specification

The data will be inspected during statistical analysis to determine whether a data 
transformation is required. It is likely no transformations will be required

The analysis will include all available values. If there are values which were recorded within 4h 
after the subject had taken relief medication, a sensitivity analysis may be done which excludes 
these values.

The endpoints (FEV1 and FVC) will be analysed in separate models. The change from baseline 
in the endpoint will be analysed in a Bayesian repeated measures model, with a baseline by 
Visit covariate and Treatment by Visit class parameter. Note that the model will not include an 
intercept. The Treatment will have two levels: All NEMI and All Placebo, and the Visit will have 
two levels: Day 28 and Day 84. No fixed assumption around the structure of the covariance 
matrix will be enforced. The priors for the mean vector for each of the parameters (i.e. 
covariates) will each follow a normal distribution and the prior for the variance-covariance will 
follow an inverse Wishart distribution. Sensitivity analysis will be conducted to select 
appropriate parameters for both distributions such that the priors are non-informative with 
respect to the posterior.

The change from baseline at each of the Visits will be represented via adjusted posterior 
medians for each of the Treatment Arms, as well as their associated 95% HPD-tailed credible 
intervals. These results will also be presented in a tabular format.

The difference between the treatment arms, for the change from baseline will be represented 
via adjusted posterior medians for each of the Treatment Arms, as well as their associated 
95% HPD-tailed credible intervals. These results will also be presented in tabular format.

The probabilities that the treatment difference is greater or less than 0 (depending on direction 
of the endpoint), in addition to other values appropriately selected based on the data, will also 
be computed for each Visit. These results will be presented in tabular format.
 
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Model Checking & Diagnostics

Model assumptions will be applied, but appropriate adjustments maybe made based on the 
data. For example, if data do not approximately follow a normal distribution then attempt will be 
made to find a suitable transformation.

A comprehensive investigation into a suitable model should be initiated. For example,
additional covariates will be investigated

An unstructured covariance structure will be used. However, in the event that this model fails to 
converge, alternative correlation structures may be considered. 

Models with a Bayesian Framework will use vague priors. If appropriate, conjugate priors will 
be used. For example, for a multivariate model, the prior for the variance covariance matrix will 
be an inverse Wishart distribution.
Model Results Presentation

Output from the repeated measures modelling detailed above will be tabulated. In particular, 
the estimated change from baseline, 95% CI, standard error, and posterior probabilities at each 
time point and for the active treatment comparison with placebo. 
Subgroup Analyses

For FEV1, a subgroup analysis will be conducted by index exacerbation severity (refer to 
Section 5.3 Examination of Covariates and Subgroups). A similar model as described in Model 
specification will be fitted but will also include a Severity*Treatment*Visit term within the model. 

The results of the subgroup analysis will be reported in a separate table.
8.2.
Secondary Efficacy Analyses (From HRCT Analyses)
8.2.1.
Endpoint / Variables
To evaluate the effect of once daily repeat inhaled doses of nemiralisib on lung
parameters derived from HRCT scans in subjects with acute exacerbation of COPD,
compared to placebo. Ratio from baseline in siVaw, iVaw, iRaw, siRaw, trachea length 
and diameter at FRC and TLC after 12 days of treatment and after 28 days of treatment. 
8.2.2.
Summary Measure
Each HRCT scan will be conducted at two lung volumes: total lung capacity (TLC) and 
functional residual capacity (FRC); these will be referred to as scan conditions. The 
HRCT images will be processed to derive the HRCT parameters at FRC and TLC, 
however these conditions are not applicable for all parameters. 
The HRCT scans will be conducted at Screening, Day 12 and Day 28. The 3 HRCT 
images will then be processed to derive the HRCT parameters at each scan; this data will 
be referred to as the untrimmed data. The untrimmed data measures all airways that are 
present in each scan.
However partially due to positioning of subjects whilst taking a scan, it can be that some 
airways are visible in some scans and not in other scans. For these reasons, some HRCT 
 
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imaging endpoints will be calculated to include only airways that are visible in both 
scans. Therefore, the scans were grouped into three scan trimming pairs where, within 
each scan trimming pair, the airways that were not present in both scans were 
removed/trimmed. 
The three scan trimming pairs, and subsequent timepoints, are: 

The scan trimming pair SCRD28, which contains the Screening (SCRD28:SCR) and 
Day 28 (SCRD28:D28) timepoints, where only airways that were present in both 
screening and day 28 scans are accounted for.

The scan trimming pair SCRD12, which contains the Screening (SCRD12:SCR) and 
Day 12 (SCRD12:D12) timepoints where only airways that were present in both 
screening and day 12 scan are accounted for.

The scan trimming pair (D12D28), which contains the Day 12 (D12D28:D12) and 
Day 28 (D12D28:D28) timepoints, where only airways that were present in both day 
12 and day 28 scans are accounted for.
These 6 HRCT images were then processed to derive the HRCT parameters at each of 
these scan-trimming pair time points; this data will be referred to as the scan trimmed 
data. The scan trimmed data considers only airways that were present in both scans 
within the scan trimming pair. This ensures the airway models are the same length 
although the cross-sectional area of the airway may vary. For example, the schematic 
below shows visible airways on Screening alone and Day 12 alone. It then shows the 
airways that are visible on both Screening & Day 12 scans, through removing/trimming 
airways that are not present in both scans.
Screening:
Day 12:
Scan Trimming Screening & Day 12:
The HRCT scans can identify the 5 different lobes of the lungs and these lobes can then 
be categorized into and up to 5 regions depending on the endpoint. The 5 lobes are Right 
Upper Lobe (RUL), Left Upper Lobe (LUL), Right Middle Lobe (RML), Right Lower 
Lobe (RLL) and Left Lower Lobe (LLL). The 5 regions are Upper (comprising of RUL, 
RML and LUL), Lower (comprising of RLL and LLL), Central (the main bronchi 
between the lobes and the trachea), Distal (comprising of Upper and Lower) and Total 
(comprising of Distal and Central). 
The endpoints for which the 5 regions apply include: 

Specific imaging airway volume (siVaw)

Imaging airway volume (iVaw)

Specific imaging airway resistance (siRaw)

Imaging airway resistance (iRaw)

Specific imaging airway wall volume (siVaww) 

Imaging airway wall volume (iVaww)
 
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The endpoints for which only 3 regions (upper, lower & total) apply include: 

Imaging lobe volume (iVlobe)

Percent predicted lobar volume (iVlobepred)

Low attenuation score (LAS)

Air trapping score (AT)

Blood vessel density (BVD)
The endpoint for which only 2 regions (upper & lower) apply is: 

Internal airflow lobar distribution (IALD)
For the measures iVaw, iRaw and iVaww, standardization within a subject for the size of 
the lobar volume was conducted. These specific measures can be adjusted for the 
individual’s lobar volume by correcting for the corresponding lobe/region. Note the 
central region is not applicable for lobar volumes, instead the corresponding region for 
the central, distal and total regions is the total lobar volume region. For example:

To calculate siVaw, the lobes/regions of iVaw being divided by the corresponding 
lobes/regions of iVlobe to calculate the lobes/regions of siVaw, thus siVaw can be 
defined as a measure of volume in an individual’s airways, corrected for the 
individual’s lobar volume. 

To calculate siRaw, the lobes/regions of iRaw were multiplied by the 
corresponding lobes/regions of iVlobe.

To calculate siVaww, the lobes/regions of iVaww were divided by the 
corresponding lobes/regions of iVlobe. 
For such reasons, the table below shows the HRCT endpoints and the results that will be 
captured: 
 
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Table 2
HRCT Endpoints (and results that will be captured)
Untrimmed 
Scan Trimming, based on:
Endpoints
Units
Screening 
Day 
12 
Day 28 
Screening 
and Day 12 
scans
Screening 
and Day 28 
scans
Day 12 and 
Day 28 scans
iVaw
mL
x
x
x
x (Screening) 
x (Day 12)
x (Screening) 
x (Day 28)
x (Day 12) 
x (Day 28)
siVaw
mL/L
x
x
x
x (Screening) 
x (Day 12)
x (Screening) 
x (Day 28)
x (Day 12) 
x (Day 28)
iRaw
KPa*s/L
x (Screening) 
x (Day 12)
x (Screening) 
x (Day 28)
x (Day 12) 
x (Day 28)
siRaw
KPa*s
x (Screening) 
x (Day 12)
x (Screening) 
x (Day 28)
x (Day 12) 
x (Day 28)
iVlobe
L
x
x
x
Percent 
Predicted iVlobe
% of 
Predicted 
value
x
x
x
IALD [3]
%
x
x
x
LAS [1]
% of 
iVlobe
x
x
x
AT [2]
% of 
iVlobe
x
x
x
BVD [1]
% of 
iVlobe
x
x
x
iVaww [1]
mL
x
x
x
x (Screening) 
x (Day 12)
x (Screening) 
x (Day 28)
x (Day 12) 
x (Day 28)
siVaww [1]
mL/L
x
x
x
x (Screening) 
x (Day 12)
x (Screening) 
x (Day 28)
x (Day 12) 
x (Day 28)
Trachea length
mm
x
x
x
Trachea 
Diameter
mm
x
x
x
Trachea 
Length/Diameter
mm/mm
x
x
x
All these endpoints will be measured at TLC and FRC, except:
[1] These endpoints will only be measured at TLC
[2] This endpoint will be measured only at FRC
[3] The state (TLC/FRC) is not applicable 
 
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For the endpoints siVaw, iVaw, iRaw and siRaw appropriate transformations will be 
applied prior to summaries and statistical analyses, likely a log transformation. Summary 
statistics will be presented for absolute data and change from baseline. An attempt will be 
made to fit separate statistical models for each endpoint, scan trimming condition 
(Untrimmed or Scan Trimmed), lung volume (FRC or TLC) and Lobes (RUL, LUL, 
RML, RLL and LLL) or Regions (Upper, Lower, Central, Distal and Total) combination
as appropriate. The primary plan for statistical analyses will be to fit separate statistical 
models for:
siVaw 
o Untrimmed at FRC for all lobes, i.e. RUL, LUL, RML, RLL and LLL in 
one model.
o Untrimmed at FRC for all regions, i.e. Upper, Lower, Central, Distal and 
Total in one model.
o Scan Trimmed at FRC for Distal region only.
siRaw 
o Scan Trimmed at FRC for Distal region only.
For untrimmed data, the ratio from baseline across the different Regions (accounting for 
the average baseline associated to the Region of interest) will be represented via adjusted 
posterior medians for each of the Treatment Arms, as well as their associated 95% HPD-
tailed credible intervals. These results will be presented within tabular form, and will be 
presented after the data have been appropriately back transformed (if applicable). In 
addition, the placebo-adjusted ratio from baseline across the different Regions will be 
represented via adjusted posterior medians, as well as their associated 95% HPD-tailed 
credible intervals and posterior probabilities. These results will be presented in tabular 
form, and will be presented after the data have been appropriately back transformed to 
give median ratios (or median differences if applicable).
For scan trimmed data, the change from baseline across the different Regions (accounting 
for the average baseline associated to the Region of interest) will be represented via 
adjusted posterior medians for each of the Treatment Arms, as well as their associated 
95% HPD-tailed credible intervals. These results will be presented within tabular form, 
and will be presented after the data have been appropriately back transformed (if 
applicable). In addition, the placebo-adjusted change from baseline across the different 
Regions will be represented via adjusted posterior medians, as well as their associated 
95% HPD-tailed credible intervals and posterior probabilities. These results will be 
presented in tabular form, and will be presented after the data have been appropriately 
back transformed to give median ratios (or median differences if applicable).
For the tracheal endpoints, absolute data and change from baseline summary statistics 
will be provided for each lung volume (FRC or TLC) for trachea length, diameter and 
length/diameter.
8.2.3.
Population of Interest
The primary efficacy analyses will be based on the “All Subjects” population, unless 
otherwise specified.
 
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8.2.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 8.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
8.2.4.1.
Statistical Methodology Specification
NOTE: The description below describes the current thinking of how to analyse these 
endpoints. The proposed models will be assessed, and if not appropriate alternative 
models could be used.
Endpoint / Variables

Imaging Untrimmed endpoint siVaw at FRC
Model Specification

The data will be inspected prior to analysis to determine whether a data transformation is 
required. It is likely that the data will approximately follow a log normal distribution; however,
the most appropriate distribution should be used.

It is thought that the use of bronchodilators could affect the HRCT results. The database will 
contain information on whether relief medication was used in the 4 hours prior to each scan, 
and this information may be used in the sensitivity analyses of the HRCT results.

An attempt will be made to fit a statistical model for all Lobes (RUL, LUL, RML, RLL and LLL) 
and a separate statistical model for all Regions (Upper, Lower, Central, Distal and Total), i.e. 
two models; one for lobes, one for regions. However, should this model fail to converge or be 
deemed unsuitable potentially due to sample size, separate statistical models will be fitted for 
each Lobe/Region (RUL, LUL, RML, RLL, LLL, Upper, Lower, Central, Distal and Total), i.e. 
ten models in total, one for each lobe/region endpoint.

The log of (or other transformation as appropriate) the ratio from baseline will be analysed in a 
multivariate model), under a Bayesian framework. The model will include a Baseline*Region
term and a Treatment*Visit*Region term, as well as any co-variates of interest. Note that the 
model will not include an intercept. The Visit will consist of two levels: Day 12 and Day 28, and 
the Treatment will consist of two levels: All NEMI and All Placebo. No fixed assumption around 
the structure of the covariance matrix will be enforced. The priors for the mean vector for each 
of the parameters (i.e. covariates) will each follow a normal distribution and the prior for the 
variance-covariance will follow an inverse Wishart distribution. Sensitivity analysis will be 
conducted to select appropriate parameters for both distributions such that the priors are non-
informative with respect to the posterior.

The change from baseline (accounting for the average baseline) across the different Visits will 
be represented via adjusted posterior medians for each of the Treatment Arms, as well as their 
associated 95% HPD-tailed credible intervals. These results will also be presented within 
tabular form, and will be presented after the data have been appropriately back transformed (if 
applicable). 

The difference between the treatment arms, for the change from baseline across the different 
 
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Visits will be represented via adjusted medians, as well as their associated 95% HPD-tailed 
credible intervals. These results will also be presented within tabular form, and will be 
presented after the data have been appropriately back transformed (if applicable)

The probabilities that the treatment ratio is greater than 1 (depending on direction of the 
endpoint), in addition to other values appropriately selected based on the data, will also be 
computed for each Visit. These results will be presented in tabular format
Model Checking & Diagnostics

Model assumptions will be applied, but appropriate adjustments maybe made based on the 
data. For example, if data do not approximately follow a normal distribution then attempt will be 
made to find a suitable transformation.
Note: Should parameters require a log transformation with an offset, for each posterior sample 
(i) appropriately back transformed values will be calculated for each treatment arm, and then 
(ii) using these back transformed values, the ratio of the treatment arms (All NEMI/All Placebo) 
will be calculated for each posterior sample, and finally summarised accordingly

A comprehensive investigation into a suitable model should be initiated. For example,
additional covariates will be investigated such as age, BMI, gender etc.
Note: when investigating fitting separate statistical models for Lobes (RUL, LUL, RML, RLL and 
LLL) and Regions (Upper, Lower, Central, Distal and Total), i.e. two models; one for lobes, one 
for regions. If there are convergence issues an alternative structure of fitting separate statistical 
models for each Lobe (RUL, LUL, RML, RLL and LLL) and each Region (Upper, Lower, 
Central, Distal and Total), i.e. ten models; five for lobes, five for regions. a similar model as 
described in Model Specification should be tested but will include a baseline and a 
Treatment*Visit term instead of a Baseline*Region term and a Treatment*Visit*Region term,
respectively.
Note: It may also be prudent to investigate a model fitting baseline as a timepoint in which case 
the log of (or other transformation as appropriate) the absolute results will be analysed in a 
multivariate model, under a Bayesian framework. The model could include a 
Treatment*Visit*Region parameter, as well as any co-variates of interest. Note that this model 
would not include an intercept. The Visit would consist of three levels: Baseline, Day 12 and 
Day 28, and the Treatment would consist of three levels: Null (when Visit = Screening), NEMI 
and Placebo. With assumptions as described in Model Specification.

An unstructured covariance structure will be used. However, in the event that this model fails to 
converge, alternative correlation structures may be considered. 

Models with a Bayesian Framework will use vague priors. If appropriate, conjugate priors will 
be used. For example, for a multivariate model, the prior for the variance covariance matrix will 
be an inverse Wishart distribution.
Model Results Presentation

Output from the repeated measures modelling detailed above will be tabulated. In particular, 
the estimated ratio to baseline (or change from baseline if appropriate), 95% CI, standard error 
(on the appropriate scale, likely logarithm base e), and posterior probabilities at each time point 
and for the active treatment comparison with placebo. The scan trimming condition, lung 
volume and lobe or region description will be included in the outputs.
Sensitivity and Supportive Analyses

It is thought that the use of bronchodilators could affect the HRCT results. The database will 
contain information on if relief medication was used in the 4 hours prior to each scan, and this 
 
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information may be used in the sensitivity analyses of the HRCT results including only those 
who did not take bronchodilator relief medication in the 4 hours prior to HRCT scan.
Endpoint / Variables

Imaging Scan Trimmed endpoints siVaw and siRaw at FRC in the Distal Region only.
Model Specification

It is likely that the data will approximately follow a log normal distribution; however, the most 
appropriate distribution should be used.

Separate statistical models will be fitted for each endpoint, i.e. two models; one for siVaw (scan 
trimmed at FRC in Distal region), one for siRaw (scan trimmed at FRC in Distal region).

The responses of interest are the change from baseline based on (i) Airways present on scans 
taken at Screening and Day 12, (ii) Airways present on scans taken at Screening and Day 28, 
and (iii) Airways present on scans taken at Day 12 and Day 28. The baselines for each of 
these endpoints are provided in the table below.
(i) Screening & Day12 
Scan trimming
(ii) Screening & Day28 
Scan trimming
(iii) Day 12 & Day 28 
Scan trimming
Screening Result
(baseline)
(baseline)
Day 12 Result
(post dose)
(baseline)
Day 28 Result
(post dose)
(post dose)

The modelling below assumes that the Scan trimming endpoints (Screening&Day12, 
Screening&Day28 and Day12&Day28) will be analysed in a single multivariate model. This is 
subject to sensitivity analysis.

The log of (or other transformation as appropriate) the change from baseline (where baseline is 
defined in the table above) will be analysed in a multivariate model to account for the 
correlation between the multiple Scan Trimmings (Screening&Day12, Screening&Day28 and 
Day12&Day28), under a Bayesian framework. The model will have a separate intercept for 
each Scan Trimming combination (by fitting a class parameter Scan Trimming, and having no 
overall intercept), and will also include a baseline*Scan Trimming and a Treatment*Scan 
Trimming parameter. The Visit will consist of two levels: Day 12 and Day 28, the scan trimming 
will consist of three levels Screening&Day12, Screening&Day28 and Day12&Day28, and the 
Treatment will consist of two levels: All NEMI and All Placebo. No fixed assumption around the 
structure of the covariance matrix will be enforced. The priors for the mean vector for each of 
the parameters (i.e. covariates) will each follow a normal distribution and the prior for the 
variance-covariance will follow an inverse Wishart distribution. Sensitivity analysis will be 
conducted to select appropriate parameters for both distributions such that the priors are non-
informative with respect to the posterior. 

The change from baseline across the different Scan Trimming pairs (accounting for the 
average baseline) will be represented via adjusted posterior medians for each of the Treatment 
Arms, as well as their associated 95% HPD-tailed credible intervals. These results will also be 
 
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presented within tabular form, and will be presented after the data have been appropriately 
back transformed (if applicable). 

The difference between the treatment arms, for the change from baseline across the different 
Scan Trimming pairs will be represented via adjusted medians, as well as their associated 95% 
HPD-tailed credible intervals. These results will also be presented in tabular form, and will be 
presented after the data have been appropriately back transformed to give median ratios (if 
applicable). For parameters that require a log transformation with an offset, for each posterior 
sample (i) appropriately back transformed values will be calculated for each treatment arm, and 
then (ii) using these back transformed values, the ratio of the treatment arms (Active/Placebo) 
will be calculated for each posterior sample, and finally summarised accordingly. 
The probabilities that the treatment ratio is greater than 1 (for siVaw) and less than 1 (for 
siRaw), in addition to other values appropriately selected based on the data, will also be 
computed for each Visit. These results will be presented in tabular format.
Model Checking & Diagnostics

Model assumptions will be applied, but appropriate adjustments maybe made based on the 
data. For example if data do not approximately follow a normal distribution then an attempt will 
be made to find a suitable transformation.
Note: Should parameters require a log transformation with an offset, for each posterior sample 
(i) appropriately back transformed values will be calculated for each treatment arm, and then 
(ii) using these back transformed values, the ratio of the treatment arms (All NEMI/All Placebo) 
will be calculated for each posterior sample, and finally summarised accordingly

A comprehensive investigation into a suitable model should be initiated. For example,
additional covariates will be investigated

An unstructured covariance structure will be used. However, in the event that this model fails to 
converge, alternative correlation structures may be considered. 

Models with a Bayesian Framework will use vague priors. If appropriate, conjugate priors will 
be used. For example, for a multivariate model, the prior for the variance covariance matrix will 
be an inverse Wishart distribution.
Model Results Presentation

Output from the repeated measures modelling detailed above will be tabulated. In particular, 
the estimated ratio to baseline (or change from baseline if appropriate), 95% CI, standard error 
(on the appropriate scale, likely logarithm base e), and posterior probabilities at each time point 
and for the active treatment comparison with placebo. The scan trimming condition, lung 
volume and lobe or region description will be included in the outputs.
Sensitivity and Supportive Analyses

It is thought that the use of bronchodilators could affect the HRCT results. The database will 
contain information on if relief medication was used in the 4 hours prior to each scan, and this 
information may be used in the sensitivity analyses of the HRCT results including only those 
who did not take bronchodilator relief medication in the 4 hours prior to HRCT scan.
 
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8.3.
Exploratory Efficacy Analyses (From HRCT Analyses)
8.3.1.
Endpoint / Variables
To assess the changes in other HRCT parameters such as low attenuation score after once 
daily repeat inhaled doses of nemiralisib 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.
8.3.2.
Summary Measure
The structure of HRCT endpoints is as described in Section 8.2.2, exploratory endpoints 
include:

iVlobe

Percent Predicted iVlobe

IALD

LAS

AT

BVD

iVaww

siVaww
For all endpoints, the data will be inspected prior to analyses to determine whether a data 
transformation is required. Appropriate transformations will be applied prior to 
summaries and statistical analyses. It is likely a log transformation will be required for 
iVlobe, LAS, IALD, BVD iVaww and siVaww, and that no transformation will be 
required for Percent Predicted iVlobe and AT, however, the most appropriate distribution 
should be used
Summary statistics will be presented for absolute data and change from baseline. 
Separate statistical models will be fitted for each scan trimming condition (Untrimmed or 
Scan Trimmed), lung volume (FRC or TLC) and Regions (Upper, Lower, Central, Distal 
and Total) combination as appropriate, note: statistical analyses will only be conducted 
on:
IALD for upper and lower regions only (within the same model)
LAS at TLC for total region only
AT at FRC for total region only 
BVD at TLC for total region only

siVaww untrimmed data at TLC for distal region only
For the endpoints: LAS, AT and BVD, separate statistical models will be fitted for the 
Total region only. The change from baseline (accounting for the average baseline 
associated to the region) will be represented via adjusted posterior medians for each of 
the Treatment Arms, as well as their associated 95% HPD-tailed credible intervals. These 
results will also be presented within tabular form, and will be presented after the data 
have been appropriately back transformed (if applicable). The difference between the 
treatment arms, for the change from baseline will be represented via adjusted medians, as 
 
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well as their associated 95% HPD-tailed credible intervals. These results will also be 
presented in tabular form, and will be presented after the data have been appropriately 
back transformed to give median ratios (or median differences if applicable).
For the endpoint IALD, a statistical model will be fitted for both the Upper and Lower 
regions. The change from baseline across the different regions (accounting for the 
average baseline associated to the region of interest) will be represented via adjusted 
posterior medians for each of the Treatment Arms, as well as their associated 95% HPD-
tailed credible intervals. These results will also be presented within tabular form, and will 
be presented after the data have been appropriately back transformed (if applicable). The 
difference between the treatment arms, for the change from baseline across the different 
regions will be represented via adjusted medians, as well as their associated 95% HPD-
tailed credible intervals. These results will also be presented in tabular form, and will be 
presented after the data have been appropriately back transformed to give median ratios 
(or median differences if applicable).
For the endpoint siVaww, a statistical model will be fitted for the distal region using 
untrimmed data. The change from baseline (accounting for the average baseline 
associated to the region) will be represented via adjusted posterior medians for each of 
the Treatment Arms, as well as their associated 95% HPD-tailed credible intervals. These 
results will also be presented within tabular form, and will be presented after the data 
have been appropriately back transformed (if applicable). The difference between the 
treatment arms, for the change from baseline will be represented via adjusted medians, as 
well as their associated 95% HPD-tailed credible intervals. These results will also be 
presented in tabular form, and will be presented after the data have been appropriately 
back transformed to give median ratios (or median differences if applicable).
8.3.3.
Population of Interest 
The secondary efficacy analyses will be based on the “All Subjects” population, unless 
otherwise specified.
8.3.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 8.3.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
8.3.4.1.
Statistical Methodology Specification
For statistical analyses of IALD in the upper and lower regions refer to Section 8.2.4.1 for the
analysis of untrimmed siVaw but note that it is likely only 1 statistical model would be fitted for the 
upper and lower regions only. If appropriate this could be adapted into two models; one for upper, 
one for lower. The probability that the treatment ratio is greater than 1 will be presented for the 
lower region and the probability that the treatment ratio is less than 1 will be presented for the 
upper region, in addition to other values appropriately selected based on the data.
 
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For statistical analyses of LAS at TLC in the total region only, refer to Section 8.2.4.1 for the 
analysis of untrimmed siVaw but note only 1 statistical model would be fitted for the Total regions 
only. The probability that the treatment ratio is less than 1 will be presented, in addition to other 
values appropriately selected based on the data.
For statistical analyses of AT at FRC in the total region only, refer to Section 8.2.4.1 for the 
analysis of untrimmed siVaw however it is likely that no transformation will be required for this 
endpoint in which case the absolute change from baseline will be fitted and probabilities that the 
true treatment difference is less than 1, in addition to other values appropriately selected based on 
the data, will also be computed for each Visit. Note only 1 statistical model would be fitted for the 
Total regions only. 
For statistical analyses of BVD at TLC in the total region only, refer to Section 8.2.4.1 for the 
analysis of untrimmed siVaw but note only 1 statistical model would be fitted for the Total regions 
only.
For statistical analyses of siVaww at TLC in the distal region only, refer to Section 8.2.4.1 for the 
analysis of untrimmed siVaw but note only 1 statistical model would be fitted for the Distal regions 
only. The probability that the treatment ratio is less than 1, in addition to other values appropriately 
selected based on the data will be presented.
8.4.
Exploratory Efficacy Analyses (Not from HRCT Analyses)
8.4.1.
Endpoint / Variables
Additional exploratory endpoints include the severity of index exacerbation, where 
exacerbations requiring hospitalisations are defined as severe and those not requiring 
hospitalisation are defined as moderate.
8.4.2.
Summary Measure
For the severity of index exacerbation, a summary table detailing the number and 
percentage of subjects who had moderate or severe index exacerbations. Note: 
exacerbations requiring hospitalisations are defined as severe and those not requiring 
hospitalisation are defined as moderate.
If available, data on exacerbations occurring during the study will be summarised. This 
may include investigator defined exacerbations (including information on moderate or 
severe) and/or concomitant medication defined exacerbations. Concomitant medication 
defined exacerbations may be defined as treatment with systemic/oral corticosteroids 
and/or antibiotics where the exacerbation is deemed to have ended if no additional 
treatment with systemic/oral corticosteroids and/or antibiotics is required within < 7days 
from the end of treatment for the primary exacerbation. 
8.4.3.
Population of Interest 
The secondary efficacy analyses will be based on the “All Subjects” population, unless 
otherwise specified. 
 
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8.4.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 8.4.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
9.
RELATIONSHIP BETWEEN THE PHARMACODYNAMIC
AND BIOMARKER DATA AND THE HRCT DATA
9.1.
Relationship between the mRNA data and the HRCT data
The relationship between a selection of the mRNA data and the HRCT data may be 
performed as an exploratory analysis. This may include scatter plots of individual 
participant data, linear regression lines, Pearson’s correlation coefficient and 95% 
confidence intervals plots as appropriate. This data will be produced following SAC.
10.
SAFETY ANALYSES
The safety analyses will be based on the “All Subjects” population, unless otherwise 
specified.
10.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs)
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 10: List of Data Displays.
10.2.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, 
Haematology laboratory tests, Urinalysis, and liver function tests will be based on GSK 
Core Data Standards. The details of the planned displays are in Appendix 10: List of Data 
Displays.
10.3.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 10: List of Data Displays.
 
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11.
PHARMACOKINETIC ANALYSES
11.1.
Secondary Pharmacokinetic Analyses
11.1.1.
Endpoint / Variables
11.1.1.1.
Drug Concentration Measures 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 13.5.3
Reporting Standards for Pharmacokinetic)
11.1.1.2.
Derived Pharmacokinetic Parameters
No non-compartmental analysis will be conducted for this study as such there will be no 
derived pharmacokinetic parameters.
11.1.2.
Summary Measure
The concentrations of the samples will be summarised.
11.1.3.
Population of Interest 
The secondary pharmacokinetic analyses will be based on the “Pharmacokinetic” 
population, unless otherwise specified.
 
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12.
REFERENCES
Quanjer Ph.H, Tammeling G.J, Cotes J.E., Pedersen O.F, Peslin R, Yernault J-C. Lung 
volumes and forced ventilatory flows; European Respiratory Journal 1993 6: 5-40
 
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13.
APPENDICES
13.1.
Appendix 1: Protocol Deviation Management 
13.1.1.
Important Protocol Deviations
Based on an assessment of the important protocol deviations listed in the PDMP, partial 
data exclusions or time-point exclusions may occur which may not remove a subject from 
the analysis population, but may exclude a portion of the subject’s data.
 
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13.2.
Appendix 2: Schedule of Activities
13.2.1.
Protocol Defined Schedule of Events
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.
 
 
 
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Procedure
Screening 
(up to 3 days prior to Visit 1)
Follow-up
(7-14 days post-last dose)
Notes
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
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 of Protocol Amendment 4 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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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.
FEV1and 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 of Protocol Amendment 4
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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13.3.
Appendix 3: Assessment Windows
13.3.1.
Definitions of Assessment Windows for Analyses
Population
Target 
Analysis Window
Analysis 
Timepoint
Beginning Timepoint
Ending Timepoint
Screening
NA
3 days prior to Visit 1 
(Day 1)
Day 1
Screening
Safety, 
Efficacy, Study 
population and 
all other 
assessments
NA – Day of first dose 
NA
NA
Visit 1
If subject was hospitalised:
Target = On discharge
If subject wasn’t hospitalised:
Target = Within 48 hours of 
first dose administration 
Target -1 day
Target +1 day
Visit 2
Day 12 
Target -2 day
Target +3 day
Visit 3
Day 28
Target -4 day
Target +2 day
Visit 4
Day 56
Target -7 day
Target +6 day
Visit 5
Day 84
Target -8 day
Target +4 day
Visit 6
Follow-up
NA
1 week following last day 
of dose
4 weeks following 
the last day of dose
Follow-up
 
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13.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
13.4.1.
Study Phases
Assessments and events will be classified according to the time of occurrence relative to 
the study treatment, unless otherwise specified
Study Phase
Definition
Pre-Treatment 
Date ≤ Study Treatment Start Date
On-Treatment
Study Treatment Start Date < Date ≤ Study Treatment Stop Date
Post-Treatment
Date > Study Treatment Stop Date 
13.4.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is prior to screening visit
Concomitant
Any medication that is not a prior
NOTES: 

Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.
13.4.2.
Treatment States for Adverse Events
Flag
Definition
Pre-Treatment

If AE onset date is before the treatment start date.

AE Start Date < Study Treatment Start Date
Treatment 
Emergent
(On-Treatment)

If AE onset date is on or after treatment start date & on or before treatment stop 
date.

Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date.
Post-Treatment

If AE onset date is after the treatment stop date.

AE Start Date > Study Treatment Stop Date
Onset Time Since 
1st Dose (Days)

If Treatment Start Date ˃ AE Onset Date, then 
Onset Time = AE Onset Date - Treatment Start Date

If Treatment Start Date ≤ AE Onset Date, then 
Onset Time = AE Onset Date - Treatment Start Date +1

Missing otherwise.
Duration (Days)

AE Resolution Date – AE Onset Date + 1
Drug-related

If relationship is marked ‘YES’ on [Inform/CRF OR value is missing].
NOTES: 

If the study treatment stop date is missing, then the AE will be considered to be On-Treatment.

Time of study treatment dosing and start/stop time of AEs should be considered, if collected.
 
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13.5.
Appendix 5: Data Display Standards & Handling 
Conventions
13.5.1.
Reporting Process
Software

The currently supported versions of SAS software (version 9.4) will be used.
Reporting Area
HARP Server
: UK1SALX00175.corpnet2.com
HARP Compound
: ARPROD/GSK2269557/mid201928
Note: the current planned reporting effort is final_01, this may be superseded. 
Analysis Datasets 

Analysis datasets will be created according to Legacy GSK A&R dataset standards and Integrated Data 
Standards Library
Generation of RTF Files

RTF files will be generated for all tables
13.5.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 

Do not include subject level listings in the main body of the GSK Clinical Study Report. All subject level 
listings should be located in the modular appendices as ICH or non-ICH listings

A project wide decision was made to present GSK2269557 as Nemiralisib (abbreviated to NEMI) refer 
to Section 5.1 for further details. 
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may be
adjusted to a clinically interpretable number of DP’s.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 
 
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
Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will be 
included in listings but omitted from figures, summaries and statistical analyses.
Unscheduled Visits

Unscheduled visits will not be included in summary tables.

Unscheduled visits will not be included in summary figures

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.

All graphics will be done using the SGPLOT/SGPANEL/SG template procedures
13.5.3.
Reporting Standards for Pharmacokinetic
Pharmacokinetic Concentration Data
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
Note: Use the separate NEMI DISKUS and NEMI ELLIPTA treatment groups
NONMEM/Pop PK 
File
Not applicable.
NONMEM/PK/PD 
File
Not applicable.
 
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13.6.
Appendix 6: Derived and Transformed Data
13.6.1.
General
Multiple Measurements at One Analysis Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented.

If there are two values within a time window (as per Section 13.3.1) the value closest to the target day 
for that window will be used. If values are the same distance from the target, then the mean will be 
taken.

Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables.
Study Day

Calculated as the number of days from First Dose Date:

Ref Date = Missing              → Study Day = Missing 

Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date

Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1  
13.6.2.
Study Population
Treatment Compliance

Treatment compliance will be calculated based on the formula:
Treatment Compliance = Counter Readings / (Actual Treatment Duration in Days * Frequency)

Treatment compliance could be greater than 100% if there are events of overdose. 
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1

If there are any treatment breaks during the study, exposure data will be adjusted accordingly.

Participants who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure. 

The cumulative dose will be based on the formula:
Cumulative Dose = Sum of (Counter Readings x Study Drug Dose)
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age at Screening where birth date will be imputed as 
follows:
o
Any subject with a missing date and month will have this imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.

