A Phase IIb, Randomized (Stratified), Double-Blind (Sponsor Open), Parallel-Group, Placebo-Controlled, Dose-Finding Study of Nemiralisib (GSK2269557) Added to Standard of Care (SoC) Versus SoC Alone in Participants Diagnosed With an Acute Moderate or Severe Exacerbation of Chronic Obstructive Pulmonary Disease (COPD)
Phase: PHASE2
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: GlaxoSmithKline

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GlaxoSmithKline group of companies
200879
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TITLE PAGE
Protocol Title: A Phase IIb, Randomized (Stratified), Double-Blind (Sponsor Open), 
Parallel-Group, Placebo-Controlled, Dose-Finding Study of Nemiralisib (GSK2269557) 
Added to Standard of Care (SoC) Versus SoC Alone in Participants Diagnosed with an 
Acute Moderate or Severe Exacerbation of Chronic Obstructive Pulmonary Disease 
(COPD)
Protocol Number: 200879/ Amendment 02
Short Title: A Phase IIb, Placebo-Controlled, Dose-Finding Study of Nemiralisib 
(GSK2269557) Added to Standard of Care (SoC) Versus SoC Alone in Participants 
Diagnosed with an Acute Moderate or Severe Exacerbation of Chronic Obstructive 
Pulmonary Disease (COPD)
Compound Number:
GSK2269557
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information: Can be found in the Study 
Reference Manual
Regulatory Agency Identifying Number(s): FDA IND Number:125676; EudraCT #: 
2017-001074-42
Approval Date: 14-DEC-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
Document
Date
Amendment02 – Global Amendment
(Document Number 2017N317218_05)
14-DECEMBER-2017
Amendment 01 – Country Amendment – Korea
(Document Number 2017N317218_04)
26-SEPTEMBER-2017
Amendment 01 – Global Amendment
(Non-tracked changes version: document number 2017N317218_03 –
to re-insert the missing text shown in bold that was present in the 
tracked changes version of Amendment 1 (document number 
2017N317218_01), but inadvertently missing from the non-tracked 
changes version of Amendment 1(document number 
2017N317218_02) for Exclusion Criterion #6: “6. Other respiratory 
disorders: A diagnosis of 1-antitrypsin deficiency as the underlying cause of 
COPD, active tuberculosis, lung cancer, clinically overt bronchiectasis 
(Note: focal bronchiectasis is not exclusionary), sarcoidosis, pulmonary 
fibrosis (Note: focal fibrotic pulmonary lesions are not exclusionary), primary 
pulmonary hypertension, interstitial lung diseases, 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.” 
26-SEPTEMBER-2017
Amendment 01 – Global Amendment
(Non-tracked changes version: document number 2017N317218_02)
15-SEPTEMBER-2017
Amendment 01 – Global Amendment
(Tracked changes version: document number 2017N317218_01)
24-AUGUST-2017
Original Protocol
(document number 2017N317218_00)
15-JUNE-2017
Amendment 02 14-DEC-2017
Overall Rationale for the Amendment:  The rationale for this amendment is to add an 
additional lower strength(s) of nemiralisib, to remove the restrictions on theophylline use, 
to adjust withdrawal from study and discontinuation of treatment criteria, to adjust the 
flow for participants that discontinue IP, to remove the recording of SAEs between 
signing of informed consent form and start of study treatment, and to provide clarification 
of local and central lab requirements.  Additionally, inconsistencies in protocol 
amendment 1 were corrected and wording was clarified where necessary.
This protocol amendment applies to all participating Investigators globally.
 
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Section # and Name
Description of Change
Brief Rationale
Synopsis, Study 
Rationale, Study 
Schematic, Section 
5.2, 7.1, 7.2, 10.1, 
10.2, 
12.5mcg dose strength has been added and anticipated 
participant numbers in each dose arm adjusted accordingly.  
Provision for 25mcg to be included at a later date has also 
been added.  Randomisation ratio has been updated to add 
the 12.5mcg dose strength and to allow for the 25mcg dose 
strength. Explanation for this change has been added where 
appropriate and wording related to the planning of this 
change has been removed.
Additional lower dose strengths have been added to fully profile 
the dose response.  This was planned in the original protocol
Section 6.2, 
Exclusion 20
Exclusion criteria related to QTc adjusted to permit triplicate 
ECGs as opposed to single ECGs for assessment of QTc 
interval criteria.
Adjusted in line with permissible GSK safety requirements.
Section 6.2, 
Exclusion 13, 
Appendix 10
Exclusion 13 adjusted to clarify wording and to remove the 
restriction of theophylline.  Associated Appendix 10 removed
Theophylline can be used in accordance with standard 
practicein light of emerging drug:drug interaction data.
Section 6.2, 
Exclusion 16, Section 
7.7
Exclusion 16 removed and wording in Permitted Medication 
section clarified
Discussion between respiratory and sleep experts indicate that 
if participants are on a stable dose of CPAP or NIPPV that 
started prior to screening this is acceptable and won’t interfere 
with efficacy endpoints.
Section 8.1, 8.2
The following events were moved from the Withdrawal From 
Study section to the Discontinuation of Study Treatment 
section:
Pneumonia
Acute Respiratory Acidosis/invasive mechanical ventilation
Significant changes to ECG, Vital signs, Lab tests.
Pregnancy
None of these events require withdrawal from study.  
Participants that discontinue IP due to these events may remain 
in the study.
Section 9.2.1
Time period for collection of SAES has been adjusted to only 
collect SAEs between ICF and start of study treatment if they 
are assessed to be related to study participation, or related to 
a GSK product.
Collection of ALL SAEs between the signing of ICF and start of 
study treatment was agreed to be unnecessary.  The 
requirement has reverted to the GSK standard for the time 
period for collection of SAEs.
SoA, Section 8.1
Study flow adjusted so that participants that discontinue 
Adjusted in recognition of the fact that 12 weeks of post 
 
 
 
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Section # and Name
Description of Change
Brief Rationale
study treatment move directly into the 12-week post 
treatment follow up period rather than continuing for the 
remainder of the 12-week treatment period.
treatment follow up is sufficient for participants who discontinue 
study treatment. 
Synopsis, Overall 
Design, Section 3.1, 
5.1, 5.5, 7.1
Clarification provided that dosing at V2 can be performed up 
to 3pm, extended from 12midday in the previous protocol.
Extended in recognition that there a large number of 
assessments to be performed and Visits 1 and 2 prior to dosing.  
Accumulation of drug is observed in the repeat dose 
pharmacokinetics of nemiralisib of approximately at least 2-fold 
and therefore dosing up until 3:00 pm on Day 1 does not pose a 
risk of overdosing on Day 2 when the Day 2 dose is 
administered in the morning (as early as 6:00 am [i.e., 
approximately 15 hours after the previous day’s dose])
Section 6.2, 
Exclusion 9, Section 
9
Exclusion 9 clarified to allow randomisation ahead of receipt 
of virology results, with participants to be withdrawn if 
subsequently found to be positive.  Other sections updated to 
further explain this
Turnaround time of virology is greater than the 48h screening 
window
Synopsis,
Study Rationale, 
Section 5.1, 7.1
Start of SoC was defined
This was not clear previously
Section 7.1, Section 9
Clarified throughout that the time of randomisation is 
anchored to the start of SoC (i.e. 48hrs from start of SoC)
This was clarified because some sections anchored time of 
randomisation to completing screening assessments whilst 
other anchored time of randomisation to start of SoC which was 
difficult to interpret/manage.
SoA,
Section 9.1
Confirmation added that V1 and V2 can be combined and 
clarification given on what assessments to be done if V1 and 
V2 combined
Clarified following feedback from investigators
SoA
Removed requirement for Laboratory assessments at V2
Recognition that only one laboratory assessment is required 
prior to randomisation.
3.3 Benefit/Risk 
Assessment
Information about interaction with inhibitors of CYP304 
inhibitors and CYP3A4 substrates has been added
This risk was omitted previously
 
 
 
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Section # and Name
Description of Change
Brief Rationale
3.3 Benefit/Risk 
Assessment
Risk of patient s performing spirometry during a moderate or 
severe exacerbation has been added
Highlighted as a risk by Investigators. Benefit:Risk assessment 
remains unchanged.
Synopsis, Section 
5.1, 7.2, Appendix 3
Required membership of the iSRC has been adjusted.
Independent clinician with experience in respiratory and general 
medicine was agreed to be adequate by the safety group in 
place of a respiratory clinician and a cardiologist.
SoA
SoA updated to add IRT visit at Week 3
Previously omitted in error
Section 5.1
Definition of moderate and severe exacerbations added in 
Section 5.1 for clarity
Previously this was only in the appendix which could have been 
overlooked
Section 6.3.4
Clarification that if participants are unable to withhold their 
usual scheduled COPD medications on the day of a clinic 
visit the visit may still take place.
This was added to recognise the fact that some patients may 
not be able to withhold their usual COPD medications if 
experiencing an exacerbation.
Section 7.1
Clarification provided that treatment of subsequent 
exacerbations during the study do not need to follow the SoC 
definition for the Index exacerbation
Clarified following feedback by investigators
SoA, Section 7.6
The requirement to enter dose counter information, and date 
and time of each dose administered in the clinic into the 
eCRF in countries where the propeller health sensor is used 
has been added
Previously omitted in error
Section 7.7
Reference to prohibited CYP3A4 inhibitors and narrow
therapeutic index substrates added here directing the reader 
to Exclusion no. 13
Added so that important prohibited medication information is not 
missed.
Section 9
Central lab volumes updated in line with central lab 
specifications
Precise central lab volumes were not available at writing of the 
protocol
Section 9
Clarification added that local laboratory results must be 
received prior to randomisation to allow review of Exclusion 9 
and 18
This was not previously clear.
Section 9.1
Reminder added to the section on spirometry that rescue 
medication and usual daily COPD medications should be 
withheld on the moring of spirometry assessments
Added because this is an important element of the spirometry 
assessment.
 
 
 
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Section # and Name
Description of Change
Brief Rationale
Section 9.1
Clarification added that the first EXACT-PRO will be 
completed in the morning whilst for the remainder of the 
study it will be performed in the evening.
This is because it is important that at randomisation the 
EXACT-PRO is completed before any other assessments are 
completed.
Section 9.2.7,
Appendix 9
The section relating to DREs was simplified as previous 
wording was not clear.  Appendix 9 was updated in line with 
this.
To clarify how and when to record exacerbations, which are 
considered DREs, in the eCRF
Section 9.3
Text regarding the treatment of overdose was adjusted
To ensure that definition of an overdose and required actions 
are clear and appropriate for a double-blind study.
Section 9.4.1
Clarification added around when a complete physical exam is 
required and when a brief physical exam is required
Previously this was not documented in the protocol.
Section 9.4.2
Timing of vital signs was adjusted 
Previously it was not consistent with other sections.
Section 9.4.3
Paragraph referring to other QT correction formula has been 
removed
Previously this was inconsistent with other paragraphs/sections
Section9.4.3
Clarification added that a local ECG can be used to assess 
eligibility criteria however a central ECG must be performed 
at screening
This was implicit previously and so has ben mad explicit 
following feedback from investigators
Section 9.4.4, 
Appendix 2
Use of local labs at screening has been made mandatory
This is because the turnaround time of safety labs results from 
the central lab is longer than the 48hr screening window.
Section 9.4.4
Requirement to record non protocol specified local labs in the 
eCRF has been removed
There is no facility in the eCRF to record local labs
Seciton 10.2
Definition of All Patients Enrolled (APE) Population redefined
To define a more appropriate APE population in line with the 
RAP
Appendix 9
Further information provided for the definition of Severe 
COPD exacerbation
Clarified following feedback from Investigators
Various Sections
Repetition of information was removed from various sections 
To simplify the protocol
 
 
 
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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS.............................................................................................................12
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................23
3.
INTRODUCTION....................................................................................................29
3.1.
Study Rationale ..........................................................................................29
3.2.
Background ................................................................................................30
3.3.
Benefit/Risk Assessment ............................................................................34
3.3.1.
Risk Assessment .........................................................................35
3.3.2.
Benefit Assessment.....................................................................42
3.3.3.
Overall Benefit:Risk Conclusion...................................................42
4.
OBJECTIVES AND ENDPOINTS...........................................................................42
5.
STUDY DESIGN ....................................................................................................46
5.1.
Overall Design ............................................................................................46
5.2.
Number of Participants ...............................................................................49
5.3.
Participant and Study Completion...............................................................49
5.4.
Scientific Rationale for Study Design ..........................................................49
5.5.
Dose Justification........................................................................................50
6.
STUDY POPULATION...........................................................................................51
6.1.
Inclusion Criteria.........................................................................................51
6.2.
Exclusion Criteria........................................................................................52
6.3.
Lifestyle Restrictions...................................................................................57
6.3.1.
Meals and Dietary Restrictions ....................................................57
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................57
6.3.3.
Activity .........................................................................................57
6.3.4.
Medication Use Prior to/During Study Visits.................................57
6.3.5.
Environmental Exposure..............................................................58
6.4.
Screen Failures...........................................................................................58
7.
TREATMENTS.......................................................................................................59
7.1.
Treatments Administered............................................................................59
7.1.1.
Medical Devices...........................................................................62
7.2.
Dose Modification .......................................................................................62
7.3.
Method of Treatment Assignment ...............................................................62
7.4.
Blinding.......................................................................................................63
7.5.
Preparation/Handling/Storage/Accountability..............................................63
7.6.
Treatment Compliance................................................................................64
7.6.1.
12-Week Double-Blind Treatment Period.....................................64
7.6.2.
12-Week Post-Treatment Follow-up Period .................................65
7.7.
Concomitant Therapy..................................................................................65
7.7.1.
Permitted Medications and Non-Drug Therapies..........................65
7.7.1.1.
COPD Medications and Non-Drug Therapies .............65
 
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7.7.1.2.
Non-COPD Medications and Non-Drug 
Therapies ...................................................................67
7.7.2.
Prohibited Medications and Non-Drug Therapies.........................67
7.7.2.1.
COPD Medications and Non-Drug Therapies .............67
7.7.2.2.
Non-COPD Medications and Non-Drug 
Therapies ...................................................................67
7.8.
Treatment after the End of the Study ..........................................................67
8.
DISCONTINUATION CRITERIA.............................................................................68
8.1.
Discontinuation of Study Treatment ............................................................68
8.1.1.
Liver Chemistry Stopping and Follow-up Criteria .........................68
8.1.2.
QTc Stopping Criteria ..................................................................69
8.1.3.
Pneumonia ..................................................................................70
8.1.4.
Acute respiratory acidosis/invasive mechanical ventilation ..........70
8.1.5.
Other Safety Stopping Criteria .....................................................70
8.1.6.
Pregnancy ...................................................................................70
8.1.7.
Temporary Discontinuation ..........................................................70
8.1.8.
Rechallenge.................................................................................70
8.1.8.1.
Study Treatment Restart or Rechallenge....................70
8.2.
Withdrawal from the Study..........................................................................70
8.3.
Lost to Follow Up........................................................................................71
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................72
9.1.
Efficacy Assessments.................................................................................73
9.1.1.
Spirometry Testing.......................................................................74
9.1.2.
COPD Exacerbation ....................................................................75
9.1.3.
Patient-Reported Outcomes (PRO)..............................................75
9.1.3.1.
EXAcerbations of Chronic Pulmonary Disease 
Tool Patient (EXACT-PRO and Evaluating 
Respiratory Symptoms in COPD (E-RS: 
COPD)........................................................................75
9.1.3.2.
COPD Assessment Test (CAT) ..................................76
9.1.3.3.
St. George’s Respiratory Questionnaire for 
COPD Patients (SGRQ-C)..........................................77
9.1.3.4.
Rescue Medication Use..............................................77
9.2.
Adverse Events...........................................................................................78
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................78
9.2.2.
Method of Detecting AEs and SAEs.............................................78
9.2.3.
Follow-up of AEs and SAEs.........................................................79
9.2.4.
Regulatory Reporting Requirements for SAEs .............................79
9.2.5.
Adverse Events of Special Interest (AESI) – Post-
Inhalation Cough Immediately Following Dosing..........................79
9.2.6.
Cardiovascular and Death Events................................................80
9.2.7.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs...............................................80
9.2.8.
Pregnancy ...................................................................................81
9.2.9.
Medical Device Incidents (Including Malfunctions).......................81
9.2.9.1.
Time Period for Detecting Medical Device 
Incidents.....................................................................81
9.2.9.2.
Follow-up of Medical Device Incidents........................82
 