Refer to IDSL standards for age range categories.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)2]
 
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13.6.3.
Efficacy
HRCT
Endpoints provided by FluidDA
Y = Endpoints will be provided by FluidDA.
C = Endpoints will be Calculated by GSK (see Derived Data below)
Lobes & Regions
LLL
LUL
RML
RUL
RLL
LL
UL
CENTRAL
DISTAL
TOTAL TRACHEA
iVaw
Y
Y
Y
Y
Y
C
C
Y
C
C
N/A
siVaw
C
C
C
C
C
C
C
C
C
C
N/A
iRaw
Y
Y
Y
Y
Y
C
C
Y
Y
Y
N/A
siRaw
C
C
C
C
C
C
C
C
C
C
N/A
iVlobe
Y
Y
Y
Y
Y
C
C
N/A
N/A
C
N/A
iVlobepred
Y
Y
Y
Y
Y
Y
Y
N/A
N/A
Y
N/A
LAS
Y
Y
Y
Y
Y
Y
Y
N/A
N/A
Y
N/A
IALD
C
C
C
C
C
C
C
N/A
N/A
N/A
N/A
AT
Y
Y
Y
Y
Y
Y
Y
N/A
N/A
Y
N/A
BVD
Y
Y
Y
Y
Y
Y
Y
N/A
N/A
Y
N/A
iVaww
Y
Y
Y
Y
Y
C
C
Y
C
C
N/A
siVaww
C
C
C
C
C
C
C
C
C
C
N/A
Diameter
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Y
Length
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Y
Length/Diameter
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
C
Imaging Endpoints Calculated by GSK
iVaw LL = iVaw RLL + iVaw LLL
iVaw UL = iVaw RUL + iVaw RML + iVaw LUL
iVaw DISTAL = iVaw LL + iVaw UL
iVaw TOTAL = iVaw CENTRAL + iVaw DISTAL
iRaw LL = 1/ (1/iRaw RLL + 1/iRaw LLL)
iRaw UL = 1/ (1/iRaw RUL + 1/iRaw RML + 1/iRaw LUL)
iVlobe LL = iVlobe RLL + iVlobe LLL
iVlobe UL = iVlobe RUL + iVlobe RML + iVlobe LUL
iVlobe TOTAL = iVlobe LL + iVlobe UL
iVaww LL = iVaww RLL + iVaww LLL
iVaww UL = iVaww RUL + iVaww RML + iVaww LUL
iVaww DISTAL = iVaww LL + iVaww UL
iVaww TOTAL = iVaww CENTRAL + iVaww DISTAL
siVaw LLL = iVaw LLL / iVlobe LLL
siVaw LUL = iVaw LUL / iVlobe LUL
siVaw RML = iVaw RML / iVlobe RML
siVaw RUL = iVaw RUL / iVlobe RUL
siVaw RLL = iVaw RLL / iVlobe RLL
siVaw LL = iVaw LL / iVlobe LL
siVaw UL = iVaw UL / iVlobe UL
siVaw CENTRAL = iVaw CENTRAL / iVlobe TOTAL
siVaw DISTAL = iVaw DISTAL / iVlobe TOTAL
siVaw TOTAL = iVaw TOTAL / iVlobe TOTAL
siRaw LLL = iRaw LLL * iVlobe LLL
siRaw LUL = iRaw LUL * iVlobe LUL
siRaw RML = iRaw RML * iVlobe RML
siRaw RUL = iRaw RUL * iVlobe RUL
siRaw RLL = iRaw RLL * iVlobe RLL
siRaw LL = iRaw LL * iVlobe LL
siRaw UL = iRaw UL * iVlobe UL
 
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siRaw CENTRAL = iRaw CENTRAL * iVlobe TOTAL
siRaw DISTAL = iRaw DISTAL * iVlobe TOTAL
siRaw TOTAL = iRaw TOTAL * iVlobe TOTAL
siVaww LLL = iVaww LLL / iVlobe LLL
siVaww LUL = iVaww LUL / iVlobe LUL
siVaww RML = iVaww RML / iVlobe RML
siVaww RUL = iVaww RUL / iVlobe RUL
siVaww RLL = iVaww RLL / iVlobe RLL
siVaww LL = iVaww LL / iVlobe LL
siVaww UL = iVaww UL / iVlobe UL
siVaww CENTRAL = iVaww CENTRAL / iVlobe TOTAL
siVaww DISTAL = iVaww DISTAL / iVlobe TOTAL
siVaww TOTAL = iVaww TOTAL / iVlobe TOTAL
IALD LLL = 100 * (iVlobe LLL TLC - iVlobe LLL FRC) / (iVlobe TOTAL TLC - iVlobe TOTAL FRC)
IALD LUL = 100 * (iVlobe LUL TLC - iVlobe LUL FRC) / (iVlobe TOTAL TLC - iVlobe TOTAL FRC)
IALD RML = 100 * (iVlobe RML TLC - iVlobe RML FRC) / (iVlobe TOTAL TLC - iVlobe TOTAL FRC)
IALD RUL = 100 * (iVlobe RUL TLC - iVlobe RUL FRC) / (iVlobe TOTAL TLC - iVlobe TOTAL FRC)
IALD RLL = 100 * (iVlobe RLL TLC - iVlobe RLL FRC) / (iVlobe TOTAL TLC - iVlobe TOTAL FRC)
IALD LL = IALD RLL + IALD LLL
IALD UL = IALD RUL + IALD RML + IALD LUL
Lung Function Parameters
Lung Function Parameters Calculated by GSK

FEV1 % Predicted (Men) = 4.30*Height – 0.029*Age – 2.49

FEV1 % Predicted (Women) = 3.95*Height – 0.025*Age – 2.60
Formulas have been taken from Quanjer, 1993 Lung volumes and forced ventilator flows [accessed: 23rd 
July 2015] where height is measured in metres and age in years at screening.
Rescue Medication Endpoints
Number of occasions bronchodilator taken in the last 24 per hours 4-week period derived by GSK

Number of occasions bronchodilator taken in the last 24 hours were collected in the daily diary

The table below shows which daily diary records are used to calculate the daily diary endpoints for 
each analysis time period. Any diary data collected in the post-treatment phase of the study will not 
be slotted.
Daily Record
Analysis Time Period
Beginning Timepoint 
(day)
Ending Timepoint
(day)
1
28
Weeks 1 – 4
29
56
Weeks 5 – 8
57
84
Weeks 9 – 12
Note: There is no Day 0. Any records with actual day>84 will not be assigned to a time period. Any records with actual 
day<0 may be assigned to a Week -1 (Baseline) time period
Note: Daily diary records that were not assigned to a time period will not be used in calculation of daily diary endpoints.

For a subject to be counted in any time period for a given endpoint they must have at 
least one diary entry recorded for that endpoint during that time period.

Any daily diary data that were collected post-study treatment discontinuation will be 
excluded from analysis, including four weekly period data summaries.

If a subject has more than one daily diary record for any given day, the worst-case
response on that day for each endpoint will be used in the summaries and analyses. i.e. 
 
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the maximum number of occasions of bronchodilator use reported will be counted for 
the day in question and used to determine if it was a rescue-free day

The mean number of occasions of rescue use per day and percentage of rescue-free 
days, will be calculated for each subject during the four weekly periods defined above.
13.6.4.
Safety
ECG Parameters
RR Interval

IF RR interval (msec) is not provided directly, then RR can be derived as:
[1]
If QTcB is machine read & QTcF is not provided, then:
[2]
If QTcF is machine read and QTcB is not provided, then: 

If ECGs are manually read, the RR value preceding the measurement QT interval should be a collected value then 
do not derive.
Corrected QT Intervals

When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and Fridericia’s (QTcF) formulas 
will be calculated, in msec, depending on the availability of other measurements.

IF RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as:
Laboratory Values

If a laboratory value which is expected to have a numeric value for summary purposes, has a non-detectable level 
reported in the database, where the numeric value is missing, but typically a character value starting with ‘<x’ or 
‘>x’ (or indicated as less than x or greater than x in the comment field) is present, the number of significant digits in 
the observed values will be used to determine how much to add or subtract in order to impute the corresponding 
numeric value. 
o
Example 1: 2 Decimal Places = ‘< x’ becomes x – 0.01
o
Example 2: 1 Decimal Places = ‘> x’ becomes x + 0.1
o
Example 3: 0 Decimal Places = ‘< x’ becomes x – 1
 
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13.6.5.
Pharmacodynamic and Biomarker
Biomarker Category
Analyte
Method
Lab
Matrix
Total samples
InflammatoryCytokine
IL-8
MSD
Quest
Sputum
4
IL-6
MSD
Quest
Sputum
4
TNF
MSD
Quest
Sputum
4
Microbiome
Bacterial DNA
16SRNA
GSK-RTP
Sputum
4
Bacterial DNA
qPCR
GSK-RTP
Sputum
4
Viral DNA
qPCR
GSK-RTP
Sputum
4
Transcriptomics
Human RNA
Affymetrix
Expression 
Analysis
Blood
4
NOTES:

Sampling times: Screening, day 12, day 28 and day 84

Inflammatory cytokine biomarkers are elevated in COPD patients. Expected to reduce with treatment.

Microbiome biomarkers are drivers of exacerbations in COPD and are inhibited in preclinical disease studies

PI3Ktranscriptome analysis in FTIH study has 16 genes identified (sputum) showing a consistent response with 
dose – all are down regulated.
Pharmacodynamic and Biomarker
Pharmacodynamic
PMNs Differentials

Percentage data may be arc-sine transformed especially if many of the percentage values are smaller than 20% or 
larger than 80%. The response variable, y, measured in radians, is sin-1sqrt{0.01*p} where p is the differential 
percentage.

If transformations are used then the results will be reported on the back-transformed scale, except where a 
transformed value:
o
exceeds 0.01*p/2 then the back-transformed value will be set equal to 100% 
o
is less than 0 then the back-transformed value will be set equal to 0%. 
Biomarkers 
Inflammatory Cytokines

In general, it is assumed that biomarker endpoints will require variance stabilising transformations, such as taking a 
loge transformation prior to analysis (and that summary statistics appropriate to loge normally distributed data will 
apply for all summaries). However, this assumption will be considered for each endpoint Individually prior to the 
generation of summary tables or statistical analysis, and if deemed more appropriate, a loge transformation will not 
be applied, or non-parametric methods may be employed.

If transformations are used, then the results will be reported on the back-transformed scale unless otherwise 
stated.
RNA transcriptome

Affymetrix microarray mRNA data will be normalised using RMA in ARRAY STUDIO v8.0 or later by the Statistical 
Consultancy Group (SCG) within GSK. After normalisation, the data will be quality assessed and any samples 
deemed as QC fails will be excluded from any further analysis. This quality assessment will involve looking for 
outlying signals in both the normalised expression data and the MAS5 QC metrics generated from each sample. If 
any samples are excluded, the remaining data will be re-normalised. The output from the normalization will be log2 
transformed mRNA intensity data.

Summary mRNA data will be reviewed and a decision made on which probe sets are to be included in the SI 
dataset.

Treatment ratios from the statistical analyses of mRNA intensity data will be converted to fold changes as follows:
o
If ratio 1 then fold change = ratio
o
If ratio < 1 then fold change = -1/ratio
 
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The primary pharmacodynamic endpoint is based on a subset of probe sets defined as 
those that have previously identified immune cell mechanisms specifically related to 
neutrophil function.
The gene list that meets this criterion based on PII115119 D14 vs D1 gene changes, 
PII115117 and Metacore neutrophil pathways identified in PII115119 study. This gene 
list identified 258 genes in total after filtering for redundancy and was agreed by the 
study team is presented in Table 3. 
Table 3
Gene List that have previously identified immune cell mechanisms 
specifically related to neutrophil function
Gene 
Source
Gene 
Source
CD177
PII115119 - Neutrophil migration
ITGAL
Metacore: IL8 Neutrophil migration
CXCR1
PII115119 - Neutrophil migration
ADAM17
Metacore: Inhibition of neutrophil migration
CXCR2
PII115119 - Neutrophil migration
C5
Metacore: Inhibition of neutrophil migration
FPR2
PII115119 - Neutrophil migration
C5AR1
Metacore: Inhibition of neutrophil migration
LTB4R
PII115119 - Neutrophil migration
CCR5
Metacore: Inhibition of neutrophil migration
PAK1
PII115119 - Neutrophil migration
CD34
Metacore: Inhibition of neutrophil migration
PXN
PII115119 - Neutrophil migration
CALM1
Metacore: Inhibition of neutrophil migration
PREX1
PII115119 - Neutrophil migration
CALM2
Metacore: Inhibition of neutrophil migration
TLN1
PII115119 - Neutrophil migration
CALM3
Metacore: Inhibition of neutrophil migration
SSH2
PII115119 - Neutrophil migration
FPR1
Metacore: Inhibition of neutrophil migration
F2RL1 
PII115119 - Neutrophil infection response ICAM2
Metacore: Inhibition of neutrophil migration
TLR10
PII115119 - Neutrophil infection response IL1B
Metacore: Inhibition of neutrophil migration
CEACAM3 PII115119 - Neutrophil infection response IL1R1
Metacore: Inhibition of neutrophil migration
TREML2
PII115119 - Neutrophil infection response ITPR1
Metacore: Inhibition of neutrophil migration
DEFB124
PII115119 - Neutrophil infection response ITPR2
Metacore: Inhibition of neutrophil migration
CLEC4C
PII115119 - Neutrophil infection response ITPR3
Metacore: Inhibition of neutrophil migration
IFITM1
PII115119 - Neutrophil infection response SELL
Metacore: Inhibition of neutrophil migration
CR1
PII115119 - Neutrophil infection response MSN
Metacore: Inhibition of neutrophil migration
PMAIP1
FTIH - GSK'557 response
NFKB1
Metacore: Inhibition of neutrophil migration
S100P
FTIH - GSK'557 response
NFKB2
Metacore: Inhibition of neutrophil migration
PTGS2
FTIH - GSK'557 response
REL
Metacore: Inhibition of neutrophil migration
CCL20
FTIH - GSK'557 response
RELA
Metacore: Inhibition of neutrophil migration
EGR3
FTIH - GSK'557 response
RELB
Metacore: Inhibition of neutrophil migration
H1F0
FTIH - GSK'557 response
PECAM1
Metacore: Inhibition of neutrophil migration
NCOA3
FTIH - GSK'557 response
PRKCA
Metacore: Inhibition of neutrophil migration
TARP
FTIH - GSK'557 response
PRKCB
Metacore: Inhibition of neutrophil migration
CEACAM1 FTIH - GSK'557 response
PRKCD
Metacore: Inhibition of neutrophil migration
TTPAL
FTIH - GSK'557 response
PRKCE
Metacore: Inhibition of neutrophil migration
VPS37B
FTIH - GSK'557 response
PRKCG
Metacore: Inhibition of neutrophil migration
SYAP1
FTIH - GSK'557 response
PRKCH
Metacore: Inhibition of neutrophil migration
SPTBN1
FTIH - GSK'557 response
PRKCI
Metacore: Inhibition of neutrophil migration
 
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Gene 
Source
Gene 
Source
EGR1
FTIH - GSK'557 response
PRKCQ
Metacore: Inhibition of neutrophil migration
OSM
FTIH - GSK'557 response
PRKD1
Metacore: Inhibition of neutrophil migration
TBC1D22A FTIH - GSK'557 response
PRKD2
Metacore: Inhibition of neutrophil migration
AKT1
Metacore: IL8 Neutrophil migration
PRKD3
Metacore: Inhibition of neutrophil migration
AKT2
Metacore: IL8 Neutrophil migration
PLCB2
Metacore: Inhibition of neutrophil migration
AKT3
Metacore: IL8 Neutrophil migration
PTAFR
Metacore: Inhibition of neutrophil migration
ACTA1
Metacore: IL8 Neutrophil migration
TLR2
Metacore: Inhibition of neutrophil migration
ACTA2
Metacore: IL8 Neutrophil migration
TLR4
Metacore: Inhibition of neutrophil migration
ACTB
Metacore: IL8 Neutrophil migration
TNFRSF1A Metacore: Inhibition of neutrophil migration
ACTC1
Metacore: IL8 Neutrophil migration
TNFRSF1B Metacore: Inhibition of neutrophil migration
ACTG1
Metacore: IL8 Neutrophil migration
TNF
Metacore: Inhibition of neutrophil migration
ACTG2
Metacore: IL8 Neutrophil migration
VAV1
Metacore: Inhibition of neutrophil migration
MYH1
Metacore: IL8 Neutrophil migration
EZR
Metacore: Inhibition of neutrophil migration
MYH10
Metacore: IL8 Neutrophil migration
VCL
Metacore: Inhibition of neutrophil migration
MYH11
Metacore: IL8 Neutrophil migration
ITGAM
Metacore: Inhibition of neutrophil migration
MYH13
Metacore: IL8 Neutrophil migration
ABL1
Metacore: Inhibition of neutrophil migration
MYH14
Metacore: IL8 Neutrophil migration
JUN
Metacore: Inhibition of neutrophil migration
MYH15
Metacore: IL8 Neutrophil migration
FOS
Metacore: Inhibition of neutrophil migration
MYH16
Metacore: IL8 Neutrophil migration
MAPK11
Metacore: Inhibition of neutrophil migration
MYH2
Metacore: IL8 Neutrophil migration
MAPK12
Metacore: Inhibition of neutrophil migration
MYH3
Metacore: IL8 Neutrophil migration
MAPK13
Metacore: Inhibition of neutrophil migration
MYH4
Metacore: IL8 Neutrophil migration
MAPK14
Metacore: Inhibition of neutrophil migration
MYH6
Metacore: IL8 Neutrophil migration
BDKRB1
Metacore: Neutrophil migration in Asthma
MYH7
Metacore: IL8 Neutrophil migration
CCL15
Metacore: Neutrophil migration in Asthma
MYH8
Metacore: IL8 Neutrophil migration
CCL2
Metacore: Neutrophil migration in Asthma
MYH9
Metacore: IL8 Neutrophil migration
CCL5
Metacore: Neutrophil migration in Asthma
MYL1
Metacore: IL8 Neutrophil migration
CCL7
Metacore: Neutrophil migration in Asthma
MYL12A
Metacore: IL8 Neutrophil migration
CCR1
Metacore: Neutrophil migration in Asthma
MYL12B
Metacore: IL8 Neutrophil migration
CCR2
Metacore: Neutrophil migration in Asthma
MYL2
Metacore: IL8 Neutrophil migration
CCR3
Metacore: Neutrophil migration in Asthma
MYL3
Metacore: IL8 Neutrophil migration
CXCL5
Metacore: Neutrophil migration in Asthma
MYL4
Metacore: IL8 Neutrophil migration
CXCL1
Metacore: Neutrophil migration in Asthma
MYL5
Metacore: IL8 Neutrophil migration
CXCL2
Metacore: Neutrophil migration in Asthma
MYL6
Metacore: IL8 Neutrophil migration
CXCL3
Metacore: Neutrophil migration in Asthma
MYL6B
Metacore: IL8 Neutrophil migration
HSPA14
Metacore: Neutrophil migration in Asthma
MYL7
Metacore: IL8 Neutrophil migration
HSPA1A
Metacore: Neutrophil migration in Asthma
MYL9
Metacore: IL8 Neutrophil migration
HSPA1B
Metacore: Neutrophil migration in Asthma
MYLPF
Metacore: IL8 Neutrophil migration
HSPA1L
Metacore: Neutrophil migration in Asthma
ACTN1
Metacore: IL8 Neutrophil migration
HSPA2
Metacore: Neutrophil migration in Asthma
ACTN2
Metacore: IL8 Neutrophil migration
HSPA4
Metacore: Neutrophil migration in Asthma
ACTN3
Metacore: IL8 Neutrophil migration
HSPA5
Metacore: Neutrophil migration in Asthma
 
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Gene 
Source
Gene 
Source
ACTN4
Metacore: IL8 Neutrophil migration
HSPA6
Metacore: Neutrophil migration in Asthma
ACTR2
Metacore: IL8 Neutrophil migration
HSPA7
Metacore: Neutrophil migration in Asthma
ACTR3
Metacore: IL8 Neutrophil migration
HSPA8
Metacore: Neutrophil migration in Asthma
ACTR3B
Metacore: IL8 Neutrophil migration
HSPA9
Metacore: Neutrophil migration in Asthma
ARPC1A
Metacore: IL8 Neutrophil migration
MIF
Metacore: Neutrophil migration in Asthma
ARPC1B
Metacore: IL8 Neutrophil migration
CCL3
Metacore: Neutrophil migration in Asthma
ARPC2
Metacore: IL8 Neutrophil migration
PGF
Metacore: Neutrophil migration in Asthma
ARPC3
Metacore: IL8 Neutrophil migration
TAC1
Metacore: Neutrophil migration in Asthma
ARPC4
Metacore: IL8 Neutrophil migration
TACR1
Metacore: Neutrophil migration in Asthma
ARPC5
Metacore: IL8 Neutrophil migration
KLK1
Metacore: Neutrophil migration in Asthma
CFL1
Metacore: IL8 Neutrophil migration
KLK10
Metacore: Neutrophil migration in Asthma
CFL2
Metacore: IL8 Neutrophil migration
KLK11
Metacore: Neutrophil migration in Asthma
MAPK1
Metacore: IL8 Neutrophil migration
KLK12
Metacore: Neutrophil migration in Asthma
MAPK3
Metacore: IL8 Neutrophil migration
KLK13
Metacore: Neutrophil migration in Asthma
GNAI1
Metacore: IL8 Neutrophil migration
KLK14
Metacore: Neutrophil migration in Asthma
GNAI2
Metacore: IL8 Neutrophil migration
KLK15
Metacore: Neutrophil migration in Asthma
GNAI3
Metacore: IL8 Neutrophil migration
KLK2
Metacore: Neutrophil migration in Asthma
GNAO1
Metacore: IL8 Neutrophil migration
KLK3
Metacore: Neutrophil migration in Asthma
GNAZ
Metacore: IL8 Neutrophil migration
KLK4
Metacore: Neutrophil migration in Asthma
GNB1
Metacore: IL8 Neutrophil migration
KLK5
Metacore: Neutrophil migration in Asthma
GNB2
Metacore: IL8 Neutrophil migration
KLK6
Metacore: Neutrophil migration in Asthma
GNB3
Metacore: IL8 Neutrophil migration
KLK7
Metacore: Neutrophil migration in Asthma
GNB4
Metacore: IL8 Neutrophil migration
KLK8
Metacore: Neutrophil migration in Asthma
GNB5
Metacore: IL8 Neutrophil migration
KLK9
Metacore: Neutrophil migration in Asthma
GNG10
Metacore: IL8 Neutrophil migration
FLT1
Metacore: Neutrophil migration in Asthma
GNG11
Metacore: IL8 Neutrophil migration
RUNX1
Metacore: Transcription regulation of granulocytes
GNG12
Metacore: IL8 Neutrophil migration
CEBPA
Metacore: Transcription regulation of granulocytes
GNG13
Metacore: IL8 Neutrophil migration
CEBPE
Metacore: Transcription regulation of granulocytes
GNG2
Metacore: IL8 Neutrophil migration
ANPEP
Metacore: Transcription regulation of granulocytes
GNG3
Metacore: IL8 Neutrophil migration
PTPRC
Metacore: Transcription regulation of granulocytes
GNG4
Metacore: IL8 Neutrophil migration
E2F1
Metacore: Transcription regulation of granulocytes
GNG5
Metacore: IL8 Neutrophil migration
CSF3
Metacore: Transcription regulation of granulocytes
GNG7
Metacore: IL8 Neutrophil migration
CSF3R
Metacore: Transcription regulation of granulocytes
GNG8
Metacore: IL8 Neutrophil migration
GATA1
Metacore: Transcription regulation of granulocytes
GNGT1
Metacore: IL8 Neutrophil migration
JAK1
Metacore: Transcription regulation of granulocytes
GNGT2
Metacore: IL8 Neutrophil migration
JAK2
Metacore: Transcription regulation of granulocytes
ICAM1
Metacore: IL8 Neutrophil migration
LRG1
Metacore: Transcription regulation of granulocytes
CXCL8
Metacore: IL8 Neutrophil migration
LTF
Metacore: Transcription regulation of granulocytes
ITGB2
Metacore: IL8 Neutrophil migration
ELANE
Metacore: Transcription regulation of granulocytes
LIMK1
Metacore: IL8 Neutrophil migration
LYZ
Metacore: Transcription regulation of granulocytes
MYLK
Metacore: IL8 Neutrophil migration
MXD1
Metacore: Transcription regulation of granulocytes
 
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Gene 
Source
Gene 
Source
MYLK2
Metacore: IL8 Neutrophil migration
MAX
Metacore: Transcription regulation of granulocytes
MYLK3
Metacore: IL8 Neutrophil migration
PRTN3
Metacore: Transcription regulation of granulocytes
PPP1CB
Metacore: IL8 Neutrophil migration
MPO
Metacore: Transcription regulation of granulocytes
PPP1R12A Metacore: IL8 Neutrophil migration
SPI1
Metacore: Transcription regulation of granulocytes
PDPK1
Metacore: IL8 Neutrophil migration
RARA
Metacore: Transcription regulation of granulocytes
PIK3CG
Metacore: IL8 Neutrophil migration
RXRA
Metacore: Transcription regulation of granulocytes
PIK3R5
Metacore: IL8 Neutrophil migration
SOCS3
Metacore: Transcription regulation of granulocytes
PIP5K1A
Metacore: IL8 Neutrophil migration
STAT3
Metacore: Transcription regulation of granulocytes
PIP5K1B
Metacore: IL8 Neutrophil migration
STAT5A
Metacore: Transcription regulation of granulocytes
PIP5K1C
Metacore: IL8 Neutrophil migration
STAT5B
Metacore: Transcription regulation of granulocytes
PRKCZ
Metacore: IL8 Neutrophil migration
FES
Metacore: Transcription regulation of granulocytes
PLD1
Metacore: IL8 Neutrophil migration
MYB
Metacore: Transcription regulation of granulocytes
PLPP6
Metacore: IL8 Neutrophil migration
MYC
Metacore: Transcription regulation of granulocytes
RAC1
Metacore: IL8 Neutrophil migration
CYBB
Metacore: Transcription regulation of granulocytes
RAC2
Metacore: IL8 Neutrophil migration
NCF1
Metacore: Transcription regulation of granulocytes
TLN2
Metacore: IL8 Neutrophil migration
NCF2
Metacore: Transcription regulation of granulocytes
Gene names converted to Affymetrix probe ID, resulted in 638 probes in total, these are 
presented in Table 4. 
Table 4
Probe Set that have previously identified immune cell mechanisms 
specifically related to neutrophil function
Gene
Probe ID
Gene
Probe ID
ABL1
202123_s_at
KLK7
239381_at
ACTA1
203872_at
KLK8
1552319_a_at
ACTA2
200974_at
KLK8
206125_s_at
ACTA2
215787_at
KLK9
233687_s_at
ACTA2
243140_at
LIMK1
204356_at
ACTB
200801_x_at
LIMK1
204357_s_at
ACTB
213867_x_at
LIMK1
208372_s_at
ACTB
224594_x_at
LRG1
228648_at
ACTB
AFFX-HSAC07/X00351_3_at
LTB4R
210128_s_at
ACTB
AFFX-HSAC07/X00351_5_at
LTB4R
216388_s_at
ACTB
AFFX-HSAC07/X00351_M_at
LTB4R
236172_at
ACTC1
205132_at
LTF
202018_s_at
ACTG1
201550_x_at
LYZ
1555745_a_at
ACTG1
211970_x_at
LYZ
213975_s_at
ACTG1
211983_x_at
MAPK1
1552263_at
ACTG1
211995_x_at
MAPK1
1552264_a_at
ACTG1
212363_x_at
MAPK1
208351_s_at
ACTG1
212988_x_at
MAPK1
212271_at
ACTG1
213214_x_at
MAPK1
224620_at
ACTG1
221607_x_at
MAPK1
224621_at
ACTG1
224585_x_at
MAPK1
229847_at
ACTG2
202274_at
MAPK11
206040_s_at
ACTG2
241148_at
MAPK11
211499_s_at
 
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Gene
Probe ID
Gene
Probe ID
ACTN1
208636_at
MAPK11
211500_at
ACTN1
208637_x_at
MAPK12
1556340_at
ACTN1
211160_x_at
MAPK12
1556341_s_at
ACTN1
237401_at
MAPK12
206106_at
ACTN2
203861_s_at
MAPK13
210058_at
ACTN2
203862_s_at
MAPK13
210059_s_at
ACTN2
203863_at
MAPK14
202530_at
ACTN2
203864_s_at
MAPK14
210449_x_at
ACTN3
206891_at
MAPK14
211087_x_at
ACTN4
200601_at
MAPK14
211561_x_at
ACTR2
1554390_s_at
MAPK3
212046_x_at
ACTR2
1558015_s_at
MAX
208403_x_at
ACTR2
200727_s_at
MAX
209331_s_at
ACTR2
200728_at
MAX
209332_s_at
ACTR2
200729_s_at
MAX
210734_x_at
ACTR2
234210_x_at
MAX
214108_at
ACTR2
234212_at
MIF
217871_s_at
ACTR3
200996_at
MPO
203948_s_at
ACTR3
213101_s_at
MPO
203949_at
ACTR3
213102_at
MSN
200600_at
ACTR3
228603_at
MSN
233749_at
ACTR3
239170_at
MXD1
206877_at
ACTR3B
1555487_a_at
MXD1
226275_at
ACTR3B
218868_at
MXD1
228846_at
ADAM17
205745_x_at
MYB
204798_at
ADAM17
205746_s_at
MYB
215152_at
ADAM17
213532_at
MYC
202431_s_at
ADAM17
237897_at
MYH1
205951_at
AKT1
207163_s_at
MYH10
212372_at
AKT2
1560689_s_at
MYH10
213067_at
AKT2
203808_at
MYH11
1568760_at
AKT2
203809_s_at
MYH11
201495_x_at
AKT2
211453_s_at
MYH11
201496_x_at
AKT2
225471_s_at
MYH11
201497_x_at
AKT2
226156_at
MYH11
207961_x_at
AKT2
236664_at
MYH11
228133_s_at
AKT3
212607_at
MYH11
228134_at
AKT3
212609_s_at
MYH11
239307_at
AKT3
219393_s_at
MYH13
208208_at
AKT3
222880_at
MYH14
217545_at
AKT3
224229_s_at
MYH14
217660_at
AKT3
242876_at
MYH14
219946_x_at
AKT3
242879_x_at
MYH14
226988_s_at
ANPEP
202888_s_at
MYH14
232977_x_at
ANPEP
234458_at
MYH14
234290_x_at
ANPEP
234576_at
MYH15
215331_at
ARPC1A
200950_at
MYH16
1564072_at
ARPC1B
201954_at
MYH2
204631_at
ARPC2
207988_s_at
MYH3
205940_at
ARPC2
208679_s_at
MYH4
208148_at
ARPC2
213513_x_at
MYH6
214468_at
ARPC3
208736_at
MYH7
204737_s_at
ARPC4
211672_s_at
MYH7
216265_x_at
ARPC4
217817_at
MYH8
206717_at
 
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Gene
Probe ID
Gene
Probe ID
ARPC4
217818_s_at
MYH8
34471_at
ARPC5
1555797_a_at
MYH9
211926_s_at
ARPC5
1569325_at
MYL1
209888_s_at
ARPC5
211963_s_at
MYL12A
1555976_s_at
ARPC5
237387_at
MYL12A
1555977_at
BDKRB1
207510_at
MYL12A
1555978_s_at
C5
205500_at
MYL12A
201318_s_at
C5AR1
220088_at
MYL12A
201319_at
CCL15
210390_s_at
MYL12B
221474_at
CCL2
216598_s_at
MYL2
209742_s_at
CCL20
205476_at
MYL3
205589_at
CCL3
205114_s_at
MYL4
210088_x_at
CCL5
1405_i_at
MYL4
210395_x_at
CCL5
1555759_a_at
MYL4
216054_x_at
CCL5
204655_at
MYL4
217274_x_at
CCL7
208075_s_at
MYL5
205145_s_at
CCR1
205098_at
MYL6
212082_s_at
CCR1
205099_s_at
MYL6
214002_at
CCR2
206978_at
MYL6B
204173_at
CCR2
207794_at
MYL7
219942_at
CCR3
208304_at
MYL9
201058_s_at
CCR5
206991_s_at
MYL9
244149_at
CD177
219669_at
MYLK
1563466_at
CD34
209543_s_at
MYLK
1568770_at
CEACAM1
206576_s_at
MYLK
1569956_at
CEACAM1
209498_at
MYLK
202555_s_at
CEACAM1
210610_at
MYLK
224823_at
CEACAM1
211883_x_at
MYLK2
231792_at
CEACAM1
211889_x_at
MYLK3
1562411_at
CEACAM3
208052_x_at
MYLK3
1568925_at
CEACAM3
210789_x_at
MYLK3
1568926_x_at
CEACAM3
217209_at
MYLK3
217623_at
CEBPA
204039_at
MYLK3
238834_at
CEBPE
214523_at
MYLPF
205163_at
CFL1
1555730_a_at
NCF1
204961_s_at
CFL1
200021_at
NCF1
214084_x_at
CFL1
230870_at
NCF2
209949_at
CFL1
236792_at
NCOA3
1562439_at
CFL2
224352_s_at
NCOA3
207700_s_at
CFL2
224663_s_at
NCOA3
209060_x_at
CFL2
233496_s_at
NCOA3
209061_at
CLEC4C
1552552_s_at
NCOA3
209062_x_at
CLEC4C
1555687_a_at
NCOA3
211352_s_at
CR1
206244_at
NFKB1
209239_at
CR1
208488_s_at
NFKB2
207535_s_at
CR1
217484_at
NFKB2
209636_at
CR1
217552_x_at
NFKB2
211524_at
CR1
244313_at
OSM
214637_at
CSF3
207442_at
OSM
230170_at
CSF3R
1553297_a_at
PAK1
1565772_at
CSF3R
203591_s_at
PAK1
209615_s_at
CXCL1
204470_at
PAK1
226507_at
CXCL2
1569203_at
PAK1
230100_x_at
CXCL2
209774_x_at
PDPK1
204524_at
 
2018N375139_00


CONFIDENTIAL
201928
56
Gene
Probe ID
Gene
Probe ID
CXCL2
230101_at
PDPK1
221244_s_at
CXCL3
207850_at
PDPK1
224986_s_at
CXCL5
207852_at
PDPK1
244629_s_at
CXCL5
214974_x_at
PDPK1
244630_at
CXCL5
215101_s_at
PDPK1
32029_at
CXCL8
202859_x_at
PECAM1
1558397_at
CXCL8
211506_s_at
PECAM1
1559921_at
CXCR1
207094_at
PECAM1
208981_at
CXCR2
207008_at
PECAM1
208982_at
CYBB
203922_s_at
PECAM1
208983_s_at
CYBB
203923_s_at
PGF
209652_s_at
CYBB
217431_x_at
PGF
215179_x_at
CYBB
233538_s_at
PIK3CG
206369_s_at
DEFB124
1568375_at
PIK3CG
206370_at
DEFB124
1568377_x_at
PIK3CG
239294_at
E2F1
2028_s_at
PIK3R5
220566_at
E2F1
204947_at
PIK3R5
227553_at
EGR1
201693_s_at
PIK3R5
227645_at
EGR1
201694_s_at
PIP5K1A
207391_s_at
EGR1
227404_s_at
PIP5K1A
210256_s_at
EGR3
206115_at
PIP5K1A
211205_x_at
ELANE
206871_at
PIP5K1B
205632_s_at
EZR
208621_s_at
PIP5K1B
217477_at
EZR
208622_s_at
PIP5K1C
212518_at
EZR
208623_s_at
PLCB2
204046_at
EZR
217230_at
PLCB2
210388_at
EZR
217234_s_at
PLD1
1557126_a_at
FES
205418_at
PLD1
177_at
FLT1
204406_at
PLD1
205203_at
FLT1
210287_s_at
PLD1
215723_s_at
FLT1
222033_s_at
PLD1
215724_at
FLT1
226497_s_at
PLD1
226636_at
FLT1
226498_at
PLD1
232530_at
FLT1
232809_s_at
PLPP6
227385_at
FOS
209189_at
PMAIP1
204285_s_at
FPR1
205118_at
PMAIP1
204286_s_at
FPR1
205119_s_at
PPP1CB
201407_s_at
FPR2
210772_at
PPP1CB
201408_at
FPR2
210773_s_at
PPP1CB
201409_s_at
GATA1
1555590_a_at
PPP1CB
228222_at
GATA1
210446_at
PPP1R12A
201602_s_at
GNAI1
209576_at
PPP1R12A
201603_at
GNAI1
227692_at
PPP1R12A
201604_s_at
GNAI2
201040_at
PREX1
224909_s_at
GNAI2
215996_at
PREX1
224925_at
GNAI2
217271_at
PRKCA
1560074_at
GNAI3
201179_s_at
PRKCA
206923_at
GNAI3
201180_s_at
PRKCA
213093_at
GNAI3
201181_at
PRKCA
215194_at
GNAO1
204762_s_at
PRKCA
215195_at
GNAO1
204763_s_at
PRKCB
207957_s_at
GNAO1
215912_at
PRKCB
209685_s_at
GNAO1
231951_at
PRKCB
227817_at
GNAZ
204993_at
PRKCB
227824_at
 
2018N375139_00


CONFIDENTIAL
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57
Gene
Probe ID
Gene
Probe ID
GNB1
200744_s_at
PRKCB
228795_at
GNB1
200745_s_at
PRKCB
230437_s_at
GNB1
200746_s_at
PRKCD
202545_at
GNB2
200852_x_at
PRKCE
206248_at
GNB3
206047_at
PRKCE
226101_at
GNB4
223487_x_at
PRKCE
234089_at
GNB4
223488_s_at
PRKCE
236459_at
GNB4
225710_at
PRKCE
239011_at
GNB5
1554346_at
PRKCG
206270_at
GNB5
204000_at
PRKCG
236195_x_at
GNB5
207124_s_at
PRKCH
206099_at
GNB5
211871_x_at
PRKCH
218764_at
GNB5
242404_at
PRKCH
230124_at
GNG10
201921_at
PRKCI
209677_at
GNG11
204115_at
PRKCI
209678_s_at
GNG11
239942_at
PRKCI
213518_at
GNG12
1555240_s_at
PRKCQ
210038_at
GNG12
212294_at
PRKCQ
210039_s_at
GNG12
222834_s_at
PRKCZ
1569748_at
GNG13
220806_x_at
PRKCZ
202178_at
GNG2
1555766_a_at
PRKD1
205880_at
GNG2
223943_s_at
PRKD1
217705_at
GNG2
224964_s_at
PRKD2
209282_at
GNG2
224965_at
PRKD2
241669_x_at
GNG3
222005_s_at
PRKD2
38269_at
GNG4
1555765_a_at
PRKD3
1554910_at
GNG4
1555867_at
PRKD3
211084_x_at
GNG4
1566513_a_at
PRKD3
218236_s_at
GNG4
205184_at
PRKD3
222565_s_at
GNG5
207157_s_at
PRKD3
242549_at
GNG7
206896_s_at
PRTN3
207341_at
GNG7
214227_at
PTAFR
206278_at
GNG7
228831_s_at
PTAFR
211661_x_at
GNG7
232043_at
PTAFR
227184_at
GNG8
233416_at
PTGS2
1554997_a_at
GNG8
234284_at
PTGS2
204748_at
GNGT1
207166_at
PTPRC
1552480_s_at
GNGT2
235139_at
PTPRC
1569830_at
H1F0
208886_at
PTPRC
207238_s_at
HSPA14
219212_at
PTPRC
212587_s_at
HSPA14
226887_at
PTPRC
212588_at
HSPA14
227650_at
PXN
201087_at
HSPA1L
210189_at
PXN
211823_s_at
HSPA1L
233694_at
RAC1
1567457_at
HSPA2
211538_s_at
RAC1
1567458_s_at
HSPA4
208814_at
RAC1
208640_at
HSPA4
208815_x_at
RAC1
208641_s_at
HSPA4
211015_s_at
RAC2
207419_s_at
HSPA4
211016_x_at
RAC2
213603_s_at
HSPA5
211936_at
RARA
1565358_at
HSPA5
230031_at
RARA
203749_s_at
HSPA6
117_at
RARA
203750_s_at
HSPA6
213418_at
RARA
211605_s_at
HSPA8
208687_x_at
RARA
216300_x_at
 
2018N375139_00


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Gene
Probe ID
Gene
Probe ID
HSPA8
210338_s_at
REL
206035_at
HSPA8
221891_x_at
REL
206036_s_at
HSPA8
224187_x_at
REL
228812_at
HSPA9
200690_at
REL
235242_at
HSPA9
200691_s_at
REL
239486_at
HSPA9
200692_s_at
RELA
201783_s_at
HSPA9
232200_at
RELA
209878_s_at
ICAM1
202637_s_at
RELA
230202_at
ICAM1
202638_s_at
RELB
205205_at
ICAM1
215485_s_at
RXRA
202426_s_at
ICAM2
204683_at
RXRA
202449_s_at
ICAM2
213620_s_at
S100P
204351_at
IFITM1
201601_x_at
SELL
204563_at
IFITM1
214022_s_at
SOCS3
206359_at
IL1B
205067_at
SOCS3
206360_s_at
IL1B
39402_at
SOCS3
214105_at
IL1R1
202948_at
SOCS3
227697_at
IL1R1
215561_s_at
SPI1
205312_at
ITGAL
1554240_a_at
SPTBN1
200671_s_at
ITGAL
213475_s_at
SPTBN1
200672_x_at
ITGAM
205785_at
SPTBN1
212071_s_at
ITGAM
205786_s_at
SPTBN1
213914_s_at
ITGB2
1555349_a_at
SPTBN1
214856_at
ITGB2
202803_s_at
SPTBN1
215918_s_at
ITGB2
236988_x_at
SPTBN1
226342_at
ITPR1
1562373_at
SPTBN1
226765_at
ITPR1
203710_at
SPTBN1
228246_s_at
ITPR1
211323_s_at
SPTBN1
230540_at
ITPR1
216944_s_at
SPTBN1
242220_at
ITPR1
240052_at
SSH2
1554114_s_at
ITPR2
202660_at
SSH2
1555423_at
ITPR2
202661_at
SSH2
1555425_x_at
ITPR2
202662_s_at
SSH2
1560306_at
ITPR2
211360_s_at
SSH2
226080_at
ITPR3
201187_s_at
STAT3
208991_at
ITPR3
201188_s_at
STAT3
208992_s_at
ITPR3
201189_s_at
STAT3
225289_at
ITPR3
239542_at
STAT3
243213_at
JAK1
1552610_a_at
STAT5A
203010_at
JAK1
1552611_a_at
STAT5B
1555086_at
JAK1
201648_at
STAT5B
1555088_x_at
JAK1
239695_at
STAT5B
205026_at
JAK1
240613_at
STAT5B
212549_at
JAK2
1562031_at
STAT5B
212550_at
JAK2
205841_at
SYAP1
225154_at
JAK2
205842_s_at
TAC1
206552_s_at
JUN
201464_x_at
TACR1
208048_at
JUN
201465_s_at
TACR1
208049_s_at
JUN
201466_s_at
TACR1
210637_at
JUN
213281_at
TACR1
230908_at
KLK1
216699_s_at
TARP
211144_x_at
KLK10
209792_s_at
TARP
216920_s_at
KLK10
215808_at
TARP
217381_s_at
KLK11
205470_s_at
TBC1D22A
209650_s_at
 
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Gene
Probe ID
Gene
Probe ID
KLK12
220782_x_at
TBC1D22A
210144_at
KLK12
233586_s_at
TBC1D22A
33778_at
KLK12
234316_x_at
TLN1
203254_s_at
KLK13
205783_at
TLN1
232763_at
KLK13
216670_at
TLN1
236132_at
KLK13
217315_s_at
TLN2
212701_at
KLK14
220573_at
TLN2
212703_at
KLK15
221462_x_at
TLN2
232625_at
KLK15
233477_at
TLR10
223750_s_at
KLK15
234495_at
TLR10
223751_x_at
KLK15
234966_at
TLR2
204924_at
KLK2
1555545_at
TLR4
1552798_a_at
KLK2
209854_s_at
TLR4
221060_s_at
KLK2
209855_s_at
TLR4
224341_x_at
KLK2
210339_s_at
TLR4
232068_s_at
KLK3
204582_s_at
TNF
1563357_at
KLK3
204583_x_at
TNF
207113_s_at
KLK3
231629_x_at
TNFRSF1A
207643_s_at
KLK4
1555697_at
TNFRSF1B
203508_at
KLK4
1555737_a_at
TREML2
219748_at
KLK4
224062_x_at
TTPAL
219633_at
KLK4
231782_s_at
TTPAL
228031_at
KLK4
233854_x_at
VAV1
206219_s_at
KLK5
222242_s_at
VCL
200930_s_at
KLK6
204733_at
VCL
200931_s_at
KLK7
205778_at
VPS37B
221704_s_at
 
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13.7.
Appendix 7: Reporting Standards for Missing Data
13.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as Subject
whom have completed their final visit (day 84).

Withdrawn subjects will not be replaced in the study.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.
13.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:
o
These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
PD

Any values below the Lower Limit of Quantification (LLQ) will be assigned a value of ½ 
LLQ for display purposes in Figures and for computation of summary statistics. Any 
values above the Upper Limit of Quantification (ULQ) will be assigned to the ULQ for 
display purposes in Figures and for computation of summary statistics. Where 
biomarker concentrations are from an assay of an increased dilution factor the LLQ and 
ULQ will be multiplied by this factor.
Note: Values sent to biostatistics are raw and have not taken into account dilution 
factor. LLQ and ULQ need to be taken into account prior to dilution factor and then 
imputed. Then Dilution factor needs to be applied. E.g. if raw value is 10 and dilution 
factor is 1:2 and ULD is 15, then this value is valid, but the final value should be 20.

If the number of LLQ (and/or ULQ) values is large for an individual biomarker then an 
alternative analysis method, such as TOBIT analysis, may be required. “Large” is hard 
to define prospectively and may depend upon the dataset in question. Any such 
methodology will be documented in the statistical contributions to the study report.

Imputed values will be used in tables and figures, unless the proportion of imputed 
values at a given time point is large, in which case the summary statistics may not be 
presented for that time point and/or alternative actions will be taken and documented in 
the study report.

Where values are imputed, the number of such imputations will be included as a 
summary statistic in the relevant summary tables.
HRCT

No missing data imputation methods will be used.

Note that for the HRCT data, there may be instances such that measurements from a 
particular Lobe cannot be distinguished between another Lobe, for example the iVlobe 
may be measured from both the LLL and LUL lobes. In such a case, the Lobe will be 
denoted as LLL + LUL. Therefore, for the statistical analysis purpose, since analysis is 
 
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Element
Reporting Detail
performed on a lobar level, the LLL and LUL Lobes will be set to missing and will 
therefore not be included in the analysis. Below is a table of all possible scenarios, 
where the data is set to missing and not used in the statistical analysis:
Lobes
Label
RUL
RML
RLL
LUL
LLL
x
x
RUL + RML
x
x
RML + RLL
x
x
RUL + RLL
x
x
x
RUL + RML + RLL
x
x
LUL + LLL
13.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to be 
recorded for AE start and end dates; that is, the day of the month may be missing. In 
such a case, the following conventions will be applied for calculating the time to onset 
and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is before the start 
date of study treatment; in this case the study treatment start date will be used and 
hence the event is considered On-treatment as per Appendix 4: Study Phases and 
Treatment Emergent Adverse Events.
o
Missing Stop Day: Last day of the month will be used, unless this is after the stop 
date of study treatment; in this case the study treatment stop date will be used.

Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing.
Concomitant 
Medications/
Medical 
History

Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.
 
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13.8.
Appendix 8: Values of Potential Clinical Importance
13.8.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 
1
Male
0.54
Female
0.54
Haemoglobin 
g/L
Male
180
Female
180
Lymphocytes 
x109/ L
0.8
Neutrophil Count 
x109/ L
1.5
Platelet Count 
x109/ L
100
550
While Blood Cell Count (WBC)
x109/ L
3
20
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Albumin 
g/L
30
Calcium
mmol/L
2
2.75
Glucose
mmol/L
3
9
Magnesium
mmol/L
0.5
1.23
Phosphorus
mmol/L
0.8
1.6
Potassium
mmol/L
3
5.5
Sodium
mmol/L
130
150
Total CO2
mmol/L
18
32
Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
≥ 2x ULN
AST/SGOT 
U/L
High
≥ 2x ULN
AlkPhos 
U/L
High
≥ 2x ULN
T Bilirubin 
µmol/L
High
≥ 1.5xULN
T. Bilirubin + ALT
µmol/L
High
≥1.5xULN T. Bilirubin
+
U/L
≥ 2x ULN ALT
 
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13.8.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 500 [1]
Absolute PR Interval
msec
< 110 [1]
> 220 [2]
Absolute QRS Interval
msec
< 75 [1]
> 110 [2]
NOTES:
[1] An upper limit of 450 would represent standard ECG values of PCI for HV studies, this has been extended to 500 as 
often with exacerbations the treatment can result in a short term prolongation of QTc up to 500.
[2] Represent standard ECG values of PCI for HV studies
13.8.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 85
> 160
Diastolic Blood Pressure
mmHg
< 45
> 100
Heart Rate
bpm
< 40
> 110
 
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13.9.
Appendix 9: Abbreviations & Trade Marks
13.9.1.
Abbreviations
Abbreviation
Description
A&R
Analysis and Reporting
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
AT
Air Trapping Score (% of iVlobe)
BVD
Blood Vessel Density (% of iVlobe)
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CENTRAL
Central lung region
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CT
Computed tomography
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DBF
Database Freeze
DBR
Database Release
Diameter
Diameter
DISTAL
Distal lung region
DLco
Diffusion capacity
DOB
Date of Birth
DP
Decimal Places
ECG
Electrocardiogram
eCRF
Electronic Case Record Form
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
FEV1
Forced expiratory volume in 1 second
FRI
Functional respiratory imaging
FRC
Functional residual capacity
GSK
GlaxoSmithKline
GUI
Guidance
HRCT
High Resolution Computed Tomography
IA
Interim Analysis
IALD
Internal Airflow Lobar Distribution
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IL-8
Interleukin 8
IL-6
Interleukin 6
 
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Abbreviation
Description
IMMS
International Modules Management System
IP
Investigational Product
iRaw
Imaging Airway Resistance
ITT
Intent-To-Treat
iVlobe
Lobar Volume
iVlobepred
Percent Predicted Lobar Volume
iVaw
Imaging Airway Volume
iVaww
Airway Wall Volume
LAS
Low Attenuation Score (% of iVlobe)
Length
Length
LL
Lung, lower lobes
LLL
Lung, left lower lobe
LOC
Last Observation Carries Forward
LUL
Lung, left upper lobe
LUL+LLL
Lung, left upper and lower lobe
MMP9
Matrix metallopeptidase 9
MMRC
Modified Medical Research Council
MMRM
Mixed Model Repeated Measures
NQ
Non-quantifiable
OTU
Operational Taxonomic Unit
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PEF
peak expiratory flow
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
QC
Quality Control
qPCR
Quantitative polymerase chain reaction
QTcF
Fridericia’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
RLL
Lung, right lower lobe
RML
Lung, right middle lobe
RML+RLL
Lung, right middle and lower lobe
RUL
Lung, right upper lobe
RUL+RLL
Lung, right upper and lower lobe
RUL+RML
Lung, right upper and middle lobe
RUL+RML+RLL
Lung, right upper, middle and lower lobe
SAC
Statistical Analysis Complete
SDSP
Study Data Standardization Plan
SDTM
Study Data Tabulation Model
sGaw
Specific conductance
siRaw
Specific Imaging Airway Resistance
 
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Abbreviation
Description
siVaw
Specific Imaging Airway Volume
siVaww
Specific Airway Wall Volume
SoC
Standard of Care
SOP
Standard Operation Procedure
sRaw
Specific Resistance
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
TLC
Total lung capacity
TNFα 
Tumor necrosis factor alpha
TOTAL
Total lung region
TRACHEA
Trachea
UL
Lung, upper lobes
13.9.2.
Trademarks
Trademarks of the GlaxoSmithKline Group 
of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
ELLIPTA
FluidDA
HARP
Quest
RAMOS NG
SAS
RANDALL NG
WinNonlin
 
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13.10.
Appendix 10: List of Data Displays
13.10.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.17
N/A
Efficacy
2.1 to 2.68
2.1 
Safety
3.1 to 3.20
N/A
Pharmacokinetic
4.1 to 4.4
4.1 
Pharmacodynamic and / or Biomarker
6.1 to 6.21
6.1 
Section
Listings
ICH Listings
1 to 34
Other Listings
35 to 49
13.10.2.
Deliverables
Delivery
Description
SAC
Final Statistical Analysis Complete
 
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13.10.3.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
Subject Disposition
1.1.
All Subjects
ES1
Summary of Subject Disposition
ICH E3, FDAAA, EudraCT
SAC
1.2.
All Subjects
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
ICH E3
SAC
1.3.
APE
ES6
Summary of Screening Status and Reasons for Screen Failure
Journal Requirements
SAC
1.4.
All Subjects
NS1
Summary of Number of Participant by Country and Site ID
EudraCT/Clinical Operations
SAC
Protocol Deviation
1.5.
All Subjects
DV1
Summary of Important Protocol Deviations
ICH E3
SAC
Population Analysed
1.6.
APE
SP1 
Summary of Study Populations 
IDSL
SAC
1.7.
All Subjects
IE1
Summary of Inclusion/Exclusion Criteria Deviations
SAC
Demographic and Baseline Characteristics
1.8.
All Subjects
DM1 
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
SAC
1.9.
APE
DM11
Summary of Age Ranges
EudraCT
SAC
1.10.
All Subjects
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, EudraCT
SAC
1.11.
All Subjects
DM6
Summary of Race and Racial Combinations Details
SAC
1.12.
All Subjects
PII116678/final/ 
Table 2.109
Summary of Index Exacerbation Severity
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
Prior and Concomitant Medications
1.13.
All Subjects
MH1
Summary of Current Medical Conditions
ICH E3 
SAC
1.14.
All Subjects
MH1
Summary of Past Medical Conditions
ICH E3 
SAC
1.15.
All Subjects
CM1
Summary of Prior Medications
ICH E3
SAC
1.16.
All Subjects
CM1
Summary of Concomitant Medications
ICH E3
SAC
Exposure and Treatment Compliance
1.17.
All Subjects
EX1
Summary of Exposure to Study Treatment
ICH E3
Include Daily Dose, Cumulative 
does and Days on study drug per 
template.
SAC
Family History of Cardiovascular Risk Factors
1.18.
All Subjects
FH1
Summary of Family History of Cardiovascular Risk Factors
SAC
 
 
 
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13.10.4.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
HRCT Imaging Endpoints
2.1.
All Subjects
PII116678/ final/ 
Table 2.1
Summary of iVaw (mL) (Absolute), for Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
Footnote any transformations used
SAC
2.2.
All Subjects
PII116678/ final/ 
Table 2.2
Summary of iVaw (mL) (Change from Baseline), for Individual 
Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
Footnote any transformations used
Footnote baseline
SAC
2.3.
All Subjects
PII116678/ final/ 
Table 2.3
Summary of iVaw (mL) (Absolute), for Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Footnote any transformations used
SAC
2.4.
All Subjects
PII116678/ final/ 
Table 2.4
Summary of iVaw (mL) (Change from Baseline), for Individual 
Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Footnote any transformations used
Footnote baseline
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.5.
All Subjects
PII116678/ final/ 
Table 2.9
Summary of siVaw (mL/L) (Absolute), for Individual Lobes 
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
Footnote any transformations used
SAC
2.6.
All Subjects
PII116678/ final/ 
Table 2.10
Summary of siVaw (mL/L) (Change from Baseline), for 
Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
Footnote any transformations used
Footnote baseline
SAC
2.7.
All Subjects
PII116678/final/ 
Table 2.11
Summary of siVaw (mL/L) (Absolute), for Individual Regions 
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Footnote any transformations used
SAC
2.8.
All Subjects
PII116678/final/ 
Table 2.12
Summary of siVaw (mL/L) (Change from Baseline), for 
Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Footnote any transformations used
Footnote baseline
SAC
2.9.
All Subjects
PII116678/final/ 
Table 2.17
Summary of iRaw (kPa*s/L) (Absolute), for Individual Lobes 
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
No longitudinal endpoints
Footnote any transformations used
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.10.
All Subjects
PII116678/final/ 
Table 2.18
Summary of iRaw (kPa*s/L) (Change from Baseline), for 
Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
No longitudinal endpoints
Footnote any transformations used
Footnote baseline
SAC
2.11.
All Subjects
PII116678/final/ 
Table 2.19
Summary of iRaw (kPa*s/L) (Absolute), for Individual Regions 
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
No longitudinal endpoints
Footnote any transformations used
SAC
2.12.
All Subjects
PII116678/final/ 
Table 2.20
Summary of iRaw (kPa*s/L) (Change from Baseline), for 
Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
No longitudinal endpoints
Footnote any transformations used
Footnote baseline
SAC
2.13.
All Subjects
PII116678/final/ 
Table 2.25
Summary of siRaw (kPa*s) (Absolute), for Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
No longitudinal endpoints
Footnote any transformations used
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.14.
All Subjects
PII116678/final/ 
Table 2.26
Summary of siRaw (kPa*s) (Change from Baseline), for 
Individual Lobes
Ensure no overlapping information
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
No longitudinal endpoints
Footnote any transformations used
Footnote baseline
SAC
2.15.
All Subjects
PII116678/final/ 
Table 2.27
Summary of siRaw (kPa*s) (Absolute), for Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
No longitudinal endpoints
Footnote any transformations used
SAC
2.16.
All Subjects
PII116678/final/ 
Table 2.28
Summary of siRaw (kPa*s) (Change from Baseline), for 
Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
No longitudinal endpoints
Footnote any transformations used
Footnote baseline
SAC
2.17.
All Subjects
PII116678/final/ 
Table 2.33
Summary of iVlobe (L) (Absolute), for Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
No Scan Trimming endpoints
Footnote any transformations used
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.18.
All Subjects
PII116678/final/ 
Table 2.34
Summary of iVlobe (L) (Change from Baseline), for Individual 
Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
No Scan Trimming endpoints
Footnote any transformations used
Footnote baseline
SAC
2.19.
All Subjects
PII116678/final/ 
Table 2.35
Summary of iVlobe (L) (Absolute), for Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Regions Central and Distal do not 
exist 
No Scan Trimming endpoints
Footnote any transformations used
SAC
2.20.
All Subjects
PII116678/final/ 
Table 2.36
Summary of iVlobe (L) (Change from Baseline), for Individual 
Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Regions Central and Distal do not 
exist 
No Scan Trimming endpoints
Footnote any transformations used
Footnote baseline
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.21.
All Subjects
PII116678/final/ 
Table 2.41
Summary of Percent Predicted iVlobe (%) (Absolute), for 
Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page 
No Scan Trimming endpoints
Footnote any transformations used 
Note in HARP to output (%) it may 
be necessary to input (%%)
SAC
2.22.
All Subjects
PII116678/final/ 
Table 2.42
Summary of Percent Predicted iVlobe (%) (Change from 
Baseline), for Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page 
No Scan Trimming endpoints
Footnote any transformations used
Footnote baseline 
Note in HARP to output (%) it may 
be necessary to input (%%)
SAC
2.23.
All Subjects
PII116678/final/ 
Table 2.43
Summary of Percent Predicted iVlobe (%) (Absolute), for 
Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Regions Central and Distal do not 
exist 
No Scan Trimming endpoints
Footnote any transformations used 
Note in HARP to output (%) it may 
be necessary to input (%%)
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.24.
All Subjects
PII116678/final/ 
Table 2.44
Summary of Percent Predicted iVlobe (%) (Change from 
Baseline), for Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Regions Central and Distal do not 
exist 
No Scan Trimming endpoints
Footnote any transformations used
Footnote baseline 
Note in HARP to output (%) it may 
be necessary to input (%%)
SAC
2.25.
All Subjects
PII116678/final/ 
Table 2.49
Summary of LAS (% of iVlobe) (Absolute), for Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page 
No Scan Trimming endpoints
Footnote any transformations used
SAC
2.26.
All Subjects
PII116678/final/ 
Table 2.50
Summary of LAS (% of iVlobe) (Change from Baseline), for 
Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page 
No Scan Trimming endpoints
Footnote any transformations used
Footnote baseline
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.27.
All Subjects
PII116678/final/ 
Table 2.51
Summary of LAS (% of iVlobe) (Absolute), for Individual 
Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Regions Central and Distal do not 
exist 
No Scan Trimming endpoints
Footnote any transformations used
SAC
2.28.
All Subjects
PII116678/final/ 
Table 2.52
Summary of LAS (% of iVlobe) (Change from Baseline), for 
Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Regions Central and Distal do not 
exist 
No Scan Trimming endpoints
Footnote any transformations used
Footnote baseline
SAC
2.29.
All Subjects
PII116678/final/ 
Table 2.55
Summary of IALD (%) (Absolute), for Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page 
No Scan Trimming endpoints
Footnote any transformations used
SAC
2.30.
All Subjects
PII116678/final/ 
Table 2.56
Summary of IALD (%) (Change from Baseline), for Individual 
Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page 
No Scan Trimming endpoints
Footnote any transformations used
Footnote baseline
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.31.
All Subjects
PII116678/final/ 
Table 2.57
Summary of IALD (%) (Absolute), for Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Regions Central, Distal and Total 
do not exist 
No Scan Trimming endpoints
Footnote any transformations used
SAC
2.32.
All Subjects
PII116678/final/ 
Table 2.58
Summary of IALD (%) (Change from Baseline), for Individual 
Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Regions Central, Distal and Total 
do not exist 
No Scan Trimming endpoints
Footnote any transformations used
Footnote baseline
SAC
2.33.
All Subjects
PII116678/final/ 
Table 2.61
Summary of AT (% of iVlobe) (Absolute), for Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page 
No Scan Trimming endpoints
Footnote any transformations used
SAC
2.34.
All Subjects
PII116678/final/ 
Table 2.62
Summary of AT (% of iVlobe) (Change from Baseline), for 
Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page 
No Scan Trimming endpoints
Footnote any transformations used
Footnote baseline
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.35.
All Subjects
PII116678/final/ 
Table 2.63
Summary of AT (% of iVlobe) (Absolute), for Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Regions Central and Distal do not 
exist 
No Scan Trimming endpoints
Footnote any transformations used
SAC
2.36.
All Subjects
PII116678/final/ 
Table 2.64
Summary of AT (% of iVlobe) (Change from Baseline), for 
Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Regions Central and Distal do not 
exist 
No Scan Trimming endpoints
Footnote any transformations used
Footnote baseline
SAC
2.37.
All Subjects
PII116678/final/ 
Table 2.67
Summary of BVD (% of iVlobe) (Absolute), for Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page 
No Scan Trimming endpoints
Footnote any transformations used
SAC
2.38.
All Subjects
PII116678/final/ 
Table 2.68
Summary of BVD (% of iVlobe) (Change from Baseline), for 
Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page 
No Scan Trimming endpoints
Footnote any transformations used
Footnote baseline
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.39.
All Subjects
PII116678/final/ 
Table 2.69
Summary of BVD (% of iVlobe) (Absolute), for Individual 
Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Regions Central and Distal do not 
exist 
No Scan Trimming endpoints
Footnote any transformations used
SAC
2.40.
All Subjects
PII116678/final/ 
Table 2.70
Summary of BVD (% of iVlobe) (Change from Baseline), for 
Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Regions Central and Distal do not 
exist 
No Scan Trimming endpoints
Footnote any transformations used
Footnote baseline
SAC
2.41.
All Subjects
PII116678/final/ 
Table 2.73
Summary of iVaww (mL) (Absolute), for Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
Footnote any transformations used
SAC
2.42.
All Subjects
PII116678/final/ 
Table 2.74
Summary of iVaww (mL) (Change from Baseline), for Individual 
Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
Footnote any transformations used
Footnote baseline
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.43.
All Subjects
PII116678/final/ 
Table 2.75
Summary of iVaww (mL) (Absolute), for Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Footnote any transformations used
SAC
2.44.
All Subjects
PII116678/final/ 
Table 2.76
Summary of iVaww (mL) (Change from Baseline), for Individual 
Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Footnote any transformations used
Footnote baseline
SAC
2.45.
All Subjects
PII116678/final/ 
Table 2.79
Summary of siVaww (mL/L) (Absolute), for Individual Lobes 
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
Footnote any transformations used
SAC
2.46.
All Subjects
PII116678/final/ 
Table 2.80
Summary of siVaww (mL/L) (Change from Baseline), for 
Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
Footnote any transformations used
Footnote baseline
SAC
2.47.
All Subjects
PII116678/final/ 
Table 2.81
Summary of siVaww (mL/L) (Absolute), for Individual Regions 
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Footnote any transformations used
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.48.
All Subjects
PII116678/final/ 
Table 2.82
Summary of siVaww (mL/L) (Change from Baseline), for 
Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Footnote any transformations used
Footnote baseline
SAC
2.49.
All Subjects
PII116678/final/ 
Table 2.85
Summary of Trachea Length (mm), Diameter (mm) and Length 
/Diameter (mm/mm) (Absolute)
Footnote any transformations used
SAC
2.50.
All Subjects
PII116678/final/ 
Table 2.86
Summary of Trachea Length (mm), Diameter (mm) and Length 
/Diameter (mm/mm) (Change from Baseline)
Footnote any transformations used
Footnote baseline
SAC
2.51.
All Subjects
PII116678/final/ 
Table 2.14
Summary of Statistical Analysis for siVaw (mL/L), for Individual 
Lobes at FRC using Untrimmed Data
Ensure no overlapping information 
across pages for each Lobe
Footnote to include the statistical 
analysis conducted, including 
covariates, co-variance matrix and 
prior assumptions.
Footnote any transformations used
Footnote baseline
SAC
2.52.
All Subjects
PII116678/final/ 
Table 2.16
Summary of Statistical Analysis for siVaw (mL/L), for Individual 
Regions at FRC using Untrimmed Data
Ensure no overlapping information 
across pages for each Lobe
Footnote to include the statistical 
analysis conducted, including 
covariates, co-variance matrix and 
prior assumptions.
Footnote any transformations used
Footnote baseline
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.53.
All Subjects
Refer to: 
PII116678/final/ 
Table 2.16
Note: there will 
be less regions
Summary of Statistical Analysis for siVaw (mL/L), for Distal 
Region at FRC using Scan Trimmed Data
Ensure no overlapping information 
across pages for each Lobe
Footnote to include the statistical 
analysis conducted, including 
covariates, co-variance matrix and 
prior assumptions.
Footnote any transformations used
Footnote baseline
SAC
2.54.
All Subjects
Refer to: 
PII116678/final/ 
Table 2.29
Note: there will 
be less regions
Summary of Statistical Analysis for siRaw (kPa*s), for Distal 
Region at FRC
Ensure no overlapping information 
across pages for each Region
No longitudinal endpoints
Footnote to include the statistical 
analysis conducted, including 
covariates, co-variance matrix and 
prior assumptions.
Footnote any transformations used
Footnote baseline
SAC
2.55.
All Subjects
Refer to: 
PII116678/final/ 
Table 2.54
Note: there will 
be less regions
Summary of Statistical Analysis for LAS (% of iVlobe), for Total
Region at TLC
Ensure no overlapping information 
across pages for each Region
No longitudinal endpoints
Footnote to include the statistical 
analysis conducted, including 
covariates, co-variance matrix and 
prior assumptions.
Footnote any transformations used
Footnote baseline
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.56.
All Subjects
Refer to: 
PII116678/final/ 
Table 2.60
Note: there will 
be less regions
Summary of Statistical Analysis for IALD (%), for Upper and 
Lower Regions
Ensure no overlapping information 
across pages for each Region
No longitudinal endpoints
Footnote to include the statistical 
analysis conducted, including 
covariates, co-variance matrix and 
prior assumptions.
Footnote any transformations used
Footnote baseline
SAC
2.57.
All Subjects
Refer to: 
PII116678/final/ 
Table 2.66
Note: there will 
be less regions
Summary of Statistical Analysis for AT (% of iVlobe), for Total 
Region at FRC
Ensure no overlapping information 
across pages for each Region
No longitudinal endpoints
Footnote to include the statistical 
analysis conducted, including 
covariates, co-variance matrix and 
prior assumptions.
Footnote any transformations used
Footnote baseline
SAC
2.58.
All Subjects
Refer to: 
PII116678/final/ 
Table 2.72
Note: there will 
be less regions
Summary of Statistical Analysis for BVD (% of iVlobe), for Total 
Region at TLC
Ensure no overlapping information 
across pages for each Region
No longitudinal endpoints
Footnote to include the statistical 
analysis conducted, including 
covariates, co-variance matrix and 
prior assumptions.
Footnote any transformations used
Footnote baseline
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.59.
All Subjects
Refer to: 
PII116678/final/ 
Table 2.84
Note: there will 
be less regions
Summary of Statistical Analysis for siVaww (mL/L), for Distal 
Region at TLC using Untrimmed Data
Ensure no overlapping information 
across pages for each Region
No longitudinal endpoints
Footnote to include the statistical 
analysis conducted, including 
covariates, co-variance matrix and 
prior assumptions.
Footnote any transformations used
Footnote baseline
SAC
Lung Function
2.60.
All Subjects
PII115119/
Part_A /Table
3.18
Summary of FEV1 (L) and FVC (L) (Absolute Values)
Summaries by Visit
Footnote any transformations used
SAC
2.61.
All Subjects
PII115119/
Part_A /Table
3.19
Summary of FEV1 (L) and FVC (L) (Change from Baseline)
Summaries by Visit
Footnote any transformations used
Footnote Baseline
SAC
2.62.
All Subjects
PII116678/ final 
/Table 2.88
Summary of Statistical Analysis for FEV1 (L) (Change from 
Baseline)
Footnote to include the statistical 
analysis conducted, including 
covariates, co-variance matrix and 
prior assumptions.
Footnote any transformations used
Footnote baseline
SAC
2.63.
All Subjects
PII116678/ 
postcsr_2017_01 
/Table 2.1
Sub Group Analysis: by Index Exacerbation Severity
Summary of Statistical Analysis for FEV1 (L) (Change from 
Baseline)
Footnote to include the statistical 
analysis conducted, including 
covariates, co-variance matrix and 
prior assumptions.
Footnote any transformations used
Footnote baseline
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.64.
All Subjects
PII116678/ final 
/Table 2.88
Summary of Statistical Analysis for FVC (L) (Change from 
Baseline)
Footnote to include the statistical 
analysis conducted, including 
covariates, co-variance matrix and 
prior assumptions.
Footnote any transformations used
Footnote baseline
SAC
Relief Medication
2.65.
All Subjects
Refer to 
programming 
notes
Summary of Rescue Medication Free Days
Use the standard 
tu_sumstatsinrows to summarise 
Rescue Medication Free days by
time period and treatment.
Include columns for time period, 
treatment, N, n, mean, 95% CI, SD, 
median, min and max
SAC
2.66.
All Subjects
Refer to 
programming 
notes
Summary of Mean Number of Occasions of Rescue Use per 
Day
Use the standard 
tu_sumstatsinrows to summarise 
Mean Number of Occasions of 
Rescue Use per Day by time period 
and treatment.
Include columns for timeperiod, 
treatment, N, n, mean, 95% CI, SD, 
median, min and max
SAC
 
 
 
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87
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Exacerbations
2.67.
All Subjects
Refer to 
PII116678/ final 
/Table 2.97
And 
programming 
notes
Summary of Investigator Defined Exacerbations
Update rows to be consistent with 
data i.e. include 6, 7, etc
exacerbations as appropriate
SAC
2.68.
All Subjects
Refer to 
PII116678/ final 
/Table 2.116
And 
programming 
notes
Summary of Investigator Reported Exacerbations
Requiring Concomitant Medication Treatment
Update rows to be consistent with 
data i.e. include 6, 7, etc
exacerbations as appropriate
SAC
 
 
 
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13.10.5.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
Lung Function
2.1.
All Subjects
Refer to 
PII116678/final/ 
Table 2.2
but update the 
number of plots 
based on the 
data as 
appropriate
Summary of PEF (morning)
X-axis to contain each Day, with 
Means and confidence intervals, 
grouped by Treatment.
Include baseline as a subheading 
per example shell
SAC
 
 
 
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13.10.6.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable 
Adverse Events (AEs)
3.1.
All 
Subjects
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term
ICH E3
SAC
3.2.
All 
Subjects
AE3
Summary of Common (>=5%) Adverse Events by Overall 
Frequency
ICH E3
SAC
3.3.
All 
Subjects
AE1
Summary All Drug-Related Adverse Events by System Organ 
Class and Preferred Term
ICH E3
Include flag for serious
SAC
3.4.
All 
Subjects
AE15
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of 
Participant and Occurrences)
FDAAA, EudraCT
SAC
Serious and Other Significant Adverse Events
3.5.
All 
Subjects
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences)
FDAAA, EudraCT
SAC
3.6.
All 
Subjects
AE1
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study
by System Organ Class and Preferred Term
IDSL
SAC
Laboratory: Chemistry 
3.7.
All 
Subjects
LB1
Summary of Chemistry 
ICH E3
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Safety: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable 
3.8.
All 
Subjects
LB15
Summary of Worst Case Emergent Laboratory Chemistry 
Results Post-Baseline Relative to Baseline
SAC
Laboratory: Hematology
3.9.
All 
Subjects
LB1
Summary of Hematology 
ICH E3
SAC
3.10.
All 
Subjects
LB15
Summary of Worst Case Emergent Laboratory Hematology 
Results Post-Baseline Relative to Baseline
SAC
Laboratory: Hepatobiliary (Liver)
3.11.
All 
Subjects
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting
IDSL
SAC
3.12.
All 
Subjects
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities
IDSL
SAC
ECG
3.13.
All 
Subjects
EG1
Summary of ECG Findings 
IDSL
SAC
3.14.
All 
Subjects
EG2
Summary of ECG Values by Visit
SAC
3.15.
All 
Subjects
EG2
Summary of Change from Baseline in ECG Values by Visit
IDSL
SAC
Vital Signs
3.16.
All 
Subjects
VS1
Summary of Vital Signs
SAC
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable 
3.17.
All 
Subjects
VS1
Summary of Change from Baseline in Vital Signs
ICH E3
Includes Baseline Values
SAC
3.18.
All 
Subjects
VS7
Summary of Worst Case Vital Sign Results Relative to Potential 
Clinical Importance (PCI) Criteria Post-Baseline Relative to 
Baseline
SAC
 
 
 
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13.10.7.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
Plasma Concentration
4.1.
PK
PK01
PII116678/final/Table 
4.1
Summary of Plasma Nemiralisib Pharmacokinetic Concentration 
– Time Data (ng/mL)
All visits/timepoints, include a 
column for visit. Summarise PK 
data on original scale. Produce 
95% CIs
Note: Use the separate NEMI 
Diskus and NEMI ELLIPTA 
treatment groups
Excluding the two subjects who 
were noted to not comply with 
inhalation instructions – include 
footnote
SAC
 
 
 
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Pharmacokinetic: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
4.2.
PK
PK01
PII116678/final/Table 
4.2
Summary of Plasma Nemiralisib Pharmacokinetic Concentration 
– Time Data (ng/mL) 
Including All PK Concentrations Analysed
All visits/timepoints, include a 
column for visit. Summarise PK 
data on original scale. Produce 
95% CIs
Note: Use the separate NEMI 
Diskus and NEMI ELLIPTA 
treatment groups 
Including the two subjects who 
were noted to not comply with 
inhalation instructions – include 
footnote
SAC
4.3.
PK
PII116678/final/Table 
4.3
Summary of Log-Transformed Plasma Nemiralisib 
Pharmacokinetic Concentration – Time Data (ng/mL)
All visits/timepoints, include a 
column for visit and planned time.
Summarise PK data on original 
scale. Produce n, No. imputed, 
geometric mean and corresponding 
95% Cis SD Logs and %CVb
Note: Use the separate NEMI 
Diskus and NEMI ELLIPTA 
treatment groups
Excluding the two subjects who 
were noted to not comply with 
inhalation instructions – include 
footnote
SAC
 