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9.2.9.3.
Prompt Reporting of Medical Device Incidents 
to Sponsor..................................................................82
9.2.9.4.
Regulatory Reporting Requirements for 
Medical Device Incidents............................................82
9.3.
Treatment of Overdose...............................................................................82
9.4.
Safety Assessments ...................................................................................83
9.4.1.
Physical Examinations.................................................................83
9.4.2.
Vital Signs....................................................................................83
9.4.3.
Electrocardiograms......................................................................83
9.4.4.
Clinical Safety Laboratory Assessments ......................................84
9.4.5.
Medical Problems and Concomitant Medications.........................85
9.5.
Pharmacokinetics .......................................................................................85
9.6.
Pharmacodynamics ....................................................................................86
9.7.
Genetics .....................................................................................................86
9.8.
Biomarkers .................................................................................................86
9.9.
Spontaneous Sputum .................................................................................86
9.10.
Health Care Resource Utilization (HCRU) and Health Economics ..............87
9.11.
Smoking Cessation Counseling ..................................................................87
10. STATISTICAL CONSIDERATIONS........................................................................88
10.1.
Sample Size Determination ........................................................................88
10.1.1.
Sample Size for Primary Objective: To Characterize the 
Dose Response of Nemiralisib when Administered in 
Addition to SoC on Change from Baseline in Clinic Visit 
FEV1 at Day 84............................................................................89
10.1.2.
Sample Size for Key Secondary Objective: To Evaluate 
Treatment Effect of Nemiralisib Compared with Placebo 
on the Rate of Exacerbations.......................................................91
10.2.
Populations for Analyses ............................................................................92
10.3.
Statistical Analyses.....................................................................................92
10.3.1.
Efficacy Analyses.........................................................................92
10.3.2.
Safety Analyses...........................................................................93
10.3.3.
Population PK..............................................................................94
10.3.4.
Pharmacokinetic/Pharmacodynamic Analyses.............................94
10.3.5.
Interim Analyses ..........................................................................94
11. REFERENCES.......................................................................................................96
12. APPENDICES......................................................................................................101
12.1.
Appendix 1: Abbreviations and Trademarks..............................................101
12.2.
Appendix 2: Clinical Laboratory Tests.......................................................104
12.3.
Appendix 3: Study Governance Considerations........................................106
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................111
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................117
12.6.
Appendix 6: Genetics................................................................................121
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ............................................................................................122
12.7.1.
Phase II Liver Chemistry Stopping Criteria.................................122
12.7.2.
Phase II Liver Chemistry Increased Monitoring Criteria 
with Continued Therapy.............................................................124
 
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12.8.
Appendix 8: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................125
12.9.
Appendix 9:  Guidelines for COPD Exacerbation Identification, 
Categorization, Reporting, and Treatment ................................................127
12.9.1.
Guidelines for Identifying an Acute Exacerbation of COPD........127
12.9.2.
COPD Exacerbation Severity.....................................................127
12.9.3.
Subsequent COPD Exacerbation(s)...........................................128
12.9.4.
Collection of COPD Exacerbation Data......................................129
12.9.4.1.
Guideline for Determining Exacerbation Onset 
and Resolution Dates ...............................................129
12.9.4.2.
Guideline for Assessing Multiple Mild 
Exacerbations...........................................................129
12.9.4.3.
Guideline for Assessing Exacerbations that 
Increase in Severity..................................................130
12.9.5.
Treatment of COPD Exacerbations............................................130
12.9.6.
Guidelines for Distinguishing Between Continuation of an 
Existing Exacerbation versus a Subsequent New 
Exacerbation..............................................................................130
12.9.7.
Pneumonia ................................................................................130
12.10. Appendix 10: Protocol Amendment History...............................................132
 
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1.
SYNOPSIS
Protocol Title: A Phase IIb, Randomized (Stratified), Double-Blind (Sponsor Open), 
Parallel-Group, Placebo-Controlled, Dose-Finding Study of Nemiralisib (GSK2269557) 
Added to Standard of Care (SoC) Versus SoC Alone in Participants Diagnosed with an 
Acute Moderate or Severe Exacerbation of Chronic Obstructive Pulmonary Disease 
(COPD)
Short Title: A Dose-Finding Study of Nemiralisib (GSK2269557) Added to Standard of 
Care (SoC) Versus SoC Alone in Participants Diagnosed with an Acute Moderate or 
Severe Exacerbation of Chronic Obstructive Pulmonary Disease (COPD)
Rationale:
GSK2269557 (hereafter referred to according to the generic name ‘nemiralisib,’ with the 
exception of reference to a previous study[ies] that used an earlier formulation of 
GSK2269557) is a potent and highly selective inhaled Phosphoinositide 3-Kinase Delta 
(PI3Kd) inhibitor being developed as an anti-inflammatory for the treatment of 
inflammatory airways disease. To date, nemiralisib has been administered to participants 
with an acute exacerbation of chronic obstructive pulmonary disease (COPD), asthma, 
and to healthy volunteers (both smokers and former smokers).
This study will be undertaken in COPD participants diagnosed with an acute moderate or 
severe exacerbation of COPD requiring treatment with SoC.  Standard of Care (SoC) for 
the index exacerbation is defined for this protocol as treatment with oral/systemic 
corticosteroid(s) (prednisone 40 mg/day or equivalent) for 5 days and antibiotic[s] for 7 
days; the dose and/or duration of prednisone (40 mg or equivalent) and/or the antibiotic 
can be modified according to the Investigator’s/medically qualified designee’s judgement 
or according to local country/institution practice.  The start of SoC is defined as the start 
of either oral/systemic corticosteroids[s] or antibiotic[s] whichever is earliest.
Participants will be treated with nemiralisib or placebo in addition to SoC.  The study is 
designed to assess the dose response, efficacy, safety, and pharmacokinetics of 
nemiralisib across a range of doses (up to 750 mcg) compared with placebo for 12 weeks, 
with an additional 12-week post-treatment follow-up period.  The range of doses to be 
evaluated in this study should be sufficient to enable full characterization of the dose 
response curve of nemiralisib, with respect to the primary endpoint (change from baseline 
in Clinic Visit trough forced expiratory volume in one second [FEV1] measured post-
bronchodilator at Day 84).  This study is also designed to estimate the rate reduction of 
re-exacerbations on a selected dose of nemiralisib compared with placebo.
The information obtained from study 200879 will be used to select the optimally 
effective and safe dose of nemiralisib for further COPD studies.  In addition, this study 
will evaluate and confirm the pharmacokinetic (PK) profile of nemiralisib within a subset 
of the patient population. 
 
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Objectives and Endpoints:
Objective
Endpoint
Primary
To characterize the dose response of 
nemiralisib administered in addition to SoC 
compared with placebo and SoC in participants 
diagnosed with an acute moderate or severe 
exacerbation of COPD
Change from baseline in Clinic Visit trough FEV1
at Day 84 measured post-bronchodilator
Baseline is defined as the post-bronchodilator 
FEV1 measured prior to the first dose of double-
blind study treatment on Day 1.
Secondary

To characterize the dose response, and 
efficacy, of nemiralisib administered in 
addition to SoC compared with placebo 
and SoC in participants diagnosed with an 
acute moderate or severe exacerbation of 
COPD

To evaluate the treatment effect of 
nemiralisib in addition to SoC compared 
with placebo and SoC on symptoms 
indicative of an exacerbation and on health 
status using Patient-Reported Outcomes 
(PROs) in participants diagnosed with an 
acute moderate or severe exacerbation of 
COPD

Rate of moderate and severe exacerbations 
over the 12-Week Treatment Period

Time to next moderate/severe exacerbation 
following index exacerbation.

Change from baseline in clinic visit trough 
FEV1 measured pre and post-
bronchodilator at Days 14, 28, 56, and 84 
(Day 84: post-bronchodilator is the primary 
endpoint; pre-bronchodilator is a secondary 
endpoint) and at hospital discharge (only 
for participants who are hospitalized for the 
index exacerbation)

Change from hospital discharge in clinic 
visit trough FEV1 measured pre- and post-
bronchodilator at Days, 14, 28, 56, and 84 
(in participants hospitalized for index 
exacerbation only)
EXAcerbations of Chronic Pulmonary Disease 
Tool (EXACT-PRO)

Proportion of participants achieving the 
EXACT definition of recovery from the index 
exacerbation by Days 14, 28, 56, and 84

Time to recovery from index exacerbation

Severity of subsequent Health Care 
Resource Utilization (HCRU)-defined 
moderate and severe exacerbation(s) 
defined by EXACT
 
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Objective
Endpoint

To evaluate the usage of rescue 
medication in participants diagnosed with 
an acute moderate or severe exacerbation 
of COPD

To evaluate the population 
pharmacokinetics of nemiralisib in 
participants diagnosed with an acute 
moderate or severe exacerbation of COPD

To assess the safety and tolerability of 
nemiralisib and placebo in participants 
diagnosed with an acute moderate or 
COPD Assessment Test (CAT)

Proportion of responders using the CAT at 
Treatment Days 28, 56, and 84, and 
following EXACT defined recovery from the 
index exacerbation

Change from baseline (Day 1) in CAT total 
score at Days 28, 56, and 84 and following 
EXACT defined recovery from the index 
exacerbation
St. George’s Respiratory Questionnaire (SGRQ) 
Total Score

Proportion of responders on the SGRQ total 
score as measured by the SGRQ for COPD 
Patients (SGRQ-C) at Days 28, 56, and 84

Change from baseline (Day 1) in SGRQ total 
score at Days 28, 56, and 84 

Rescue medication use (occasions/day), 
averaged over each week of treatment and 
over the 84-day treatment period.

The percentage of rescue-free days (24-
hour periods) during each week of treatment 
and over the 84-day treatment period

Plasma nemiralisib concentrations and 
derived PK parameters (e.g., area under the 
curve [AUC (0-24) and AUC(0-t)], maximum 
concentration [Cmax], time at maximum 
concentration [Tmax], Ctrough) as 
appropriate will be collected in a subset of 
randomized participants (approximately 300) 
at selected sites as follows: trough (pre-
dose) for the study treatment and post-dose 
for the study treatment from 0-1 hour and >1 
hour to 6 hours on Days 14 and 28 of the 
12-Week Treatment Period

Incidence of adverse events (AEs; including 
serious AEs and AE of Special Interest 
 
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Objective
Endpoint
severe exacerbation of COPD
[AESI])

Vital signs (pulse rate, systolic and diastolic 
blood pressure) (measured at each clinic 
visit up through Visit 7 [Day 112] or Early 
Withdrawal Visit)

12-lead electrocardiogram (ECG) 
assessments (performed at clinic Visits 1 
[Screening], 3 [Day 14], 6 [Day 84], and 7 
[Day 112] or Early Withdrawal Visit)

Clinical laboratory tests (hematology and 
chemistry; performed at each clinic visit up 
through Visit 7 [Day 112] or Early 
Withdrawal Visit)

Incidence of COPD exacerbations
Exploratory – 12-Week Treatment Period

To further characterize the dose response, 
and efficacy, of nemiralisib administered in
addition to SoC compared with placebo 
and SoC in participants diagnosed with an 
acute moderate or severe exacerbation of 
COPD

To evaluate the treatment effect of 
nemiralisib in addition to SoC compared 
with placebo and SoC on symptom stability 
following an exacerbation using Patient-
Reported Outcomes in participants 
diagnosed with an acute moderate or 
severe exacerbation of COPD

To explore the PK/PD relationship for 
nemiralisib

To evaluate the treatment effect of 
nemiralisib in addition to SoC compared 

Rate of mild exacerbations over the 12-
Week Treatment Period

Rate of all exacerbations (mild, moderate 
and severe combined) over the 12-Week 
Treatment Period

Time to next exacerbation (mild, moderate 
and severe combined)

Stability of symptoms post recovery 
measured using E-RS:COPD (Evaluating 
Respiratory Symptoms in COPD) and 
subscales from Randomization (Visit 2) to 
Day 84 (Visit 6)

Relationship between drug exposure and 
Pharmacodynamic responses (e.g. efficacy, 
heart rate, clinical laboratory analytes and 
blood biomakers) in the PK subset of 
participants (approximately 300) at selected 
sites.
 
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Objective
Endpoint
with placebo and SoC on HCRU in 
participants who experience a severe 
exacerbation of COPD

To evaluate the compliance with study 
treatment

To evaluate inflammatory markers in blood 
in relation to acute exacerbation of COPD

To evaluate inflammatory and infective 
markers in sputum in relation to acute 
exacerbation of COPD

Measures of HCRU related to severe 
exacerbations (e.g., hospitalizations, length 
of hospital stay, re-hospitalization within 30 
days, number of Emergency Room [ER] 
visits, etc.)