 
 
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Pharmacokinetic: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
4.4.
PK
PII116678/final/Table 
4.4
Summary of Log-Transformed Plasma Nemiralisib 
Pharmacokinetic Concentration – Time Data (ng/mL) 
Including All PK Concentrations Analysed
All visits/timepoints, include a 
column for visit and planned time. 
Summarise PK data on original 
scale. Produce n, No. imputed, 
geometric mean and corresponding 
95% Cis SD Logs and %CVb
Note: Use the separate NEMI 
Diskus and NEMI ELLIPTA 
treatment groups
Including the two subjects who 
were noted to not comply with 
inhalation instructions – include 
footnote
SAC
 
 
 
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13.10.8.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
Plasma Concentration
4.1.
PK
Refer to 
PII116678/ 
final/ Figure 4.1
But include 
additional 
timepoints per 
programming 
notes
Box and Whisker Plot of Plasma Concentration 
Two figures to be created:
1st: Plasma Concentration at Day 1 
(5 min and 24 hours post-dose) and 
Day 12
2nd: Plasma Concentration at Day 
12, Day 28, Day 56 and Day 84
Note: Use the separate NEMI 
Diskus and NEMI ELLIPTA 
SAC
 
 
 
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13.10.9.
Pharmacodynamic and Biomarker Tables
Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
MRNa
6.1.
All Subjects
PII115119/
Part A/
Listing 40
Summary of Statistical Analysis of mRNA Transcriptome in
Induced Sputum (Selected Probe Sets Related to Neutrophil 
Function)
Summarise ratio, 95% CI and p-
values. Sort alphabetically on probe 
set ID
SAC
6.2.
All Subjects
PII115119/
Part A/
Listing 40
Summary of Statistical Analysis of mRNA Transcriptome in
Blood (All Probe Sets)
Biostatistics will await guidance 
following unblinded regarding 
which, if any, probe sets should 
be presented for the exploratory 
analysis and confirmation if a cut 
off criteria other than p-
value<0.05 AND (fold change> 
1.5 OR fold change< -1.5) 
should be used in determining 
which comparisons for the probe 
sets should be presented.
Summarise ratio, 95% CI and p-
values.
SAC
 
 
 
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97
Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
6.3.
All Subjects
PII115119/
Part A/
Listing 40
Summary of Additional Statistical Analysis of mRNA 
Transcriptome in Induced Sputum (All Probe Sets)
Biostatistics will await guidance 
following unblinded regarding 
which, if any, probe sets should 
be presented for the exploratory 
analysis and confirmation if a cut 
off criteria other than p-
value<0.05 AND (fold change> 
1.5 OR fold change< -1.5) 
should be used in determining 
which comparisons for the probe 
sets should be presented.
Summarise ratio, 95% CI and p-
values.
SAC
Cell Count Data and PMN Differentials
6.4.
All Subjects
PII115119/
Part A/Table 
5.7
Summary Statistics (Absolute): Total Cell Count Data in Sputum 
by Treatment and Time.
Appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
6.5.
All Subjects
PII115119/
Part A/Table 
5.8
Summary Statistics (Change from Baseline): Total Cell Count 
Data in Sputum by Treatment and Time
Appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
 
 
 
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98
Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
6.6.
All Subjects
PII115119/
Part A/Table 
5.9
Summary Statistics (Absolute): PMNs Differentials in Sputum by 
Treatment and Time
Appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
6.7.
All Subjects
PII115119/
Part A/Table 
5.10
Summary Statistics (Change from Baseline): PMNs Differentials 
in Sputum by Treatment and Time
Appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
6.8.
All Subjects
PII115119/
Part A/Table 
5.11
Summary Statistics (Absolute): Total Cell Count Data in Blood 
by Treatment and Time.
Appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
6.9.
All Subjects
PII115119/
Part A/Table 
5.12
Summary Statistics (Change from Baseline): Total Cell Count 
Data in Blood by Treatment and Time
Appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
6.10.
All Subjects
PII115119/
Part A/Table 
5.13
Summary Statistics (Absolute): PMNs Differentials in Blood by 
Treatment and Time 
Appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
 
 
 
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Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
6.11.
All Subjects
PII115119/
Part A/Table 
5.14
Summary Statistics (Change from Baseline): PMNs Differentials 
in Blood by Treatment and Time
Appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
Inflammatory Biomarkers
6.12.
All Subjects
PII115119/
Part A/Table 
5.17
Summary Statistics (Absolute): Inflammatory Biomarkers by 
Treatment and Time
It is expected that no transformation 
will be required for this Table (6.12) 
and a log transformation will be
required for Table 6.14. However 
appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
6.13.
All Subjects
PII115119/
Part A/Table 
5.18
Summary Statistics (Change from Baseline): Inflammatory 
Biomarkers by Treatment and Time
It is expected that no transformation 
will be required for this Table (6.13) 
and a log transformation will be
required for Table 6.15. However 
appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
 
 
 
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Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
6.14.
All Subjects
PII115119/
Part A/Table 
5.19
Summary Statistics (Log-Transformed Absolute) Inflammatory 
Biomarkers by Treatment and Time
It is expected that no transformation 
will be required for Table 6.12 and a 
log transformation will be required
for this Table (6.14). However 
appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
6.15.
All Subjects
PII115119/
Part A/Table 
5.20
Summary Statistics (Log-Transformed Change from Baseline)
Inflammatory Biomarkers by Treatment and Time
It is expected that no transformation 
will be required for Table 6.13 and a 
log transformation will be required 
for this Table (6.15). However 
appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
Microbiome (16S rRNA) and qPCR
6.16.
All Subjects
PD4 
and Refer to 
programming 
notes
Summary Statistics (Absolute): Microbiome (16S rRNA) Relative 
Abundance by Treatment and Time
If Data available 
Appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
 
 
 
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Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
6.17.
All Subjects
PD4 
and Refer to 
programming 
notes
Summary Statistics (Percentage Change from Baseline): 
Microbiome (16S rRNA) Relative Abundance by Treatment and 
Time
If Data available. 
Appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
6.18.
All Subjects
PII115119/
Part A/Table 
5.24
Summary Statistics (Absolute): qPCR delta Ct by Treatment and 
Time
If Data available.
Appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
6.19.
All Subjects
PII115119/
Part A/Table 
5.25
Summary Statistics (Log-Transformed Absolute): qPCR fold 
change by Treatment and Time
If Data available.
Appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
Bacterial Culture
6.20.
All Subjects
PII115119/
Part A/Table 
5.26
Frequency Table of Bacterial Culture (Presence) by Treatment 
and Time
SAC
 
 
 
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13.10.10. ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
Subject Disposition
1.
APE
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
SAC
2.
All Subjects
ES2
Listing of Reasons for Study Withdrawal
ICH E3
SAC
3.
All Subjects
SD2
Listing of Reasons for Study Treatment Discontinuation
ICH E3
SAC
4.
All Subjects
BL1
Listing of Participants for Whom the Treatment Blind was Broken
ICH E3
SAC
5.
All Subjects
TA1
Listing of Planned and Actual Treatments
IDSL
SAC
Protocol Deviations
6.
All Subjects
DV2
Listing of Important Protocol Deviations 
ICH E3
SAC
7.
All Subjects
IE3
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations
ICH E3
SAC
Populations Analysed
8.
APE
SP3
Listing of Participants Excluded from Any Population
ICH E3
SAC
Demographic and Baseline Characteristics
9.
All Subjects
DM2
Listing of Demographic Characteristics
ICH E3
SAC
10.
All Subjects
DM9
Listing of Race
ICH E3
SAC
Prior and Concomitant Medications
11.
All Subjects
CM3
Listing of Concomitant Medications
IDSL
SAC
Exposure and Treatment Compliance
12.
All Subjects
EX3
Listing of Exposure Data
ICH E3
SAC
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
Adverse Events
13.
All Subjects
AE8
Listing of All Adverse Events
ICH E3
SAC
14.
All Subjects
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
SAC
15.
All Subjects
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
IDSL
SAC
Serious and Other Significant Adverse Events
16.
All Subjects
AE8 
Listing of Fatal Serious Adverse Events
ICH E3
SAC
17.
All Subjects
AE8 
Listing of Non-Fatal Serious Adverse Events
ICH E3
SAC
18.
All Subjects
AE14
Listing of Reasons for Considering as a Serious Adverse Event
ICH E3
SAC
19.
All Subjects
AE8 
Listing of Adverse Events Leading to Withdrawal from Study or
Permanent Discontinuation of Study Treatment
ICH E3
SAC
Hepatobiliary (Liver)
20.
All Subjects
MH2
Listing of Medical Conditions for Participants with Liver Stopping 
Events
IDSL
SAC
21.
All Subjects
SU2
Listing of Substance Use for Participants with Liver Stopping 
Events
IDSL
SAC
22.
All Subjects
LIVER5
Listing of Liver Monitoring/Stopping Event Reporting
SAC
23.
All Subjects
LIVER7
Listing of Liver Biopsy Details
SAC
24.
All Subjects
LIVER8
Listing of Liver Imaging Details
SAC
All Laboratory
25.
All Subjects
LB5
Listing of All Laboratory Data for Participants with Any Value of 
Potential Clinical Importance
ICH E3
SAC
26.
All Subjects
LB5
Listing of Laboratory Values of Potential Clinical Importance
SAC
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
27.
All Subjects
LB14
Listing of Laboratory Data with Character Results
ICH E3
SAC
ECG
28.
All Subjects
EG3 
Listing of All ECG Values for Participants with Any Value of 
Potential Clinical Importance
IDSL
SAC
29.
All Subjects
EG3 
Listing of ECG Values of Potential Clinical Importance
IDSL
SAC
30.
All Subjects
CP_EG5
Listing of All ECG Findings for Participants with an Abnormal 
ECG Finding
IDSL
SAC
31.
All Subjects
EG5
Listing of Abnormal ECG Findings
IDSL
SAC
Vital Signs
32.
All Subjects
VS4
Listing of All Vital Signs Data for Participants with Any Value of 
Potential Clinical Importance
IDSL
SAC
33.
All Subjects
VS4
Listing of Vital Signs of Potential Clinical Importance
IDSL
SAC
 
 
 
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13.10.11. Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
Demography and Baseline Characteristics
34.
All Subjects
FH1
Summary of Family History of Cardiovascular Risk Factors
SAC
35.
All Subjects
Refer to 
Programming 
notes
COPD Disease duration and Exacerbation Duration
Include investigator ID, subject ID, 
country, treatment group, COPD 
Disease Duration (in years and 
months) and Exacerbation History 
(number requiring oral/systemic 
corticosteroids and/or antibiotics 
and number requiring 
hospitalisation) as columns
SAC
36.
All Subjects
PREG1a
Listing of Subjects Who Became Pregnant During the Study
Also indicate if the female partners 
of subjects became pregnant during 
the study
SAC
Labs
37.
All Subjects
LB13
Listing of Laboratory Reference Ranges
SAC
38.
All Subjects
CP_LB5
Listing of Laboratory Values Outside Normal Reference Range
SAC
PK
39.
PK
PK07
Listing of Individual Subjects Plasma Concentrations at all time 
points
SAC
PD/Biomarkers
40.
All Subjects
PII115119/
Part A/Listing 25
Listing of Sputum Collection
Include sample ID if available
SAC
 
 
 
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Non-ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
41.
All Subjects
PII115119/
Part A/Listing 26
Listing of Blood Collection for RNA
SAC
42.
All Subjects
PII115119/
Part A/Listing 31
Listing of Cell Count Data
SAC
43.
All Subjects
PII115119/
Part A/Listing 32
Listing of PMNs Differentials
SAC
44.
All Subjects
PII115119/
Part A/Listing 34
Listing of Individual Subject Inflammatory Cytokine Biomarker 
Data
SAC
45.
All Subjects
PII115119/
Part A/Listing 35
Listing of Microbiome (16S rRNA) Biomarker Data
SAC
46.
All Subjects
PII115119/
Part A/Listing 36
Listing of qPCR Data
SAC
47.
All Subjects
PII115119/
Part A/Listing 37
Listing of Bacterial Culture Data
SAC
Compliance and Drug Accountability
48.
All Subjects
Example Shell 
POP_L1
Listing of Overall Compliance
Adaptation of IDSL Shell COMP2
SAC
49.
All Subjects
POP_L2
Listing of Drug Accountability Data
Adaptation of IDSL Shell COMP3A
SAC
Patient Profiles
50.
All Subjects
CVEND1
Patient Profile for Congestive Heart Failure
Listing for subject with Myocardial 
infarction/unstable angina
SAC
 
 
 
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Non-ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
51.
All Subjects
Refer to IDSL 
Library 
Arrythmias 
Statistical 
Display 
Standards
Patient Profile for Arrythmias
Listing for subject with 
Arrhythmias
SAC
52.
All Subjects
Refer to IDSL 
Library  
Cerebrovascular 
Events, Stroke 
And Transient 
Ischemic Attack 
Statistical 
Display 
Standards
Patient Profile for Cerebrovascular Events, Stroke and 
Transient Ischemic Attack
Listing for subject with 
Cerebrovascular events/stroke 
and transient ischemic attack 
SAC
 
 
 
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13.11.
Appendix 11: Example Mock Shells for Data Displays
Available Upon Request
 
 
 
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CONFIDENTIAL
The GlaxoSmithKline group of companies
201928
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for Study 201928: 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
Effective Date 
:
26-JUN-2018
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 201928.

This RAP is intended to describe the pharmacodynamic/biomarker, safety, 
pharmacokinetic and efficacy analyses required for the study. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
Approver
Statistician (Clinical Statistics)
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.
Unauthorised copying or use of this information is prohibited.
 
 
 
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The GlaxoSmithKline group of companies
201928
2
RAP Team Approvals:
Approver
Date
Approval Method
11-JUN-2018
Email
Study Accountable Person (Clinical 
Development)
14-JUN-2018
Email
Study Manager (Clinical Development)
20-JUN-2018
Email
Head (Respiratory HUB)
19-JUN-2018
Email
Medical Director (Safety Lead)
11-JUN-2018
Email
Data Quality Lead (Data Management)
15-JUN-2018
Email
Clinical Pharmacokineticist (PK)
11-JUN-2018
Email
Director (Human Translational Models and 
Biomarkers)
19-JUN-2018
Email
Senior Director (Target Sciences Computational 
Biology)
11-JUN-2018
Email
Principal Programmer (Clinical Programming)
Notes:
[1] Approval of the gene list
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
20-JUN-2018
email
Director (Clinical Statistics)
26-JUN-2018
email
Manager (Clinical Programming)
 
 
 
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CONFIDENTIAL
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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Objective(s) and Endpoint(s)...............................................................7
2.3.
Study Design ................................................................................................9
2.4.
Statistical Analyses.......................................................................................9
2.4.1.
Primary Analyses...........................................................................9
3.
PLANNED ANALYSES ..........................................................................................11
3.1.
Final Analyses ............................................................................................11
4.
ANALYSIS POPULATIONS ...................................................................................11
4.1.
Protocol Deviations.....................................................................................11
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................13
5.1.
Study Treatment & Sub-group Display Descriptors.....................................13
5.2.
Baseline Definitions ....................................................................................14
5.3.
Examination of Covariates and Subgroups .................................................15
5.3.1.
Covariates and Other Strata ........................................................15
5.3.2.
Examination of Subgroups...........................................................15
5.4.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................15
6.
STUDY POPULATION ANALYSES .......................................................................16
6.1.
Overview of Planned Study Population Analyses........................................16
7.
PHARMACODYNAMIC AND BIOMARKER ANALYSES........................................17
7.1.
Primary Pharmacodynamic and Biomarker Analyses..................................17
7.1.1.
Endpoint / Variables.....................................................................17
7.1.2.
Summary Measure ......................................................................18
7.1.3.
Population of Interest...................................................................18
7.1.4.
Statistical Analyses / Methods .....................................................18
7.1.4.1.
Statistical Methodology Specification..........................18
7.2.
Exploratory Pharmacodynamic and Biomarker Analyses............................19
7.2.1.
Endpoint / Variables.....................................................................19
7.2.2.
Summary Measure ......................................................................20
7.2.3.
Population of Interest...................................................................20
7.2.4.
Statistical Analyses / Methods .....................................................21
8.
EFFICACY ANALYSES..........................................................................................22
8.1.
Secondary Efficacy Analyses (Not From HRCT Analyses)..........................22
8.1.1.
Endpoint / Variables.....................................................................22
8.1.2.
Summary Measure ......................................................................22
8.1.3.
Population of Interest...................................................................22
8.1.4.
Statistical Analyses / Methods .....................................................22
8.1.4.1.
Statistical Methodology Specification..........................22
 
 
 
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8.2.
Secondary Efficacy Analyses (From HRCT Analyses) ................................24
8.2.1.
Endpoint / Variables.....................................................................24
8.2.2.
Summary Measure ......................................................................24
8.2.3.
Population of Interest...................................................................28
8.2.4.
Statistical Analyses / Methods .....................................................28
8.2.4.1.
Statistical Methodology Specification..........................28
8.3.
Exploratory Efficacy Analyses (From HRCT Analyses) ...............................32
8.3.1.
Endpoint / Variables.....................................................................32
8.3.2.
Summary Measure ......................................................................32
8.3.3.
Population of Interest...................................................................33
8.3.4.
Statistical Analyses / Methods .....................................................34
8.3.4.1.
Statistical Methodology Specification..........................34
8.4.
Exploratory Efficacy Analyses (Not from HRCT Analyses)..........................34
8.4.1.
Endpoint / Variables.....................................................................34
8.4.2.
Summary Measure ......................................................................34
8.4.3.
Population of Interest...................................................................35
8.4.4.
Statistical Analyses / Methods .....................................................35
9.
RELATIONSHIP BETWEEN THE PHARMACODYNAMIC AND 
BIOMARKER DATA AND THE HRCT DATA..........................................................36
9.1.
Relationship between the mRNA data and the HRCT data.........................36
10. SAFETY ANALYSES .............................................................................................37
10.1.
Adverse Events Analyses ...........................................................................37
10.2.
Clinical Laboratory Analyses.......................................................................37
10.3.
Other Safety Analyses ................................................................................37
11. PHARMACOKINETIC ANALYSES.........................................................................38
11.1.
Secondary Pharmacokinetic Analyses........................................................38
11.1.1.
Endpoint / Variables.....................................................................38
11.1.1.1.
Drug Concentration Measures....................................38
11.1.1.2.
Derived Pharmacokinetic Parameters.........................38
11.1.2.
Summary Measure ......................................................................38
11.1.3.
Population of Interest...................................................................38
12. REFERENCES.......................................................................................................39
13. APPENDICES........................................................................................................40
13.1.
Appendix 1: Protocol Deviation Management .............................................40
13.1.1.
Important Protocol Deviations......................................................40
13.2.
Appendix 2: Schedule of Activities ..............................................................41
13.2.1.
Protocol Defined Schedule of Events...........................................41
13.3.
Appendix 3: Assessment Windows .............................................................45
13.3.1.
Definitions of Assessment Windows for Analyses........................45
13.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................46
13.4.1.
Study Phases ..............................................................................46
13.4.1.1.
Study Phases for Concomitant Medication .................46
13.4.2.
Treatment States for Adverse Events ..........................................46
13.5.
Appendix 5: Data Display Standards & Handling Conventions....................47
13.5.1.
Reporting Process .......................................................................47
13.5.2.
Reporting Standards....................................................................47
 
 
 
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13.5.3.
Reporting Standards for Pharmacokinetic....................................48
13.6.
Appendix 6: Derived and Transformed Data ...............................................49
13.6.1.
General........................................................................................49
13.6.2.
Study Population..........................................................................49
13.6.3.
Efficacy........................................................................................50
13.6.4.
Safety ..........................................................................................52
13.6.5.
Pharmacodynamic and Biomarker ...............................................52
13.7.
Appendix 7: Reporting Standards for Missing Data.....................................64
13.7.1.
Premature Withdrawals................................................................64
13.7.2.
Handling of Missing Data.............................................................64
13.7.2.1.
Handling of Missing and Partial Dates ........................65
13.8.
Appendix 8: Values of Potential Clinical Importance ...................................66
13.8.1.
Laboratory Values........................................................................66
13.8.2.
ECG.............................................................................................67
13.8.3.
Vital Signs....................................................................................67
13.9.
Appendix 9: Abbreviations & Trade Marks ..................................................68
13.9.1.
Abbreviations...............................................................................68
13.9.2.
Trademarks .................................................................................70
13.10. Appendix 10: List of Data Displays..............................................................71
13.10.1. Data Display Numbering..............................................................71
13.10.2. Deliverables.................................................................................71
13.10.3. Study Population Tables..............................................................72
13.10.4. Efficacy Tables ............................................................................74
13.10.5. Efficacy Figures ...........................................................................92
13.10.6. Safety Tables...............................................................................93
13.10.7. Pharmacokinetic Tables...............................................................95
13.10.8. Pharmacokinetic Figures .............................................................98
13.10.9. Pharmacodynamic and Biomarker Tables....................................99
13.10.10.ICH Listings ...............................................................................104
13.10.11.Non-ICH Listings........................................................................107
 
 
 
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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol:
Revision Chronology:
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-2
Amendment No. 4
Replace the administration of GSK2269557 via the DISKUSTM device (1000 µg) by a
comparable dose administered via the ELLIPTATM device (700 µg). 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.
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1.
 
 
 
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Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes

Total lung capacity and lung lobar 
volumes included in HRCT 
secondary endpoint parameters

Total lung capacity and lung lobar 
volumes dropped from HRCT 
secondary endpoint parameters 
included as an exploratory 
endpoint parameter instead

The clinically relevant 
HRCT parameters are still 
to be decided. However, 
there was no clinical benefit 
seen in the comparison 
between GSK2269557 
1000 mcg and Placebo in 
these parameters.

Analysis 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.

Pharmacokinetic
Subjects in the ‘All subject’ 
population for whom a 
pharmacokinetic sample was 
obtained and analysed.

Analysis 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.

Pharmacokinetic
Subjects in the ‘All subject’ 
population for whom a 
pharmacokinetic sample was 
obtained and analysed.
Note: The two subjects who were 
not compliant with inhaler 
instructions will be excluded from 
the outcome summaries if they 
received active treatment but will 
be included if they received 
placebo

2 subjects were not 
compliant with inhaler 
instructions and may not 
have received the full dose 
in amendment 4. Therefore,
these subjects will be 
excluded from the outcome 
summaries if they received 
active treatment but will be 
included if they received 
placebo. Sensitivity 
analyses may be conducted 
including these subjects.
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

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 Objectives
Secondary Endpoints

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
 
 
 
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Objectives
Endpoints

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.

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.
Exploratory Objectives
Exploratory Endpoints

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.

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 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
 
 
 
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2.3.
Study Design
Overview of Study Design and Key Features
Design
Features

Multi-centre and Multi-Country

Randomised

Double-blind

Placebo-controlled

Parallel group
Dosing

Once daily, in the morning for 84 days

Administered through the Diskus dry powder Inhaler
Time & 
Events

Refer to Appendix 2: Schedule of Activities
Treatment 
Assignment

Initially planned for approximately 30 subjects randomised to receive either 1000 g 
GSK2269557 (Diskus) or matching Placebo in a 1:1 ratio as it was anticipated that 10 
patients would drop-out. Twenty-eight subjects were randomised to this schedule,
however, due to expiration date there was a protocol amendment following which
additional subjects were subsequently randomised to receive either 700 g 
GSK2269557 (Ellipta) or matching Placebo (Ellipta) in a 1:1 ratio. The protocol was 
updated such that approximately 45 subjects with an acute exacerbation of COPD 
would 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.

Subjects are assigned to treatment in accordance with the randomisation schedule 
generated by Clinical Statistics, using validated software.
Interim 
Analysis

No formal interim analysis will be conducted
2.4.
Statistical Analyses
2.4.1.
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 
 
 
 
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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.
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 are provided in Section 7.1.
 
 
 
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3.
PLANNED ANALYSES
3.1.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All participants have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management.
3.
All criteria for unblinding the randomisation codes have been met. 
4.
Randomisation codes have been distributed according to RandAll NG procedures.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Participants 
Enrolled (APE)

All subjects who were screened for eligibility

Study Population
All Subject 

Comprised of all subjects who were randomised.

This population will be based on the treatment the 
subject actually received.
o
If participants receive >1 treatment, then they 
will be summarised according to the most 
frequently dosed treatment. In cases where 
the frequency is equal, the participant will be 
assigned the lowest dose strength of 
nemiralisib. 
o
If participants receive no treatment, then they 
will be summarised according to “No 
Treatment”

Study Population

Pharmacodynamics
and Biomarker

Safety

Efficacy
Pharmacokinetic 
(PK)

Subjects in the ‘All Subject’ population for whom a 
pharmacokinetic sample was obtained and analysed.

PK
Refer to Appendix 10: List of Data Displays which details the population used for each display.
Note: The two subjects who were not compliant with inhaler instructions will be excluded from the outcome summaries 
if they received active treatment but will be included if they received placebo
4.1.
Protocol Deviations
During the course of the study it was noted that two subjects did not complete dosing 
instructions as required. The primary plan is if the subjects received active treatment they
will be excluded from the study outcome summaries; if the subject received placebo 
treatment, they will be included in the study outcome summaries. It has not yet been 
identified if they received placebo or active treatment. A footnote will be applied to all 
relevant displays stating the rationale, subject number, treatment and if they were 
excluded, e.g. “Subjects X & Y did not complete dosing instructions as required; subject 
X received nemiralisib and was therefore excluded, subject Y received placebo and was 
therefore included.” The footnote may be tweaked for aesthetic purposes.
 
 
 
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Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan, refer to Appendix 1.
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations are captured and categorised on the protocol deviations 
dataset. 
o This dataset will be the basis for the summaries and listings of protocol 
deviations.
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF.
 
 
 
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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order in TLF 
This will be derived as subjects who did not 
receive any treatment
No Treatment
1
This will be derived as subjects in RandALL 
codes A or C
All Placebo
2
This will be derived as subjects in RandALL 
codes B or D
All NEMI
3
A
Placebo
Placebo Diskus
4
B
GSK2269557 1000 mcg
NEMI Diskus
5
C
Placebo via Ellipta
Placebo Ellipta
6
D
GSK2269557 700 mcg
NEMI Ellipta
7
NOTES:
1.
The following footnote will be presented on displays which use the “Placebo Diskus”, “NEMI Diskus”, “Placebo 
Ellipta” or “NEMI Ellipta” treatment groups:
NEMI Diskus =1000 mcg Nemiralisib administered via the Diskus device; NEMI Ellipta =700 mcg Nemiralisib 
administered via the Ellipta device
2.
Order represents treatments being presented in TFL, as appropriate
Treatment groups “Placebo” and “Placebo via Ellipta” (RandAll NG codes A and C) will 
be combined into “All Placebo” treatment group. Similarly, treatment groups 
“GSK2269557 700 mcg” and “GSK2269557 1000 mcg” (RandAll NG codes B and D) 
will be combined into “All NEMI” treatment group. 
Treatment comparisons will be displayed as follows using the descriptors as specified:
1.
All NEMI vs All Placebo
Notes: 

The “All Placebo” and “All NEMI” groups and “All NEMI vs All Placebo” 
treatment comparison will be presented for Pharmacodynamic and biomarker, 
efficacy and study population summaries unless otherwise specified.

The “Placebo Diskus”, “NEMI Diskus”, “Placebo Ellipta” or “NEMI Ellipta” 
treatment groups will be presented for Pharmacokinetic and safety summaries 
unless otherwise specified.

The “Placebo Diskus”, “NEMI Diskus”, “Placebo Ellipta” or “NEMI Ellipta” 
treatment groups will be presented for all listings
 
 
 
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5.2.
Baseline Definitions
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment with a non-missing value, including those from unscheduled 
visits. If time is not collected, Day 1 assessments are assumed to be taken prior to first 
dose and used as baseline.
Parameter
Study Assessments Considered as Baseline
Baseline 
Used in Data 
Display
Screening
Day 1 
(Pre-
Treatment)
Day 2 
Within 
48H/discharge
(On Treatment)
Day 12 
(On 
Treatment)
Safety
Labs including 
Haematology
X
X
Day 1
ECG
X
X
Day 1
Vitals
X
X
Day 1
Efficacy
HRCT Untrimmed
X
Screening
HRCT Scan 
Trimmed
     
Screening&Day12
X
Screening
     
Screening&Day28
X
Screening
     Day12&Day28
X
Day 12
FEV1 and FVC
X
X
Day 1[1]
Daily PEF [2]
X
Day 1
Mean of Days 
1 to 3
Maximum of 
Days 1 to 3
Pharmacodynamic
Sputum and Blood
X
Screening
Genetic sample 
(PGx) [3]
X
NOTES:

Unless otherwise stated, the mean of replicate assessments at any given time point will be used as the value for 
that time point.

[1] Baseline will be investigated to ensure there is sufficient data and will be footnoted as appropriate

[2] For PEF 3 different baselines will be calculated: Day 1, mean of Days 1 to 3 and Maximum of Days 1 to 3.
TFLs will be footnoted with the relevant baseline.

[3] Collected at any time after randomisation
 
 
 
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Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing.
5.3.
Examination of Covariates and Subgroups
5.3.1.
Covariates and Other Strata
The list of covariates may be used in descriptive summaries and statistical analyses, some 
of which may also be used for subgroup analyses. Additional covariates of clinical 
interest may also be considered.
Category
Details
Covariates
Age, Sex, BMI, Country, Primary exacerbation severity
5.3.2.
Examination of Subgroups
The list of subgroups may be used in descriptive summaries and statistical analyses.
Additional subgroups of clinical interest may also be considered.

If the percentage of subjects is small within a particular subgroup, then the subgroup 
categories may be refined prior to unblinding the trial.

If the category cannot be refined further, then descriptive rather than statistical 
comparisons may be performed for the particular subgroup.
Subgroup
Categories 
Primary exacerbation severity
Moderate or Severe [1]
Country
Country
NOTES:
[1] Exacerbations are defined as severe if they require hospitalisation, otherwise they are defined 
as moderate
5.4.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
13.3
Appendix 3: Assessment Windows
13.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
13.5
Appendix 5: Data Display Standards & Handling Conventions
13.6
Appendix 6: Derived and Transformed Data
13.7
Appendix 7: Reporting Standards for Missing Data
13.8
Appendix 8: Values of Potential Clinical Importance
 
 
 
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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the “All Subject” population, unless 
otherwise specified.
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.
Details of the planned displays are presented in Appendix 10: List of Data Displays.
 
 
 
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7.
PHARMACODYNAMIC AND BIOMARKER ANALYSES
7.1.
Primary Pharmacodynamic and Biomarker Analyses
7.1.1.
Endpoint / Variables
Sputum RNA will be extracted and hybridised using a balanced batch design. An 
appropriate microarray platform will be determined at the time of hybridisation, to allow 
for improvements in technology. The quality of the data will be assessed and then 
normalised using appropriate methodologies and software.
Microarray mRNA data will be normalised using gcRMA or RMA in Array Studio v5.0 
or later. After normalisation, the data will be quality assessed and any samples deemed as 
QC fails will be excluded from any further analysis. This quality assessment will involve 
looking for outlying signals in both the normalised expression data and the MAS5 QC 
metrics generated from each sample. If any samples are excluded, the remaining data will 
be re-normalised. The output from the normalisation will be log2 transformed mRNA 
intensity data (measured in arbitrary units).
Since the data will be log2 transformed prior to the analysis the treatment effects will be 
expressed as ratios after back transformation (2^). These ratios can be converted from 
treatment ratios to fold change values as follows:

If ratio ≥ 0 then fold change = ratio

If ratio <0 then fold change = -1/ratio
Microarray data consists of expression values (log2-transformed) derived from individual 
probe sets designed against coding regions of individual genes. More than one probe set
can exist per gene. This analysis will be conducted at the probe set level.
The mRNA data gives results from ~14000 genes encoded by ~54000 probe sets. To 
establish the PI3Kδ-dependent changes in previously identified immune cell mechanisms 
specifically related to neutrophil function using mRNA, we identified 258 gene to subset 
our data on, refer to Section 13.6.5. The gene names were converted to Affymetrix probe 
IDs, this resulted in 638 probes refer to Section 13.6.5.
To compare the expression value between treatments for each probe set, linear repeated 
measures mixed effects model will be fitted to each probe set, with log2 (intensity) as the 
response variable. Note: log2 (intensity) may also be referred to as mRNA intensities 
(logarithm base 2 scale). Alteration in previously identified immune cell mechanisms 
specifically related to neutrophil function will be determined by changes in mRNA 
transcriptomics in induced sputum after 12, 28 and 84 days of treatment by the analysis 
of mRNA intensities (logarithm base 2 scale) subset by the 638 probes identified in 
Section 13.6.5.
 
 
 
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7.1.2.
Summary Measure
A repeated measures modelling analysis will be performed on the subset of 638 probes 
which have previously identified immune cell mechanisms specifically related to 
neutrophil function. 
The model will be used to estimate the baseline adjusted fold changes for active treatment 
and placebo calculated for Day 12, Day 28 and Day 84 along with the corresponding 95% 
confidence intervals and unadjusted P-values. Additionally, baseline adjusted ratios of the 
change between active treatment and placebo will be calculated along with 95% 
confidence intervals and unadjusted P-values.
7.1.3.
Population of Interest 
The primary pharmacodynamic analyses will be based on the “All Subject” population, 
unless otherwise specified.
7.1.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and
listed.
7.1.4.1.
Statistical Methodology Specification
Endpoint / Variables

Alterations in the 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. The response variable will be mRNA intensities 
(logarithm base 2 scale).
Model Specification
The mRNA data gives results from ~14000 genes encoded by ~54000 probe sets. A subset of 638 
probe sets specifically relating to the cell mechanisms of neutrophil function is specified in Section 
13.6.5 This subset will comprise the primary statistical analysis dataset.
The repeated measures modeling analysis will be performed for each probe set separately. 
To estimate differences in mRNA intensities between treatment groups, a repeated measures 
model will be fitted to mRNA intensities at Screening, Day 12, Day 28 and Day 84. The Screening 
time point will be considered Baseline. The model will include terms for treatment group (All 
Placebo or All NEMI), time and a treatment group by time interaction. An unstructured (UN) 
covariance structure will be fitted, however, in the event that this structure results in a model failing 
to converge then attempts will be made to fit a model that converges i.e. alternative covariance 
structures may be considered. The denominator degrees of freedom for use in significance testing 
 
 
 
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will be computed using the Kenward Rogers approximation.
Back transformed baseline-adjusted means along with 95% CIs will be calculated for each 
treatment group and time-point. Additionally, baseline adjusted fold changes between All NEMI and 
All Placebo will be calculated for Day 12, Day 28 and Day 84 as well as the ratio between the 
baseline adjusted fold changes for All NEMI vs. All Placebo at day 12, 28 and 84, along with 95% 
CI and two-sided unadjusted p-values. Additionally, the fold change between All NEMI vs. All 
Placebo at day 84 may be investigate along with 95% CI and two-sided unadjusted p-values and 
other comparisons of interest.
To enable review by the study team a spreadsheet will be created containing the output for all 
probe sets in scope for the primary statistical analysis will be generated and ranked by p-value for 
the comparison All NEMI vs. All Placebo at day 12, 28 and 84 in separate tabs. A separate 
spreadsheet will be created containing only probe sets where the p-value for the comparison All 
NEMI vs. All Placebo is <0.05, with day 12, 28 and 84 in separate tabs. Such probe sets will be 
ranked by fold change, with the expectation that, in general, a greater than a 1.5-fold change is 
scientifically meaningful. To comply with guidance regarding QC, each tab will be stored as a SAS 
dataset to ensure QC can be audited.
Following review by the study team of the results, a subset of probe sets will be identified and may 
be used for further reporting.
Model Checking & Diagnostics

The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used.

An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ on 
the REPEATED line.

In the event that this model fails to converge, alternative correlation structures may be 
considered
Model Results Presentation
The subset of probe sets where the p-value for the comparison All NEMI vs. All Placebo at day 12, 
28 and 84, is <0.05 will be reported as described below:
Output from the repeated measures modelling detailed above will be tabulated. In particular, the 
estimated baseline adjusted fold changes, 95% CI, standard error (on the logarithm base 2 scale), 
unadjusted p-values at each time point and for the active treatment comparison with placebo. The 
probe set, gene/gene description will be included in the outputs.
7.2.
Exploratory Pharmacodynamic and Biomarker Analyses
7.2.1.
Endpoint / Variables
In addition to the primary analysis, there is an exploratory objective to establish any other 
PI3Kδ-dependent changes in mRNA in sputum or blood from patients with an 
exacerbation of COPD, with or without treatment with GSK2269557. To address this 
blood and sputum mRNA data, as described in Section 7.1,but analyses will be conducted 
 
 
 
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on the complete mRNA data, i.e. the results from ~14000 genes encoded by ~54000 
probe sets.
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. Endpoints may include, but not limited to, cytokines (IL-6, IL-8, 
TNFα), microbiome (by 16SrRNA), bacterial qPCR, total cell counts and PMNs 
differentials.
To explore the pharmacodynamic effects in blood of once daily repeat inhaled doses of 
GSK2269557 administered to subjects with acute exacerbation of COPD, compared to 
placebo. Endpoints may include, but not limited to, total cell counts and PMNs 
differentials.
7.2.2.
Summary Measure
To establish any other PI3Kδ-dependent changes in mRNA in sputum or blood from 
patients with an exacerbation of COPD, with or without treatment with GSK2269557. A 
repeated measures modelling analysis will be performed on the complete probe set. The 
model will be used to estimate the baseline adjusted fold changes for active treatment and 
placebo calculated for Day 12, Day 28 and Day 84 along with the corresponding 95% 
confidence intervals and unadjusted P-values. Additionally, baseline adjusted ratios of the 
change between active treatment and placebo will be calculated along with 95% 
confidence intervals and unadjusted P-values.
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. Summary statistics of endpoints may include, but not limited to,
cytokines (IL-6, IL-8, TNFα), microbiome (by 16SrRNA), bacterial qPCR, total cell 
counts and PMNs differentials.
To explore the pharmacodynamic effects in blood of once daily repeat inhaled doses of 
GSK2269557 administered to subjects with acute exacerbation of COPD, compared to 
placebo. Summary statistics of endpoints may include, but not limited to, total cell counts
and PMNs differentials.
7.2.3.
Population of Interest 
The exploratory pharmacodynamic analyses will be based on the “All Subjects” 
population, unless otherwise specified.
As previously discussed for the two subjects that did not follow inhalation instructions, if 
the subjects received active treatment they will be excluded from the study outcome 
summaries; if the subject received placebo treatment, they will be included in the study 
outcome summaries. 
 
 
 
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7.2.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Refer to Section 7.1.4.1 for statistical methodology specification, however, for the 
exploratory analysis, the models will be fitted but on the complete dataset ~14000 genes 
encoded by ~54000 probe sets; sputum and blood data will be analysed separately.
Unless otherwise specified, endpoints / variables defined in Section 7.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. For each endpoint, the values will be inspected to determine whether a data
transformation is required. It is expected that: cytokines may require a transformed on the 
natural logarithm scale
 
 
 
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8.
EFFICACY ANALYSES
8.1.
Secondary Efficacy Analyses (Not From HRCT Analyses)
8.1.1.
Endpoint / Variables
To evaluate the effect of once daily repeat inhaled doses of nemiralisib on lung function 
parameters in subjects with acute exacerbation of COPD compared to placebo. Lung 
function parameters including: 

PEF

FEV1 and FVC at clinic prior to sputum induction 

reliever usage
8.1.2.
Summary Measure
For PEF, summary statistics for the change from baseline PEF will be presented in 
tabular form, mean and 95% CIs of AM PEF readings will be plotted by study treatment 
vs. Study Day. 
For FEV1 (mL) and FVC (mL), a change from baseline statistical analysis will be 
conducted and presented via tables of predicted adjusted medians for each Treatment arm 
at each visit, and the difference between treatment arms at each visit. 
For reliever use, bronchodilator use recorded in the diary will be summarised as the mean 
number of occasions of rescue use per day and the percentage of rescue-free days in four-
week interval periods as described in Section 13.6.3, where a rescue-free day is defined 
as a 24-hour period in which the number of occasions bronchodilator taken is zero.
Summary tables will display estimates for each 4-weekly period for mean number of 
occasions of rescue use per day and percentage of rescue-free days separately.
8.1.3.
Population of Interest
The primary efficacy analyses will be based on the “All Subjects” population, unless 
otherwise specified. 
8.1.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 8.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
8.1.4.1.
Statistical Methodology Specification
NOTE: The description below describes the current thinking of how to analyse these 
endpoints. The proposed models will be assessed, and if not appropriate alternative 
models could be used.
 
 
 
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Endpoint / Variables

FEV1 (ml), FVC(ml)
Model Specification

The data will be inspected during statistical analysis to determine whether a data 
transformation is required. It is likely no transformations will be required

The analysis will include all available values. If there are values which were recorded within 4h 
after the subject had taken relief medication, a sensitivity analysis may be done which excludes 
these values.

The endpoints (FEV1 and FVC) will be analysed in separate models. The change from baseline 
in the endpoint will be analysed in a Bayesian repeated measures model, with a baseline by 
Visit covariate and Treatment by Visit class parameter. Note that the model will not include an 
intercept. The Treatment will have two levels: All NEMI and All Placebo, and the Visit will have 
two levels: Day 28 and Day 84. No fixed assumption around the structure of the covariance 
matrix will be enforced. The priors for the mean vector for each of the parameters (i.e. 
covariates) will each follow a normal distribution and the prior for the variance-covariance will 
follow an inverse Wishart distribution. Sensitivity analysis will be conducted to select 
appropriate parameters for both distributions such that the priors are non-informative with 
respect to the posterior.

The change from baseline at each of the Visits will be represented via adjusted posterior 
medians for each of the Treatment Arms, as well as their associated 95% HPD-tailed credible 
intervals. These results will also be presented in a tabular format.

The difference between the treatment arms, for the change from baseline will be represented 
via adjusted posterior medians for each of the Treatment Arms, as well as their associated 
95% HPD-tailed credible intervals. These results will also be presented in tabular format.

The probabilities that the treatment difference is greater or less than 0 (depending on direction 
of the endpoint), in addition to other values appropriately selected based on the data, will also 
be computed for each Visit. These results will be presented in tabular format.
Model Checking & Diagnostics

Model assumptions will be applied, but appropriate adjustments maybe made based on the 
data. For example, if data do not approximately follow a normal distribution then attempt will be 
made to find a suitable transformation.

A comprehensive investigation into a suitable model should be initiated. For example,
additional covariates will be investigated

An unstructured covariance structure will be used. However, in the event that this model fails to 
converge, alternative correlation structures may be considered. 

Models with a Bayesian Framework will use vague priors. If appropriate, conjugate priors will 
be used. For example, for a multivariate model, the prior for the variance covariance matrix will 
be an inverse Wishart distribution.
Model Results Presentation

Output from the repeated measures modelling detailed above will be tabulated. In particular, 
the estimated change from baseline, 95% CI, standard error, and posterior probabilities at each 
time point and for the active treatment comparison with placebo. 
 
 
 
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Subgroup Analyses

For FEV1, a subgroup analysis will be conducted by index exacerbation severity (refer to 
Section 5.3 Examination of Covariates and Subgroups). A similar model as described in Model 
specification will be fitted but will also include a Severity*Treatment*Visit term within the model. 

The results of the subgroup analysis will be reported in a separate table.
8.2.
Secondary Efficacy Analyses (From HRCT Analyses)
8.2.1.
Endpoint / Variables
To evaluate the effect of once daily repeat inhaled doses of nemiralisib on lung
parameters derived from HRCT scans in subjects with acute exacerbation of COPD,
compared to placebo. Ratio from baseline in siVaw, iVaw, iRaw, siRaw, trachea length 
and diameter at FRC and TLC after 12 days of treatment and after 28 days of treatment. 
8.2.2.
Summary Measure
Each HRCT scan will be conducted at two lung volumes: total lung capacity (TLC) and 
functional residual capacity (FRC); these will be referred to as scan conditions. The 
HRCT images will be processed to derive the HRCT parameters at FRC and TLC, 
however these conditions are not applicable for all parameters. 
The HRCT scans will be conducted at Screening, Day 12 and Day 28. The 3 HRCT 
images will then be processed to derive the HRCT parameters at each scan; this data will 
be referred to as the untrimmed data. The untrimmed data measures all airways that are 
present in each scan.
However partially due to positioning of subjects whilst taking a scan, it can be that some 
airways are visible in some scans and not in other scans. For these reasons, some HRCT 
imaging endpoints will be calculated to include only airways that are visible in both 
scans. Therefore, the scans were grouped into three scan trimming pairs where, within 
each scan trimming pair, the airways that were not present in both scans were 
removed/trimmed. 
The three scan trimming pairs, and subsequent timepoints, are: 

The scan trimming pair SCRD28, which contains the Screening (SCRD28:SCR) and 
Day 28 (SCRD28:D28) timepoints, where only airways that were present in both 
screening and day 28 scans are accounted for.

The scan trimming pair SCRD12, which contains the Screening (SCRD12:SCR) and 
Day 12 (SCRD12:D12) timepoints where only airways that were present in both 
screening and day 12 scan are accounted for.

The scan trimming pair (D12D28), which contains the Day 12 (D12D28:D12) and 
Day 28 (D12D28:D28) timepoints, where only airways that were present in both day 
12 and day 28 scans are accounted for.
These 6 HRCT images were then processed to derive the HRCT parameters at each of 
these scan-trimming pair time points; this data will be referred to as the scan trimmed 
 
 
 
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data. The scan trimmed data considers only airways that were present in both scans 
within the scan trimming pair. This ensures the airway models are the same length 
although the cross-sectional area of the airway may vary. For example, the schematic 
below shows visible airways on Screening alone and Day 12 alone. It then shows the 
airways that are visible on both Screening & Day 12 scans, through removing/trimming 
airways that are not present in both scans.
Screening:
Day 12:
Scan Trimming Screening & Day 12:
The HRCT scans can identify the 5 different lobes of the lungs and these lobes can then 
be categorized into and up to 5 regions depending on the endpoint. The 5 lobes are Right 
Upper Lobe (RUL), Left Upper Lobe (LUL), Right Middle Lobe (RML), Right Lower 
Lobe (RLL) and Left Lower Lobe (LLL). The 5 regions are Upper (comprising of RUL, 
RML and LUL), Lower (comprising of RLL and LLL), Central (the main bronchi 
between the lobes and the trachea), Distal (comprising of Upper and Lower) and Total 
(comprising of Distal and Central). 
The endpoints for which the 5 regions apply include: 

Specific imaging airway volume (siVaw)

Imaging airway volume (iVaw)

Specific imaging airway resistance (siRaw)

Imaging airway resistance (iRaw)

Specific imaging airway wall volume (siVaww) 

Imaging airway wall volume (iVaww)
The endpoints for which only 3 regions (upper, lower & total) apply include: 

Imaging lobe volume (iVlobe)

Percent predicted lobar volume (iVlobepred)

Low attenuation score (LAS)

Air trapping score (AT)

Blood vessel density (BVD)
The endpoint for which only 2 regions (upper & lower) apply is: 

Internal airflow lobar distribution (IALD)
For the measures iVaw, iRaw and iVaww, standardization within a subject for the size of 
the lobar volume was conducted. These specific measures can be adjusted for the 
individual’s lobar volume by correcting for the corresponding lobe/region. Note the 
central region is not applicable for lobar volumes, instead the corresponding region for 
the central, distal and total regions is the total lobar volume region. For example:

To calculate siVaw, the lobes/regions of iVaw being divided by the corresponding 
lobes/regions of iVlobe to calculate the lobes/regions of siVaw, thus siVaw can be 
 
 
 
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defined as a measure of volume in an individual’s airways, corrected for the 
individual’s lobar volume. 

To calculate siRaw, the lobes/regions of iRaw were multiplied by the 
corresponding lobes/regions of iVlobe.

To calculate siVaww, the lobes/regions of iVaww were divided by the 
corresponding lobes/regions of iVlobe. 
For such reasons, the table below shows the HRCT endpoints and the results that will be 
captured: 
Table 2
HRCT Endpoints (and results that will be captured)
Untrimmed 
Scan Trimming, based on:
Endpoints
Units
Screening 
Day 
12 
Day 28 
Screening 
and Day 12 
scans
Screening 
and Day 28 
scans
Day 12 and 
Day 28 scans
iVaw
mL
x
x
x
x (Screening) 
x (Day 12)
x (Screening) 
x (Day 28)
x (Day 12) 
x (Day 28)
siVaw
mL/L
x
x
x
x (Screening) 
x (Day 12)
x (Screening) 
x (Day 28)
x (Day 12) 
x (Day 28)
iRaw
KPa*s/L
x (Screening) 
x (Day 12)
x (Screening) 
x (Day 28)
x (Day 12) 
x (Day 28)
siRaw
KPa*s
x (Screening) 
x (Day 12)
x (Screening) 
x (Day 28)
x (Day 12) 
x (Day 28)
iVlobe
L
x
x
x
Percent 
Predicted iVlobe
% of 
Predicted 
value
x
x
x
IALD [3]
%
x
x
x
LAS [1]
% of 
iVlobe
x
x
x
AT [2]
% of 
iVlobe
x
x
x
BVD [1]
% of 
iVlobe
x
x
x
iVaww [1]
mL
x
x
x
x (Screening) 
x (Day 12)
x (Screening) 
x (Day 28)
x (Day 12) 
x (Day 28)
siVaww [1]
mL/L
x
x
x
x (Screening) 
x (Day 12)
x (Screening) 
x (Day 28)
x (Day 12) 
x (Day 28)
 
 
 
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Untrimmed 
Scan Trimming, based on:
Endpoints
Units
Screening 
Day 
12 
Day 28 
Screening 
and Day 12 
scans
Screening 
and Day 28 
scans
Day 12 and 
Day 28 scans
Trachea length
mm
x
x
x
Trachea 
Diameter
mm
x
x
x
Trachea 
Length/Diameter
mm/mm
x
x
x
All these endpoints will be measured at TLC and FRC, except:
[1] These endpoints will only be measured at TLC
[2] This endpoint will be measured only at FRC
[3] The state (TLC/FRC) is not applicable 
For the endpoints siVaw, iVaw, iRaw and siRaw appropriate transformations will be 
applied prior to summaries and statistical analyses, likely a log transformation. Summary 
statistics will be presented for absolute data and change from baseline. An attempt will be 
made to fit separate statistical models for each endpoint, scan trimming condition 
(Untrimmed or Scan Trimmed), lung volume (FRC or TLC) and Lobes (RUL, LUL, 
RML, RLL and LLL) or Regions (Upper, Lower, Central, Distal and Total) combination
as appropriate. The primary plan for statistical analyses will be to fit separate statistical 
models for:
siVaw 
o Untrimmed at FRC for all lobes, i.e. RUL, LUL, RML, RLL and LLL in 
one model.
o Untrimmed at FRC for all regions, i.e. Upper, Lower, Central, Distal and 
Total in one model.
o Scan Trimmed at FRC for Distal region only.
siRaw 
o Scan Trimmed at FRC for Distal region only.
For untrimmed data, the ratio from baseline across the different Regions (accounting for 
the average baseline associated to the Region of interest) will be represented via adjusted 
posterior medians for each of the Treatment Arms, as well as their associated 95% HPD-
tailed credible intervals. These results will be presented within tabular form, and will be 
presented after the data have been appropriately back transformed (if applicable). In 
addition, the placebo-adjusted ratio from baseline across the different Regions will be 
represented via adjusted posterior medians, as well as their associated 95% HPD-tailed 
credible intervals and posterior probabilities. These results will be presented in tabular 
form, and will be presented after the data have been appropriately back transformed to 
give median ratios (or median differences if applicable).
For scan trimmed data, the change from baseline across the different Regions (accounting 
for the average baseline associated to the Region of interest) will be represented via 
adjusted posterior medians for each of the Treatment Arms, as well as their associated 
 
 
 
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95% HPD-tailed credible intervals. These results will be presented within tabular form, 
and will be presented after the data have been appropriately back transformed (if 
applicable). In addition, the placebo-adjusted change from baseline across the different 
Regions will be represented via adjusted posterior medians, as well as their associated 
95% HPD-tailed credible intervals and posterior probabilities. These results will be 
presented in tabular form, and will be presented after the data have been appropriately 
back transformed to give median ratios (or median differences if applicable).
For the tracheal endpoints, absolute data and change from baseline summary statistics 
will be provided for each lung volume (FRC or TLC) for trachea length, diameter and 
length/diameter.
8.2.3.
Population of Interest
The primary efficacy analyses will be based on the “All Subjects” population, unless 
otherwise specified.
8.2.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 8.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
8.2.4.1.
Statistical Methodology Specification
NOTE: The description below describes the current thinking of how to analyse these 
endpoints. The proposed models will be assessed, and if not appropriate alternative 
models could be used.
Endpoint / Variables

Imaging Untrimmed endpoint siVaw at FRC
Model Specification

The data will be inspected prior to analysis to determine whether a data transformation is 
required. It is likely that the data will approximately follow a log normal distribution; however,
the most appropriate distribution should be used.

It is thought that the use of bronchodilators could affect the HRCT results. The database will 
contain information on whether relief medication was used in the 4 hours prior to each scan, 
and this information may be used in the sensitivity analyses of the HRCT results.

An attempt will be made to fit a statistical model for all Lobes (RUL, LUL, RML, RLL and LLL) 
and a separate statistical model for all Regions (Upper, Lower, Central, Distal and Total), i.e. 
two models; one for lobes, one for regions. However, should this model fail to converge or be 
deemed unsuitable potentially due to sample size, separate statistical models will be fitted for 
each Lobe/Region (RUL, LUL, RML, RLL, LLL, Upper, Lower, Central, Distal and Total), i.e. 
ten models in total, one for each lobe/region endpoint.
 
 
 
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
The log of (or other transformation as appropriate) the ratio from baseline will be analysed in a 
multivariate model), under a Bayesian framework. The model will include a Baseline*Region
term and a Treatment*Visit*Region term, as well as any co-variates of interest. Note that the 
model will not include an intercept. The Visit will consist of two levels: Day 12 and Day 28, and 
the Treatment will consist of two levels: All NEMI and All Placebo. No fixed assumption around 
the structure of the covariance matrix will be enforced. The priors for the mean vector for each 
of the parameters (i.e. covariates) will each follow a normal distribution and the prior for the 
variance-covariance will follow an inverse Wishart distribution. Sensitivity analysis will be 
conducted to select appropriate parameters for both distributions such that the priors are non-
informative with respect to the posterior.

The change from baseline (accounting for the average baseline) across the different Visits will 
be represented via adjusted posterior medians for each of the Treatment Arms, as well as their 
associated 95% HPD-tailed credible intervals. These results will also be presented within 
tabular form, and will be presented after the data have been appropriately back transformed (if 
applicable). 

The difference between the treatment arms, for the change from baseline across the different 
Visits will be represented via adjusted medians, as well as their associated 95% HPD-tailed 
credible intervals. These results will also be presented within tabular form, and will be 
presented after the data have been appropriately back transformed (if applicable) 

The probabilities that the treatment ratio is greater than 1 (depending on direction of the 
endpoint), in addition to other values appropriately selected based on the data, will also be 
computed for each Visit. These results will be presented in tabular format
Model Checking & Diagnostics

Model assumptions will be applied, but appropriate adjustments maybe made based on the 
data. For example, if data do not approximately follow a normal distribution then attempt will be 
made to find a suitable transformation.
Note: Should parameters require a log transformation with an offset, for each posterior sample 
(i) appropriately back transformed values will be calculated for each treatment arm, and then 
(ii) using these back transformed values, the ratio of the treatment arms (All NEMI/All Placebo) 
will be calculated for each posterior sample, and finally summarised accordingly

A comprehensive investigation into a suitable model should be initiated. For example,
additional covariates will be investigated such as age, BMI, gender etc.
Note: when investigating fitting separate statistical models for Lobes (RUL, LUL, RML, RLL and 
LLL) and Regions (Upper, Lower, Central, Distal and Total), i.e. two models; one for lobes, one 
for regions. If there are convergence issues an alternative structure of fitting separate statistical 
models for each Lobe (RUL, LUL, RML, RLL and LLL) and each Region (Upper, Lower, 
Central, Distal and Total), i.e. ten models; five for lobes, five for regions. a similar model as 
described in Model Specification should be tested but will include a baseline and a 
Treatment*Visit term instead of a Baseline*Region term and a Treatment*Visit*Region term,
respectively.
Note: It may also be prudent to investigate a model fitting baseline as a timepoint in which case 
the log of (or other transformation as appropriate) the absolute results will be analysed in a 
multivariate model, under a Bayesian framework. The model could include a 
Treatment*Visit*Region parameter, as well as any co-variates of interest. Note that this model 
would not include an intercept. The Visit would consist of three levels: Baseline, Day 12 and 
Day 28, and the Treatment would consist of three levels: Null (when Visit = Screening), NEMI 
 
 
 
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and Placebo. With assumptions as described in Model Specification.

An unstructured covariance structure will be used. However, in the event that this model fails to 
converge, alternative correlation structures may be considered. 

Models with a Bayesian Framework will use vague priors. If appropriate, conjugate priors will 
be used. For example, for a multivariate model, the prior for the variance covariance matrix will 
be an inverse Wishart distribution.
Model Results Presentation

Output from the repeated measures modelling detailed above will be tabulated. In particular, 
the estimated ratio to baseline (or change from baseline if appropriate), 95% CI, standard error 
(on the appropriate scale, likely logarithm base e), and posterior probabilities at each time point 
and for the active treatment comparison with placebo. The scan trimming condition, lung 
volume and lobe or region description will be included in the outputs.
Sensitivity and Supportive Analyses

It is thought that the use of bronchodilators could affect the HRCT results. The database will 
contain information on if relief medication was used in the 4 hours prior to each scan, and this 
information may be used in the sensitivity analyses of the HRCT results including only those 
who did not take bronchodilator relief medication in the 4 hours prior to HRCT scan.
Endpoint / Variables

Imaging Scan Trimmed endpoints siVaw and siRaw at FRC in the Distal Region only.
Model Specification

It is likely that the data will approximately follow a log normal distribution; however, the most 
appropriate distribution should be used.

Separate statistical models will be fitted for each endpoint, i.e. two models; one for siVaw (scan 
trimmed at FRC in Distal region), one for siRaw (scan trimmed at FRC in Distal region).

The responses of interest are the change from baseline based on (i) Airways present on scans 
taken at Screening and Day 12, (ii) Airways present on scans taken at Screening and Day 28, 
and (iii) Airways present on scans taken at Day 12 and Day 28. The baselines for each of 
these endpoints are provided in the table below.
(i) Screening & Day12 
Scan trimming
(ii) Screening & Day28 
Scan trimming
(iii) Day 12 & Day 28 
Scan trimming
Screening Result
(baseline)
(baseline)
Day 12 Result
(post dose)
(baseline)
Day 28 Result
(post dose)
(post dose)

The modelling below assumes that the Scan trimming endpoints (Screening&Day12, 
Screening&Day28 and Day12&Day28) will be analysed in a single multivariate model. This is 
subject to sensitivity analysis.
 
 
 
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
The log of (or other transformation as appropriate) the change from baseline (where baseline is 
defined in the table above) will be analysed in a multivariate model to account for the 
correlation between the multiple Scan Trimmings (Screening&Day12, Screening&Day28 and 
Day12&Day28), under a Bayesian framework. The model will have a separate intercept for 
each Scan Trimming combination (by fitting a class parameter Scan Trimming, and having no 
overall intercept), and will also include a baseline*Scan Trimming and a Treatment*Scan 
Trimming parameter. The Visit will consist of two levels: Day 12 and Day 28, the scan trimming 
will consist of three levels Screening&Day12, Screening&Day28 and Day12&Day28, and the 
Treatment will consist of two levels: All NEMI and All Placebo. No fixed assumption around the 
structure of the covariance matrix will be enforced. The priors for the mean vector for each of 
the parameters (i.e. covariates) will each follow a normal distribution and the prior for the 
variance-covariance will follow an inverse Wishart distribution. Sensitivity analysis will be 
conducted to select appropriate parameters for both distributions such that the priors are non-
informative with respect to the posterior. 

The change from baseline across the different Scan Trimming pairs (accounting for the 
average baseline) will be represented via adjusted posterior medians for each of the Treatment 
Arms, as well as their associated 95% HPD-tailed credible intervals. These results will also be 
presented within tabular form, and will be presented after the data have been appropriately 
back transformed (if applicable). 

The difference between the treatment arms, for the change from baseline across the different 
Scan Trimming pairs will be represented via adjusted medians, as well as their associated 95% 
HPD-tailed credible intervals. These results will also be presented in tabular form, and will be 
presented after the data have been appropriately back transformed to give median ratios (if 
applicable). For parameters that require a log transformation with an offset, for each posterior 
sample (i) appropriately back transformed values will be calculated for each treatment arm, and 
then (ii) using these back transformed values, the ratio of the treatment arms (Active/Placebo) 
will be calculated for each posterior sample, and finally summarised accordingly. 
The probabilities that the treatment ratio is greater than 1 (for siVaw) and less than 1 (for 
siRaw), in addition to other values appropriately selected based on the data, will also be 
computed for each Visit. These results will be presented in tabular format.
Model Checking & Diagnostics

Model assumptions will be applied, but appropriate adjustments maybe made based on the 
data. For example if data do not approximately follow a normal distribution then an attempt will 
be made to find a suitable transformation.
Note: Should parameters require a log transformation with an offset, for each posterior sample 
(i) appropriately back transformed values will be calculated for each treatment arm, and then 
(ii) using these back transformed values, the ratio of the treatment arms (All NEMI/All Placebo) 
will be calculated for each posterior sample, and finally summarised accordingly

A comprehensive investigation into a suitable model should be initiated. For example,
additional covariates will be investigated

An unstructured covariance structure will be used. However, in the event that this model fails to 
converge, alternative correlation structures may be considered. 

Models with a Bayesian Framework will use vague priors. If appropriate, conjugate priors will 
be used. For example, for a multivariate model, the prior for the variance covariance matrix will 
be an inverse Wishart distribution.
 
 
 
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Model Results Presentation

Output from the repeated measures modelling detailed above will be tabulated. In particular, 
the estimated ratio to baseline (or change from baseline if appropriate), 95% CI, standard error 
(on the appropriate scale, likely logarithm base e), and posterior probabilities at each time point 
and for the active treatment comparison with placebo. The scan trimming condition, lung 
volume and lobe or region description will be included in the outputs.
Sensitivity and Supportive Analyses

It is thought that the use of bronchodilators could affect the HRCT results. The database will 
contain information on if relief medication was used in the 4 hours prior to each scan, and this 
information may be used in the sensitivity analyses of the HRCT results including only those 
who did not take bronchodilator relief medication in the 4 hours prior to HRCT scan.
8.3.
Exploratory Efficacy Analyses (From HRCT Analyses)
8.3.1.
Endpoint / Variables
To assess the changes in other HRCT parameters such as low attenuation score after once 
daily repeat inhaled doses of nemiralisib 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.
8.3.2.
Summary Measure
The structure of HRCT endpoints is as described in Section 8.2.2, exploratory endpoints 
include:

iVlobe

Percent Predicted iVlobe

IALD

LAS

AT

BVD

iVaww

siVaww
For all endpoints, the data will be inspected prior to analyses to determine whether a data 
transformation is required. Appropriate transformations will be applied prior to 
summaries and statistical analyses. It is likely a log transformation will be required for 
iVlobe, LAS, IALD, BVD iVaww and siVaww, and that no transformation will be
required for Percent Predicted iVlobe and AT, however, the most appropriate distribution 
should be used
Summary statistics will be presented for absolute data and change from baseline. 
Separate statistical models will be fitted for each scan trimming condition (Untrimmed or 
Scan Trimmed), lung volume (FRC or TLC) and Regions (Upper, Lower, Central, Distal 
 
 
 
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and Total) combination as appropriate, note: statistical analyses will only be conducted 
on:
IALD for upper and lower regions only (within the same model)
LAS at TLC for total region only
AT at FRC for total region only 
BVD at TLC for total region only

siVaww untrimmed data at TLC for distal region only
For the endpoints: LAS, AT and BVD, separate statistical models will be fitted for the 
Total region only. The change from baseline (accounting for the average baseline 
associated to the region) will be represented via adjusted posterior medians for each of 
the Treatment Arms, as well as their associated 95% HPD-tailed credible intervals. These 
results will also be presented within tabular form, and will be presented after the data 
have been appropriately back transformed (if applicable). The difference between the 
treatment arms, for the change from baseline will be represented via adjusted medians, as 
well as their associated 95% HPD-tailed credible intervals. These results will also be 
presented in tabular form, and will be presented after the data have been appropriately 
back transformed to give median ratios (or median differences if applicable).
For the endpoint IALD, a statistical model will be fitted for both the Upper and Lower 
regions. The change from baseline across the different regions (accounting for the 
average baseline associated to the region of interest) will be represented via adjusted 
posterior medians for each of the Treatment Arms, as well as their associated 95% HPD-
tailed credible intervals. These results will also be presented within tabular form, and will 
be presented after the data have been appropriately back transformed (if applicable). The 
difference between the treatment arms, for the change from baseline across the different 
regions will be represented via adjusted medians, as well as their associated 95% HPD-
tailed credible intervals. These results will also be presented in tabular form, and will be 
presented after the data have been appropriately back transformed to give median ratios 
(or median differences if applicable).
For the endpoint siVaww, a statistical model will be fitted for the distal region using 
untrimmed data. The change from baseline (accounting for the average baseline 
associated to the region) will be represented via adjusted posterior medians for each of 
the Treatment Arms, as well as their associated 95% HPD-tailed credible intervals. These 
results will also be presented within tabular form, and will be presented after the data 
have been appropriately back transformed (if applicable). The difference between the 
treatment arms, for the change from baseline will be represented via adjusted medians, as 
well as their associated 95% HPD-tailed credible intervals. These results will also be 
presented in tabular form, and will be presented after the data have been appropriately 
back transformed to give median ratios (or median differences if applicable).
8.3.3.
Population of Interest 
The secondary efficacy analyses will be based on the “All Subjects” population, unless 
otherwise specified.
 
 
 
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8.3.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 8.3.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
8.3.4.1.
Statistical Methodology Specification
For statistical analyses of IALD in the upper and lower regions refer to Section 8.2.4.1 for the
analysis of untrimmed siVaw but note that it is likely only 1 statistical model would be fitted for the 
upper and lower regions only. If appropriate this could be adapted into two models; one for upper, 
one for lower. The probability that the treatment ratio is greater than 1 will be presented for the 
lower region and the probability that the treatment ratio is less than 1 will be presented for the 
upper region, in addition to other values appropriately selected based on the data.
For statistical analyses of LAS at TLC in the total region only, refer to Section 8.2.4.1 for the 
analysis of untrimmed siVaw but note only 1 statistical model would be fitted for the Total regions 
only. The probability that the treatment ratio is less than 1 will be presented, in addition to other 
values appropriately selected based on the data.
For statistical analyses of AT at FRC in the total region only, refer to Section 8.2.4.1 for the 
analysis of untrimmed siVaw however it is likely that no transformation will be required for this 
endpoint in which case the absolute change from baseline will be fitted and probabilities that the 
true treatment difference is less than 1, in addition to other values appropriately selected based on 
the data, will also be computed for each Visit. Note only 1 statistical model would be fitted for the 
Total regions only. 
For statistical analyses of BVD at TLC in the total region only, refer to Section 8.2.4.1 for the 
analysis of untrimmed siVaw but note only 1 statistical model would be fitted for the Total regions 
only.
For statistical analyses of siVaww at TLC in the distal region only, refer to Section 8.2.4.1 for the 
analysis of untrimmed siVaw but note only 1 statistical model would be fitted for the Distal regions 
only. The probability that the treatment ratio is less than 1, in addition to other values appropriately 
selected based on the data will be presented.
8.4.
Exploratory Efficacy Analyses (Not from HRCT Analyses)
8.4.1.
Endpoint / Variables
Additional exploratory endpoints include the severity of index exacerbation, where 
exacerbations requiring hospitalisations are defined as severe and those not requiring 
hospitalisation are defined as moderate.
8.4.2.
Summary Measure
For the severity of index exacerbation, a summary table detailing the number and 
percentage of subjects who had moderate or severe index exacerbations. Note: 
 
 
 
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exacerbations requiring hospitalisations are defined as severe and those not requiring 
hospitalisation are defined as moderate.
If available, data on exacerbations occurring during the study will be summarised. This 
may include investigator defined exacerbations (including information on moderate or 
severe) and concomitant medication defined exacerbations. Concomitant medication 
defined exacerbations will be defined as treatment with systemic/oral corticosteroids 
and/or antibiotics where the exacerbation is deemed to have ended if no additional 
treatment with systemic/oral corticosteroids and/or antibiotics is required within < 7days 
from the end of treatment for the primary exacerbation. 
8.4.3.
Population of Interest 
The secondary efficacy analyses will be based on the “All Subjects” population, unless 
otherwise specified. 
8.4.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 8.4.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
 
 
 
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9.
RELATIONSHIP BETWEEN THE PHARMACODYNAMIC 
AND BIOMARKER DATA AND THE HRCT DATA
9.1.
Relationship between the mRNA data and the HRCT data
The relationship between a selection of the mRNA data and the HRCT data may be 
performed as an exploratory analysis. This may include scatter plots of individual 
participant data, linear regression lines, Pearson’s correlation coefficient and 95% 
confidence intervals plots as appropriate. This data will be produced following SAC.
 
 
 
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10.
SAFETY ANALYSES
The safety analyses will be based on the “All Subjects” population, unless otherwise 
specified.
10.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs)
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 10: List of Data Displays.
10.2.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, 
Haematology laboratory tests, Urinalysis, and liver function tests will be based on GSK 
Core Data Standards. The details of the planned displays are in Appendix 10: List of Data 
Displays.
10.3.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 10: List of Data Displays.
 
 
 
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11.
PHARMACOKINETIC ANALYSES
11.1.
Secondary Pharmacokinetic Analyses
11.1.1.
Endpoint / Variables
11.1.1.1.
Drug Concentration Measures 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 13.5.3
Reporting Standards for Pharmacokinetic)
11.1.1.2.
Derived Pharmacokinetic Parameters
No non-compartmental analysis will be conducted for this study as such there will be no 
derived pharmacokinetic parameters.
11.1.2.
Summary Measure
The concentrations of the samples will be summarised.
11.1.3.
Population of Interest 
The secondary pharmacokinetic analyses will be based on the “Pharmacokinetic” 
population, unless otherwise specified.
 
 
 
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12.
REFERENCES
Quanjer Ph.H, Tammeling G.J, Cotes J.E., Pedersen O.F, Peslin R, Yernault J-C. Lung 
volumes and forced ventilatory flows; European Respiratory Journal 1993 6: 5-40
 
 
 
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13.
APPENDICES
13.1.
Appendix 1: Protocol Deviation Management 
13.1.1.
Important Protocol Deviations
Based on an assessment of the important protocol deviations listed in the PDMP, partial 
data exclusions or time-point exclusions may occur which may not remove a subject from 
the analysis population, but may exclude a portion of the subject’s data.
 
 
 
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13.2.
Appendix 2: Schedule of Activities
13.2.1.
Protocol Defined Schedule of Events
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.
 
 
 
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Procedure
Screening 
(up to 3 days prior to Visit 1)
Follow-up
(7-14 days post-last dose)
Notes
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
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 of Protocol Amendment 4 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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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.
FEV1and 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 of Protocol Amendment 4
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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13.3.
Appendix 3: Assessment Windows
13.3.1.
Definitions of Assessment Windows for Analyses
Population
Target 
Analysis Window
Analysis 
Timepoint
Beginning Timepoint
Ending Timepoint
Screening
NA
3 days prior to Visit 1 
(Day 1)
Day 1
Screening
Safety, 
Efficacy, Study 
population and 
all other 
assessments
NA – Day of first dose 
NA
NA
Visit 1
If subject was hospitalised:
Target = On discharge
If subject wasn’t hospitalised:
Target = Within 48 hours of 
first dose administration 
Target -1 day
Target +1 day
Visit 2
Day 12 
Target -2 day
Target +2 day
Visit 3
Day 28
Target -2 day
Target +2 day
Visit 4
Day 56
Target -4 day
Target +2 day
Visit 5
Day 84
Target -4 day
Target +2 day
Visit 6
Follow-up
NA
1 week following last day 
of dose
2 weeks following 
the last day of dose
Follow-up
 
 
 
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13.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
13.4.1.
Study Phases
Assessments and events will be classified according to the time of occurrence relative to 
the study treatment, unless otherwise specified
Study Phase
Definition
Pre-Treatment 
Date ≤ Study Treatment Start Date
On-Treatment
Study Treatment Start Date < Date ≤ Study Treatment Stop Date
Post-Treatment
Date > Study Treatment Stop Date 
13.4.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is prior to screening visit
Concomitant
Any medication that is not a prior
NOTES: 

Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.
13.4.2.
Treatment States for Adverse Events
Flag
Definition
Pre-Treatment

If AE onset date is before the treatment start date.

AE Start Date < Study Treatment Start Date
Treatment 
Emergent
(On-Treatment)

If AE onset date is on or after treatment start date & on or before treatment stop 
date.

Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date.
Post-Treatment

If AE onset date is after the treatment stop date.

AE Start Date > Study Treatment Stop Date
Onset Time Since 
1st Dose (Days)

If Treatment Start Date ˃ AE Onset Date, then 
Onset Time = AE Onset Date - Treatment Start Date

If Treatment Start Date ≤ AE Onset Date, then 
Onset Time = AE Onset Date - Treatment Start Date +1

Missing otherwise.
Duration (Days)

AE Resolution Date – AE Onset Date + 1
Drug-related

If relationship is marked ‘YES’ on [Inform/CRF OR value is missing].
NOTES: 

If the study treatment stop date is missing, then the AE will be considered to be On-Treatment.