Number of actuations of the double-blind 
study treatment as measured by the clip-on 
Propeller Sensor (for countries where the 
Propeller Sensor for ELLIPTA is available)

Blood samples collected at Screening 
through Visit 7 (as part of the clinical 
laboratory blood samples) for analysis of 
blood eosinophil counts and inflammatory 
mediators

Blood samples for analysis of inflammatory 
biomarkers (including but not limited to: high 
sensitivity C-reactive protein [hs-CRP], 
chemokine interferon-inducible protein 10 
kDa (CXCL10)], and procalcitonin) collected 
at Visit 1 (Screening)

Spontaneous sputum sample for analysis of 
inflammatory and infective markers collected 
at Screening/Day 1 (pre-dose) and Day 56 in 
participants who are willing and able to 
provide a sample
 
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Objective
Endpoint
Exploratory – Post-Treatment Follow-Up 
Period
To evaluate the potential post-treatment impact 
of double-blind study medication during the 12-
Week Post-Treatment Follow-Up Period

Change from baseline (Day 84) in Clinic 
Visit trough FEV1 measured pre- and post-
bronchodilator at Day 112, 140, and 168 

Rate of moderate and severe COPD 
exacerbation(s) during the 12-Week Follow-
Up Period

Rate of moderate and severe COPD 
exacerbation(s) over the 24-week study 
duration

Time to next exacerbation following 
cessation of double-blind study treatment

Proportion of responders using the CAT at 
Days 112 and 168 

Change from baseline (Day 1) in CAT Total 
score at Days 112 and 168 

Proportion of responders on the SGRQ 
Total Score as measured by the SGRQ-C 
at Days 112 and 168

Change from baseline (Day 1) in SGRQ total 
score at Days 112 and 168

Severity of subsequent HCRU exacerbation 
defined by EXACT

E-RS: COPD and subscales from last dose 
of double-blind treatment

Rescue medication use up to Day 112
Overall Design:
This is a Phase IIb, multicenter, randomized, stratified, double-blind (Sponsor Open), 
placebo-controlled, parallel-group study in participants who present with an acute 
moderate or severe exacerbation of COPD requiring SoC.  Standard of Care (SoC) for the 
index exacerbation is defined for this protocol as treatment with oral/systemic 
corticosteroid[s] (prednisone 40 mg/day or equivalent) for 5 days and antibiotic[s] for 7 
days; the dose and/or duration of prednisone (40 mg/day or equivalent) and/or the 
antibiotic can be modified according to the Investigator’s/medically qualified designee’s 
judgement or according to local country/institution practice.  The start of SoC is defined 
as the start of either oral/systemic corticosteroids[s] or antibiotic[s] whichever is earliest. 
In addition to double-blind study treatment and SoC treatment for the COPD 
 
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exacerbation, other treatment(s) for the exacerbation (i.e., bronchodilators) and regular 
COPD maintenance therapy are permitted.
This study consists of a Screening Period, a 12-Week Treatment Period and a 12-Week 
Post-Treatment Follow-Up Period.  Participants will visit the hospital (participants who 
are hospitalized for the index exacerbation of COPD)/clinic a minimum of eight (if 
Screening and Randomization visit combined) to nine times over a 24-week period as 
shown in the Study Schematic below.  Randomization and the first dose of the double-
blind study treatment administration (Visit 2/Day 1) should take place in the morning, as 
soon as possible following determination of eligibility and completion of the baseline 
PRO measures, including the EXACT-PRO questionnaire for the day of randomization, 
and FEV1 measurement and no later than 48hrs after the start of SoC.
Note: In the event that completion of the assessments/procedures at Visit 2 (or in cases 
where Visit 1 and Visit 2 are conducted on the same day) extends past noon, the first dose 
of the double-blind study treatment administration may occur up until 3:00 pm on Day 1.  
After Day 1, dosing should take place in the morning each day through the end of the 12-
Week Double-Blind Treatment Period.  The total duration of study participation is 
approximately 6 months (170 days).
Study Schematic
QD=once daily; SoC=Standard of Care
1.
Inhalation Powder administered once-daily in the morning via the ELLIPTA inhaler 
2.
For this study, SoC for the index exacerbation is defined for this protocol as treatment of the COPD exacerbation 
with oral/systemic corticosteroid[s] (prednisone 40 mg/day or equivalent) for 5 days and antibiotic[s] for 7 days; 
the dose and/or duration of prednisone (or equivalent) and/or the antibiotic can be modified according to local 
Treatment Period (12-Weeks)
Clinic Visit: 1
25
3
4
5                        66      
   7
8
      97
Day:
-2 to -1  1       14 (3)   28 (3)      56 (-4/+3)
       84(-4/+3)     112 (-4/+3)      140 (-4/+3)      168 (-4/+3)
Screening (-2 to -1/0)
Placebo QD1 + SoC2 (N=340) 3,4
Nemiralisib 50 mcg QD1 + SoC2 (N=114)3,4
Nemiralisib 100 mcg QD1 + SoC2 (N=114) 3,4
Nemiralisib 250 mcg QD1 + SoC2 (N=114) 3,4
Nemiralisib 500 mcg QD1 + SoC2 (N=114) 3,4
Nemiralisib 750 mcg QD1 + SoC2 (N=340) 3,4
Post-Treatment
Follow-Up Period
(12 Weeks)
Nemiralisib 12.5 mcg QD1 + SoC2 (N=114)3,4
[ Nemiralisib 25 mcg QD1 + SoC 2,3,4,8]
 
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country/institution practice.  The start of SoC is defined as the start of either oral/systemic corticosteroids[s] or 
antibiotic[s] whichever is earliest
3.
Note: subjects may receive additional treatment[s] for the exacerbation (e.g., bronchodilator) and will be on a 
background of regular COPD maintenance therapy
4.
These figures are approximate and assume that no further adjustments to the randomization ratio are made.  The 
actual sample sizes at the end of the study may be different, depending upon whether changes are made 
following the results of the unblinded interim analysis which may modify the planned allocation.
5.
Randomization and first dose of double-blind (Sponsor Open) study treatment
6.
End of Treatment Period (last dose of double-blind [Sponsor Open] study treatment)
7.
Last day of study
8.
The option to add a dose strength of 25 mcg following the results of an unblinded interim analysis has been 
included if further characterization of the lower end of the dose response curve is required
PK Subgroup: Sparse PK sampling will be conducted at selected sites.  The PK 
Subgroup will be identical to the main study in terms of the study population, design, and 
conduct, with the exception of blood draws (3 per visit on Days 14 and 28) for PK 
analysis.
An internal Safety Review Committee (iSRC) will have study oversight to ensure that it 
meets the highest standards of ethics and participant safety and to carry out the planned 
interim safety data analyses/data reviews.  Data will be reviewed by the iSRC on a 
periodic basis, as defined in the iSRC Charter.  The iSRC, which will comprise a 
minimum of 3 people (including an independent statistician, and an independent clinician
with experience in respiratory and general medicine), will be authorized to review 
unblinded interim safety analyses/data during the study.
Number of Participants:
Approximately 1,667 participants will be screened (assumes an approximate 25% Screen 
Failure rate) to achieve approximately 1,250 randomized participants who present with an 
acute moderate or severe exacerbation of COPD, such that approximately 1,000 
participants (assumes an approximate 20% withdrawal rate) complete the 12-Week 
Treatment Period.  Randomization will be stratified by index COPD exacerbation 
severity (moderate or severe) and by whether or not that participant is in the PK 
Subgroup, to ensure a balance across treatments within each strata.  The plan is to 
randomize approximately 340 participants each to the placebo and nemiralisib 750 mcg 
groups and approximately 570 participants across the other nemiralisib groups.  The 
reason for inflating the sample size for a selected dose of nemiralisib (planned as the 750 
mcg dose) and the placebo group is for the aim to increase precision around the pair-wise 
comparison between them for the key secondary objective of the reduction in the rate of 
re-exacerbations.
Treatment Groups and Duration:
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the participant 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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This study consists of a Screening Period, a 12-Week Treatment Period and a 12-Week 
Post-Treatment Follow-Up Period.  Participants will visit the hospital/clinic a minimum 
of eight  to nine times over a 24-week period as shown in the Study Schematic above.  
Following determination of eligibility, participants will be randomized into the study at 
Visit 2 (Randomization/Day 1).  The total duration of study participation is 
approximately 6 months (170 days).
Participants will be required to participate in the following:
Screening (-2 to -1/0 Days Prior to Visit 2 [Randomization/Day 1]): Following 
diagnosis of an acute moderate/severe exacerbation of COPD during outpatient 
assessment by the Investigator, or designated physician, or during an Emergency 
Department visit or acute admission to hospital:
1. The start of the SoC for the index exacerbation is defined as the start of either 
oral/systemic corticosteroids[s] or antibiotic[s] whichever is earliest and is 
expected to start shortly after diagnosis, though it may already have been 
started before formal diagnosis of COPD exacerbation.  If SoC is started >48 
hours prior to diagnosis, the participant is not eligible to participate, but may 
be re-screened in the future as described in the main protocol.
2. All Screening/baseline assessments should be completed within 48hrs of start 
of SoC.
12-Week Double-Blind Treatment Period: Once-daily study treatment 
administration will start on Day 1 (Visit 2).
At the end of the Screening Period (-2 to -1/0 days), participants who meet all of the 
Inclusion Criteria and none of the Exclusion Criteria will complete Visit 2 
(Randomization Visit/Day 1).  If a participant meets all of the eligibility criteria, it is 
possible for him/her to complete the Screening Visit and the Randomization Visit on 
the same day (e.g., outpatient participant who presents with an acute moderate 
exacerbation of COPD).
At this visit, participants will be randomized to receive one of the doses of 
nemiralisib QD or placebo QD in addition to SoC for 12 weeks.  
Randomization and the first dose of the double-blind study treatment administration 
should take place in the morning, as soon as possible following determination of 
eligibility and completion of the baseline PRO measures, including the EXACT-PRO 
questionnaire for the day of randomization, and FEV1 measurement and no later than 
48hrs after the start of SoC.
Note: In the event that completion of the assessments/procedures at Visit 2 (or in 
cases where Visit 1 and Visit 2 are conducted on the same day) extends past noon, the 
first dose of the double-blind study treatment administration may occur up until 3:00 
pm on Day 1.  After Day 1, dosing should take place in the morning each day through 
the end of the 12-Week Double-Blind Treatment Period.
 
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Participants will be permitted to continue taking inhaled maintenance COPD 
medications (e.g., long-acting bronchodilators, long-acting beta2-
agonist/corticosteroid combinations, long-acting muscarinic antagonist/long-acting 
bronchodilator combinations, etc.).  Study-supplied rescue medication (albuterol 
[salbutamol] metered-dose inhaler [MDI] or nebules) for treatment of acute 
symptoms of COPD will also be permitted.  Other concomitant medications, may be 
allowed at the discretion of the GSK Medical Monitor and/or Investigator
Participants will then dose at home each morning until Day 84 (– 4 / + 3 days), with 
the exception of the days when participants come to the clinic. On those days, they 
will dose at the clinic. 
During the 12-week Treatment Period, participants will return to the clinic on an 
outpatient basis for Visits 3-6 on Study Days 14 (± 3 day), 28 (± 3 days), 56 (– 4 / + 3 
days) and 84 (– 4 / + 3 days) to complete the assessments described in the Schedule 
of Assessments.
Participants who withdraw from the study before completing the 12-week Treatment 
Period will be asked to return to the clinic within 24 hours (or as soon as possible) for 
end of treatment assessments (Early Withdrawal Visit).
If a participant is withdrawn from study treatment, he/she will continue existing 
maintenance COPD therapy or will be prescribed appropriate treatment for COPD 
and will move directly to the 12-Week Post-Treatment Follow-Up Period for 
collection of data starting with Visit 7, 28 days after the discontinuation of study 
treatment.
12-Week Post-Treatment Follow-up Period: The 12-week period following the last 
dose of double-blind study treatment.
During the 12-week Post-Treatment Follow-Up Period, participants will return to the 
clinic on an outpatient basis for Visits 7-9 on Study Days 112 (– 4 / + 3 days), 140 (–
4 / + 3 days), and 168 (– 4 / + 3 days) to complete the assessments described in the 
Schedule of Assessments.
Participants who withdraw from the study before completing the 12-week Post-
Treatment Follow-Up Period will be asked to return to the clinic within 24 hours (or 
as soon as possible) for end of study assessments (Early Withdrawal Visit).
Interim analyses may be performed, recruitment rate permitting, to potentially adapt the 
randomization ratio across the doses to help characterize the dose response profile of 
FEV1, to stop the study for futility, to assess the initial study assumptions and to change 
the proportions for the stratification of index exacerbation by severity (moderate or 
severe). 
Also, depending upon the findings of the iSRC reviews (See Appendix 3), participants in 
this protocol will continue to be randomized according to the current randomization 
schedule (i.e., 3:1:1:1:1:1:3) or randomization to a given study treatment arm(s) may be 
reduced/halted and the randomization allocation for the given study treatment arm(s) may 
 
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be re-allocated to another study treatment arm(s).  A dose strength of nemiralisib 25 mcg 
may be added following the results of an unblinded interim analysis if further 
characterization of the lower end of the dose response curve is required.
 
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2.
SCHEDULE OF ACTIVITIES (SOA)
12-Week Double-Blind Treatment Period
Procedure
Screening
Double-Blind Treatment Period
Early Withdrawal
Visit
1
2
3
4
5
6
Early Withdrawal
Day
-2 to -1
1
(Randomization)1
14
28
56
84
Visit window
N/A
3 days
3
days
- 4/+3 
days
- 4/+3 
days
Informed consent
X
PGx informed consent
X
Demography
X
Medical history (includes COPD history, COPD 
exacerbation history, substance usage and family 
history of premature CV disease
X
Chest X-Ray (or CT scan)
X
Past and current medical conditions (including
cardiovascular medical history and therapy history)
X
Register visit in IRT
X
X
X
X
X
EFFICACY ASSESSMENTS
Dispense eDiary and initiate training module within
X
Review eDiary
====================================================
Collect eDiary
X
EXACT2
====================================================
CAT3
X
X
X
X
X
SGRQ-C4
X
X
X
X
X
COPD exacerbation assessment
X
X
X
X
X
X
Clinic Visit FEV1
X5,6
X5
X5
X5
X5
X
 
 
 
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Procedure
Screening
Double-Blind Treatment Period
Early Withdrawal
Visit
1
2
3
4
5
6
Early Withdrawal
Day
-2 to -1
1
(Randomization)1
14
28
56
84
Visit window
N/A
3 days
3
days
- 4/+3 
days
- 4/+3 
days
SAFETY ASSESSMENTS
AE/SAE review
====================================================
Double-blind study treatment tolerability 
assessment (within 5 minutes immediately 
following dosing)
X
X
X
X
X
Concomitant medication review
X
X
X
X
X
X
X
Physical exam, including height and weight
X
X
X
X
X
X
X
Vital signs
X
X7
X7
X7
X7
X7
X
12-lead ECG
X8
X7,8
X7,8
X8
Laboratory assessments (including hematology 
and biochemisty)
X9
X7
X7
X7
X7
X
Hep B and Hep C screen
X10
HIV screen
X10
Serum pregnancy test (only WOCBP)
X
Urine pregnancy test (only WOCBP)
X11
X11
X11
X11
BIOMARKERS/GENETICS/SPUTUM/PHARMACOKINETICS
Blood sample for biomarker analysis
X12
X12
X12
Genetic sample
X13,14
Spontaneous sputum sample
X15
X15
Serial blood samples for PK analysis (selected 
sites only)
X13,16
X13,16
OTHER
Review smoking status
X
X
X
X
X
X
X
 
 
 
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Procedure
Screening
Double-Blind Treatment Period
Early Withdrawal
Visit
1
2
3
4
5
6
Early Withdrawal
Day
-2 to -1
1
(Randomization)1
14
28
56
84
Visit window
N/A
3 days
3
days
- 4/+3 
days
- 4/+3 
days
Smoking cessation counselling
X
X
X
X
X
X
X
Health Care Resource Utilization (HCRU) Review
==========================================================
STUDY TREATMENT/RESCUE MEDICATION
Inhaler and Propeller Sensor training
X17
Randomization
X18
Double-blind study drug administration18
=========================================
Assessment of study treatment compliance
X19
X19
X19
X19
X19
Rescue medication use20
====================================================
AM=morning; CAT=COPD Assessment Test; CV=cardiovascular; EXACT=EXAcerbations of Chronic Pulmonary Disease Tool; FEV1=forced expiratory volume in one second; 
HIV=Human Immunodeficiency Virus; IRT=Interactive Response Technology; PGx=pharmacogentics research; PK=pharmacokinetic; WOCBP=women of child-bearing potential
1.
If a participant meets all of the Inclusion Criteria and none of the Exclusion Criteria, it is possible for him/her to complete the Screening Visit and the Randomization Visit on the 
same day (e.g., outpatient participant who presents with an acute moderate exacerbation of COPD).  In this case, the following assessments/procedures only need to be 
conducted once: concomitant medication assessment, physical exam, vital signs (including height and weight), and review of smoking status and smoking cessation counselling.
2.
Subjects should complete the EXACT as follows: Visit 2: Completed during the Visit (prior to completing other study assessments/procedures); thereafter: completed daily in the 
evening
3.
Subjects should complete the CAT at the visits noted as well as 7 days post EXACT-defined day of recovery after index exacerbation (for the latter, the CAT will be triggered to 
appear in the e-Dairy on the evening following confirmation of recovery from an EXACT-defined event).; the CAT will be completed prior to the SGRQ-C and other study 
assessments/procedures
4.
Subjects should complete the SGRQ-C after completing the CAT and prior to other study assessments/ procedures
5.
Spirometry will be performed in the morning (i.e., initiated between 6:00AM and 12:00PM) prior to the first dose of double-blind study treatment (Day 1)/ pre-dose at trough 
(approximately 24 hours following the previous morning’s dose of double-blind study treatment [all other visits]) at two time points each: pre-bronchodilator and post-bronchodilator 
(approximately 10 to 30 minutes following treatment with albuterol [salbutamol], administered as either four inhalations via the metered-dose inhaler [MDI] (i.e., 400 mcg) with 
valved-holding chamber or one nebulized treatment)
6.
For participants hospitalized for the index exacerbation at Screening, spirometry (as noted in the bullet above) should also be performed in the morning on the day of discharge
7.
Pre-dose
8.
Single assessment
 