Time of study treatment dosing and start/stop time of AEs should be considered, if collected.
 
 
 
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13.5.
Appendix 5: Data Display Standards & Handling 
Conventions
13.5.1.
Reporting Process
Software

The currently supported versions of SAS software (version 9.4) will be used.
Reporting Area
HARP Server
: UK1SALX00175.corpnet2.com
HARP Compound
: ARPROD/GSK2269557/mid201928
Note: the current planned reporting effort is final_01, this may be superseded. 
Analysis Datasets 

Analysis datasets will be created according to Legacy GSK A&R dataset standards and Integrated Data 
Standards Library
Generation of RTF Files

RTF files will be generated for all tables
13.5.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 

Do not include subject level listings in the main body of the GSK Clinical Study Report. All subject level 
listings should be located in the modular appendices as ICH or non-ICH listings

A project wide decision was made to present GSK2269557 as Nemiralisib (abbreviated to NEMI) refer 
to Section 5.1 for further details. 
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may be
adjusted to a clinically interpretable number of DP’s.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 
 
 
 
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
Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will be 
included in listings but omitted from figures, summaries and statistical analyses.
Unscheduled Visits

Unscheduled visits will not be included in summary tables.

Unscheduled visits will not be included in summary figures

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.

All graphics will be done using the SGPLOT/SGPANEL/SG template procedures
13.5.3.
Reporting Standards for Pharmacokinetic
Pharmacokinetic Concentration Data
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
Note: Use the separate NEMI DISKUS and NEMI ELLIPTA treatment groups
NONMEM/Pop PK 
File
Not applicable.
NONMEM/PK/PD 
File
Not applicable.
 
 
 
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13.6.
Appendix 6: Derived and Transformed Data
13.6.1.
General
Multiple Measurements at One Analysis Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented.

If there are two values within a time window (as per Section 13.3.1) the value closest to the target day 
for that window will be used. If values are the same distance from the target, then the mean will be 
taken.

Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables.
Study Day

Calculated as the number of days from First Dose Date:

Ref Date = Missing              → Study Day = Missing 

Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date

Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1  
13.6.2.
Study Population
Treatment Compliance

Treatment compliance will be calculated based on the formula:
Treatment Compliance = Number of Actual Doses / (Planned Treatment Duration in Days * 
Frequency)

Treatment compliance could be greater than 100% if there are events of overdose. Cumulative 
compliance (since Day 1) at each visit will be calculated.

Planned Treatment Duration is defined as 84 days.
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1

Participants who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure. 

The cumulative dose will be based on the formula:
Cumulative Dose = Sum of (Number of Days x Total Daily Dose)

If there are any treatment breaks during the study, exposure data will be adjusted accordingly.
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed as follows:
o
Any subject with a missing date and month will have this imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)2]
 
 
 
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13.6.3.
Efficacy
HRCT
Endpoints provided by FluidDA
Y = Endpoints will be provided by FluidDA.
C = Endpoints will be Calculated by GSK (see Derived Data below)
Lobes & Regions
LLL
LUL
RML
RUL
RLL
LL
UL
CENTRAL
DISTAL
TOTAL TRACHEA
iVaw
Y
Y
Y
Y
Y
C
C
Y
C
C
N/A
siVaw
C
C
C
C
C
C
C
C
C
C
N/A
iRaw
Y
Y
Y
Y
Y
C
C
Y
Y
Y
N/A
siRaw
C
C
C
C
C
C
C
C
C
C
N/A
iVlobe
Y
Y
Y
Y
Y
C
C
N/A
N/A
C
N/A
iVlobepred
Y
Y
Y
Y
Y
Y
Y
N/A
N/A
Y
N/A
LAS
Y
Y
Y
Y
Y
Y
Y
N/A
N/A
Y
N/A
IALD
C
C
C
C
C
C
C
N/A
N/A
N/A
N/A
AT
Y
Y
Y
Y
Y
Y
Y
N/A
N/A
Y
N/A
BVD
Y
Y
Y
Y
Y
Y
Y
N/A
N/A
Y
N/A
iVaww
Y
Y
Y
Y
Y
C
C
Y
C
C
N/A
siVaww
C
C
C
C
C
C
C
C
C
C
N/A
Diameter
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Y
Length
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Y
Length/Diameter
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
C
Imaging Endpoints Calculated by GSK
iVaw LL = iVaw RLL + iVaw LLL
iVaw UL = iVaw RUL + iVaw RML + iVaw LUL
iVaw DISTAL = iVaw LL + iVaw UL
iVaw TOTAL = iVaw CENTRAL + iVaw DISTAL
iRaw LL = 1/ (1/iRaw RLL + 1/iRaw LLL)
iRaw UL = 1/ (1/iRaw RUL + 1/iRaw RML + 1/iRaw LUL)
iVlobe LL = iVlobe RLL + iVlobe LLL
iVlobe UL = iVlobe RUL + iVlobe RML + iVlobe LUL
iVlobe TOTAL = iVlobe LL + iVlobe UL
iVaww LL = iVaww RLL + iVaww LLL
iVaww UL = iVaww RUL + iVaww RML + iVaww LUL
iVaww DISTAL = iVaww LL + iVaww UL
iVaww TOTAL = iVaww CENTRAL + iVaww DISTAL
siVaw LLL = iVaw LLL / iVlobe LLL
siVaw LUL = iVaw LUL / iVlobe LUL
siVaw RML = iVaw RML / iVlobe RML
siVaw RUL = iVaw RUL / iVlobe RUL
siVaw RLL = iVaw RLL / iVlobe RLL
siVaw LL = iVaw LL / iVlobe LL
siVaw UL = iVaw UL / iVlobe UL
siVaw CENTRAL = iVaw CENTRAL / iVlobe TOTAL
siVaw DISTAL = iVaw DISTAL / iVlobe TOTAL
siVaw TOTAL = iVaw TOTAL / iVlobe TOTAL
siRaw LLL = iRaw LLL * iVlobe LLL
siRaw LUL = iRaw LUL * iVlobe LUL
siRaw RML = iRaw RML * iVlobe RML
siRaw RUL = iRaw RUL * iVlobe RUL
siRaw RLL = iRaw RLL * iVlobe RLL
siRaw LL = iRaw LL * iVlobe LL
siRaw UL = iRaw UL * iVlobe UL
 
 
 
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HRCT
siRaw CENTRAL = iRaw CENTRAL * iVlobe TOTAL
siRaw DISTAL = iRaw DISTAL * iVlobe TOTAL
siRaw TOTAL = iRaw TOTAL * iVlobe TOTAL
siVaww LLL = iVaww LLL / iVlobe LLL
siVaww LUL = iVaww LUL / iVlobe LUL
siVaww RML = iVaww RML / iVlobe RML
siVaww RUL = iVaww RUL / iVlobe RUL
siVaww RLL = iVaww RLL / iVlobe RLL
siVaww LL = iVaww LL / iVlobe LL
siVaww UL = iVaww UL / iVlobe UL
siVaww CENTRAL = iVaww CENTRAL / iVlobe TOTAL
siVaww DISTAL = iVaww DISTAL / iVlobe TOTAL
siVaww TOTAL = iVaww TOTAL / iVlobe TOTAL
IALD LLL = 100 * (iVlobe LLL TLC - iVlobe LLL FRC) / (iVlobe TOTAL TLC - iVlobe TOTAL FRC)
IALD LUL = 100 * (iVlobe LUL TLC - iVlobe LUL FRC) / (iVlobe TOTAL TLC - iVlobe TOTAL FRC)
IALD RML = 100 * (iVlobe RML TLC - iVlobe RML FRC) / (iVlobe TOTAL TLC - iVlobe TOTAL FRC)
IALD RUL = 100 * (iVlobe RUL TLC - iVlobe RUL FRC) / (iVlobe TOTAL TLC - iVlobe TOTAL FRC)
IALD RLL = 100 * (iVlobe RLL TLC - iVlobe RLL FRC) / (iVlobe TOTAL TLC - iVlobe TOTAL FRC)
IALD LL = IALD RLL + IALD LLL
IALD UL = IALD RUL + IALD RML + IALD LUL
Lung Function Parameters
Lung Function Parameters Calculated by GSK

FEV1 % Predicted (Men) = 4.30*Height – 0.029*Age – 2.49

FEV1 % Predicted (Women) = 3.95*Height – 0.025*Age – 2.60
Formulas have been taken from Quanjer, 1993 Lung volumes and forced ventilator flows [accessed: 23rd 
July 2015] where height is measured in metres and age in years at screening.
Rescue Medication Endpoints
Number of occasions bronchodilator taken in the last 24 per hours 4-week period derived by GSK

Number of occasions bronchodilator taken in the last 24 hours were collected in the daily diary

The table below shows which daily diary records are used to calculate the daily diary endpoints for 
each analysis time period. Any diary data collected in the post-treatment phase of the study will not 
be slotted.
Daily Record
Analysis Time Period
Beginning Timepoint 
(day)
Ending Timepoint
(day)
1
28
Weeks 1 – 4
29
56
Weeks 5 – 8
57
84
Weeks 9 – 12
Note: There is no Day 0. Any records with actual day>84 will not be assigned to a time period. Any records with actual 
day<0 may be assigned to a Week -1 (Baseline) time period
Note: Daily diary records that were not assigned to a time period will not be used in calculation of daily diary endpoints.

For a subject to be counted in any time period for a given endpoint they must have at 
least one diary entry recorded for that endpoint during that time period.

Any daily diary data that were collected post-study treatment discontinuation will be 
excluded from analysis, including four weekly period data summaries.

If a subject has more than one daily diary record for any given day, the worst-case
 
 
 
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Rescue Medication Endpoints
response on that day for each endpoint will be used in the summaries and analyses. i.e. 
the maximum number of occasions of bronchodilator use reported will be counted for 
the day in question and used to determine if it was a rescue-free day

The mean number of occasions of rescue use per day and percentage of rescue-free 
days, will be calculated for each subject during the four weekly periods defined above.
13.6.4.
Safety
ECG Parameters
RR Interval

IF RR interval (msec) is not provided directly, then RR can be derived as:
[1]
If QTcB is machine read & QTcF is not provided, then:
[2]
If QTcF is machine read and QTcB is not provided, then: 

If ECGs are manually read, the RR value preceding the measurement QT interval should be a collected value then 
do not derive.
Corrected QT Intervals

When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and Fridericia’s (QTcF) formulas 
will be calculated, in msec, depending on the availability of other measurements.

IF RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as:
13.6.5.
Pharmacodynamic and Biomarker
Biomarker Category
Analyte
Method
Lab
Matrix
Total samples
InflammatoryCytokine
IL-8
MSD
Quest
Sputum
4
IL-6
MSD
Quest
Sputum
4
TNF
MSD
Quest
Sputum
4
Microbiome
Bacterial DNA
16SRNA
GSK-RTP
Sputum
4
Bacterial DNA
qPCR
GSK-RTP
Sputum
4
Viral DNA
qPCR
GSK-RTP
Sputum
4
Transcriptomics
Human RNA
Affymetrix
Expression 
Analysis
Blood
4
NOTES:

Sampling times: Screening, day 12, day 28 and day 84

Inflammatory cytokine biomarkers are elevated in COPD patients. Expected to reduce with treatment.

Microbiome biomarkers are drivers of exacerbations in COPD and are inhibited in preclinical disease studies

PI3Ktranscriptome analysis in FTIH study has 16 genes identified (sputum) showing a consistent response with 
dose – all are down regulated.
 
 
 
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Pharmacodynamic and Biomarker
Pharmacodynamic
PMNs Differentials

Percentage data may be arc-sine transformed especially if many of the percentage values are smaller than 20% or 
larger than 80%. The response variable, y, measured in radians, is sin-1sqrt{0.01*p} where p is the differential 
percentage.

If transformations are used then the results will be reported on the back-transformed scale, except where a 
transformed value:
o
exceeds 0.01*p/2 then the back-transformed value will be set equal to 100% 
o
is less than 0 then the back-transformed value will be set equal to 0%. 
Biomarkers 
Inflammatory Cytokines

In general, it is assumed that biomarker endpoints will require variance stabilising transformations, such as taking a 
loge transformation prior to analysis (and that summary statistics appropriate to loge normally distributed data will 
apply for all summaries). However, this assumption will be considered for each endpoint Individually prior to the 
generation of summary tables or statistical analysis, and if deemed more appropriate, a loge transformation will not 
be applied, or non-parametric methods may be employed.

If transformations are used, then the results will be reported on the back-transformed scale unless otherwise 
stated.
RNA transcriptome

Affymetrix microarray mRNA data will be normalised using RMA in ARRAY STUDIO v8.0 or later by the Statistical 
Consultancy Group (SCG) within GSK. After normalisation, the data will be quality assessed and any samples 
deemed as QC fails will be excluded from any further analysis. This quality assessment will involve looking for 
outlying signals in both the normalised expression data and the MAS5 QC metrics generated from each sample. If 
any samples are excluded, the remaining data will be re-normalised. The output from the normalization will be log2 
transformed mRNA intensity data.

Summary mRNA data will be reviewed and a decision made on which probe sets are to be included in the SI 
dataset.

Treatment ratios from the statistical analyses of mRNA intensity data will be converted to fold changes as follows:
o
If ratio 1 then fold change = ratio
o
If ratio < 1 then fold change = -1/ratio
The primary pharmacodynamic endpoint is based on a subset of probe sets defined as 
those that have previously identified immune cell mechanisms specifically related to 
neutrophil function.
The gene list that meets this criterion based on PII115119 D14 vs D1 gene changes, 
PII115117 and Metacore neutrophil pathways identified in PII115119 study. This gene 
list identified 258 genes in total after filtering for redundancy and was agreed by the 
study team is presented in Table 3. 
 
 
 
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Table 3
Gene List that have previously identified immune cell mechanisms 
specifically related to neutrophil function
Gene 
Source
Gene 
Source
CD177
PII115119 - Neutrophil migration
ITGAL
Metacore: IL8 Neutrophil migration
CXCR1
PII115119 - Neutrophil migration
ADAM17
Metacore: Inhibition of neutrophil migration
CXCR2
PII115119 - Neutrophil migration
C5
Metacore: Inhibition of neutrophil migration
FPR2
PII115119 - Neutrophil migration
C5AR1
Metacore: Inhibition of neutrophil migration
LTB4R
PII115119 - Neutrophil migration
CCR5
Metacore: Inhibition of neutrophil migration
PAK1
PII115119 - Neutrophil migration
CD34
Metacore: Inhibition of neutrophil migration
PXN
PII115119 - Neutrophil migration
CALM1
Metacore: Inhibition of neutrophil migration
PREX1
PII115119 - Neutrophil migration
CALM2
Metacore: Inhibition of neutrophil migration
TLN1
PII115119 - Neutrophil migration
CALM3
Metacore: Inhibition of neutrophil migration
SSH2
PII115119 - Neutrophil migration
FPR1
Metacore: Inhibition of neutrophil migration
F2RL1 
PII115119 - Neutrophil infection response ICAM2
Metacore: Inhibition of neutrophil migration
TLR10
PII115119 - Neutrophil infection response IL1B
Metacore: Inhibition of neutrophil migration
CEACAM3
PII115119 - Neutrophil infection response IL1R1
Metacore: Inhibition of neutrophil migration
TREML2
PII115119 - Neutrophil infection response ITPR1
Metacore: Inhibition of neutrophil migration
DEFB124
PII115119 - Neutrophil infection response ITPR2
Metacore: Inhibition of neutrophil migration
CLEC4C
PII115119 - Neutrophil infection response ITPR3
Metacore: Inhibition of neutrophil migration
IFITM1
PII115119 - Neutrophil infection response SELL
Metacore: Inhibition of neutrophil migration
CR1
PII115119 - Neutrophil infection response MSN
Metacore: Inhibition of neutrophil migration
PMAIP1
FTIH - GSK'557 response
NFKB1
Metacore: Inhibition of neutrophil migration
S100P
FTIH - GSK'557 response
NFKB2
Metacore: Inhibition of neutrophil migration
PTGS2
FTIH - GSK'557 response
REL
Metacore: Inhibition of neutrophil migration
CCL20
FTIH - GSK'557 response
RELA
Metacore: Inhibition of neutrophil migration
EGR3
FTIH - GSK'557 response
RELB
Metacore: Inhibition of neutrophil migration
H1F0
FTIH - GSK'557 response
PECAM1
Metacore: Inhibition of neutrophil migration
NCOA3
FTIH - GSK'557 response
PRKCA
Metacore: Inhibition of neutrophil migration
TARP
FTIH - GSK'557 response
PRKCB
Metacore: Inhibition of neutrophil migration
CEACAM1
FTIH - GSK'557 response
PRKCD
Metacore: Inhibition of neutrophil migration
TTPAL
FTIH - GSK'557 response
PRKCE
Metacore: Inhibition of neutrophil migration
VPS37B
FTIH - GSK'557 response
PRKCG
Metacore: Inhibition of neutrophil migration
SYAP1
FTIH - GSK'557 response
PRKCH
Metacore: Inhibition of neutrophil migration
SPTBN1
FTIH - GSK'557 response
PRKCI
Metacore: Inhibition of neutrophil migration
EGR1
FTIH - GSK'557 response
PRKCQ
Metacore: Inhibition of neutrophil migration
OSM
FTIH - GSK'557 response
PRKD1
Metacore: Inhibition of neutrophil migration
TBC1D22A FTIH - GSK'557 response
PRKD2
Metacore: Inhibition of neutrophil migration
AKT1
Metacore: IL8 Neutrophil migration
PRKD3
Metacore: Inhibition of neutrophil migration
AKT2
Metacore: IL8 Neutrophil migration
PLCB2
Metacore: Inhibition of neutrophil migration
AKT3
Metacore: IL8 Neutrophil migration
PTAFR
Metacore: Inhibition of neutrophil migration
ACTA1
Metacore: IL8 Neutrophil migration
TLR2
Metacore: Inhibition of neutrophil migration
ACTA2
Metacore: IL8 Neutrophil migration
TLR4
Metacore: Inhibition of neutrophil migration
 
 
 
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Gene 
Source
Gene 
Source
ACTB
Metacore: IL8 Neutrophil migration
TNFRSF1A Metacore: Inhibition of neutrophil migration
ACTC1
Metacore: IL8 Neutrophil migration
TNFRSF1B Metacore: Inhibition of neutrophil migration
ACTG1
Metacore: IL8 Neutrophil migration
TNF
Metacore: Inhibition of neutrophil migration
ACTG2
Metacore: IL8 Neutrophil migration
VAV1
Metacore: Inhibition of neutrophil migration
MYH1
Metacore: IL8 Neutrophil migration
EZR
Metacore: Inhibition of neutrophil migration
MYH10
Metacore: IL8 Neutrophil migration
VCL
Metacore: Inhibition of neutrophil migration
MYH11
Metacore: IL8 Neutrophil migration
ITGAM
Metacore: Inhibition of neutrophil migration
MYH13
Metacore: IL8 Neutrophil migration
ABL1
Metacore: Inhibition of neutrophil migration
MYH14
Metacore: IL8 Neutrophil migration
JUN
Metacore: Inhibition of neutrophil migration
MYH15
Metacore: IL8 Neutrophil migration
FOS
Metacore: Inhibition of neutrophil migration
MYH16
Metacore: IL8 Neutrophil migration
MAPK11
Metacore: Inhibition of neutrophil migration
MYH2
Metacore: IL8 Neutrophil migration
MAPK12
Metacore: Inhibition of neutrophil migration
MYH3
Metacore: IL8 Neutrophil migration
MAPK13
Metacore: Inhibition of neutrophil migration
MYH4
Metacore: IL8 Neutrophil migration
MAPK14
Metacore: Inhibition of neutrophil migration
MYH6
Metacore: IL8 Neutrophil migration
BDKRB1
Metacore: Neutrophil migration in Asthma
MYH7
Metacore: IL8 Neutrophil migration
CCL15
Metacore: Neutrophil migration in Asthma
MYH8
Metacore: IL8 Neutrophil migration
CCL2
Metacore: Neutrophil migration in Asthma
MYH9
Metacore: IL8 Neutrophil migration
CCL5
Metacore: Neutrophil migration in Asthma
MYL1
Metacore: IL8 Neutrophil migration
CCL7
Metacore: Neutrophil migration in Asthma
MYL12A
Metacore: IL8 Neutrophil migration
CCR1
Metacore: Neutrophil migration in Asthma
MYL12B
Metacore: IL8 Neutrophil migration
CCR2
Metacore: Neutrophil migration in Asthma
MYL2
Metacore: IL8 Neutrophil migration
CCR3
Metacore: Neutrophil migration in Asthma
MYL3
Metacore: IL8 Neutrophil migration
CXCL5
Metacore: Neutrophil migration in Asthma
MYL4
Metacore: IL8 Neutrophil migration
CXCL1
Metacore: Neutrophil migration in Asthma
MYL5
Metacore: IL8 Neutrophil migration
CXCL2
Metacore: Neutrophil migration in Asthma
MYL6
Metacore: IL8 Neutrophil migration
CXCL3
Metacore: Neutrophil migration in Asthma
MYL6B
Metacore: IL8 Neutrophil migration
HSPA14
Metacore: Neutrophil migration in Asthma
MYL7
Metacore: IL8 Neutrophil migration
HSPA1A
Metacore: Neutrophil migration in Asthma
MYL9
Metacore: IL8 Neutrophil migration
HSPA1B
Metacore: Neutrophil migration in Asthma
MYLPF
Metacore: IL8 Neutrophil migration
HSPA1L
Metacore: Neutrophil migration in Asthma
ACTN1
Metacore: IL8 Neutrophil migration
HSPA2
Metacore: Neutrophil migration in Asthma
ACTN2
Metacore: IL8 Neutrophil migration
HSPA4
Metacore: Neutrophil migration in Asthma
ACTN3
Metacore: IL8 Neutrophil migration
HSPA5
Metacore: Neutrophil migration in Asthma
ACTN4
Metacore: IL8 Neutrophil migration
HSPA6
Metacore: Neutrophil migration in Asthma
ACTR2
Metacore: IL8 Neutrophil migration
HSPA7
Metacore: Neutrophil migration in Asthma
ACTR3
Metacore: IL8 Neutrophil migration
HSPA8
Metacore: Neutrophil migration in Asthma
ACTR3B
Metacore: IL8 Neutrophil migration
HSPA9
Metacore: Neutrophil migration in Asthma
ARPC1A
Metacore: IL8 Neutrophil migration
MIF
Metacore: Neutrophil migration in Asthma
ARPC1B
Metacore: IL8 Neutrophil migration
CCL3
Metacore: Neutrophil migration in Asthma
ARPC2
Metacore: IL8 Neutrophil migration
PGF
Metacore: Neutrophil migration in Asthma
ARPC3
Metacore: IL8 Neutrophil migration
TAC1
Metacore: Neutrophil migration in Asthma
 
 
 
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Gene 
Source
Gene 
Source
ARPC4
Metacore: IL8 Neutrophil migration
TACR1
Metacore: Neutrophil migration in Asthma
ARPC5
Metacore: IL8 Neutrophil migration
KLK1
Metacore: Neutrophil migration in Asthma
CFL1
Metacore: IL8 Neutrophil migration
KLK10
Metacore: Neutrophil migration in Asthma
CFL2
Metacore: IL8 Neutrophil migration
KLK11
Metacore: Neutrophil migration in Asthma
MAPK1
Metacore: IL8 Neutrophil migration
KLK12
Metacore: Neutrophil migration in Asthma
MAPK3
Metacore: IL8 Neutrophil migration
KLK13
Metacore: Neutrophil migration in Asthma
GNAI1
Metacore: IL8 Neutrophil migration
KLK14
Metacore: Neutrophil migration in Asthma
GNAI2
Metacore: IL8 Neutrophil migration
KLK15
Metacore: Neutrophil migration in Asthma
GNAI3
Metacore: IL8 Neutrophil migration
KLK2
Metacore: Neutrophil migration in Asthma
GNAO1
Metacore: IL8 Neutrophil migration
KLK3
Metacore: Neutrophil migration in Asthma
GNAZ
Metacore: IL8 Neutrophil migration
KLK4
Metacore: Neutrophil migration in Asthma
GNB1
Metacore: IL8 Neutrophil migration
KLK5
Metacore: Neutrophil migration in Asthma
GNB2
Metacore: IL8 Neutrophil migration
KLK6
Metacore: Neutrophil migration in Asthma
GNB3
Metacore: IL8 Neutrophil migration
KLK7
Metacore: Neutrophil migration in Asthma
GNB4
Metacore: IL8 Neutrophil migration
KLK8
Metacore: Neutrophil migration in Asthma
GNB5
Metacore: IL8 Neutrophil migration
KLK9
Metacore: Neutrophil migration in Asthma
GNG10
Metacore: IL8 Neutrophil migration
FLT1
Metacore: Neutrophil migration in Asthma
GNG11
Metacore: IL8 Neutrophil migration
RUNX1
Metacore: Transcription regulation of granulocytes
GNG12
Metacore: IL8 Neutrophil migration
CEBPA
Metacore: Transcription regulation of granulocytes
GNG13
Metacore: IL8 Neutrophil migration
CEBPE
Metacore: Transcription regulation of granulocytes
GNG2
Metacore: IL8 Neutrophil migration
ANPEP
Metacore: Transcription regulation of granulocytes
GNG3
Metacore: IL8 Neutrophil migration
PTPRC
Metacore: Transcription regulation of granulocytes
GNG4
Metacore: IL8 Neutrophil migration
E2F1
Metacore: Transcription regulation of granulocytes
GNG5
Metacore: IL8 Neutrophil migration
CSF3
Metacore: Transcription regulation of granulocytes
GNG7
Metacore: IL8 Neutrophil migration
CSF3R
Metacore: Transcription regulation of granulocytes
GNG8
Metacore: IL8 Neutrophil migration
GATA1
Metacore: Transcription regulation of granulocytes
GNGT1
Metacore: IL8 Neutrophil migration
JAK1
Metacore: Transcription regulation of granulocytes
GNGT2
Metacore: IL8 Neutrophil migration
JAK2
Metacore: Transcription regulation of granulocytes
ICAM1
Metacore: IL8 Neutrophil migration
LRG1
Metacore: Transcription regulation of granulocytes
CXCL8
Metacore: IL8 Neutrophil migration
LTF
Metacore: Transcription regulation of granulocytes
ITGB2
Metacore: IL8 Neutrophil migration
ELANE
Metacore: Transcription regulation of granulocytes
LIMK1
Metacore: IL8 Neutrophil migration
LYZ
Metacore: Transcription regulation of granulocytes
MYLK
Metacore: IL8 Neutrophil migration
MXD1
Metacore: Transcription regulation of granulocytes
MYLK2
Metacore: IL8 Neutrophil migration
MAX
Metacore: Transcription regulation of granulocytes
MYLK3
Metacore: IL8 Neutrophil migration
PRTN3
Metacore: Transcription regulation of granulocytes
PPP1CB
Metacore: IL8 Neutrophil migration
MPO
Metacore: Transcription regulation of granulocytes
PPP1R12A Metacore: IL8 Neutrophil migration
SPI1
Metacore: Transcription regulation of granulocytes
PDPK1
Metacore: IL8 Neutrophil migration
RARA
Metacore: Transcription regulation of granulocytes
PIK3CG
Metacore: IL8 Neutrophil migration
RXRA
Metacore: Transcription regulation of granulocytes
PIK3R5
Metacore: IL8 Neutrophil migration
SOCS3
Metacore: Transcription regulation of granulocytes
PIP5K1A
Metacore: IL8 Neutrophil migration
STAT3
Metacore: Transcription regulation of granulocytes
 
 
 
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Gene 
Source
Gene 
Source
PIP5K1B
Metacore: IL8 Neutrophil migration
STAT5A
Metacore: Transcription regulation of granulocytes
PIP5K1C
Metacore: IL8 Neutrophil migration
STAT5B
Metacore: Transcription regulation of granulocytes
PRKCZ
Metacore: IL8 Neutrophil migration
FES
Metacore: Transcription regulation of granulocytes
PLD1
Metacore: IL8 Neutrophil migration
MYB
Metacore: Transcription regulation of granulocytes
PLPP6
Metacore: IL8 Neutrophil migration
MYC
Metacore: Transcription regulation of granulocytes
RAC1
Metacore: IL8 Neutrophil migration
CYBB
Metacore: Transcription regulation of granulocytes
RAC2
Metacore: IL8 Neutrophil migration
NCF1
Metacore: Transcription regulation of granulocytes
TLN2
Metacore: IL8 Neutrophil migration
NCF2
Metacore: Transcription regulation of granulocytes
Gene names converted to Affymetrix probe ID, resulted in 638 probes in total, these are 
presented in Table 4. 
Table 4
Probe Set that have previously identified immune cell mechanisms 
specifically related to neutrophil function
Gene
Probe ID
Gene
Probe ID
ABL1
202123_s_at
KLK7
239381_at
ACTA1
203872_at
KLK8
1552319_a_at
ACTA2
200974_at
KLK8
206125_s_at
ACTA2
215787_at
KLK9
233687_s_at
ACTA2
243140_at
LIMK1
204356_at
ACTB
200801_x_at
LIMK1
204357_s_at
ACTB
213867_x_at
LIMK1
208372_s_at
ACTB
224594_x_at
LRG1
228648_at
ACTB
AFFX-HSAC07/X00351_3_at
LTB4R
210128_s_at
ACTB
AFFX-HSAC07/X00351_5_at
LTB4R
216388_s_at
ACTB
AFFX-HSAC07/X00351_M_at
LTB4R
236172_at
ACTC1
205132_at
LTF
202018_s_at
ACTG1
201550_x_at
LYZ
1555745_a_at
ACTG1
211970_x_at
LYZ
213975_s_at
ACTG1
211983_x_at
MAPK1
1552263_at
ACTG1
211995_x_at
MAPK1
1552264_a_at
ACTG1
212363_x_at
MAPK1
208351_s_at
ACTG1
212988_x_at
MAPK1
212271_at
ACTG1
213214_x_at
MAPK1
224620_at
ACTG1
221607_x_at
MAPK1
224621_at
ACTG1
224585_x_at
MAPK1
229847_at
ACTG2
202274_at
MAPK11
206040_s_at
ACTG2
241148_at
MAPK11
211499_s_at
ACTN1
208636_at
MAPK11
211500_at
ACTN1
208637_x_at
MAPK12
1556340_at
ACTN1
211160_x_at
MAPK12
1556341_s_at
ACTN1
237401_at
MAPK12
206106_at
ACTN2
203861_s_at
MAPK13
210058_at
ACTN2
203862_s_at
MAPK13
210059_s_at
ACTN2
203863_at
MAPK14
202530_at
ACTN2
203864_s_at
MAPK14
210449_x_at
ACTN3
206891_at
MAPK14
211087_x_at
ACTN4
200601_at
MAPK14
211561_x_at
ACTR2
1554390_s_at
MAPK3
212046_x_at
 
 
 
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Gene
Probe ID
Gene
Probe ID
ACTR2
1558015_s_at
MAX
208403_x_at
ACTR2
200727_s_at
MAX
209331_s_at
ACTR2
200728_at
MAX
209332_s_at
ACTR2
200729_s_at
MAX
210734_x_at
ACTR2
234210_x_at
MAX
214108_at
ACTR2
234212_at
MIF
217871_s_at
ACTR3
200996_at
MPO
203948_s_at
ACTR3
213101_s_at
MPO
203949_at
ACTR3
213102_at
MSN
200600_at
ACTR3
228603_at
MSN
233749_at
ACTR3
239170_at
MXD1
206877_at
ACTR3B
1555487_a_at
MXD1
226275_at
ACTR3B
218868_at
MXD1
228846_at
ADAM17
205745_x_at
MYB
204798_at
ADAM17
205746_s_at
MYB
215152_at
ADAM17
213532_at
MYC
202431_s_at
ADAM17
237897_at
MYH1
205951_at
AKT1
207163_s_at
MYH10
212372_at
AKT2
1560689_s_at
MYH10
213067_at
AKT2
203808_at
MYH11
1568760_at
AKT2
203809_s_at
MYH11
201495_x_at
AKT2
211453_s_at
MYH11
201496_x_at
AKT2
225471_s_at
MYH11
201497_x_at
AKT2
226156_at
MYH11
207961_x_at
AKT2
236664_at
MYH11
228133_s_at
AKT3
212607_at
MYH11
228134_at
AKT3
212609_s_at
MYH11
239307_at
AKT3
219393_s_at
MYH13
208208_at
AKT3
222880_at
MYH14
217545_at
AKT3
224229_s_at
MYH14
217660_at
AKT3
242876_at
MYH14
219946_x_at
AKT3
242879_x_at
MYH14
226988_s_at
ANPEP
202888_s_at
MYH14
232977_x_at
ANPEP
234458_at
MYH14
234290_x_at
ANPEP
234576_at
MYH15
215331_at
ARPC1A
200950_at
MYH16
1564072_at
ARPC1B
201954_at
MYH2
204631_at
ARPC2
207988_s_at
MYH3
205940_at
ARPC2
208679_s_at
MYH4
208148_at
ARPC2
213513_x_at
MYH6
214468_at
ARPC3
208736_at
MYH7
204737_s_at
ARPC4
211672_s_at
MYH7
216265_x_at
ARPC4
217817_at
MYH8
206717_at
ARPC4
217818_s_at
MYH8
34471_at
ARPC5
1555797_a_at
MYH9
211926_s_at
ARPC5
1569325_at
MYL1
209888_s_at
ARPC5
211963_s_at
MYL12A
1555976_s_at
ARPC5
237387_at
MYL12A
1555977_at
BDKRB1
207510_at
MYL12A
1555978_s_at
C5
205500_at
MYL12A
201318_s_at
C5AR1
220088_at
MYL12A
201319_at
CCL15
210390_s_at
MYL12B
221474_at
CCL2
216598_s_at
MYL2
209742_s_at
CCL20
205476_at
MYL3
205589_at
 
 
 
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Gene
Probe ID
Gene
Probe ID
CCL3
205114_s_at
MYL4
210088_x_at
CCL5
1405_i_at
MYL4
210395_x_at
CCL5
1555759_a_at
MYL4
216054_x_at
CCL5
204655_at
MYL4
217274_x_at
CCL7
208075_s_at
MYL5
205145_s_at
CCR1
205098_at
MYL6
212082_s_at
CCR1
205099_s_at
MYL6
214002_at
CCR2
206978_at
MYL6B
204173_at
CCR2
207794_at
MYL7
219942_at
CCR3
208304_at
MYL9
201058_s_at
CCR5
206991_s_at
MYL9
244149_at
CD177
219669_at
MYLK
1563466_at
CD34
209543_s_at
MYLK
1568770_at
CEACAM1
206576_s_at
MYLK
1569956_at
CEACAM1
209498_at
MYLK
202555_s_at
CEACAM1
210610_at
MYLK
224823_at
CEACAM1
211883_x_at
MYLK2
231792_at
CEACAM1
211889_x_at
MYLK3
1562411_at
CEACAM3
208052_x_at
MYLK3
1568925_at
CEACAM3
210789_x_at
MYLK3
1568926_x_at
CEACAM3
217209_at
MYLK3
217623_at
CEBPA
204039_at
MYLK3
238834_at
CEBPE
214523_at
MYLPF
205163_at
CFL1
1555730_a_at
NCF1
204961_s_at
CFL1
200021_at
NCF1
214084_x_at
CFL1
230870_at
NCF2
209949_at
CFL1
236792_at
NCOA3
1562439_at
CFL2
224352_s_at
NCOA3
207700_s_at
CFL2
224663_s_at
NCOA3
209060_x_at
CFL2
233496_s_at
NCOA3
209061_at
CLEC4C
1552552_s_at
NCOA3
209062_x_at
CLEC4C
1555687_a_at
NCOA3
211352_s_at
CR1
206244_at
NFKB1
209239_at
CR1
208488_s_at
NFKB2
207535_s_at
CR1
217484_at
NFKB2
209636_at
CR1
217552_x_at
NFKB2
211524_at
CR1
244313_at
OSM
214637_at
CSF3
207442_at
OSM
230170_at
CSF3R
1553297_a_at
PAK1
1565772_at
CSF3R
203591_s_at
PAK1
209615_s_at
CXCL1
204470_at
PAK1
226507_at
CXCL2
1569203_at
PAK1
230100_x_at
CXCL2
209774_x_at
PDPK1
204524_at
CXCL2
230101_at
PDPK1
221244_s_at
CXCL3
207850_at
PDPK1
224986_s_at
CXCL5
207852_at
PDPK1
244629_s_at
CXCL5
214974_x_at
PDPK1
244630_at
CXCL5
215101_s_at
PDPK1
32029_at
CXCL8
202859_x_at
PECAM1
1558397_at
CXCL8
211506_s_at
PECAM1
1559921_at
CXCR1
207094_at
PECAM1
208981_at
CXCR2
207008_at
PECAM1
208982_at
CYBB
203922_s_at
PECAM1
208983_s_at
CYBB
203923_s_at
PGF
209652_s_at
 
 
 