 
 
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9.
Screening: Due to the short screening window, local laboratory results will be used for purposes of determining subject eligibility for randomization. If local laboratory results are 
already available within 48 hours from diagnosis of the index COPD exacerbation, these results can be used for determination of subject eligibility; there is no need to take another 
sample for local analysis. A sample for central laboratory analysis should also be obtained.
10. Presence of hepatitis B surface antigen (HBsAg) and/or positive hepatitis C antibody test result at Screening or within 3 months prior to first dose of study treatment or positive test 
for HIV antibody is exclusionary.   NOTE: Participants with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C
RNA test is obtained.  Positive hepatitis C RNA test result at Screening or within 3 months prior to first dose of study treatment is exclusionary. NOTE: Hepatitis C RNA test is 
optional and participants with negative Hepatitis C antibody test are not required to also undergo Hepatitis C RNA testing.  Because of the short window for Screening, double-
blind study treatment may start before the results of the hepatitis and HIV tests have been received. If subsequently the test(s) is(are) found to be positive, the participant will need 
to be withdrawn from study treatment and may also be withdrawn from the study as judged by the Principal Investigator in consultation with the Medical Monitor.
11. If the urine pregnancy text result is positive, a blood sample for serum pregnancy testing will need to be conducted to confirm pregnancy status
12. Approximately 20 mL (4 teaspoons) of blood will be collected in all participants at each time point noted; at Screening, the sample should be collected as soon as possible after 
the participant has completed the informed consent and PRO assessments
13. Informed consent for optional sub-studies (e.g. genetics research, PK) must be obtained before collecting a sample/performing procedure
14. Collected at Visit 2 or any time post-randomization if unable to collect at Visit 2
15. A spontaneous sputum sample will be collected at Screening/Day 1 (pre-dose) and Day 56 in participants who are willing and able to spontaneously produce sputum
16. PK Subgroup: Subset of participants (approximately 300) at selected sites – blood samples will be collected on site at Visit 3 (Day 14) and Visit 4 (Day 28) at trough (pre-dose), 
between 0-1 hour post-dose and between >1 hour to 6 hours post-dose (total of 3 samples at each visit).
17. Inhaler and Propeller Sensor training conducted by reviewing the Patient Information Leaflet and Propeller Sensor Instructions for Use Guide, respectively, with the participant.  
Additional training may be conducted at the discretion of the Investigator.
18. Day 1: Randomization and the first dose of double-blind study treatment administration (Visit 2/Day 1) should take place in the morning, as soon as possible following 
determination of eligibility and completion of the baseline PRO measures, including the EXACT-PRO questionnaire for the day of randomization, and FEV1 measurement and no 
later than 24 hours after completing these assessments.
19. Daily recording via the clip-on Propeller Sensor for ELLIPTA and in the eCRF via review of the dose counter at Visits 3-6 (for countries where the Propeller Sensor for ELLIPTA is 
available) or in the eCRF only via review of the dose counter at Visits 3-6 (for countries where the Propeller Sensor for ELLIPTA is not available)
20. Daily recording via the clip-on Propeller Sensor for MDI and via the eDiary (for countries where the Propeller Sensor for MDI is available) or via the eDiary (for countries where the 
Propeller Sensor for MDI is not available or if nebulized albuterol [salbutamol] is used)
 
 
 
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SoA: 12-Week Post-Treatment Follow-Up Period
Procedure
Post-Treatment Follow-Up Period
Visit
7
8
9
Early Withdrawal
Day
Study Day 112 10
(Day 28 of the 
Follow-Up Period
Study Day 140 10
(Day 56 of the 
Follow-Up Period
Study Day 168 10
(Day 84 of the 
Follow-Up Period
Visit window
- 4/+3 days
- 4/+3 days
- 4/+3 days
EFFICACY ASSESSMENTS
Review eDiary
==============================================================
Collect eDiary
X
X
EXACT1
==============================================================
CAT2
X
X
X
SGRQ-C3
X
X
X
Clinic Visit FEV14
X
X
X
X
Rescue medication use5
X
SAFETY ASSESSMENTS
AE/SAE review
X
X
X
X
Concomitant medication review
X
X
X
X
COPD Exacerbation Assessment
X
X
X
X
Physical exam
X
X
Vital signs6
X
X8
12-lead ECG6,7
X
X8
Laboratory assessments (including hematology and 
biochemisty)6
X
X8
Urine pregnancy test (only WOCBP)
X9
X8
 
 
 
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Procedure
Post-Treatment Follow-Up Period
Visit
7
8
9
Early Withdrawal
Day
Study Day 112 10
(Day 28 of the 
Follow-Up Period
Study Day 140 10
(Day 56 of the 
Follow-Up Period
Study Day 168 10
(Day 84 of the 
Follow-Up Period
Visit window
- 4/+3 days
- 4/+3 days
- 4/+3 days
OTHER
Review smoking status
X
X
X
X
Smoking cessation counselling
X
X
X
X
Health Care Resource Utilization (HCRU) Review
< ==================================================================>
CAT=COPD Assessment Test; EXACT=EXAcerbations of Chronic Pulmonary Disease Tool; FEV1=forced expiratory volume in one second; IRT=Interactive Response Technology; 
WOCBP=women of child-bearing potential
1.
Completed daily in the evening
2.
Subjects should complete the CAT at the visits noted as well as 7 days post EXACT-defined day of recovery after exacerbation; the CAT will be completed prior to the SGRQ-C 
and other study assessments/procedures
3.
Subjects should complete the SGRQ-C after completing the CAT and prior to other study assessments/procedures
4.
Performed prior to dosing of concurrent COPD treatment(s) and pre-bronchodilator and post-bronchodilator (approximately 10 to 30 minutes following treatment with albuterol 
[salbutamol], administered as either four inhalations via the metered-dose inhaler [MDI] (i.e., 400 mcg) with valved-holding chamber or one nebulized treatment)
5.
Daily recording via the clip-on Propeller Sensor for MDI and via the eDiary (for countries where the Propeller Sensor for MDI is available) or via the eDiary only (for countries 
where the Propeller Sensor for MDI is not available or if nebulized albuterol [salbutamol] is used)
6.
Prior to dosing of concurrent COPD medication(s)
7.
Single assessment
8.
Procedure completed only if the Early Withdrawal Visit occurs prior to Day 112
9.
If the urine pregnancy text result is positive, a blood sample for serum pregnancy testing will need to be conducted to confirm pregnancy status
10. Participants who discontinue from study treatment will move directly into the 12-Week Post Treatment Follow Up Period starting with Visit 7.  Visits for these participants will not 
align to Day 112, 140, 168, rather will occur every 28 weeks following the study treatment discontinuation date.
 
 
 
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
The timing and number of planned study assessments, including efficacy 
(including PRO), safety, PK, biomarkers, health economics or medical resource 
utilization, or others assessments may be altered during the course of the study 
based on newly available data (e.g., to obtain data closer to the time of peak 
plasma concentrations) to ensure appropriate monitoring. 

Any changes in the timing or addition of time points for any planned study 
assessments, along with any changes to the randmisation including the possible 
addition of the 25mcg dose strength, must be documented and approved by the 
relevant study team member and then archived in the sponsor and site study 
files, but will not constitute a protocol amendment. The IRB/IEC will be 
informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the ICF.
3.
INTRODUCTION
3.1.
Study Rationale
Chronic obstructive pulmonary disease (COPD) refers to the two disease processes 
chronic bronchitis and emphysema.  Inflammation in the lung has been linked to the 
pathogenesis of COPD.  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 lung.  The inflammation associated with COPD is 
characterized by a prominent infiltration of neutrophils in lung tissue and the airways.  It 
is believed that the neutrophil, via elaboration of tissue destructive proteases and 
inflammatory mediators, plays a key role in the tissue destruction and decline in lung 
function that occurs in COPD.  
Phosphoinositide 3-Kinase Delta (PI3Kd), a lipid kinase expressed predominately in 
leukocytes, is thought to hold much promise as a therapeutic target for inflammatory 
conditions such as chronic obstructive pulmonary disease (COPD) and asthma.  PI3Kd is 
a member of the Class IA family of phosphoinositides 3-kinases (PI3Ks) that are 
involved in many cellular processes including cell growth, differentiation and migration. 
PI3Kd is thought to play a role in various epithelial responses relevant for the 
development of COPD.  Therefore, a PI3Kd inhibitor may suppress a number of these 
processes [Kim, 2010].  Macrophages appear to be alternatively activated in COPD and 
their competence to phagocytose infective pathogens is reduced as a result of this 
alternative action.  PI3Kd is one of the mediators involved in determining this alternative 
phenotype and therefore its inhibition could rebalance the macrophage activation towards 
a classic phagocytic phenotype [Weisser, 2011].  Macrophages would then be more 
competent in clearing bacterial infection, a major cause of exacerbations in COPD.  The 
neutrophil and T cell are the two major inflammatory cells types of COPD and both are 
targeted by PI3Kd inhibitors.  For example, a PI3Kd inhibitor prevents release of 
neutrophil elastase and reactive oxygen species (ROS) [Sadhu, 2003] and therefore could 
be useful in limiting tissue damage and prevent remodeling of the airways which leads to 
compromised lung function.  In contract, PI3Kd should not globally inhibit neutrophil 
functions required for innate immune defense such as phagocytosis and bacterial killing.
 
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PI3Kd inhibitors may also provide benefits in preventing infections by common airway 
bacterial pathogens such as S. pneumonia [Fallah, 2011].  In this report PI3Kd is shown 
to reduce the macrophage-derived cytokines required to mount an effective antibody 
response to S. pneumonia in the elderly.  Furthermore, PI3Kd inhibition restores age-
associated aberrant neutrophil migration [Sapey, 2014].  Activation of the PI3Kd 
pathway in critically ill patients has been linked to impairment neutrophil phagocytosis, 
which could be restored with a PI3Kd selective inhibitor [Morris, 2011].  Finally, PI3Kd 
activating mutations have recently been identified in groups of primary immunodeficient 
patients that suffer from viral infections and recurring lung bacterial infections due to 
mainly S. pneumonia and H. influenza.  This results in progressive pulmonary sepsis and 
increasing morbidity and mortality [Angulo, 2013; Lucas, 2014].
Nemiralisib is a potent and highly selective inhaled PI3Kd inhibitor being developed as 
an anti-inflammatory for the treatment of inflammatory airways diseases.  Therefore, it 
has the potential to be a novel therapy in patients with COPD.  
This double-blind (Sponsor Open) study is primarily designed to assess the dose 
response, efficacy and safety of six dose regimens of nemiralisib (12.5, 50, 100, 250, 500, 
and 750 mcg QD) and placebo in addition to standard of care (SoC) for 12-weeks in 
participants with COPD who present with a moderate or severe acute exacerbation of 
COPD. The option to add a dose strength of 25 mcg following the results of an unblinded 
interim analysis has been included if further characterization of the lower end of the dose 
response curve is required.
Standard of Care (SOC) for the index exacerbation is defined for this protocol as 
treatment with oral/systemic corticosteroid(s) (prednisone 40 mg/day or equivalent) for 5 
days and antibiotic[s] for 7 days; the dose and/or duration of prednisone (40 mg/day or 
equivalent) and/or the antibiotic can be modified according to the 
Investigator’s/medically qualified designee’s judgement or according to local 
country/institution practice.  The start of SoC is defined as the start of either 
oral/systemic corticosteroids[s] or antibiotic[s] whichever is earliest.  In addition, this 
study includes a 12-week Post-Treatment Follow-up Period to assess the potential benefit 
of nemiralisib following completion of treatment.
All study treatments will be administered once-daily in the morning (with the exception 
of Visit 2 where the dose may be administered up to 3:00pm, in cases where completion 
of the study assessments/procedures extends past noon) via the ELLIPTA inhaler with the 
clip-on Propeller Sensor (where available).  In addition to double-blind study treatment 
and SoC treatment for the COPD exacerbation, other treatment(s) for the exacerbation 
(i.e., bronchodilators) and regular COPD maintenance therapy are permitted. 
The information obtained from study 200879 will be used to select the optimally 
effective and safe dose of nemiralisib for further COPD studies.  In addition, this study 
will evaluate and confirm the pharmacokinetic (PK) profile of nemiralisib.
3.2.
Background
Chronic obstructive pulmonary disease (COPD) is a common, preventable and treatable 
disease that is characterized by persistent respiratory symptoms and airflow limitation 
 
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that is due to airway and/or alveolar abnormalities usually caused by significant exposure 
to noxious particles or gases [GOLD, 2017].  COPD is a major cause of disability, 
morbidity, and mortality, resulting in millions of deaths annually worldwide [GOLD, 
2017] contributing significantly to health care costs [Darnell, 2013; Chapman, 2006].  In 
the United States, COPD is now the third leading cause of death [National Center for 
Health Statistics, 2016].  The morbidity and mortality associated with COPD are 
continuing to increase.  Globally, it is estimated that about 3 million deaths were caused 
by COPD in 2015 (that is, 5% of all deaths globally in that year); and, by the year 2030, 
COPD is expected to be the third leading cause of death worldwide [WHO, 2016].
COPD is characterized by symptoms of chronic and progressive breathlessness (or 
dyspnea), cough, and sputum production which can be a major cause of disability and 
anxiety associated with the disease. Most COPD patients also suffer from periodic 
worsening of their COPD symptoms (COPD exacerbations).  COPD exacerbations 
account for a significant proportion of COPD-related and total health care costs and are 
associated with an accelerated decline in lung function, health status, and increased risk 
for mortality with the cumulative risk for a next exacerbation or mortality increasing with 
each successive exacerbation [Donaldson, 2006; Suissa, 2012].  Despite several available 
therapies that have been shown to impact COPD exacerbations, many COPD patients 
continue to experience exacerbations of their disease, resulting in a large unmet medical 
need.  Thus, therapies effective in further reducing COPD exacerbations and improving 
the respiratory symptoms associated with COPD will have a substantial impact on 
healthcare utilization and most importantly improvement in COPD patients' quality of 
life.
COPD refers to the two disease processes chronic bronchitis and emphysema, and 
inflammation in the lung has been linked to the pathogenesis of COPD.  In COPD, 
tobacco smoke, other irritants, and/or bacterial colonization activate epithelial cells and 
macrophages to release inflammatory mediators such as chemokines that attract 
neutrophils and T cells to the lungs.
Exacerbations in COPD are driven by episodes of acute inflammation, usually following 
a viral or bacterial infection.  The rate of moderate exacerbations (i.e., those treated with
antibiotics and/or oral corticosteroids), as reported in a large observational clinical cohort 
study of patients diagnosed with COPD in the United States and the United Kingdom 
(Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints,
ECLIPSE) was 0.99 per patient year [Hurst, 2010].  The rate of severe exacerbations (i.e., 
those resulting in hospital admission) from the same observational study was 0.22 per 
patient year [Hurst, 2010]. Between a quarter (25% [McGhan, 2007]) and half (50% 
[Corral-Gudino, 2011]) of patients hospitalized for a COPD exacerbation will be re-
hospitalized for another COPD exacerbation within the following 12 months. 
While current maintenance therapies may reduce the rate of moderate to severe 
exacerbations in patients with COPD, some patients are particularly susceptible to
repeated exacerbation events, resulting in frequent use of oral/systemic corticosteroids 
and/or antibiotics and, in some cases, recurrent hospital admissions.  This patient 
phenotype is referred to as ‘frequent exacerbator’ [Hurst, 2010].  ‘Frequent exacerbators’ 
are now recognized as a major phenotype of COPD [Wedzicha, 2013; Miravitlles 2013].  
 
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The ECLIPSE clinical cohort study demonstrated that the prevalence of ‘frequent 
exacerbators’ varies by severity of COPD, from 22% in patients with Moderate COPD 
(GOLD Stage 2) to 47% in patients with Very Severe COPD (GOLD Stage 4) [Hurst, 
2010].
Despite treatment, some patients do not regain their baseline lung function following a 
COPD exacerbation [Seemungal, 2000] and repeated events can lead to an accelerated 
decline in lung function, resulting in a worsening overall health related quality of life for 
patients and a significant burden on healthcare resources. 
COPD patients with a viral infection have a significantly increased risk of developing a 
secondary bacterial infection [George, 2014].  Moreover, exacerbating patients with co-
infections experience significantly increased lung impairment and longer hospitalizations 
[Papi, 2006].  There is an increased risk of a recurrent exacerbation during the first 8 
weeks following an initial moderate to severe exacerbation [Hurst, 2009].  Thus, there is 
an unmet need for novel therapies that can treat moderate to severe COPD exacerbations 
more effectively by reducing the duration and severity, and can then also prevent the 
occurrence of respiratory bacterial infections.  It is widely recognized that antibiotic 
resistance is a significant and growing global public health issue [Antibiotic Resistance. 
WHO Fact Sheet, 2016 (WHO, 2016), ; FDA: Combating Antibiotic Resistance, 
Consumer Health Information, 2011 (FDA, 2011); Public Health England ESPAUR 
Report, 2016 (ESPAUR, 2016)] and FDA and CHMP guidelines on development of 
drugs for treatment of bacterial infections [FDA, 2012; CPMP/EWP/558/95; 2011; 
EMA/CHMP/351889/2013, 2014] recognise the importance of the development of new 
anti-bacterials to human health; any medicine that has the potential to reduce the need for 
repeated courses of antibiotics will be an important addition to the treatment options in 
this setting.
PI3Kd is a lipid kinase expressed predominantly in leukocytes and thought to hold much 
promise as a therapeutic target for inflammatory respiratory conditions such as COPD 
and asthma [Barnes, 2003; Stark, 2015].  PI3Kd is a member of the Class IA family of 
phosphoinositides 3-kinases (PI3Ks) that are involved in many cellular processes, 
including cell growth, differentiation and migration.  PI3Ks 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. PI3Kd 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 PI3Kd 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. PI3Kd is thought to play a role in a number of epithelial responses relevant for 
the development of COPD. Therefore, a PI3Kd 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. PI3Kd is one of the mediators involved 
 
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in determining this alternative phenotype in macrophages and therefore it is proposed that 
inhibition of PI3Kd 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 PI3Kd inhibitors. 
Nemiralisib has demonstrated the ability to protect against and control bacterial 
infections in preclinical rodent models. This is coupled with recent observations that 
PI3Kd 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 PI3Kd has recently been characterized 
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 suggests that repeat dosing with nemiralisib could potentially 
reduce the impact of an acute exacerbation, or prevent the onset of a secondary 
exacerbation.
Proinflammatory cytokines have been reduced by nemiralisib, both in preclinical rodent 
bacterial models, and COPD patient samples treated in vitro.
To date, nemiralisib has been administered to:

Participants with COPD in three, Phase IIa studies:
o Completed Studies:

PII115119: A double-blind (sponsor unblind), placebo controlled, 
randomised, parallel group study to evaluate the safety, tolerability 
and pharmacokinetics of multiple doses of GSK2269557 
administered as a dry powder to COPD patients and assessment of 
dose response using sputum biomarkers.

PII116678: A randomised, double-blind (sponsor unblinded), 
placebo controlled, parallel-group, multicentre study to evaluate 
the efficacy and safety of GSK2269557 administered in addition 
to standard of care in adult subjects diagnosed with an acute 
exacerbation of Chronic Obstructive Pulmonary Disease
o Ongoing 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).

Participants with asthma in a concluded (i.e., study conduct complete, reporting 
ongoing), Phase IIa study
 
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o 201543: A multi-centre, randomised, double-blind, placebo-controlled, 
crossover study to investigate the efficacy, safety, and tolerability of 
repeat doses of inhaled GSK2269557 in adults with persistent, 
uncontrolled asthma

Participants with Activated Phosphoinositide 3-kinase Delta Syndrome (APDS), 
also referred to as p110delta-Activating mutation causing senescent T cells, 
Lymphadenopathy and Immunodeficiency (PASLI), in an ongoing, Phase IIa 
study (204745)

Healthy volunteers – smokers and non-smokers 
A detailed description of the chemistry, pharmacology, efficacy, and safety of nemiralisib 
is provided in the Nemiralisib (GSK2269557) Investigator’s Brochure (IB)/IB 
Supplement(s).
3.3.
Benefit/Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK2269557 can be found in the corresponding Nemiralisib (GSK2269557)
Investigator’s Brochure (IB)/IB Supplement(s).  The following section outlines the risk 
assessment and mitigation strategy for this protocol.
 
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3.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP): Nemiralisib
Bronchospasm
Inhaled treatment
Participants will be allowed to continue regular 
COPD treatments and have SoC.  More severe 
participants will have their treatment started in 
hospital. 
Mucosal irritancy
Detected in 13-week toxicology study in the dog
Participants will be regularly monitored for AEs 
and a participant eDiary kept. Thus far, mucosal 
irritancy has not been observed in clinical 
studies.
Post-inhalation cough immediately following 
inhalation of study treatment (nemiralisib)
In the Proof-of-Concept (PoC) study PII116678, 
which was conducted in 126 randomized 
participants from a population similar to this 
protocol and a previous formulation of nemiralisib 
(DISKUS formulation blended with only one 
excipient, lactose), there was a higher incidence 
of treatment-related, mild and moderate adverse 
events of cough (Preferred Term) reported 
immediately after dosing in exacerbating 
subjects in the nemiralisib DISKUS 1000 mcg 
QD group (n=22 [35%] compared exacerbating 
subjects in the placebo DISKUS group (n=2 
[3%]).  For the 22 subjects in the nemiralisib 
1000 mcg group, the events for 20 of the 
subjects were considered by the Investigator to 
be related to study treatment.  From the review 
of reported terms, cough often occurred 
To further evaluate this finding of post-inhalation 
cough immediately following dosing, during study 
Visits 2-6 in the 12-Week Double-Blind 
Treatment Period, Investigators (or medically 
qualified designees) will observe participants for 
post-inhalation cough within 5 minutes 
immediately following dosing.  If coughing is 
observed, details will be recorded in the source 
documentation and in the eDiary/eCRF.
In addition, outside of the clinic visits, 
participants will have the opportunity to report 
post-inhalation cough (as well as other changes 
in medical conditions/changes in medications) in 
the eDiary, which will be reviewed by the 
Investigator/medically qualified designee for 
reporting of any AEs/SAEs (See Section 9.2).
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
immediately after dosing and in some subjects it 
seemed to repeat on most of the dosing days.  
Cough was reported to be generally mild or 
moderate and resolved after stopping dosing.  
Three subjects (all in the nemiralisib DISKUS 
1000 mcg QD group) discontinued the study due 
to cough.  Additional details are provided in the 
Nemiralisib (GSK2269557) Investigator’s 
Brochure.
The ICF will inform participants that in previous 
clinical trials, post-inhalation cough has been 
reported following nemiralisib administration via 
the DISKUS inhaler and that the post-inhalation 
cough is considered at least possibly causally 
related to nemiralisib.  The ICF will instruct 
participants to promptly contact the investigative 
site if they experience post-inhalation cough, 
especially if the post-inhalation cough prevents 
them from correctly using the ELLIPTA inhaler, 
so that they can be further evaluated.
An internal Safety Review Committee (iSRC) will 
have study oversight to ensure participant safety 
in study 200879 (See Appendix 3).  Data 
(including data related to post-inhalation cough) 
will be reviewed by the iSRC on a periodic basis, 
as defined in the iSRC Charter, which is 
available upon request.
Nemiralisib may be a victim of cytochrome P450 
3A4 (CYP3A4) drug interactions
There is a risk that co-administration of 
nemiralisib with potent CYP3A4 inhibitors may 
increase systemic exposure to nemiralisib
Nemiralisib is an in vitro substrate of 
CYP3A4CyP3A4.  Currently only limited in vivo 
information is available on the in vivo metabolism 
of nemiralisib in humans.
In toxicology studies, no systemic toxicities were 
observed in any species following administration 
of nemiralisib via a variety of routes in studies of 
up to 3-month duration.  These studies included 
Co-administration with strong CYP3A4 inhibitors 
are not permitted.  Acute administration (up to 
14-day dosing) of some of the 3A4 inhibitors 
voriconazole, fluconazole, erythromycin and 
clarithromycin is, however, permitted.  The extent 
of drug interaction between these inhibitors and 
midazolam (as a very worst case) can be 
interrogated using the Washington database 
[Hachad, 2010].
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
systemic exposure at no adverse effect levels > 
approximately 10-fold the systemic exposure 
following the maximum proposed clinical dose of 
500 mcg.
Considering the low sub milligram maximum 
dose selected of 750 mcg, any impact on 
metabolic inhibition by CYP3A4 inhibitors to 
increasing systemic exposure to above those 
tested in early studies (at/up to 6400 mcg) is 
considered minimal
Changes in systemic exposure to midazolam on 
co-administration with voriconazole, fluconazole, 
erythromycin and clarithromycin are predicted as 
< 10-fold, which is judged to be a safe acute 
threshold for nemiralisib, considering the lack of 
systemic toxicology in animal studies.  
Itraconazole, ketoconazole, and ritonavir are fully 
excluded since changes in systemic exposure 
are predicted as > 10-fold.  Intravenous 
clarithromycin is permitted since the intravenous 
dose also reduces first pass exposure to the 
intestine and liver and it is only likely to be given 
for short durations.
It is not necessary to exclude CYP3A4 enzyme 
inducers since any resulting decrease in 
systemic exposure (due to upregulation of 
CYP3A4) will reduce systemic exposure, thus 
reducing the risk of systemic toxicity.
Nemiralisib may be a perpetrator of CYP3A4 
drug interactions due to the time dependent 
inhibition of 3A4 by nemaralisbib
There is a risk that co-administration of 
nemiralisib with potent narrow therapeutic 
CYP3A4 substrates may increase systemic 
exposure of the 3A4 substrate
Nemiralisib is time-dependent inhibitor of 
CYP3A4.  Although nemiralisib is a low dose 
inhaled drug, with predicted free Cmax at steady 
state < 1 nM, the influence of CYP3A4 time
dependent inhibition is yet to be fully explored.
Sensitive CYP3A4 substrates with narrow 
therapeutic range; alfentanil, cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus, and tacrolimus 
are contraindicated.  The use of theophylline 
however will be allowed, according to the 
approved label/Prescribing Information, via 
both intravenous and oral routes, since a 
mechanistic model constructed for nemiralisib, 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
when co-administered with theophylline, 
suggests a negligible effect on theophylline 
exposure.  Monitoring of participants receiving IV 
theophylline should be performed in line with 
normal practice.
Unknown risks to an embryo, fetus (unborn 
baby) or nursing infant
There are no studies with nemiralisib in pregnant 
women.
Nemiralisib did not cause gene mutation or 
chromosomal damage in a bacterial mutagen 
assay, in vitro mouse lymphoma L5178Y cell 
assay and an in vivo mouse micronucleus test.  
Results suggest that nemiralisib does not 
present a genotoxic hazard to humans.
No embryo-fetal development or fertility defects 
were observed in the female rat at doses up to 
25 mg/kg/day following subcutaneous (SC) 
injection.  Test article-related embryo-fetal 
toxicity was observed in the rabbit at the 
maximum dose of 11.2 mg/kg/day; the NOAEL 
for rabbit embryo-fetal development effects is 3.4 
mg/kg/day SC.
As specified in the protocol:

Women who are pregnant, lactating or are 
planning on becoming pregnant during the 
study are not eligible to participate in this 
study

Female participants must be 
postmenopausal or using a highly effective 
method for avoidance of pregnancy while in 
this study

If a female participant becomes pregnant 
during the study, she should let the study 
doctor know immediately. The study 
treatment will be stopped and the participant 
will not be allowed to continue in the study

For women of child-bearing potential, a 
serum pregnancy test will be included in the 
laboratory panel collected at the Screening 
(Visit 1).  For these participants, a urine 
pregnancy test will be performed during the 
12-week Treatment Period at Visits 4 (Day 
28), 5 (Day 56), 6 (Day 84) or Early 
Withdrawal Visit, and 7 (Day 112 of the 
study/Day 28 of the 12-week Follow-Up 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Period).  If the urine pregnancy test result is 
positive, serum pregnancy testing will be 
conducted to confirm pregnancy status.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Procedures
Shortness of breath, coughing, light headedness 
or fainting, and/or chest tightness during the 
spirometry measurements.
As specified in the informed consent form for this 
study, if any of these symptoms should occur, 
the participant will receive appropriate medical 
treatment.
Spirometry assessments performed during a 
moderate or severe COPD exacerbation.  
If a participant is unable to achieve the required 
standard of spirometry per Section 9.1.1 during a 
moderate or severe COPD exacerbation, they 
will be permitted to continue in the study. The 
protocol has anticipated that this is likely for 
hospitalised participants and therefore 
spirometry will be repeated at discharge for a 
secondary endpoint.
Feeling faint, or experiencing mild pain, bruising, 
irritation or redness at the injection site during 
the blood withdrawals
In rare cases, an infection where the needle 
entered the skin
The medically qualified site staff conducting the 
phlebotomy will follow standard medical practice 
to minimize these risks
Skin irritation from the ECG electrodes placed on 
the participant’s chest
The medically qualified site staff conducting the 
ECG measurement will follow standard medical 
practice for performing the ECG
Risk of radiation from a chest X-ray
As specified in the protocol:

A chest X-ray (CT scan), for purposes of 
determining participant eligibility, will be 
performed only at the Screening (Visit 1).
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy

A chest X-ray (conducted within 48 hours of 
diagnosis) for confirmation of a suspected 
case of pneumonia, is encouraged rather 
than required
 
 
 