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Gene
Probe ID
Gene
Probe ID
CYBB
217431_x_at
PGF
215179_x_at
CYBB
233538_s_at
PIK3CG
206369_s_at
DEFB124
1568375_at
PIK3CG
206370_at
DEFB124
1568377_x_at
PIK3CG
239294_at
E2F1
2028_s_at
PIK3R5
220566_at
E2F1
204947_at
PIK3R5
227553_at
EGR1
201693_s_at
PIK3R5
227645_at
EGR1
201694_s_at
PIP5K1A
207391_s_at
EGR1
227404_s_at
PIP5K1A
210256_s_at
EGR3
206115_at
PIP5K1A
211205_x_at
ELANE
206871_at
PIP5K1B
205632_s_at
EZR
208621_s_at
PIP5K1B
217477_at
EZR
208622_s_at
PIP5K1C
212518_at
EZR
208623_s_at
PLCB2
204046_at
EZR
217230_at
PLCB2
210388_at
EZR
217234_s_at
PLD1
1557126_a_at
FES
205418_at
PLD1
177_at
FLT1
204406_at
PLD1
205203_at
FLT1
210287_s_at
PLD1
215723_s_at
FLT1
222033_s_at
PLD1
215724_at
FLT1
226497_s_at
PLD1
226636_at
FLT1
226498_at
PLD1
232530_at
FLT1
232809_s_at
PLPP6
227385_at
FOS
209189_at
PMAIP1
204285_s_at
FPR1
205118_at
PMAIP1
204286_s_at
FPR1
205119_s_at
PPP1CB
201407_s_at
FPR2
210772_at
PPP1CB
201408_at
FPR2
210773_s_at
PPP1CB
201409_s_at
GATA1
1555590_a_at
PPP1CB
228222_at
GATA1
210446_at
PPP1R12A
201602_s_at
GNAI1
209576_at
PPP1R12A
201603_at
GNAI1
227692_at
PPP1R12A
201604_s_at
GNAI2
201040_at
PREX1
224909_s_at
GNAI2
215996_at
PREX1
224925_at
GNAI2
217271_at
PRKCA
1560074_at
GNAI3
201179_s_at
PRKCA
206923_at
GNAI3
201180_s_at
PRKCA
213093_at
GNAI3
201181_at
PRKCA
215194_at
GNAO1
204762_s_at
PRKCA
215195_at
GNAO1
204763_s_at
PRKCB
207957_s_at
GNAO1
215912_at
PRKCB
209685_s_at
GNAO1
231951_at
PRKCB
227817_at
GNAZ
204993_at
PRKCB
227824_at
GNB1
200744_s_at
PRKCB
228795_at
GNB1
200745_s_at
PRKCB
230437_s_at
GNB1
200746_s_at
PRKCD
202545_at
GNB2
200852_x_at
PRKCE
206248_at
GNB3
206047_at
PRKCE
226101_at
GNB4
223487_x_at
PRKCE
234089_at
GNB4
223488_s_at
PRKCE
236459_at
GNB4
225710_at
PRKCE
239011_at
GNB5
1554346_at
PRKCG
206270_at
GNB5
204000_at
PRKCG
236195_x_at
GNB5
207124_s_at
PRKCH
206099_at
 
 
 
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Gene
Probe ID
Gene
Probe ID
GNB5
211871_x_at
PRKCH
218764_at
GNB5
242404_at
PRKCH
230124_at
GNG10
201921_at
PRKCI
209677_at
GNG11
204115_at
PRKCI
209678_s_at
GNG11
239942_at
PRKCI
213518_at
GNG12
1555240_s_at
PRKCQ
210038_at
GNG12
212294_at
PRKCQ
210039_s_at
GNG12
222834_s_at
PRKCZ
1569748_at
GNG13
220806_x_at
PRKCZ
202178_at
GNG2
1555766_a_at
PRKD1
205880_at
GNG2
223943_s_at
PRKD1
217705_at
GNG2
224964_s_at
PRKD2
209282_at
GNG2
224965_at
PRKD2
241669_x_at
GNG3
222005_s_at
PRKD2
38269_at
GNG4
1555765_a_at
PRKD3
1554910_at
GNG4
1555867_at
PRKD3
211084_x_at
GNG4
1566513_a_at
PRKD3
218236_s_at
GNG4
205184_at
PRKD3
222565_s_at
GNG5
207157_s_at
PRKD3
242549_at
GNG7
206896_s_at
PRTN3
207341_at
GNG7
214227_at
PTAFR
206278_at
GNG7
228831_s_at
PTAFR
211661_x_at
GNG7
232043_at
PTAFR
227184_at
GNG8
233416_at
PTGS2
1554997_a_at
GNG8
234284_at
PTGS2
204748_at
GNGT1
207166_at
PTPRC
1552480_s_at
GNGT2
235139_at
PTPRC
1569830_at
H1F0
208886_at
PTPRC
207238_s_at
HSPA14
219212_at
PTPRC
212587_s_at
HSPA14
226887_at
PTPRC
212588_at
HSPA14
227650_at
PXN
201087_at
HSPA1L
210189_at
PXN
211823_s_at
HSPA1L
233694_at
RAC1
1567457_at
HSPA2
211538_s_at
RAC1
1567458_s_at
HSPA4
208814_at
RAC1
208640_at
HSPA4
208815_x_at
RAC1
208641_s_at
HSPA4
211015_s_at
RAC2
207419_s_at
HSPA4
211016_x_at
RAC2
213603_s_at
HSPA5
211936_at
RARA
1565358_at
HSPA5
230031_at
RARA
203749_s_at
HSPA6
117_at
RARA
203750_s_at
HSPA6
213418_at
RARA
211605_s_at
HSPA8
208687_x_at
RARA
216300_x_at
HSPA8
210338_s_at
REL
206035_at
HSPA8
221891_x_at
REL
206036_s_at
HSPA8
224187_x_at
REL
228812_at
HSPA9
200690_at
REL
235242_at
HSPA9
200691_s_at
REL
239486_at
HSPA9
200692_s_at
RELA
201783_s_at
HSPA9
232200_at
RELA
209878_s_at
ICAM1
202637_s_at
RELA
230202_at
ICAM1
202638_s_at
RELB
205205_at
ICAM1
215485_s_at
RXRA
202426_s_at
ICAM2
204683_at
RXRA
202449_s_at
 
 
 
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Gene
Probe ID
Gene
Probe ID
ICAM2
213620_s_at
S100P
204351_at
IFITM1
201601_x_at
SELL
204563_at
IFITM1
214022_s_at
SOCS3
206359_at
IL1B
205067_at
SOCS3
206360_s_at
IL1B
39402_at
SOCS3
214105_at
IL1R1
202948_at
SOCS3
227697_at
IL1R1
215561_s_at
SPI1
205312_at
ITGAL
1554240_a_at
SPTBN1
200671_s_at
ITGAL
213475_s_at
SPTBN1
200672_x_at
ITGAM
205785_at
SPTBN1
212071_s_at
ITGAM
205786_s_at
SPTBN1
213914_s_at
ITGB2
1555349_a_at
SPTBN1
214856_at
ITGB2
202803_s_at
SPTBN1
215918_s_at
ITGB2
236988_x_at
SPTBN1
226342_at
ITPR1
1562373_at
SPTBN1
226765_at
ITPR1
203710_at
SPTBN1
228246_s_at
ITPR1
211323_s_at
SPTBN1
230540_at
ITPR1
216944_s_at
SPTBN1
242220_at
ITPR1
240052_at
SSH2
1554114_s_at
ITPR2
202660_at
SSH2
1555423_at
ITPR2
202661_at
SSH2
1555425_x_at
ITPR2
202662_s_at
SSH2
1560306_at
ITPR2
211360_s_at
SSH2
226080_at
ITPR3
201187_s_at
STAT3
208991_at
ITPR3
201188_s_at
STAT3
208992_s_at
ITPR3
201189_s_at
STAT3
225289_at
ITPR3
239542_at
STAT3
243213_at
JAK1
1552610_a_at
STAT5A
203010_at
JAK1
1552611_a_at
STAT5B
1555086_at
JAK1
201648_at
STAT5B
1555088_x_at
JAK1
239695_at
STAT5B
205026_at
JAK1
240613_at
STAT5B
212549_at
JAK2
1562031_at
STAT5B
212550_at
JAK2
205841_at
SYAP1
225154_at
JAK2
205842_s_at
TAC1
206552_s_at
JUN
201464_x_at
TACR1
208048_at
JUN
201465_s_at
TACR1
208049_s_at
JUN
201466_s_at
TACR1
210637_at
JUN
213281_at
TACR1
230908_at
KLK1
216699_s_at
TARP
211144_x_at
KLK10
209792_s_at
TARP
216920_s_at
KLK10
215808_at
TARP
217381_s_at
KLK11
205470_s_at
TBC1D22A
209650_s_at
KLK12
220782_x_at
TBC1D22A
210144_at
KLK12
233586_s_at
TBC1D22A
33778_at
KLK12
234316_x_at
TLN1
203254_s_at
KLK13
205783_at
TLN1
232763_at
KLK13
216670_at
TLN1
236132_at
KLK13
217315_s_at
TLN2
212701_at
KLK14
220573_at
TLN2
212703_at
KLK15
221462_x_at
TLN2
232625_at
KLK15
233477_at
TLR10
223750_s_at
KLK15
234495_at
TLR10
223751_x_at
KLK15
234966_at
TLR2
204924_at
 
 
 
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Gene
Probe ID
Gene
Probe ID
KLK2
1555545_at
TLR4
1552798_a_at
KLK2
209854_s_at
TLR4
221060_s_at
KLK2
209855_s_at
TLR4
224341_x_at
KLK2
210339_s_at
TLR4
232068_s_at
KLK3
204582_s_at
TNF
1563357_at
KLK3
204583_x_at
TNF
207113_s_at
KLK3
231629_x_at
TNFRSF1A
207643_s_at
KLK4
1555697_at
TNFRSF1B
203508_at
KLK4
1555737_a_at
TREML2
219748_at
KLK4
224062_x_at
TTPAL
219633_at
KLK4
231782_s_at
TTPAL
228031_at
KLK4
233854_x_at
VAV1
206219_s_at
KLK5
222242_s_at
VCL
200930_s_at
KLK6
204733_at
VCL
200931_s_at
KLK7
205778_at
VPS37B
221704_s_at
 
 
 
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13.7.
Appendix 7: Reporting Standards for Missing Data
13.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as Subject 
whom have completed their final visit (day 84).

Withdrawn subjects will not be replaced in the study.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.
13.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:
o
These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
PD

Any values below the Lower Limit of Quantification (LLQ) will be assigned a value of ½ 
LLQ for display purposes in Figures and for computation of summary statistics. Any 
values above the Upper Limit of Quantification (ULQ) will be assigned to the ULQ for 
display purposes in Figures and for computation of summary statistics. If multiple LLQ 
and /or ULQ values are available per assay (for example if multiple runs with different 
standard curves are utilised) then the LLQ and/or ULQ value used for the above 
imputation shall be the minimum of the available LLQs and/or the maximum of the 
ULQs. Where biomarker concentrations are from an assay of an increased dilution 
factor the LLQ and ULQ will be multiplied by this factor.

If the number of LLQ (and/or ULQ) values is large for an individual biomarker then an 
alternative analysis method, such as TOBIT analysis, may be required. “Large” is hard 
to define prospectively and may depend upon the dataset in question. Any such 
methodology will be documented in the statistical contributions to the study report.

Imputed values will be used in tables and figures, unless the proportion of imputed 
values at a given time point is large, in which case the summary statistics may not be 
presented for that time point and/or alternative actions will be taken and documented in 
the study report.

Where values are imputed, the number of such imputations will be included as a 
summary statistic in the relevant summary tables.
HRCT

No missing data imputation methods will be used.

Note that for the HRCT data, there may be instances such that measurements from a 
particular Lobe cannot be distinguished between another Lobe, for example the iVlobe 
may be measured from both the LLL and LUL lobes. In such a case, the Lobe will be 
denoted as LLL + LUL. Therefore, for the statistical analysis purpose, since analysis is 
performed on a lobar level, the LLL and LUL Lobes will be set to missing and will 
 
 
 
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Element
Reporting Detail
therefore not be included in the analysis. Below is a table of all possible scenarios, 
where the data is set to missing and not used in the statistical analysis:
Lobes
Label
RUL
RML
RLL
LUL
LLL
x
x
RUL + RML
x
x
RML + RLL
x
x
RUL + RLL
x
x
x
RUL + RML + RLL
x
x
LUL + LLL
13.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to be 
recorded for AE start and end dates; that is, the day of the month may be missing. In 
such a case, the following conventions will be applied for calculating the time to onset 
and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is before the start 
date of study treatment; in this case the study treatment start date will be used and 
hence the event is considered On-treatment as per Appendix 4: Study Phases and 
Treatment Emergent Adverse Events.
o
Missing Stop Day: Last day of the month will be used, unless this is after the stop 
date of study treatment; in this case the study treatment stop date will be used.

Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing.
Concomitant 
Medications/
Medical 
History

Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.
 
 
 
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13.8.
Appendix 8: Values of Potential Clinical Importance
13.8.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 
1
Male
0.54
Female
0.54
Haemoglobin 
g/L
Male
180
Female
180
Lymphocytes 
x109/ L
0.8
Neutrophil Count 
x109/ L
1.5
Platelet Count 
x109/ L
100
550
While Blood Cell Count (WBC)
x109/ L
3
20
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Albumin 
g/L
30
Calcium
mmol/L
2
2.75
Glucose
mmol/L
3
9
Magnesium
mmol/L
0.5
1.23
Phosphorus
mmol/L
0.8
1.6
Potassium
mmol/L
3
5.5
Sodium
mmol/L
130
150
Total CO2
mmol/L
18
32
Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
≥ 2x ULN
AST/SGOT 
U/L
High
≥ 2x ULN
AlkPhos 
U/L
High
≥ 2x ULN
T Bilirubin 
µmol/L
High
≥ 1.5xULN
T. Bilirubin + ALT
µmol/L
High
1.5xULN T. Bilirubin
+
U/L
≥ 2x ULN ALT
 
 
 
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13.8.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 500 [1]
Absolute PR Interval
msec
< 110 [1]
> 220 [2]
Absolute QRS Interval
msec
< 75 [1]
> 110 [2]
NOTES:
[1] An upper limit of 450 would represent standard ECG values of PCI for HV studies, this has been extended to 500 as 
often with exacerbations the treatment can result in a short term prolongation of QTc up to 500.
[2] Represent standard ECG values of PCI for HV studies
13.8.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 85
> 160
Diastolic Blood Pressure
mmHg
< 45
> 100
Heart Rate
bpm
< 40
> 110
 
 
 
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13.9.
Appendix 9: Abbreviations & Trade Marks
13.9.1.
Abbreviations
Abbreviation
Description
A&R
Analysis and Reporting
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
AT
Air Trapping Score (% of iVlobe)
BVD
Blood Vessel Density (% of iVlobe)
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CENTRAL
Central lung region
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CT
Computed tomography
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DBF
Database Freeze
DBR
Database Release
Diameter
Diameter
DISTAL
Distal lung region
DLco
Diffusion capacity
DOB
Date of Birth
DP
Decimal Places
ECG
Electrocardiogram
eCRF
Electronic Case Record Form
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
FEV1
Forced expiratory volume in 1 second
FRI
Functional respiratory imaging
FRC
Functional residual capacity
GSK
GlaxoSmithKline
GUI
Guidance
HRCT
High Resolution Computed Tomography
IA
Interim Analysis
IALD
Internal Airflow Lobar Distribution
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IL-8
Interleukin 8
IL-6
Interleukin 6
 
 
 
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Abbreviation
Description
IMMS
International Modules Management System
IP
Investigational Product
iRaw
Imaging Airway Resistance
ITT
Intent-To-Treat
iVlobe
Lobar Volume
iVlobepred
Percent Predicted Lobar Volume
iVaw
Imaging Airway Volume
iVaww
Airway Wall Volume
LAS
Low Attenuation Score (% of iVlobe)
Length
Length
LL
Lung, lower lobes
LLL
Lung, left lower lobe
LOC
Last Observation Carries Forward
LUL
Lung, left upper lobe
LUL+LLL
Lung, left upper and lower lobe
MMP9
Matrix metallopeptidase 9
MMRC
Modified Medical Research Council
MMRM
Mixed Model Repeated Measures
NQ
Non-quantifiable
OTU
Operational Taxonomic Unit
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PEF
peak expiratory flow
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
QC
Quality Control
qPCR
Quantitative polymerase chain reaction
QTcF
Fridericia’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
RLL
Lung, right lower lobe
RML
Lung, right middle lobe
RML+RLL
Lung, right middle and lower lobe
RUL
Lung, right upper lobe
RUL+RLL
Lung, right upper and lower lobe
RUL+RML
Lung, right upper and middle lobe
RUL+RML+RLL
Lung, right upper, middle and lower lobe
SAC
Statistical Analysis Complete
SDSP
Study Data Standardization Plan
SDTM
Study Data Tabulation Model
sGaw
Specific conductance
siRaw
Specific Imaging Airway Resistance
 
 
 
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Abbreviation
Description
siVaw
Specific Imaging Airway Volume
siVaww
Specific Airway Wall Volume
SoC
Standard of Care
SOP
Standard Operation Procedure
sRaw
Specific Resistance
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
TLC
Total lung capacity
TNFα 
Tumor necrosis factor alpha
TOTAL
Total lung region
TRACHEA
Trachea
UL
Lung, upper lobes
13.9.2.
Trademarks
Trademarks of the GlaxoSmithKline Group 
of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
ELLIPTA
FluidDA
HARP
Quest
RAMOS NG
SAS
RANDALL NG
WinNonlin
 
 
 
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13.10.
Appendix 10: List of Data Displays
13.10.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.17
N/A
Efficacy
2.1 to 2.68
2.1 
Safety
3.1 to 3.20
N/A
Pharmacokinetic
4.1 to 4.4
4.1 
Pharmacodynamic and / or Biomarker
6.1 to 6.21
6.1 
Section
Listings
ICH Listings
1 to 34
Other Listings
35 to 49
13.10.2.
Deliverables
Delivery
Description
SAC
Final Statistical Analysis Complete
 
 
 
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13.10.3.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
Subject Disposition
1.1.
All Subject
ES1
Summary of Subject Disposition
ICH E3, FDAAA, EudraCT
SAC
1.2.
All Subject
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
ICH E3
SAC
1.3.
APE
ES6
Summary of Screening Status and Reasons for Screen Failure
Journal Requirements
SAC
1.4.
All Subject
NS1
Summary of Number of Participant by Country and Site ID
EudraCT/Clinical Operations
SAC
Protocol Deviation
1.5.
All Subject
DV1
Summary of Important Protocol Deviations
ICH E3
SAC
Population Analysed
1.6.
APE
SP1 
Summary of Study Populations 
IDSL
SAC
1.7.
All Subject
IE1
Summary of Inclusion/Exclusion Criteria Deviations
SAC
Demographic and Baseline Characteristics
1.8.
All Subject
DM1 
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
SAC
1.9.
APE
DM11
Summary of Age Ranges
EudraCT
SAC
1.10.
All Subject
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, EudraCT
SAC
1.11.
All Subject
DM6
Summary of Race and Racial Combinations Details
SAC
1.12.
All Subject
PII116678/final/ 
Table 2.109
Summary of Index Exacerbation Severity
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
Prior and Concomitant Medications
1.13.
All Subject
MH1
Summary of Current Medical Conditions
ICH E3 
SAC
1.14.
All Subject
MH1
Summary of Past Medical Conditions
ICH E3 
SAC
1.15.
All Subject
CM1
Summary of Prior Medications
ICH E3
SAC
1.16.
All Subject
CM1
Summary of Concomitant Medications
ICH E3
SAC
Exposure and Treatment Compliance
1.17.
All Subject
EX1
Summary of Exposure to Study Treatment
ICH E3
Include Daily Dose, Cumulative 
does and Days on study drug per 
template.
SAC
 
 
 
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13.10.4.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
HRCT Imaging Endpoints
2.1.
All subjects
PII116678/ final/ 
Table 2.1
Summary of iVaw (mL) (Absolute), for Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
Footnote any transformations used
SAC
2.2.
All subjects
PII116678/ final/ 
Table 2.2
Summary of iVaw (mL) (Change from Baseline), for Individual 
Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
Footnote any transformations used
Footnote baseline
SAC
2.3.
All subjects
PII116678/ final/ 
Table 2.3
Summary of iVaw (mL) (Absolute), for Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Footnote any transformations used
SAC
2.4.
All subjects
PII116678/ final/ 
Table 2.4
Summary of iVaw (mL) (Change from Baseline), for Individual 
Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Footnote any transformations used
Footnote baseline
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.5.
All subjects
PII116678/ final/ 
Table 2.9
Summary of siVaw (mL/L) (Absolute), for Individual Lobes 
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
Footnote any transformations used
SAC
2.6.
All subjects
PII116678/ final/ 
Table 2.10
Summary of siVaw (mL/L) (Change from Baseline), for 
Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
Footnote any transformations used
Footnote baseline
SAC
2.7.
All subjects
PII116678/final/ 
Table 2.11
Summary of siVaw (mL/L) (Absolute), for Individual Regions 
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Footnote any transformations used
SAC
2.8.
All subjects
PII116678/final/ 
Table 2.12
Summary of siVaw (mL/L) (Change from Baseline), for 
Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Footnote any transformations used
Footnote baseline
SAC
2.9.
All subjects
PII116678/final/ 
Table 2.17
Summary of iRaw (kPa*s/L) (Absolute), for Individual Lobes 
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
No longitudinal endpoints
Footnote any transformations used
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.10.
All subjects
PII116678/final/ 
Table 2.18
Summary of iRaw (kPa*s/L) (Change from Baseline), for 
Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
No longitudinal endpoints
Footnote any transformations used
Footnote baseline
SAC
2.11.
All subjects
PII116678/final/ 
Table 2.19
Summary of iRaw (kPa*s/L) (Absolute), for Individual Regions 
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
No longitudinal endpoints
Footnote any transformations used
SAC
2.12.
All subjects
PII116678/final/ 
Table 2.20
Summary of iRaw (kPa*s/L) (Change from Baseline), for 
Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
No longitudinal endpoints
Footnote any transformations used
Footnote baseline
SAC
2.13.
All subjects
PII116678/final/ 
Table 2.25
Summary of siRaw (kPa*s) (Absolute), for Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
No longitudinal endpoints
Footnote any transformations used
SAC
 
 
 
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77
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.14.
All subjects
PII116678/final/ 
Table 2.26
Summary of siRaw (kPa*s) (Change from Baseline), for 
Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
No longitudinal endpoints
Footnote any transformations used
Footnote baseline
SAC
2.15.
All subjects
PII116678/final/ 
Table 2.27
Summary of siRaw (kPa*s) (Absolute), for Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
No longitudinal endpoints
Footnote any transformations used
SAC
2.16.
All subjects
PII116678/final/ 
Table 2.28
Summary of siRaw (kPa*s) (Change from Baseline), for 
Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
No longitudinal endpoints
Footnote any transformations used
Footnote baseline
SAC
2.17.
All subjects
PII116678/final/ 
Table 2.33
Summary of iVlobe (L) (Absolute), for Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
No Scan Trimming endpoints
Footnote any transformations used
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.18.
All subjects
PII116678/final/ 
Table 2.34
Summary of iVlobe (L) (Change from Baseline), for Individual 
Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
No Scan Trimming endpoints
Footnote any transformations used
Footnote baseline
SAC
2.19.
All subjects
PII116678/final/ 
Table 2.35
Summary of iVlobe (L) (Absolute), for Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Regions Central and Distal do not 
exist 
No Scan Trimming endpoints
Footnote any transformations used
SAC
2.20.
All subjects
PII116678/final/ 
Table 2.36
Summary of iVlobe (L) (Change from Baseline), for Individual 
Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Regions Central and Distal do not 
exist 
No Scan Trimming endpoints
Footnote any transformations used
Footnote baseline
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.21.
All subjects
PII116678/final/ 
Table 2.41
Summary of Percent Predicted iVlobe (%) (Absolute), for 
Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page 
No Scan Trimming endpoints
Footnote any transformations used 
Note in HARP to output (%) it may 
be necessary to input (%%)
SAC
2.22.
All subjects
PII116678/final/ 
Table 2.42
Summary of Percent Predicted iVlobe (%) (Change from 
Baseline), for Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page 
No Scan Trimming endpoints
Footnote any transformations used
Footnote baseline 
Note in HARP to output (%) it may 
be necessary to input (%%)
SAC
2.23.
All subjects
PII116678/final/ 
Table 2.43
Summary of Percent Predicted iVlobe (%) (Absolute), for 
Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Regions Central and Distal do not 
exist 
No Scan Trimming endpoints
Footnote any transformations used 
Note in HARP to output (%) it may 
be necessary to input (%%)
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.24.
All subjects
PII116678/final/ 
Table 2.44
Summary of Percent Predicted iVlobe (%) (Change from 
Baseline), for Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Regions Central and Distal do not 
exist 
No Scan Trimming endpoints
Footnote any transformations used
Footnote baseline 
Note in HARP to output (%) it may 
be necessary to input (%%)
SAC
2.25.
All subjects
PII116678/final/ 
Table 2.49
Summary of LAS (% of iVlobe) (Absolute), for Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page 
No Scan Trimming endpoints
Footnote any transformations used
SAC
2.26.
All subjects
PII116678/final/ 
Table 2.50
Summary of LAS (% of iVlobe) (Change from Baseline), for 
Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page 
No Scan Trimming endpoints
Footnote any transformations used
Footnote baseline
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.27.
All subjects
PII116678/final/ 
Table 2.51
Summary of LAS (% of iVlobe) (Absolute), for Individual 
Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Regions Central and Distal do not 
exist 
No Scan Trimming endpoints
Footnote any transformations used
SAC
2.28.
All subjects
PII116678/final/ 
Table 2.52
Summary of LAS (% of iVlobe) (Change from Baseline), for 
Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Regions Central and Distal do not 
exist 
No Scan Trimming endpoints
Footnote any transformations used
Footnote baseline
SAC
2.29.
All subjects
PII116678/final/ 
Table 2.55
Summary of IALD (%) (Absolute), for Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page 
No Scan Trimming endpoints
Footnote any transformations used
SAC
2.30.
All subjects
PII116678/final/ 
Table 2.56
Summary of IALD (%) (Change from Baseline), for Individual 
Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page 
No Scan Trimming endpoints
Footnote any transformations used
Footnote baseline
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.31.
All subjects
PII116678/final/ 
Table 2.57
Summary of IALD (%) (Absolute), for Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Regions Central, Distal and Total 
do not exist 
No Scan Trimming endpoints
Footnote any transformations used
SAC
2.32.
All subjects
PII116678/final/ 
Table 2.58
Summary of IALD (%) (Change from Baseline), for Individual 
Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Regions Central, Distal and Total 
do not exist 
No Scan Trimming endpoints
Footnote any transformations used
Footnote baseline
SAC
2.33.
All subjects
PII116678/final/ 
Table 2.61
Summary of AT (% of iVlobe) (Absolute), for Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page 
No Scan Trimming endpoints
Footnote any transformations used
SAC
2.34.
All subjects
PII116678/final/ 
Table 2.62
Summary of AT (% of iVlobe) (Change from Baseline), for 
Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence
if required start each Lobe on a 
separate page 
No Scan Trimming endpoints
Footnote any transformations used
Footnote baseline
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.35.
All subjects
PII116678/final/ 
Table 2.63
Summary of AT (% of iVlobe) (Absolute), for Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Regions Central and Distal do not 
exist 
No Scan Trimming endpoints
Footnote any transformations used
SAC
2.36.
All subjects
PII116678/final/ 
Table 2.64
Summary of AT (% of iVlobe) (Change from Baseline), for 
Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Regions Central and Distal do not 
exist 
No Scan Trimming endpoints
Footnote any transformations used
Footnote baseline
SAC
2.37.
All subjects
PII116678/final/ 
Table 2.67
Summary of BVD (% of iVlobe) (Absolute), for Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page 
No Scan Trimming endpoints
Footnote any transformations used
SAC
2.38.
All subjects
PII116678/final/ 
Table 2.68
Summary of BVD (% of iVlobe) (Change from Baseline), for 
Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page 
No Scan Trimming endpoints
Footnote any transformations used
Footnote baseline
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.39.
All subjects
PII116678/final/ 
Table 2.69
Summary of BVD (% of iVlobe) (Absolute), for Individual 
Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Regions Central and Distal do not 
exist 
No Scan Trimming endpoints
Footnote any transformations used
SAC
2.40.
All subjects
PII116678/final/ 
Table 2.70
Summary of BVD (% of iVlobe) (Change from Baseline), for 
Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Regions Central and Distal do not 
exist 
No Scan Trimming endpoints
Footnote any transformations used
Footnote baseline
SAC
2.41.
All subjects
PII116678/final/ 
Table 2.73
Summary of iVaww (mL) (Absolute), for Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
Footnote any transformations used
SAC
2.42.
All subjects
PII116678/final/ 
Table 2.74
Summary of iVaww (mL) (Change from Baseline), for Individual 
Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
Footnote any transformations used
Footnote baseline
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.43.
All subjects
PII116678/final/ 
Table 2.75
Summary of iVaww (mL) (Absolute), for Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Footnote any transformations used
SAC
2.44.
All subjects
PII116678/final/ 
Table 2.76
Summary of iVaww (mL) (Change from Baseline), for Individual 
Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Footnote any transformations used
Footnote baseline
SAC
2.45.
All subjects
PII116678/final/ 
Table 2.79
Summary of siVaww (mL/L) (Absolute), for Individual Lobes 
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
Footnote any transformations used
SAC
2.46.
All subjects
PII116678/final/ 
Table 2.80
Summary of siVaww (mL/L) (Change from Baseline), for 
Individual Lobes
Ensure no overlapping information 
across pages for each Lobe, hence 
if required start each Lobe on a 
separate page
Footnote any transformations used
Footnote baseline
SAC
2.47.
All subjects
PII116678/final/ 
Table 2.81
Summary of siVaww (mL/L) (Absolute), for Individual Regions 
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Footnote any transformations used
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.48.
All subjects
PII116678/final/ 
Table 2.82
Summary of siVaww (mL/L) (Change from Baseline), for 
Individual Regions
Ensure no overlapping information 
across pages for each Region, 
hence if required start each Region 
on a separate page
Footnote any transformations used
Footnote baseline
SAC
2.49.
All subjects
PII116678/final/ 
Table 2.85
Summary of Trachea Length (mm), Diameter (mm) and Length 
/Diameter (mm/mm) (Absolute)
Footnote any transformations used
SAC
2.50.
All subjects
PII116678/final/ 
Table 2.86
Summary of Trachea Length (mm), Diameter (mm) and Length 
/Diameter (mm/mm) (Change from Baseline)
Footnote any transformations used
Footnote baseline
SAC
2.51.
All subjects
PII116678/final/ 
Table 2.14
Summary of Statistical Analysis for siVaw (mL/L), for Individual 
Lobes at FRC using Untrimmed Data
Ensure no overlapping information 
across pages for each Lobe
Footnote to include the statistical 
analysis conducted, including 
covariates, co-variance matrix and 
prior assumptions.
Footnote any transformations used
Footnote baseline
SAC
2.52.
All subjects
PII116678/final/ 
Table 2.16
Summary of Statistical Analysis for siVaw (mL/L), for Individual 
Regions at FRC using Untrimmed Data
Ensure no overlapping information 
across pages for each Lobe
Footnote to include the statistical 
analysis conducted, including 
covariates, co-variance matrix and 
prior assumptions.
Footnote any transformations used
Footnote baseline
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.53.
All subjects
Refer to: 
PII116678/final/ 
Table 2.16
Note: there will 
be less regions
Summary of Statistical Analysis for siVaw (mL/L), for Distal 
Region at FRC using Scan Trimmed Data
Ensure no overlapping information 
across pages for each Lobe
Footnote to include the statistical 
analysis conducted, including 
covariates, co-variance matrix and 
prior assumptions.
Footnote any transformations used
Footnote baseline
SAC
2.54.
All subjects
Refer to: 
PII116678/final/ 
Table 2.29
Note: there will 
be less regions
Summary of Statistical Analysis for siRaw (kPa*s), for Distal 
Region at FRC
Ensure no overlapping information 
across pages for each Region
No longitudinal endpoints
Footnote to include the statistical 
analysis conducted, including 
covariates, co-variance matrix and 
prior assumptions.
Footnote any transformations used
Footnote baseline
SAC
2.55.
All subjects
Refer to: 
PII116678/final/ 
Table 2.54
Note: there will 
be less regions
Summary of Statistical Analysis for LAS (% of iVlobe), for Total
Region at TLC
Ensure no overlapping information 
across pages for each Region
No longitudinal endpoints
Footnote to include the statistical 
analysis conducted, including 
covariates, co-variance matrix and 
prior assumptions.
Footnote any transformations used
Footnote baseline
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.56.
All subjects
Refer to: 
PII116678/final/ 
Table 2.60
Note: there will 
be less regions
Summary of Statistical Analysis for IALD (%), for Upper and 
Lower Regions
Ensure no overlapping information 
across pages for each Region
No longitudinal endpoints
Footnote to include the statistical 
analysis conducted, including 
covariates, co-variance matrix and 
prior assumptions.
Footnote any transformations used
Footnote baseline
SAC
2.57.
All subjects
Refer to: 
PII116678/final/ 
Table 2.66
Note: there will 
be less regions
Summary of Statistical Analysis for AT (% of iVlobe), for Total 
Region at FRC
Ensure no overlapping information 
across pages for each Region
No longitudinal endpoints
Footnote to include the statistical 
analysis conducted, including 
covariates, co-variance matrix and 
prior assumptions.
Footnote any transformations used
Footnote baseline
SAC
2.58.
All subjects
Refer to: 
PII116678/final/ 
Table 2.72
Note: there will 
be less regions
Summary of Statistical Analysis for BVD (% of iVlobe), for Total 
Region at TLC
Ensure no overlapping information 
across pages for each Region
No longitudinal endpoints
Footnote to include the statistical 
analysis conducted, including 
covariates, co-variance matrix and 
prior assumptions.
Footnote any transformations used
Footnote baseline
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.59.
All subjects
Refer to: 
PII116678/final/ 
Table 2.84
Note: there will 
be less regions
Summary of Statistical Analysis for siVaww (mL/L), for Distal 
Region at TLC using Untrimmed Data
Ensure no overlapping information 
across pages for each Region
No longitudinal endpoints
Footnote to include the statistical 
analysis conducted, including 
covariates, co-variance matrix and 
prior assumptions.
Footnote any transformations used
Footnote baseline
SAC
Lung Function
2.60.
All subjects
PII115119/
Part_A /Table
3.18
Summary of FEV1 (ml) and FVC (ml) (Absolute Values)
Summaries by Visit
Footnote any transformations used
SAC
2.61.
All subjects
PII115119/
Part_A /Table
3.19
Summary of FEV1 (ml) and FVC (ml) (Change from Baseline)
Summaries by Visit
Footnote any transformations used
Footnote Baseline
SAC
2.62.
All subjects
PII116678/ final 
/Table 2.88
Summary of Statistical Analysis for FEV1 (ml) (Change from 
Baseline)
Footnote to include the statistical 
analysis conducted, including 
covariates, co-variance matrix and 
prior assumptions.
Footnote any transformations used
Footnote baseline
SAC
2.63.
All subjects
PII116678/ 
postcsr_2017_01 
/Table 2.1
Sub Group Analysis: by Index Exacerbation Severity
Summary of Statistical Analysis for FEV1 (ml) (Change from 
Baseline)
Footnote to include the statistical 
analysis conducted, including 
covariates, co-variance matrix and 
prior assumptions.
Footnote any transformations used
Footnote baseline
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.64.
All subjects
PII116678/ final 
/Table 2.88
Summary of Statistical Analysis for FVC (ml) (Change from 
Baseline)
Footnote to include the statistical 
analysis conducted, including 
covariates, co-variance matrix and 
prior assumptions.
Footnote any transformations used
Footnote baseline
SAC
Relief Medication
2.65.
All subjects
Refer to 
programming 
notes
Summary of Rescue Medication Free Days
Use the standard 
tu_sumstatsinrows to summarise 
Rescue Medication Free days by
time period and treatment.
Include columns for time period, 
treatment, N, n, mean, 95% CI, SD, 
median, min and max
SAC
2.66.
All subjects
Refer to 
programming 
notes
Summary of Mean Number of Occasions of Rescue Use per 
Day
Use the standard 
tu_sumstatsinrows to summarise 
Mean Number of Occasions of 
Rescue Use per Day by time period 
and treatment.
Include columns for timeperiod, 
treatment, N, n, mean, 95% CI, SD, 
median, min and max
SAC
 
 
 
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91
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Exacerbations
2.67.
All subjects
Refer to 
PII116678/ final 
/Table 2.97
And 
programming 
notes
Summary of Investigator Defined Exacerbations
Update rows to be consistent with 
data i.e. include 6, 7, etc
exacerbations as appropriate
SAC
2.68.
All subjects
Refer to 
PII116678/ final 
/Table 2.116
And 
programming 
notes
Summary of Concomitant Medication Defined Exacerbations
Update rows to be consistent with 
data i.e. include 6, 7, etc
exacerbations as appropriate
SAC
 