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3.3.2.
Benefit Assessment
The outcomes of this study will provide information that may produce advances in 
knowledge of treatment of COPD, particularly the unmet need for more effective 
treatment of acute moderate and severe exacerbations of COPD, leading to a potential 
health benefit in the future for patients in this target population.  The outcomes of this 
study will also help to determine the lowest effective and safe dose(s) of nemiralisib to be 
evaluated in future studies of nemiralisib.
3.3.3.
Overall Benefit:Risk Conclusion
The benefit:risk for nemiralisib is supportive of further clinical evaluation in Phase IIb 
development. Study 200879 is designed to determine whether nemiralisib could have the 
potential as a new therapeutic option for the treatment of acute moderate and severe 
exacerbations of COPD. The data from this study will also provide information that may 
contribute to advances in the knowledge of acute exacerbations of COPD and may lead to 
a potential future health benefit in the clinical management of patients in this target 
population.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To characterize the dose response of 
nemiralisib administered in addition to SoC 
compared with placebo and SoC in 
participants diagnosed with an acute 
moderate or severe exacerbation of COPD

Change from baseline in Clinic Visit trough 
forced expiratory volume in one second 
(FEV1) at Day 84 measured post-
bronchodilator

Baseline is defined as the post-
bronchodilator FEV1 measured prior to the 
first dose of double-blind study treatment 
on Day 1.
Secondary

To characterize the dose response and 
efficacy of nemiralisib administered in 
addition to SoC compared with placebo and 
SoC in participants diagnosed with an acute 
moderate or severe exacerbation of COPD

Rate of moderate and severe exacerbations 
over the 12-Week Treatment Period

Time to next moderate/severe exacerbation 
following index exacerbation

Change from baseline in Clinic Visit trough 
FEV1 measured pre and post-bronchodilator 
at Days 14, 28, 56, and 84 (Day 84: post-
bronchodilator is the primary endpoint; pre-
bronchodilator is a secondary endpoint) and 
at hospital discharge (only for participants 
who are hospitalized for the index 
 
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Objectives
Endpoints

To evaluate the treatment effect of 
nemiralisib in addition to SoC compared 
with placebo and SoC on symptoms 
indicative of an exacerbation and on health 
status using Patient-Reported Outcomes 
(PROs) in participants diagnosed with an 
acute moderate or severe exacerbation of 
COPD

To evaluate the usage of rescue medication 
in participants diagnosed with an acute 
moderate or severe exacerbation of COPD
exacerbation)

Change from hospital discharge in clinic 
visit trough FEV1 measured pre- and post-
bronchodilator at Days, 14, 28, 56, and 84 
(in participants hospitalized for index 
exacerbation only)
EXAcerbations of Chronic Pulmonary Disease 
Tool (EXACT-PRO)

Proportion of participants achieving the 
EXACT definition of recovery from the index 
exacerbation by Days 14, 28, 56, and 84

Time to recovery from index exacerbation

Severity of subsequent HCRU-defined 
exacerbation(s) defined by EXACT
COPD Assessment Test (CAT)

Proportion of responders using the CAT at 
Treatment Days 28, 56, and 84, and 
following EXACT defined recovery from the 
index exacerbation

Change from baseline (Day 1) in CAT total 
score at Days 28, 56, and 84 and following 
EXACT defined recovery from the index 
exacerbation
St. George’s Respiratory Questionnaire (SGRQ) 
Total Score

Proportion of responders on the SGRQ total 
score as measured by the SGRQ for COPD 
Patients (SGRQ-C) at Days 28, 56, and 84

Change from baseline (Day 1) in SGRQ 
total score at Days 28, 56, and 84 

Rescue medication use (occasions/day), 
averaged over each week of treatment and 
over the 84-day treatment period

The percentage of rescue-free days (24-
 
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Objectives
Endpoints

To evaluate the population 
pharmacokinetics of nemiralisib in 
participants diagnosed with an acute 
moderate or severe exacerbation of COPD

To assess the safety and tolerability of 
nemiralisib and placebo in participants 
diagnosed with an acute moderate or 
severe exacerbation of COPD
hour periods) during each week of 
treatment and over the 84-day treatment 
period

Plasma nemiralisib concentrations and 
derived PK parameters (e.g., area under the 
curve [AUC (0-24) and AUC(0-t)], maximum 
concentration [Cmax], time at maximum 
concentration [Tmax], Ctrough) as 
appropriate will be collected in a subset of 
randomized participants (approximately 
300) at selected sites as follows: trough 
(pre-dose) for the study treatment and post-
dose for the study treatment from 0-1 hour 
and >1 to 6 hours on Days 14 and 28 of the 
12-Week Treatment Period

Incidence of adverse events (AEs; including 
serious AEs and AE of Special Interest 
[AESI])

Vital signs (pulse rate, systolic and diastolic 
blood pressure) (measured at each clinic 
visit up through Visit 7 [Day 112] or Early 
Withdrawal Visit)

12-lead electrocardiogram (ECG) 
assessments (performed at clinic Visits 1 
[Screening], 3 [Day 14], 6 [Day 84], and 7  
[Day 112] or Early Withdrawal Visit)

Clinical laboratory tests (hematology and 
chemistry; performed at each clinic visit up 
through Visit 7 [Day 112] or Early 
Withdrawal Visit)

Incidence of COPD exacerbations
Exploratory – 12-Week Treatment Period

To further characterize the dose response, 
and efficacy, of nemiralisib administered in 
addition to SoC compared with placebo and 
SoC in participants diagnosed with an acute 
moderate or severe exacerbation of COPD

Rate of mild exacerbations over the 12-
Week Treatment Period

Rate of all exacerbations (mild, moderate 
and severe combined) over the 12-Week 
Treatment Period

Time to next exacerbation (mild, moderate 
 
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Objectives
Endpoints

To evaluate the treatment effect of 
nemiralisib in addition to SoC compared 
with placebo and SoC on symptom stability 
following an exacerbation using Patient-
Reported Outcomes in participants 
diagnosed with an acute moderate or 
severe exacerbation of COPD

To explore the PK/PD relationship for 
nemiralisib

To evaluate the treatment effect of 
nemiralisib in addition to SoC compared 
with placebo and SoC on HCRU in 
participants who experience a severe 
exacerbation of COPD

To evaluate the compliance with study 
treatment

To evaluate inflammatory markers in blood 
in relation to acute exacerbation of COPD

To evaluate inflammatory and infective 
markers in sputum in relation to acute 
and severe combined)

Stability of symptoms post recovery 
measured using E-RS:COPD (Evaluating 
Respiratory Symptoms in COPD) and 
subscales from Randomization (Visit 2) to 
Day 84 (Visit 6)

Relationship between drug exposure and 
Pharmacodynamic responses (e.g. efficacy, 
heart rate, clinical laboratory analytes and 
blood biomakers) in the PK subset of 
participants (approximately 300) at selected 
sites.

Measures of HCRU related to severe 
exacerbations (e.g., hospitalizations, length 
of hospital stay, re-hospitalization within 30 
days, number of Emergency Room [ER] 
visits, etc.)

Number of actuations of the double-blind 
study treatment as measured by the clip-on 
Propeller Sensor (for countries where the 
Propeller Sensor for ELLIPTA is available)

Blood samples collected at Screening 
through Visit 7 (as part of the clinical
laboratory blood samples) for analysis of 
blood eosinophil counts and inflammatory 
mediators

Blood samples for analysis of inflammatory 
biomarkers (including but not limited to: high 
sensitivity C-reactive protein [hs-CRP], 
chemokine interferon-inducible protein 10 
kDa (CXCL10)], and procalcitonin) collected 
at Visit 1 (Screening)

Spontaneous sputum sample for analysis of 
 
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Objectives
Endpoints
exacerbation of COPD
inflammatory and infective markers 
collected at Screening/Day 1 (pre-dose) and 
Day 56 in participants who are willing and 
able to provide a sample
Exploratory – Follow-Up Period
To evaluate the potential post-treatment impact 
of double-blind study treatment during the 12-
Week Post-Treatment Follow-Up Period

Change from baseline (Day 84) in Clinic 
Visit trough FEV1 measured pre- and post-
bronchodilator at Day 112, 140 and 168

Rate of moderate and severe COPD 
exacerbation(s) during the 12-Week 
Follow-Up Period

Rate of moderate and severe COPD 
exacerbation(s) over the 24-week study 
duration

Time to next exacerbation following 
cessation of double blind study treatment

Proportion of responders using the CAT at 
Days 112 and 168

Change from baseline (Day 1) in CAT Total 
score at Days 112 and 168)

Proportion of responders on the SGRQ 
Total Score as measured by the SGRQ-C 
at Days 112 and 168

Change from baseline (Day 1) in SGRQ 
total score at Days 112 and 168

Severity of subsequent HCRU 
exacerbation defined by EXACT

E-RS: COPD and subscales from last dose 
of double-blind study treatment

Rescue medication use up to Day 112
5.
STUDY DESIGN
5.1.
Overall Design
This is a Phase IIb, multicenter, randomized, stratified, double-blind (Sponsor Open), 
placebo-controlled, parallel-group study in participants who present with an acute 
moderate or severe exacerbation of COPD requiring SoC.  
 
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Standard of Care (SoC) for the index exacerbation is defined for this protocol as 
treatment with oral/systemic corticosteroid[s] (prednisone 40 mg/day or equivalent) for 5 
days and antibiotic[s] for 7 days; the dose and/or duration of prednisone (40 mg/day or 
equivalent) and/or the antibiotic can be modified according to the 
Investigator’s/medically qualified designee’s judgement or according to local 
country/institution practice.  The start of SoC is defined as the start of either 
oral/systemic corticosteroids[s] or antibiotic[s] whichever is earliest.  
In addition to double-blind study treatment and SoC treatment for the COPD 
exacerbation, other treatment(s) for the exacerbation (i.e., bronchodilators) and regular 
COPD maintenance therapy are permitted.
Participants will be randomised in a ratio of 3:1:1:1:1:1:3 to receive placebo, or 
nemiralisib doses of 12.5 mcg, 50 mcg, 100 mcg, 250 mcg, 500 mcg or 750 mcg.  The 
option to add a dose strength of 25 mcg following the results of an unblinded interim 
analysis has been included if further characterization of the lower end of the dose 
response curve is required.
Patients will be stratified according to their index exacerbation: moderate or severe, and 
whether or not they are in the PK substudy.  The definition of moderate and severe 
exacerbations is given in Appendix 9:
This study consists of a Screening Period, a 12-Week Treatment Period and a 12-Week 
Post-Treatment Follow-Up Period.  Participants will visit the hospital /clinic a minimum 
of eight to nine times over a 24-week period as shown in Figure 1.  Randomization and 
the first dose of the double-blind study treatment administration (Visit 2/Day 1) should 
take place in the morning, as soon as possible following determination of eligibility and 
completion of the baseline PRO measures, including the EXACT-PRO questionnaire for 
the day of randomization, and FEV1 measurement and no later than 48hrs after the start 
of SoC.  
Note: In the event that completion of the assessments/procedures at Visit 2 (or in cases 
where Visit 1 and Visit 2 are conducted on the same day) extends past noon, the first dose 
of the double-blind study treatment administration may occur up until 3:00 pm on Day 1.  
After Day 1, dosing should take place in the morning each day through the end of the 12-
Week Double-Blind Treatment Period
For participants who are hospitalized:
1. If discharge takes place before day 11, participants must then visit the unit/clinic 
on Day 14 (± 3 day) (Visit 3) for assessments.
2. If discharge takes place between Day 11 and Day 17 (inclusive), the assessments 
planned for Day 14 (Visit 3) may be completed on the day of discharge.
On the day of discharge, FEV1 measurements should be performed in the morning prior 
to discharge, including pre-bronchodilator measurements and post-bronchodilator 
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The total duration of study participation is approximately 170 days.
Figure 1
Study Schematic
QD=once daily; SoC=Standard of Care
1.
Inhalation Powder administered once-daily in the morning via the ELLIPTA inhaler 
2.
For this study, SoC for the index exacerbation is defined for this protocol as treatment of the COPD exacerbation 
with oral/systemic corticosteroid[s] (prednisone 40 mg/day or equivalent) for 5 days and antibiotic[s] for 7 days; 
the dose and/or duration of prednisone (or equivalent) and/or the antibiotic can be modified according to local 
country/institution practice.  The start of SoC is defined as the start of either oral/systemic corticosteroids[s] or 
antibiotic[s] whichever is earliest
3.
Note: subjects may receive additional treatment[s] for the exacerbation (e.g., bronchodilator) and will be on a 
background of regular COPD maintenance therapy
4.
These figures are approximate and assume that no further adjustments to the randomization ratio are made.  The 
actual sample sizes at the end of the study may be different, depending upon whether changes are made 
following the results of the unblinded interim analysis which may modify the planned allocation
5.
Randomization and first dose of double-blind (Sponsor Open) study treatment
6.
End of Treatment Period (last dose of double-blind [Sponsor Open] study treatment)
7.
Last day of study
8.
The option to add a dose strength of 25 mcg following the results of an unblinded interim analysis has been 
included if further characterization of the lower end of the dose response curve is required
PK Subgroup: Sparse PK sampling will be conducted at selected sites.  The PK 
Subgroup will be identical to the main study in terms of the study population, design, and 
conduct, with the exception of blood draws (3 per visit on Days 14 and 28) for PK 
analysis.
An internal Safety Review Committee (iSRC) will have study oversight to ensure that it 
meets the highest standards of ethics and participant safety and to carry out the planned 
Screening (-2 to -1/0)
Treatment Period (12-Weeks)
Placebo QD1 + SoC2(N=340) 3,4
Nemiralisib 50 mcg QD1 + SoC2 (N=114)3,4
Nemiralisib 100 mcg QD1 + SoC2(N=114) 3,4
Nemiralisib 250 mcg QD1 + SoC2(N=114) 3,4
Nemiralisib 500 mcg QD1 + SoC2 (N=114) 3,4
Nemiralisib 750 mcg QD1 + SoC2(N=340) 3,4
Post-Treatment
Follow-Up Period
(12 Weeks)
Clinic Visit: 1
25
3
4
5
66
      7
8
      97
Day:
-2 to -1
1       14 (3)   28 (3)      56 (-4/+3)
         84(-4/+3)
112 (-4/+3)      140 (-4/+3) 168 (-4/+3)
Nemiralisib 12.5 mcg QD1 + SoC2(N=114)3,4
[ Nemiralisib 25 mcg QD1 + SoC2,3,4,8 ]
 
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interim safety data analyses/data reviews.  Data will be reviewed by the iSRC on a 
periodic basis, as defined in the iSRC Charter.  The iSRC, which will comprise a 
minimum of 3 people (including an independent statistician, and an independent clinician
with experience in respiratory and general medicine), will be authorized to review 
unblinded interim safety analyses/data during the study; see Section 10.3.5.
5.2.
Number of Participants
Approximately 1,667 participants will be screened (assumes an approximate 25% Screen 
Failure rate) to achieve approximately 1,250 randomized participants (assumes an 
approximate 20% withdrawal rate) such that approximately 1,000 participants complete 
the 12-week Treatment Period.  Randomization will be stratified by index COPD 
exacerbation severity (moderate or severe) and by whether or not that participant is in the 
PK Subgroup, to ensure a balance across treatments within each strata.
The plan is to randomize approximately 340 participants each to the placebo and 
nemiralisib 750 mcg groups and approximately 570 participants across the other 
nemiralisib groups.  The reason for inflating the sample size for a selected dose of 
nemiralisib (planned as the 750 mcg dose) and the placebo group is for the aim to 
increase precision around the pair-wise comparison between them for the key secondary 
objective of the reduction in the rate of re-exacerbations.
See Section 10.1 Sample Size Determination for additional details, including how 
screening failures and non-evaluable participants are defined.
5.3.
Participant and Study Completion
A participant is considered to have completed the Treatment Period, if he/she has 
completed the last on-treatment study visit (Visit 6) and completed the study if he/she has 
completed all phases of the study including the last scheduled study visit (Visit 9).
The end of the study is defined as the date of the last visit of the last participant in the 
study or last scheduled procedure shown in the Schedule of Activities (SoA) for the last 
participant in the trial globally.
5.4.
Scientific Rationale for Study Design
This study will use a multicenter, randomized, stratified, double-blind (Sponsor Open), 
parallel-group design.  This is a well-established design to evaluate the dose response, 
efficacy and safety of an investigational drug in this phase of development.  The 12-week 
Treatment Period duration detailed in this Protocol is considered adequate in order to 
evaluate efficacy (including lung function and PROs) in response to treatment 
intervention and to collect adequate safety measurements.  The choice of a lung function 
endpoint (change from baseline in Clinic Visit trough FEV1 at Day 84 measured post-
bronchodilator) as the primary efficacy endpoint is a robust, well established, and 
objective means of demonstrating efficacy.  The 12-Week Post-Treatment Follow-Up 
Period is considered adequate to evaluate efficacy and safety after study treatment has 
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PK samples from a subset of randomized participants will also be collected in this study.  
Defining the optimum dose for later stages of development can be made more efficient by 
understanding the variability in the PK of a drug.  In addition to the efficacy and safety 
endpoints, the study will evaluate the relationship between nemiralisib drug exposures 
and any other associated pharmacodynamic responses (e.g. efficacy, heart rate, clinical 
laboratory analytes and blood biomarkers).  
This study will include a placebo arm to allow a comprehensive determination of the 
dose-response and to measure the absolute effect of nemiralisib.  Inclusion of a placebo 
arm will also allow a more robust exploration of the therapeutic index of nemiralisib.
All participants in each of the nemiralisib treatment groups and in the placebo group will 
also receive SoC for their exacerbation of COPD and continue their regular COPD 
maintenance treatment throughout the study.
5.5.
Dose Justification
Six doses of nemiralisib (12.5, 50, 100, 250, 500, and 750 mcg QD) and placebo will 
initially be evaluated in this study. An additional dose strength of 25 mcg may be added 
following the results of an unblinded interim analysis if further characterization of the 
lower end of the dose response curve is required. This study will, in an adaptive manner,
aim to provide the data to select the minimal, optimally effective and safe dose of 
nemiralisib for use in further clinical studies of COPD. 
The range of doses (12.5 mcg to 750 mcg QD) of nemiralisib in this study was selected 
based upon the results of the Proof-of-Concept (PoC) study PII116678 (similar 
population) in combination with additional clinical study PK and PK/PD information in 
patients and healthy volunteers. The PD endpoint used for dose prediction is based upon 
pharmacology, in particular the expected effect on the inhibition of the target PI3Kd 
enzyme due to the lack of precedence for this target mechanism as well as the patient 
population.  Therefore, a dose predicted to achieve a certain level of target inhibition may 
not translate into the same level on downstream processes, in particular FEV1, for 
example.  Further information on these nemiralisib studies may be found in the 
Nemiralisib (GSK2269557) Investigator’s Brochures (IB). The 12.5 mcg dose is 
expected to result in <50% target inhibition within the dosing window which for an 
inhibitor is not expected to translate to any patient outcome measure. However; since the 
precise dose response relationship is unknown within the patient population, target 
inhibition levels of <50% will be explored.  The adaptive design of the study will allow 
the modification of the dose range based on efficacy. The nemiralisib 100 mcg, 250 mcg 
and 500 mcg doses are expected to achieve > 80% target inhibition and, therefore, could 
potentially define an efficacious dose level. The 750 mcg dose is included as a potential 
supra-therapeutic dose, to help establish the therapeutic index for nemiralisib and to 
assess whether or not an efficacy plateau has been achieved.  Data from this trial will 
enable a better understanding of the relationship of the target engagement prediction with 
the downstream translation to other more clinically relevant (e.g., FEV1) outcomes within 
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By evaluating a range of doses from 12.5 mcg to 750 mcg of nemiralisib, it will be 
possible to assess the dose response of nemiralisib as measured by change from baseline 
in FEV1.  The data will provide information in determining the therapeutic index of 
nemiralisib and in selecting the minimal effective and safe dose to be carried forward in 
the Phase III COPD program.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1. 40 to 80 years of age, inclusive, at Screening (Visit 1).
Type of Participant and Disease Characteristics
2. Diagnosis: An established clinical history of COPD in accordance with the definition 
by the American Thoracic Society/European Respiratory Society [GOLD, 2017] as 
follows: 
“Chronic obstructive pulmonary disease is a common, preventable and treatable 
disease that is characterized by persistent respiratory symptoms and airflow 
limitation that is due to airway and/or alveolar abnormalities usually caused by 
significant exposure to noxious particles or gases.”
3. Smoking History: Current or former cigarette smoker with a history of cigarette 
smoking of 10 pack-years.  Former smokers are defined as those who have stopped 
smoking for at least 6 months prior to Screening (Visit 1). 
Number of pack years = (number of cigarettes per day / 20) x number of years 
smoked) (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years 
both equal 10 pack-years) 
4. Current Acute Exacerbation of COPD: Acute exacerbation of COPD requiring an 
escalation in therapy to include oral/systemic corticosteroid(s) (prednisone 40 mg/day 
or equivalent) for 5 days and antibiotic(s) for 7 days; the dose and/or duration of 
prednisone (40 mg/day or equivalent) and/or the antibiotic can be modified according 
to the Investigator’s/medically qualified designee’s judgement or according to local 
country/institution practice.  Acute exacerbation to be confirmed by an experienced 
physician and to represent a recent worsening of at least two major and one minor 
symptoms, one major and two minor symptoms, or all 3 major symptoms.
I.
Major symptoms:
i. Subjective increase in dyspnea
 
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ii. Increase in sputum volume
iii. Change in sputum colour
II.
Minor symptoms:
i. Increased cough
ii. Increased wheeze
iii. Sore throat
iv. Colds (nasal discharge and/or nasal congestion)
v. Fever (oral temperature >37.5 C) without other cause
Weight
5. Body Mass Index: Body weight 45 kg and body mass index (BMI) within the 
range 16 – 35 kg/m2 (inclusive)
Sex
6. Male and female subjects are eligible to participate in the study.
a. Female participants: 
A female participant is eligible to participate if she is not pregnant (see Appendix 5), 
not breastfeeding, and at least one of the following conditions applies:
i.
Not a woman of childbearing potential (WOCBP) as defined in Appendix 5
OR
ii. A WOCBP who agrees to follow the contraceptive guidance in Appendix 5
during the 12-Week Double-Blind Treatment Period and for at least 5 half-
lives (10 days) after the last of double-blind study treatment.
Informed Consent
7. Capable of giving signed informed consent as described in Appendix 3, which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Asthma: Current diagnosis of asthma, according to the Global Initiative for 
Asthma [GINA, 2017]. Participants with a prior history of asthma are eligible if 
they have a current diagnosis of COPD.
 
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2.
Acute respiratory acidosis/invasive mechanical ventilation: pH < 7.30 or the 
need for invasive mechanical ventilation.
3.
Moderate/severe exacerbation of COPD for which SoC was started >48 
hours since diagnosis.
4.
Chest X-ray (or CT scan): A chest X-ray (or CT scan) that reveals evidence of 
clinically significant abnormalities not believed to be due to the presence of 
COPD.  A chest X-ray (or CT scan) must be taken at Screening (Visit 1).  For 
sites in Germany: if a chest X-ray (or CT scan) within 1 year of Screening (Visit 
1) is not available, approval to conduct a diagnostic chest X-ray (CT scan) will 
need to be obtained from the Federal Office for Radiation Protection (BfS). 
5.
Pneumonia: Clinically significant pneumonia, identified by chest X-ray (CT
scan) at Screening.
6.
Other respiratory disorders: A diagnosis of 1-antitrypsin deficiency as the 
underlying cause of COPD, active tuberculosis, lung cancer, clinically overt
bronchiectasis (Note: focal bronchiectasis is not exclusionary), sarcoidosis, 
pulmonary fibrosis (Note: focal fibrotic pulmonary lesions are not exclusionary), 
primary pulmonary hypertension, interstitial lung diseases, 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.
7.
Other diseases/abnormalities:  A history or current evidence of clinically 
significant and unstable disease such as cardiovascular (e.g., patients requiring 
implanted cardioverter defibrillator [ICD], pacemaker requiring a rate set 
>60bpm, uncontrolled hypertension, New Your Heart Association Class IV 
[NYHA, 1994], known left ventricular ejection fraction <30%), neurological, 
psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled 
diabetes or thyroid disease), peptic ulcer disease, or hematological abnormalities.  
Significant is defined as any disease that, in the opinion of the investigator, would 
put the safety of the subject at risk hrough participation, or which would affect the 
efficacy or safety analysis if the disease/condition exacerbated during the study.  
(Note: Participants with adequately treated and well controlled concurrent medical 
conditions (e.g. hypertension or noninsulin-dependent diabetes mellitus 
[NIDDM]) are permitted to be entered into the study).
8.
Lung resection: Having undergone lung volume reduction surgery or lung 
resection for any other reason e.g. lung carcinoma
 
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9.
Liver disease:

ALT > 2xULN

Total Bilirubin > 1.5xULN
i. Isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated 
and direct bilirubin <35%

Current or chronic history of liver disease or known hepatic or biliary 
abnormalities (with the exception of Gilbert’s syndrome or asymptomatic 
gallstones)

Presence of hepatitis B surface antigen (HBsAg) at Screening or within 3 
months prior to first dose of study treatment

Positive hepatitis C antibody test result at Screening or within 3 months prior 
to first dose of study treatment

Participants with positive Hepatitis C antibody due to prior resolved disease 
can be enrolled, only if a confirmatory negative Hepatitis C RNA test is 
obtained 

NOTE:  due to time taken to conduct Hepatitis B and C analysis, participants
may be randomised to the study before receiving these results.  If a participant
has a positive test result, they will need be withdrawn promptly from the 
study.
10.
Positive hepatitis C RNA test result at Screening or within 3 months prior to first 
dose of study treatment. NOTE: Test is optional and participants with negative 
Hepatitis C antibody test are not required to also undergo Hepatitis C RNA testing
11.
Cancer: Carcinoma that has not been in complete remission for at least 5 years. 
Carcinoma in situ of the cervix, squamous cell carcinoma and basal cell 
carcinoma of the skin are not excluded if the participant has been considered 
cured within 5 years since diagnosis.
12.
Contraindications: History of allergy or hypersensitivity to any of the study 
medications (e.g. beta-agonists, PI3Kd inhibitors) or excipients of the inhalation 
powder (e.g., lactose).  In addition, participants with a history of severe milk 
protein allergy that, in the opinion of the investigator, contraindicates the 
participant’s participation are excluded.
Prior/Concomitant Therapy
13.
Cytochrome P450 3A4:

Strong inhibitors of cytochrome P450 3A4: Currently, only limited in vivo
information is available on the in vivo metabolism of nemiralisib; and, the 
role of cytochrome P450s (CYPs) in the elimination of nemiralisib is based 
upon in vitro data.  In vitro studies indicate that nemiralisib is predominantly 
metabolised by CYP3A4 enzymes with minor contributions from CYP1A1, 
CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2J2.  Co-
administration of nemiralisib with CYP3A4 inhibitors may result in 
 
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increased systemic exposure to nemiralisib.  Regular or chronic treatment 
with medications that are considered strong inhibitors of CYP3A4 are not
permitted:
   Antiretrovirals including protease inhibitors (e.g., indinavir, nelfinavir, 
ritonavir, saquinavir, atazanavir)
   Oral antifungal treatments such as ketoconazole and itraconazole.  Short 
courses of up to 14 days are allowed for fluconazole and voriconazole, 
but chronic administrations are not permitted. It is recommended that 
posaconazole is used as the oral antifungal treatment of choice.  

Antibiotics such as telithromycin and troleandomycin (macrolide).  
Short courses up to 14 days are allowed for mibefradil (calcium channel 
blocker), erythromycin and clarithromycin (including intravenous 
clarithromycin) but chronic administrations are not permitted.  
Azithromycin may be used chronically and is recommended as the 
macrolide antibiotic of choice.

Anti-epileptic treatments; and anti-tuberculous therapy. 
These medications must all have been stopped at least 14 days prior to first 
dose of study treatment.

Sensitive narrow therapeutic index CYP3A4 substrates:  Nemiralisib is a 
time-dependent inhibitor of CYP3A4 and co-administration of CYP3A4 
substrates with nemiralisib may result in increased systemic exposure to the 
CYP3A4 substrate.  Regular or chronic treatment with medications that are 
considered sensitive narrow therapeutic index substrates of CYP3A4 are, 
therefore, not permitted:

Alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus and tacrolimus.

Intravenous and oral theophylline will be allowed according to the 
approved label/Prescribing Information, since a specific mechanistic 
model constructed for nemiralisib co-administered with theophylline, 
suggests a negligible effect of nemiralisib on theophylline exposure.  
Monitoring of patients receiving IV theophylline will be required in line 
with normal practice.
14.
Oxygen therapy: Chronic treatment with long-term oxygen therapy (LTOT) or 
nocturnal oxygen therapy required for >15 hours a day.  Oxygen prn use (i.e., 15 
hours per day) is not exclusionary. Oxygen use during an exacerbation is 
permitted.
15.
Immunosuppressive therapy: Chronic treatment with anti-Tumour Necrosis 
Factor (anti-TNF), anti-Interleukin-1 (anti-IL1), or any other immunosuppressive 
therapy within 60 days prior to the first dose of double-blind study treatment.
 
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Prior/Concurrent Clinical Study Experience
16.
Other investigational treatment: Any other investigational treatment within the 
following time periods prior to the first dose of double-blind study treatment in 
the current study: 30 days, 5 half-lives or twice the duration of the biological 
effect of the investigational product, whichever is longer.
Note: Participants who participated in a previously completed study and/or were 
withdrawn from an ongoing study that included/includes nemiralisib are excluded 
from participating in this study.
17.
Multiple other investigational treatment: Exposure to more than 4 
investigational medicinal products within 12 months prior to the first dose of 
double-blind study treatment in the current study.
Diagnostic assessments
18.
Abnormal Clinically Significant Laboratory Finding: 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.
19.
Abnormal Clinically Significant 12-Lead ECG: abnormal, clinically significant 
ECG finding (e.g. myocardial Infarction or demonstrating a clinically significant 
arrhythmia requiring treatment) at Screening (Visit 1) or upon repeat prior to 
randomization.
20.
QTcF: QTcF >480 msec for participants with or without Bundle Branch Block, 
based on averaged QTcF values of triplicate ECGs. 
21.
HIV antibody: A positive test for HIV antibody at Screening.
NOTE:  due to time taken to conduct HIV antibody analysis, participants may be 
randomised to the study before receiving these results.  If a participant has a 
positive test result, they will need be withdrawn promptly from the study
Other Exclusions
22.
Drug/alcohol abuse: Known or suspected history of alcohol or drug abuse within 
the last 2 years.
23.
History of regular alcohol consumption: Defined as an average weekly intake 
of >28 units for males or >21 units for females within 6 months of Screening 
(Visit 1).  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.
24.
Potential of non-compliance: Participants at risk of non-compliance, or unable to 
comply with the study procedures.  Any infirmity, disability, or geographic 
location that would limit compliance for scheduled visits.
 