 
 
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13.10.5.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
Lung Function
2.1.
All subjects
Refer to 
PII116678/final/ 
Table 2.2
but update the 
number of plots 
based on the 
data as 
appropriate
Summary of PEF (morning)
X-axis to contain each Day, with 
Means and confidence intervals, 
grouped by Treatment.
Include baseline as a subheading 
per example shell
SAC
 
 
 
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13.10.6.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
Adverse Events (AEs)
3.1.
All Subject
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term
ICH E3
SAC
3.2.
All Subject
AE3
Summary of Common (>=5%) Adverse Events by Overall 
Frequency
ICH E3
SAC
3.3.
All Subject
AE1
Summary All Drug-Related Adverse Events by System Organ 
Class and Preferred Term
ICH E3
Include flag for serious
SAC
3.4.
All Subject
AE15
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Participant 
and Occurrences)
FDAAA, EudraCT
SAC
Serious and Other Significant Adverse Events
3.5.
All Subject
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences)
FDAAA, EudraCT
SAC
3.6.
All Subject
AE1
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term
IDSL
SAC
Laboratory: Chemistry 
3.7.
All Subject
LB1
Summary of Chemistry 
ICH E3
SAC
3.8.
All Subject
LB15
Summary of Worst Case Emergent Laboratory Chemistry 
Results Relative to Normal Range
SAC
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
Laboratory: Hematology
3.9.
All Subject
LB1
Summary of Hematology 
ICH E3
SAC
3.10.
All Subject
LB15
Summary of Worst Case Emergent Laboratory Hematology 
Results Relative to Normal Range
SAC
Laboratory: Urinalysis
3.11.
All Subject
LB1
Summary of Urine Concentration 
ICH E3
SAC
3.12.
All Subject
UR1
Summary of Worst Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline
SAC
Laboratory: Hepatobiliary (Liver)
3.13.
All Subject
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting
IDSL
SAC
3.14.
All Subject
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities
IDSL
SAC
ECG
3.15.
All Subject
EG1
Summary of ECG Findings 
IDSL
SAC
3.16.
All Subject
EG2
Summary of ECG Values by Visit
SAC
3.17.
All Subject
EG2
Summary of Change from Baseline in ECG Values by Visit
IDSL
SAC
Vital Signs
3.18.
All Subject
VS1
Summary of Vital Signs
SAC
3.19.
All Subject
VS1
Summary of Change from Baseline in Vital Signs
ICH E3
Includes Baseline Values
SAC
3.20.
All Subject
VS7
Summary of Emergent Vital Sign Results by Potential Clinical 
Importance (PCI) Criteria
SAC
 
 
 
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13.10.7.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
Plasma Concentration
4.1.
PK
PK01
PII116678/final/Table 
4.1
Summary of Plasma Nemiralisib Pharmacokinetic Concentration 
– Time Data (ng/mL)
All visits/timepoints, include a 
column for visit. Summarise PK 
data on original scale. Produce 
95% CIs
Note: Use the separate NEMI 
Diskus and NEMI ELLIPTA 
treatment groups
Excluding the two subjects who 
were noted to not comply with 
inhalation instructions – include 
footnote
SAC
 
 
 
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96
Pharmacokinetic: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
4.2.
PK
PK01
PII116678/final/Table 
4.2
Summary of Plasma Nemiralisib Pharmacokinetic Concentration 
– Time Data (ng/mL) 
Including All PK Concentrations Analysed
All visits/timepoints, include a 
column for visit. Summarise PK 
data on original scale. Produce 
95% CIs
Note: Use the separate NEMI 
Diskus and NEMI ELLIPTA 
treatment groups 
Including the two subjects who 
were noted to not comply with 
inhalation instructions – include 
footnote
SAC
4.3.
PK
PII116678/final/Table 
4.3
Summary of Log-Transformed Plasma Nemiralisib 
Pharmacokinetic Concentration – Time Data (ng/mL)
All visits/timepoints, include a 
column for visit and planned time.
Summarise PK data on original 
scale. Produce n, No. imputed, 
geometric mean and corresponding 
95% Cis SD Logs and %CVb
Note: Use the separate NEMI 
Diskus and NEMI ELLIPTA 
treatment groups
Excluding the two subjects who 
were noted to not comply with 
inhalation instructions – include 
footnote
SAC
 
 
 
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97
Pharmacokinetic: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
4.4.
PK
PII116678/final/Table 
4.4
Summary of Log-Transformed Plasma Nemiralisib 
Pharmacokinetic Concentration – Time Data (ng/mL) 
Including All PK Concentrations Analysed
All visits/timepoints, include a 
column for visit and planned time. 
Summarise PK data on original 
scale. Produce n, No. imputed, 
geometric mean and corresponding 
95% Cis SD Logs and %CVb
Note: Use the separate NEMI 
Diskus and NEMI ELLIPTA 
treatment groups
Including the two subjects who 
were noted to not comply with 
inhalation instructions – include 
footnote
SAC
 
 
 
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98
13.10.8.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
Plasma Concentration
4.1.
PK
Refer to 
PII116678/ 
final/ Figure 4.1
But include 
additional 
timepoints per 
programming 
notes
Box and Whisker Plot of Plasma Concentration 
Two figures to be created:
1st: Plasma Concentration at Day 1 
(5 min and 24 hours post-dose) and 
Day 12
2nd: Plasma Concentration at Day 
12, Day 28, Day 56 and Day 84
Note: Use the separate NEMI 
Diskus and NEMI ELLIPTA 
SAC
 
 
 
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99
13.10.9.
Pharmacodynamic and Biomarker Tables
Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
MRNa
6.1.
All subjects
PII115119/
Part A/
Listing 40
Summary of Statistical Analysis of mRNA Transcriptome in
Induced Sputum (Selected Probe Sets Related to Neutrophil 
Function)
Summarise fold changes, 95% CI 
and p-values. Rank by p-value and 
fold change within timepoint.
SAC
6.2.
All subjects
PII115119/
Part A/
Listing 40
Summary of Statistical Analysis of mRNA Transcriptome in 
Blood (All Probe Sets)
Summarise fold changes, 95% CI 
and p-values. Rank by p-value and 
fold change within timepoint.
SAC
6.3.
All subjects
PII115119/
Part A/
Listing 40
Summary of Additional Statistical Analysis of mRNA 
Transcriptome in Induced Sputum (All Probe Sets)
Summarise fold changes, 95% CI 
and p-values. Rank by p-value and 
fold change within timepoint.
SAC
Cell Count Data and PMN Differentials
6.4.
All subjects
PII115119/
Part A/Table 
5.7
Summary Statistics (Absolute): Total Cell Count Data in Sputum 
by Treatment and Time.
Appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
6.5.
All subjects
PII115119/
Part A/Table 
5.8
Summary Statistics (Change from Baseline): Total Cell Count 
Data in Sputum by Treatment and Time
Appropriate transformation should 
be used prior to summarising data.
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
 
 
 
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100
Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
6.6.
All subjects
PII115119/
Part A/Table 
5.9
Summary Statistics (Absolute): PMNs Differentials in Sputum by 
Treatment and Time
Appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
6.7.
All subjects
PII115119/
Part A/Table 
5.10
Summary Statistics (Change from Baseline): PMNs Differentials 
in Sputum by Treatment and Time
Appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
6.8.
All subjects
PII115119/
Part A/Table 
5.11
Summary Statistics (Absolute): Total Cell Count Data in Blood 
by Treatment and Time.
Appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
6.9.
All subjects
PII115119/
Part A/Table 
5.12
Summary Statistics (Change from Baseline): Total Cell Count 
Data in Blood by Treatment and Time
Appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
6.10.
All subjects
PII115119/
Part A/Table 
5.13
Summary Statistics (Absolute): PMNs Differentials in Blood by 
Treatment and Time 
Appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
 
 
 
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101
Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
6.11.
All subjects
PII115119/
Part A/Table 
5.14
Summary Statistics (Change from Baseline): PMNs Differentials 
in Blood by Treatment and Time
Appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
Inflammatory Biomarkers
6.12.
All subjects
PII115119/
Part A/Table 
5.17
Summary Statistics (Absolute): Inflammatory Biomarkers by 
Treatment and Time
It is expected that no transformation 
will be required for this Table (6.12) 
and a log transformation will be
required for Table 6.14. However 
appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
6.13.
All subjects
PII115119/
Part A/Table 
5.18
Summary Statistics (Change from Baseline): Inflammatory 
Biomarkers by Treatment and Time
It is expected that no transformation 
will be required for this Table (6.13) 
and a log transformation will be
required for Table 6.15. However 
appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
 
 
 
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102
Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
6.14.
All subjects
PII115119/
Part A/Table 
5.19
Summary Statistics (Log-Transformed Absolute) Inflammatory 
Biomarkers by Treatment and Time
It is expected that no transformation 
will be required for Table 6.12 and a 
log transformation will be required
for this Table (6.14). However 
appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
6.15.
All subjects
PII115119/
Part A/Table 
5.20
Summary Statistics (Log-Transformed Change from Baseline)
Inflammatory Biomarkers by Treatment and Time
It is expected that no transformation 
will be required for Table 6.13 and a 
log transformation will be required 
for this Table (6.15). However 
appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
Microbiome (16S rRNA) and qPCR
6.16.
All subjects
PD4 
and Refer to 
programming 
notes
Summary Statistics (Absolute): Microbiome (16S rRNA) Relative 
Abundance by Treatment and Time
If Data available 
Appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
 
 
 
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103
Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
6.17.
All subjects
PD4 
and Refer to 
programming 
notes
Summary Statistics (Percentage Change from Baseline): 
Microbiome (16S rRNA) Relative Abundance by Treatment and 
Time
If Data available. 
Appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
6.18.
All subjects
PII115119/
Part A/Table 
5.24
Summary Statistics (Absolute): qPCR delta Ct by Treatment and 
Time
If Data available.
Appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
6.19.
All subjects
PII115119/
Part A/Table 
5.25
Summary Statistics (Log-Transformed Absolute): qPCR fold 
change by Treatment and Time
If Data available.
Appropriate transformation should 
be used prior to summarising data. 
Ensure transformation is clearly 
documented and update column 
labels as appropriate
SAC
Bacterial Culture
6.20.
All subjects
PII115119/
Part A/Table 
5.26
Frequency Table of Bacterial Culture (Presence) by Treatment 
and Time
SAC
 
 
 
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13.10.10. ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
Subject Disposition
1.
APE
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
SAC
2.
All Subjects
ES2
Listing of Reasons for Study Withdrawal
ICH E3
SAC
3.
All Subjects
SD2
Listing of Reasons for Study Treatment Discontinuation
ICH E3
SAC
4.
All Subjects
BL1
Listing of Participants for Whom the Treatment Blind was Broken
ICH E3
SAC
5.
All Subjects
TA1
Listing of Planned and Actual Treatments
IDSL
SAC
Protocol Deviations
6.
All Subjects
DV2
Listing of Important Protocol Deviations 
ICH E3
SAC
7.
All Subjects
IE3
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations
ICH E3
SAC
Populations Analysed
8.
APE
SP3
Listing of Participants Excluded from Any Population
ICH E3
SAC
Demographic and Baseline Characteristics
9.
All Subjects
DM2
Listing of Demographic Characteristics
ICH E3
SAC
10.
All Subjects
DM9
Listing of Race
ICH E3
SAC
Prior and Concomitant Medications
11.
All Subjects
CM3
Listing of Concomitant Medications
IDSL
SAC
Exposure and Treatment Compliance
12.
All Subjects
EX3
Listing of Exposure Data
ICH E3
SAC
 
 
 
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105
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
Adverse Events
13.
All Subjects
AE8
Listing of All Adverse Events
ICH E3
SAC
14.
All Subjects
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
SAC
15.
All Subjects
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
IDSL
SAC
Serious and Other Significant Adverse Events
16.
All Subjects
AE8 
Listing of Fatal Serious Adverse Events
ICH E3
SAC
17.
All Subjects
AE8 
Listing of Non-Fatal Serious Adverse Events
ICH E3
SAC
18.
All Subjects
AE14
Listing of Reasons for Considering as a Serious Adverse Event
ICH E3
SAC
19.
All Subjects
AE8 
Listing of Adverse Events Leading to Withdrawal from Study or
Permanent Discontinuation of Study Treatment
ICH E3
SAC
Hepatobiliary (Liver)
20.
All Subjects
MH2
Listing of Medical Conditions for Participants with Liver Stopping 
Events
IDSL
SAC
21.
All Subjects
SU2
Listing of Substance Use for Participants with Liver Stopping 
Events
IDSL
SAC
22.
All Subjects
LIVER5
Listing of Liver Monitoring/Stopping Event Reporting
SAC
23.
All Subjects
LIVER7
Listing of Liver Biopsy Details
SAC
24.
All Subjects
LIVER8
Listing of Liver Imaging Details
SAC
All Laboratory
25.
All Subjects
LB5
Listing of All Laboratory Data for Participants with Any Value of 
Potential Clinical Importance
ICH E3
SAC
26.
All Subjects
LB5
Listing of Laboratory Values of Potential Clinical Importance
SAC
 
 
 
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106
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
27.
All Subjects
LB14
Listing of Laboratory Data with Character Results
ICH E3
SAC
28.
All Subjects
UR2A
Listing of Urinalysis Data for Participants with Any Value of 
Potential Clinical Importance
ICH E3
SAC
ECG
29.
All Subjects
EG3 
Listing of All ECG Values for Participants with Any Value of 
Potential Clinical Importance
IDSL
SAC
30.
All Subjects
EG3 
Listing of ECG Values of Potential Clinical Importance
IDSL
SAC
31.
All Subjects
EG5
Listing of All ECG Findings for Participants with an Abnormal 
ECG Finding
IDSL
SAC
32.
All Subjects
EG5
Listing of Abnormal ECG Findings
IDSL
SAC
Vital Signs
33.
All Subjects
VS4
Listing of All Vital Signs Data for Participants with Any Value of 
Potential Clinical Importance
IDSL
SAC
34.
All Subjects
VS4
Listing of Vital Signs of Potential Clinical Importance
IDSL
SAC
 
 
 
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107
13.10.11. Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
Demography and Baseline Characteristics
35.
All Subjects
FH1
Summary of Family History of Cardiovascular Risk Factors
SAC
36.
All Subjects
Refer to 
Programming 
notes
COPD Disease duration and Exacerbation Duration
Include investigator ID, subject ID, 
country, treatment group, COPD 
Disease Duration (in years and 
months) and Exacerbation History 
(number requiring oral/systemic 
corticosteroids and/or antibiotics 
and number requiring 
hospitalisation) as columns
SAC
37.
All Subjects
PREG1a
Listing of Subjects Who Became Pregnant During the Study
Also indicate if the female partners 
of subjects became pregnant during 
the study
Labs
38.
All Subjects
LB13
Listing of Laboratory Reference Ranges
SAC
39.
All Subjects
CP_LB5
Listing of Laboratory Values Outside Normal Reference Range
SAC
ECG
40.
All Subjects
CP_EG5
Listing of All ECG findings for Subjects with an Abnormal 
Finding
SAC
PK
41.
PK
PK07
Listing of Individual Subjects Plasma Concentrations at all time 
points
SAC
 
 
 
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108
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
PD/Biomarkers
42.
All subjects
PII115119/
Part A/Listing 
25
Listing of Sputum Collection
Include sample ID if available
SAC
43.
All subjects
PII115119/
Part A/Listing 
26
Listing of Blood Collection for RNA
SAC
44.
All subjects
PII115119/
Part A/Listing 
31
Listing of Cell Count Data
SAC
45.
All subjects
PII115119/
Part A/Listing 
32
Listing of PMNs Differentials
SAC
46.
All subjects
PII115119/
Part A/Listing 
34
Listing of Individual Subject Inflammatory Cytokine Biomarker 
Data
SAC
47.
All subjects
PII115119/
Part A/Listing 
35
Listing of Microbiome (16S rRNA) Biomarker Data
SAC
48.
All subjects
PII115119/
Part A/Listing 
36
Listing of qPCR Data
SAC
49.
All subjects
PII115119/
Part A/Listing 
37
Listing of Bacterial Culture Data
SAC
 
 
 
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CONFIDENTIAL
The GlaxoSmithKline group of companies
201928
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP) - Critical Components
Title
:
Critical Components of Reporting and Analysis Plan for 
Study 201928: 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
Effective Date 
:
25-SEP-2015
Description :
The purpose of this CC-RAP (Critical Components of the Reporting and Analysis Plan) is to 
capture the following Critical Components, by First Subject First Visit:

Analysis Population

Protocol Deviations (Reflect the agreements from the plan for managing protocol deviations 
and define the reporting & analysis of all important deviations, as defined in the ICH guidelines)

Statistical Evaluation (Primary/critical endpoints) and Statistical Analysis Considerations 
Author’s Name and Functional Area: 
25-SEP-2015
Principal Statistician (Clinical Statistics)
Copyright 2015 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
 
 
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CONFIDENTIAL
201928
2
TABLE OF CONTENTS
PAGE
1.
ANALYSIS POPULATIONS .....................................................................................3
1.1.
Protocol Deviations.......................................................................................3
2.
PRIMARY STATISTICAL ANALYSES......................................................................4
2.1.
Pharmacodynamic / Biomarker Analyses......................................................4
2.1.1.
Overview of Planned Pharmacodynamic / Biomarker 
Analyses........................................................................................4
2.1.2.
Planned Pharmacodynamic / Biomarker Statistical 
Analyses........................................................................................4
3.
SECONDARY STATISTICAL ANALYSES ...............................................................5
3.1.
Pharmacodynamic / Biomarker Analyses......................................................5
3.1.1.
Overview of Planned Pharmacodynamic / Biomarker 
Analyses........................................................................................5
3.1.2.
Planned Pharmacodynamic / Biomarker Statistical 
Analyses........................................................................................5
3.2.
Safety Analyses............................................................................................9
3.2.1.
Overview of Planned Analyses ......................................................9
3.3.
Pharmacokinetic Analyses............................................................................9
3.3.1.
Overview of Planned Pharmacokinetic Analyses ...........................9
3.4.
Efficacy Analyses..........................................................................................9
3.4.1.
Overview of Planned Efficacy Analyses .........................................9
3.4.2.
Planned Efficacy Statistical Analyses.............................................9
4.
OTHER STATISTICAL ANALYSES .......................................................................11
4.1.
Exploratory Pharmacodynamic / Biomarker Analyses.................................11
4.1.1.
Overview of Planned Exploratory Pharmacodynamic / 
Biomarker Analyses.....................................................................11
4.1.2.
Planned Exploratory Pharmacodynamic / Biomarker 
Statistical Analyses......................................................................11
 
 
 
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201928
3
1.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened
All subjects who were screened.

Demography

Screening failure 
details

Eligibility criteria

Protocol Deviations

Serious adverse 
events
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
1.1.
Protocol Deviations

Important protocol deviations (including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarised and listed.

Protocol deviations will be tracked by the study team throughout the conduct of the
study in accordance with the Protocol Deviation Management Plan.
o
Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations are captured and categorised on the protocol deviations 
dataset. 
o
This dataset will be the basis for the summaries and listings of protocol 
deviations.

A separate summary and listing of all inclusion/exclusion criteria deviations will also 
be provided. This summary will be based on data as recorded on the 
inclusion/exclusion page of the eCRF.
 
 
 
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CONFIDENTIAL
201928
4
2.
PRIMARY STATISTICAL ANALYSES
2.1.
Pharmacodynamic / Biomarker Analyses
2.1.1.
Overview of Planned Pharmacodynamic / Biomarker Analyses
The pharmacodynamic analyses will be based on the “All Subjects” population, unless 
otherwise specified.
2.1.2.
Planned Pharmacodynamic / Biomarker Statistical Analyses
Planned Statistical Analyses
Endpoint(s)

Alterations in the 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.
Model Specification

The analyses proposed in this section may be adapted before database freeze, in the light of 
emerging findings from other studies.

The analysis will be conducted by Target Sciences statistics, GSK.

The mRNA data gives results from 54000 genes captured through >54000 probe sets. The 
subset of these 54000 genes which comprise the primary endpoint data will be specified in 
advance of DBF.

For each probe set, repeated measures modelling (using measurements taken at Screening, 
Day 12, Day 28 and Day 84) will be used to estimate differences in mRNA intensities between 
treatment groups.

Back transformed screening-adjusted means along with 95% CIs will be calculated for each 
treatment group and timepoint. Additionally, screening-adjusted fold changes between 
GSK2269557 1000 mcg and placebo will be calculated for Day 12, Day 28, and Day 84 along 
with 95% CI and p-values. 

A spreadsheet containing the output from each model for all probe sets in scope for the 
primary analysis will be generated and ranked by p-value for the comparison GSK2269557 
1000 mcg vs. Placebo at Day 84. A separate tab in the spreadsheet will only include probe 
sets where the p-value for the comparison GSK2269557 1000mcg vs. placebo, is <0.05 (this 
cut-off criteria may be relaxed slightly if few probe sets are selected). Such probe sets will be 
ranked by fold change, with the expectation that, in general, a greater than a 1.5 fold change is 
scientifically meaningful.

Following review by the study team of the results, a subset of probe sets will be identified and 
included in an Excel file for further reporting.
Model Checking

Details of Model Checking and Diagnostics for Statistical Analyses will be provided in the full RAP.
 
 
 
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3.
SECONDARY STATISTICAL ANALYSES
3.1.
Pharmacodynamic / Biomarker Analyses
3.1.1.
Overview of Planned Pharmacodynamic / Biomarker Analyses
The pharmacodynamic analyses will be based on the “All Subjects” population, unless 
otherwise specified.
3.1.2.
Planned Pharmacodynamic / Biomarker Statistical Analyses
Planned Statistical Analyses
Endpoint(s)

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. 
The analyses proposed in this section may be adapted before database freeze, in the light of 
emerging findings from other studies.
Imaging: 
The HRCT scans will be conducted at Screening, Day 12 and Day 28 (longitudinal in nature).  
However due to positioning of subjects whilst taking a scan, it can be that some airways are visible 
in some scans and not in other scans.  For these reasons some HRCT imaging endpoints will be 
calculated to include only airways that are visible in both scans.  For example the schematic 
below shows visible airways on Screening alone and Day 12 alone.  It then shows the airways 
that are visible on both Screening & Day 12 scans, through removing/trimming airways that are not 
present in both scans.
Screening:
Day 12:
Scan Trimming Screening & Day 12: 
For such reasons, the table below shows the HRCT endpoints and the results that will be captured
Longitudinal 
Scan Trimming, based on:
Endpoints
Screening 
Day 12 
Day 28 
Screening and 
Day 12 scans
Screening and 
Day 28 scans
Day 12 and
Day 28 scans
iVaw
x
x
x
x (Screening) 
x (day 12)
x (Screening) 
x (day 28)
x (day12) 
x (day 28)
siVaw
x
x
x
x (Screening) 
x (day 12)
x (Screening)
x (day 28)
x (day12)
x (day 28)
iRaw
x (Screening) 
x (day 12)
x (Screening) 
x (day 28)
x (day12) 
x (day 28)
siRaw
x (Screening) 
x (day 12)
x (Screening)
x (day 28)
x (day12) 
x (day 28)
iVlobe
X
x
x
iVlobe Pred
X
x
x
 
 
 
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Trachea 
length
X
x
x
Trachea 
Diameter
X
x
x
Model Specification
Imaging Endpoints with longitudinal data (iVaw, siVaw, iVlobe, ivlobe Pred)

The data will be inspected during statistical analysis to determine whether a data 
transformation is required. It is likely that the data will approximately follow a lognormal 
distribution (for the iVaw and siVaw) and a log transformation with an offset (for the iRaw and 
siRaw); however the most appropriate distribution should be used.

It is thought that the use of bronchodilators could affect the HRCT results. The database will 
contain information on whether or not relief medication was used in the 4h prior to each scan, 
and this information may be used in sensitivity analyses of the HRCT results.

The FRC and TLC will be analysed in separate statistical models.

The change from baseline (where baseline is screening) will be analysed in a multivariate 
model to account for the correlation between the multiple Regions (Total, Lower, Upper, 
Central and Distal), under a Bayesian framework. The model will have a separate intercept for 
each Region (by fitting a class parameter, and having no overall intercept) and will also include 
a baseline*Visit*Region and a Treatment*Visit*Region parameter. The Visit will consist of two 
levels: Day 12 and Day 28, and the Treatment will consist of two levels: GSK2269557 1000 
mcg and Placebo.  The Region will consist of 5 levels: Total, Lower, Upper, Central and 
Distal, however note that if one of the Regions is a linear combination of other Regions then 
only non linear combination Regions should be fitted, however all results (e.g Treatment 
medians and differences) for that particular Region should be retrospectively calculated though 
the known linear combination. No fixed assumption around the structure of the covariance 
matrix will be enforced. The priors for the mean vector for each of the parameters (i.e 
covariates) will each follow a normal distribution and the prior for the variance-covariance will 
follow an inverse Wishart distribution. Sensitivity analysis will be conducted to select 
appropriate parameters for both distributions such that the priors are non-informative with 
respect to the posterior. 

The change from baseline across the different Visits and Regions (accounting for the average 
baseline associated to the Region of interest) will be represented via adjusted posterior 
medians for each of the Treatment Arms, as well as their associated 95% equi-tailed credible 
intervals.  These results will also be presented in tabular form, and will be presented after the 
data have been appropriately back transformed to give median ratios if applicable.  

The difference between the treatment arms, for the change from baseline across the different 
Visits and Regions will be represented via adjusted posterior medians, as well as their 
associated 95% equi-tailed credible intervals. These results will be presented in tabular form, 
and will be presented after the data have been appropriately back transformed to give median 
ratios if applicable. For parameters that require a log transformation with an offset, for each 
posterior sample (i) appropriately back transformed values will be calculated for each treatment 
arms, and then (ii) using these back transformed values, the ratio of the treatment arms 
(Active/Placebo) will be calculated for each posterior sample, and finally summarised 
accordingly. 

The probabilities that the true treatment ratio is greater than 1, in addition to any other values 
 
 
 
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appropriately selected based on the data, will also be computed for each Visit and Region.  
These results will be presented in tabular format.
Imaging Endpoints with Scan Trimming (iVaw, siVaw, iRaw, siRaw)

It is likely that the data will approximately follow a lognormal distribution (for the iVaw and 
siVaw) and a log transformation with an offset (for the iRaw and siRaw); however the most 
appropriate distribution should be used.

The FRC and TLC will be analysed in separate statistical models.

The responses of interest are the change from baseline based on (i) Airways present on scans 
taken at Screening and Day 12, (ii) Airways present on scans taken at Screening and Day 28, 
and (iii) Airways present on scans taken at Screening and Day 28.  The baselines for each of 
these endpoints are provided in the table below.
(i) Screening & 
Day12 Scan trimming
(ii) Screening & 
Day28 Scan trimming
(iii) Day 12 & Day 28
Scan trimming
Screening Result
(baseline)
(baseline)
Day 12 Result
(postdose)
(baseline)
Day 28 Result
(postdose)
(postdose)

The modeling below assumes that the Scan trimming endpoints (Screening&Day12, 
Screening&Day28 and Day12&Day28) will be analysed in a single multivariate model.  This is 
subject to sensitivity analysis.

The change from baseline (where baseline is defined in the table above) will be analysed in a 
multivariate model to account for the correlation between the multiple Scan Trimmings 
(Screening&Day12, Screening&Day28 and Day12&Day28) and Regions (Total, Lower, Upper, 
Central and Distal), under a Bayesian framework.  The model will have a separate intercept 
for each Region and Scan Trimming combination (by fitting a class parameter 
Region*ScanTrimming, and having no overall intercept), and will also include a 
baseline*ScanTrimming*Region and a Treatment*ScanTrimming*Region parameter.  The 
Visit will consist of two levels: Day 12 and Day 28, the scan trimming will consist of three levels 
Screening&Day12, Screening&Day28 and Day12&Day28, and the Treatment will consist of 
two levels: GSK2269557 1000 mcg and Placebo.  The Region will consist of 5 levels: Total, 
Lower, Upper, Central and Distal, however note that if one of the Regions is a linear 
combination of other Regions then only non linear combination Regions should be fitted, 
however all results (e.g. Treatment medians and differences) for that particular Region should 
be retrospectively calculated though the known linear combination. No fixed assumption 
around the structure of the covariance matrix will be enforced. The priors for the mean vector 
for each of the parameters (i.e. covariates) will each follow a normal distribution and the prior 
for the variance-covariance will follow an inverse Wishart distribution. Sensitivity analysis will 
be conducted to select appropriate parameters for both distributions such that the priors are 
non-informative with respect to the posterior. 

The change from baseline across the different Scan Trimmings and Regions (accounting for 
the average baseline associated to the Region of interest) will be represented via adjusted 
posterior medians for each of the Treatment Arms, as well as their associated 95% equi-tailed 
credible intervals. These results will also be presented in tabular form, and will be presented 
after the data have been appropriately back transformed to give median ratios if applicable.  
 
 
 
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
The difference between the treatment arms, for the change from baseline across the different 
Scan Trimming and Regions will be represented via adjusted posterior medians, as well as 
their associated 95% equi-tailed credible intervals. These results will also be presented in 
tabular form, and will be presented after the data have been appropriately back transformed to 
give median ratios if applicable. For parameters that require a log transformation with an offset, 
for each posterior sample (i) appropriately back transformed values will be calculated for each 
treatment arm, and then (ii) using these back transformed values, the ratio of the treatment 
arms (Active/Placebo) will be calculated for each posterior sample, and finally summarised 
accordingly. 

The probabilities that the true treatment ratio is greater than 1, in addition to other values 
appropriately selected based on the data, will also be computed for each Visit and Region.  
These results will be presented in tabular format.
Trachea Length and Diameter

The data will be inspected during statistical analysis to determine whether a data 
transformation is required. 

The FRC and TLC will be analysed in separate statistical models.

The data will be analysed in a multivariate model to account for the correlation between the 
multiple endpoints ((i)Trachea length and (ii) Trachea Diameter), under a Bayesian framework.  
The model will have separate intercepts for each endpoint (by fitting a class variable 
“Endpoint”, and having no overall intercept), and will also include a baseline*Visit*Endpoint and 
a Treatment*Visit*Endpoint parameter. The Visit will consist of two levels: Day 12 and Day 28, 
the Treatment will consist of two levels: GSK2269557 1000 mcg and Placebo, whilst the 
Endpoint will consist of two levels: Trachea Length and Diameter. No fixed assumption around 
the structure of the covariance matrix will be enforced. The priors for the mean vector for each 
of the parameters (i.e covariates) will each follow a normal distribution and the prior for the 
variance-covariance will follow an inverse Wishart distribution. Sensitivity analysis will be 
conducted to select appropriate parameters for both distributions such that the priors are non-
informative with respect to the posterior. 

The predicted values across the different Endpoints and Visits will be represented via adjusted 
posterior medians for each of the Treatment Arms, as well as their associated 95% equi-tailed 
credible intervals. These results will also be presented in a tabular format. 

The difference between the treatment arms across the different Endpoints and Visits will be 
represented via adjusted posterior medians, as well as their associated 95% equi-tailed 
credible intervals. These results will also be presented in a tabular format. 

Through the use of a Bayesian framework, for each posterior sample the following will be 
calculated:
o
The predicted Trachea Length (for each Visit and Treatment for an average baseline)
o
The predicted Trachea Diameter (for each Visit and Treatment for an average 
baseline)

The predicted Trachea length (1.) for each Visit and Treatment will be divided by the predicted 
Diameter (2.). This will be summarised and represented through calculating a posterior 
median, with 95% equi-tailed credible intervals. These results will also be presented in a 
tabular format. 

The difference between Treatment Arms (at each Visit) for the predicted Trachea / Diameter 
Ratio will be calculated using the posterior samples (generated in the bullet point above). This 
 
 
 
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will be summarised and represented through calculating a posterior median, with 95% equi-
tailed credible intervals. These results will also be presented in a tabular format. 
Model Checking

Details of Model Checking and Diagnostics for Statistical Analyses will be provided in the full RAP.
3.2.
Safety Analyses
3.2.1.
Overview of Planned Analyses
The safety analyses will be based on the “All Subjects” population, unless otherwise 
specified. Details of the analyses of safety data will be included in the full RAP.
3.3.
Pharmacokinetic Analyses
3.3.1.
Overview of Planned Pharmacokinetic Analyses
The pharmacokinetic (PK) analyses will be based on the “Pharmacokinetic” population, 
unless otherwise specified. Details of the analyses of PK data will be included in the full 
RAP.
3.4.
Efficacy Analyses
3.4.1.
Overview of Planned Efficacy Analyses
The secondary efficacy analyses will be based on the “All Subjects” population, unless 
otherwise specified.
3.4.2.
Planned Efficacy Statistical Analyses
Planned Statistical Analyses
Endpoint(s)

FEV1 and  FVC at clinic prior to sputum induction

Daily PEF

Daily reliever usage 
Model Specification
FEV1 (L) and FVC (L) at clinic prior to sputum induction

The data will be inspected prior to analysis to determine whether a data transformation is 
required.

The analysis will include all available values. If there are values which were recorded within 4h 
after the subject had taken relief medication, a sensitivity analysis may be done which 
excludes these values. 

The endpoints (FEV1,and FVC) will be analysed in separate statistical models. The change 
from baseline in the endpoint will be analysed in a Bayesian repeated measures model, with a 
baseline by Visit covariate and Treatment by Visit class parameter. The Treatment will have 
 
 
 
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two levels: GSK2269557 1000 mcg and Placebo, and the Visit will have two levels: Day 12 and 
Day 28. No fixed assumption around the structure of the covariance matrix will be enforced.  
The priors for the mean vector for each of the parameters (i.e covariates) will each follow a 
normal distribution and the prior for the variance-covariance will follow an inverse Wishart 
distribution. Sensitivity analysis will be conducted to select appropriate parameters for both 
distributions such that the priors are non-informative with respect to the posterior. 

The change from baseline at each of the Visits will be represented via adjusted posterior 
medians for each of the Treatment Arms, as well as their associated 95% equi-tailed credible 
intervals. These results will also be presented in a tabular format.

The difference between the treatment arms, for the change from baseline will be represented 
via adjusted posterior medians for each of the Treatment Arms, as well as their associated 
95% equi-tailed credible intervals. These results will also be presented in a tabular format.

The probabilities that the treatment difference is greater than 0 (or 1, if a lognormal distribution 
is used) will also be computed at each Visit, in addition to any other values appropriately 
selected based on the data. These results will be presented in tabular format.
Daily PEF

Mean and 95% CIs of AM PEF readings will be plotted by study treatment vs. Study Day
Reliever usage

A reliever medication-free day is defined for statistical analysis as a 24-hour period in which the 
number of relief medication inhalations is zero.

The number of occasions per day on which reliever medication was used will be averaged per 
day and plotted in the same way as the PEF daily endpoint above. If the data are non-normally 
distributed then the median and upper and lower quartiles will be plotted instead of the mean 
and 95% CIs. The percentage of reliever medication free days will be calculated over the 
treatment period and summarised by study treatment.
Model Checking & Diagnostics

Details of Model Checking and Diagnostics for Statistical Analyses will be provided in the full RAP.
 
 
 
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4.
OTHER STATISTICAL ANALYSES
4.1.
Exploratory Pharmacodynamic / Biomarker Analyses
4.1.1.
Overview of Planned Exploratory Pharmacodynamic / Biomarker
Analyses
The exploratory pharmacodynamic/biomarker analyses will be based on the “All 
Subjects” population, unless otherwise specified.
4.1.2.
Planned Exploratory Pharmacodynamic / Biomarker Statistical 
Analyses
Planned Statistical Analyses
Endpoint(s)

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.

Induced sputum endpoints may include, but are not limited to cytokines (IL-6, IL-8, TNF), 
microbiome (by 16SrRNA), bacterial qPCR, viral qPCR.

Change from baseline for other CT parameters including low attenuation score after 12 days of 
treatment and after 28 days of treatment.

Correlations of sputum biomarker data with CT parameters.
The table below shows the exploratory HRCT endpoints and the results that will be captured:
Longitudinal 
Scan Trimming, based on:
Endpoints
Screening 
Day 12 
Day 28 
Screening and 
Day 12 scans
Screening and 
Day 28 scans
Day 12 and
Day 28 scans
IALD
X
x
x
LAS
X
x
x
AT
X
x
x
BVD
X
x
x
iVaww
x (Screening) 
x (day 12)
x (Screening)
x (day 28)
x (day12) 
x (day 28)
siVaww
x (Screening) 
x (day 12)
x (Screening)
x (day 28)
x (day12) 
x (day 28)
Model Specification

Analyses for mRNA (from induced sputum and blood) and further CT endpoints will follow the 
methods outlined for the corresponding primary and secondary endpoints respectively, or as 
appropriate to the type of endpoint. Details will be covered in the full RAP. As noted in the 
above sections, the analyses proposed for these endpoints may be adapted before database 
freeze, in the light of emerging findings from other studies.The analysis of induced sputum 
parameters will be described in the full RAP.

An outline plan for correlations of sputum biomarker data with CT parameters will be included 
in the full RAP.

As these analyses are exploratory in nature, additional non-RAP-specified analyses may be
performed.
 
 
 
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