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25.
Questionable validity of consent: Participants with a history of psychiatric 
disease, intellectual deficiency, poor motivation or other conditions that will limit 
the validity of informed consent to participate in the study.
26.
Affiliation with investigator site: Study investigators, sub-investigators, study 
coordinators, employees of a participating investigator or immediate family 
members of the aforementioned are excluded from participating in this study.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions
Participants will refrain from consumption of grapefruit or grapefruit juice, from the first 
dose of double-blind study treatment until the last dose of double-blind study treatment 
during the 12-week Treatment Period.
6.3.2.
Caffeine, Alcohol, and Tobacco
Participants will:

refrain from consuming drinks with high levels of caffeine such as tea, coffee, and
cola drinks, on the morning of study hospital/clinic visits and prior to and during 
the spirometry and 12-lead ECG assessment (and for 6 hours prior the start of 
dosing until after collection of the PK sample[s] during a given visit for 
participants in the PK subgroup).

abstain from consuming alcohol for 12 hours prior to and during the day when 
they visit the hospital/clinic and until their discharge/completion of the study visit 
on that day

refrain from smoking (including cigarettes [including electronic cigarettes/pipes, 
vaporizers, cigars, pipes) for at least 1 hour prior to and during the spirometry and 
12-lead ECG assessments (and until after collection of the PK sample[s] during a 
given visit for participants in the PK subgroup) conducted during the study 
hospital/clinic visits.
6.3.3.
Activity

Participants will abstain from strenuous exercise for 2 hours prior to spirometry and 
ECG assessments and before each blood collection for clinical laboratory 
tests/PK/biomarkers. Participants may participate in light recreational activities 
during the study visits (e.g., watching television, reading).
6.3.4.
Medication Use Prior to/During Study Visits
Participants will:

withhold the morning dose of usual scheduled COPD medications (permitted 
and/or blinded study treatment) on the morning of and prior to the start and 
 
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during the spirometry assessments, with the exception of albuterol [salbutamol] 
for post-bronchodilator spirometry assessment and if the usual COPD 
medication is required for treatment of an acute exacerbation of COPD

withhold the use of supplemental/rescue bronchodilator (e.g., albuterol 
[salbutamol]) for 4 hours prior to pre-bronchodilator spirometry assessments, 
unless required for treatment of an acute exacerbation of COPD
If participants are unable to withhold their usual scheduled COPD medications and/or 
bronchodilator, or the investigator determines participant safety would be at risk, then 
these can be administered and the visit should proceed.  However, spirometry should be 
delayed until at least 4 hours have elapsed since bronchodilator use, if possible, and if the 
spirometry testing remains within the appropriate time frame.
6.3.5.
Environmental Exposure
Participants will avoid exposure to cold air for 15 minutes prior to and during spirometry 
assessments.
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized into the study.  A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities.  Minimal information 
includes demography, screen failure details, eligibility criteria, any serious adverse events 
(SAEs), and protocol deviation(s) (if they occurred during the screening process).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be re-screened once for the following reasons:

Meeting Exclusion Criterion 3 -Moderate/severe exacerbation of COPD for 
which SoC was started >48 hours since diagnosis.  The re-screening visit must 
be conducted at least 6 weeks following the resolution date of that exacerbation 
and at least 6 weeks following the last dose of oral/systemic corticosteroids and 
after the participant has been diagnosed with a subsequent, acute moderate or 
severe exacerbation of COPD requiring SoC 

Meeting Exclusion Criterion 5 - Clinically significant pneumonia, identified by 
chest X-ray [CT scan] at Screening.  The re-screening visit must be conducted at 
least 6 weeks following the resolution date of the pneumonia, at least 6 weeks 
following the last dose of oral/systemic corticosteroid(s) and/or antibiotic(s) 
used to treat the pneumonia, and after the participant has been diagnosed with a 
subsequent, acute moderate or severe exacerbation of COPD requiring SoC

In rare instances, participants failing for other reasons may be eligible for re-
screening.
Re-screening of participants must be approved by the central GSK team prior to re-
screening.  Only one re-screening is allowed per participant.  Re-screened participants 
 
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must be assigned a new participant number and will be entered into the eCRF again.  Re-
screened participants must provide informed consent again and must meet all of the 
protocol-specified Inclusion Criteria and none of the Exclusion criteria and must repeat 
all of the Screening Visit procedures at the Re-Screen Visit to be eligible to continue to 
randomization.
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
7.1.
Treatments Administered
GSK Clinical Trials Supplies will provide the investigational products for use in this 
study.  All blinded study treatments will be delivered via the ELLIPTA.  The ELLIPTA 
will include the clip-on Propeller Sensor for ELLIPTA for countries where the Propeller 
Sensor for ELLIPTA is available.  The ELLIPTA provides a total of 30 doses.
Participants will be assigned to treatments in accordance with the randomisation schedule 
generated by Clinical Statistics, using validated internal software.  The randomization 
will be stratified by severity of the index exacerbation, moderate or severe (per 
definitions in Section 5.1 and Section 12.9), and by whether or not the participant is in 
the PK Subgroup.
Following Screening, eligible participants will be randomized (3:1:1:1:1:1:3) to receive 
placebo or one of the following six treatments, administered as one inhalation each 
morning for 12 weeks:

Placebo 

nemiralisib 12.5 mcg

[nemiralisib 25 mcg]*

nemiralisib 50 mcg

nemiralisib 100 mcg

nemiralisib 250 mcg

nemiralisib 500 mcg

nemiralisib 750 mcg
*  The additional dose strength of nemiralisib 25 mcg may be added following the results 
of an unblinded interim analysis if further characterization of the lower end of the dose 
response curve is required.
In accordance with the adaptive design of this protocol, randomisation ratios may change 
following results of an unblinded interim analysis.
 
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Double-blind study treatment will be started as soon as possible after screening and 
baseline assessments (e.g., EXACT, CAT, SGRQ, FEV1) are completed and should be 
within 48 hrs of the start of SoC.
Note: In the event that completion of the assessments/procedures at Visit 2 (or in cases 
where Visit 1 and Visit 2 are conducted on the same day) extends past noon, the first dose 
of the double-blind study treatment administration may occur up until 3:00 pm on Day 1.  
After Day 1, dosing should take place in the morning each day through the end of the 12-
Week Double-Blind Treatment Period.
In addition, all participants will receive rescue medication e.g., supplemental albuterol 
[salbutamol] MDI or nebules to be used on an as-needed basis throughout the study up 
through Visit 7.  MDI will include the clip-on Propeller Sensor for MDI for countries 
where the Propeller Sensor for MDI is available. For all sites, this medication will be 
sourced locally where possible.  After Visit 7, Investigators will prescribe appropriate 
rescue medication.
A web-based Interactive Response Technology (IRT) will be used to assign participants 
to treatment.
Descriptions of the investigational study treatments are provided in Table 1.
 
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Table 1
Descriptions of the Investigational Study Treatments
Study Treatment Name:
Nemiralisib ELLIPTA
Placebo ELLIPTA
Dosage formulation:
Nemiralisib succinate blended 
with lactose and magnesium 
stearate1
lactose
Unit dose 
strength(s)/Dosage 
level(s):
Dry Powder Inhaler (single-strip 
presentation unless otherwise 
noted) with 30 doses per inhaler
12.5 mcg or
[25 mcg]2
50 mcg or
100 mcg or
250 mcg or
500 mcg or
750 mcg (dual-strip ELLIPTA 
with 250 mcg/blister in one strip 
and 500 mcg/blister in the 
second strip)
Dry Powder Inhaler (single-strip 
presentation) with 30 doses per 
inhaler
Route of Administration 
Oral inhalation
Oral inhalation
Dosing instructions:
Inhale ONCE in the MORNING 
as directed 3
Inhale ONCE in the MORNING 
as directed 3
Packaging and Labeling
Study Treatment will be provided 
in a foil overwrap. Each foil 
overwrap will be labeled as 
required per country 
requirement. 
Study Treatment will be 
provided in a foil overwrap. 
Each foil overwrap will be 
labeled as required per country 
requirement.
Manufacturer
GlaxoSmithKline
GlaxoSmithKline
1.
Magnesium stearate 0.4% w/w of total drug product
2.
The option to add a dose strength of 25 mcg following the results of an unblinded interim analysis has been 
included if further characterization of the lower end of the dose response curve is required
3.
The first dose taken at randomisation may be in the early afternoon, up to 3:00pm to allow for all screening and 
randomisation assessments to be performed.
 
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7.1.1.
Medical Devices

There are no GSK-manufactured medical devices (or devices manufactured for GSK 
by a third party) provided for use in this study.

Other medical devices (not manufactured by or for GSK) provided for use in this 
study are the valved-holding chamber and the clip-on Propeller Sensor.

Instructions for medical device use are provided in the corresponding manufacturer’s 
instructions for use.

GSK medical device incidents, including those resulting from malfunctions of the 
device, must be detected, documented, and reported by the investigator throughout 
the study (see Section 9.2).
7.2.
Dose Modification
This protocol allows some alteration from the currently outlined dosing schedule as 
discussed in this section; however, the maximum daily dose of nemiralisib is not planned 
to exceed 750 mcg and the total number of participants to be randomized is not planned 
to exceed approximately 1,250.
Depending upon the findings of the iSRC reviews (See Appendix 3), randomization to a 
given study treatment arm(s) may be halted and the randomization allocation for the 
given study treatment arm(s) may be re-allocated to another study treatment arm(s).
Depending upon the findings of interim analyses adjustments to the randomization ratio 
across the nemiralisib doses may be made to help optimize the characterization of the 
dose response profile.
The additional dose strength of nemiralisib 25 mcg may be added following the results of 
an unblinded interim analysis if further characterization of the lower end of the dose 
response curve is required.
7.3.
Method of Treatment Assignment
All participants will be centrally randomized using an Interactive Response Technology 
(IRT).  Before the study is initiated, the log-in information and directions for the IRT will 
be provided to each site.
A centrally randomised schedule will be utilized to randomize participants into one of the 
seven treatment arms.  Participants will be stratified by severity of the index exacerbation 
(moderate or severe) and whether or not the participant will provide PK samples.  If 
required, additional schedules will be created for each change to the randomization ratios.
Study treatment will be dispensed at the study visits summarized in the SoA.
Returned study treatment should not be dispensed to the participants.
 
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7.4.
Blinding
The IRT will be programmed with blind-breaking instructions.  
The 12-Week Treatment Period will be a double-blind (Sponsor Open) study and the 
following will apply. 

The investigator or treating physician may unblind a participant’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 participant as judged by the 
investigator. 
Note: GSK must be notified of the decision to unblind. If GSK personnel are not 
contacted before the unblinding, the investigator must notify GSK as soon as 
possible after unblinding. The date and reason for the unblinding must be fully 
documented in the eCRF.  A participant will be withdrawn from study treatment if 
the participant’s treatment code is unblinded by the investigator
Specific members of the statistics and programming teams will have access to the 
unblinded randomization schedules, where participants are only unblinded once 
randomization has taken place and purely for the purposes of unblinded efficacy interim 
analyses.  Specific members of the study team (defined in the RAP and Study Results 
Dissemination Plan [SRDP]) will be presented unblinded summary level data at interim 
analysis time points (See Section 10.3.5).
Members of the iSRC will have access to the unblinded randomization schedules, where 
participants are only unblinded once randomization has taken place and purely for the 
purposes of unblinded safety review.  Members of the iSRC will be provided unblinded 
summary level data at interim analysis time points (See Section 10.3.5).  Members of the 
iSRC and method of receipt of data will be documented in the iSRC charter.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any participant with an SAE.  If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s treatment assignment, may be sent to investigators in 
accordance with local regulations and/or GSK policy.
7.5.
Preparation/Handling/Storage/Accountability
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.
2.
Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized site staff.
 
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3.
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study treatment 
are provided in the Study Reference Manual.
5.
Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  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.
6.
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
7.6.
Treatment Compliance
7.6.1.
12-Week Double-Blind Treatment Period

During study Visit 2 (Randomization Visit/Day 1) through Visit 6 (Day 84) during 
the 12-week Treatment Period, when participants are dosed at the site, they will 
receive study treatment directly from the investigator or designee, under medical 
supervision. The date and time of each dose administered in the clinic will be 
documented in the eCRF for all participants.  For countries where the clip-on 
Propeller Sensor for ELLIPTA is available, date and time of each dose administered 
in the clinic will also be captured via the Sensor.

Between study visits during the 12-week Treatment Period, when participants self-
administer study treatment at home, compliance with double-blind study treatment 
will be assessed by the study site staff by reviewing the dose counter on the 
ELLIPTA during the inhaler dispensing and return visits and by recording the 
compliance in the eCRF.  For countries where the clip-on Propeller Sensor for 
ELLIPTA is available, compliance will also be captured via the Sensor.  

A record of the number of ELLIPTA inhalers dispensed to and taken by each 
participant must be maintained and reconciled with study treatment and compliance 
records.  Treatment start and stop dates, including dates for treatment delays will also 
be recorded in the eCRF.
Participant compliance with double-blind study treatment will be assessed at Visits 3 
through 6, by reviewing the clip-on Propeller Sensor for ELLIPTA data (for countries 
where the Propeller Sensor for ELLIPTA is available) or by reviewing the dose counter 
on the ELLIPTA (countries where the Propeller Sensor for ELLIPTA is not available).  
Participants must be ≥80% to ≤120% compliant in taking study treatment between-on-
treatment visits.  Participants who fall outside this range should be re-educated on 
treatment compliance by their site.  This re-education should be documented in the 
participant’s source document.  If the double-blind study treatment is prematurely 
discontinued during the 12-Week Double-Blind Treatment Period or study treatment 
 
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compliance repeatedly falls outside of acceptable ranges, the study sponsor/site monitor 
must be contacted to discuss participant eligibility for continued participation in the 
study.
7.6.2.
12-Week Post-Treatment Follow-up Period
During the 12-week Post-Treatment Follow-up Period, there will not be any formal 
assessment of compliance.  However, all concomitant medications (COPD and non-
COPD) will be captured in the source documents and eCRF.
7.7.
Concomitant Therapy
For participants who are randomized, any medication or vaccine (including over-the-
counter or prescription medicines, vitamins, and/or herbal supplements) that the 
participant is receiving at the time of enrollment (Screening Visit) or receives during the 
study (including the 12-week Double-Blind Treatment Period and the 12-week Post-
Treatment Follow-up Period) must be recorded in the source documents and eCRF along 
with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
In addition, all COPD medications taken within 3 months prior to Visit 1 (Screening) 
should be recorded in the participant’s source and in the eCRF.  
7.7.1.
Permitted Medications and Non-Drug Therapies
7.7.1.1.
COPD Medications and Non-Drug Therapies

To be eligible for this protocol, at Screening, participants must present with a 
moderate or severe  acute exacerbation of COPD requiring treatment with SoC.  
Standard of Care (SoC) for the index exacerbation is defined for this protocol as 
treatment with oral/systemic corticosteroid[s] (40 mg/day prednisone or 
equivalent) for 5 days and antibiotic[s] for 7 days, to be confirmed by an 
experienced physician (See Inclusion Criterion 4); the dose and/or duration of 
prednisone (40 mg/day or equivalent) and/or the antibiotic can be modified 
according to the Investigator’s/medically qualified designee’s judgement or 
according to local country/institution practice.  The start of SoC is defined as the 
start of either oral/systemic corticosteroids[s] or antibiotic[s] whichever is 
earliest. SoC must be documented in the participant’s source documentation and 
in the eCRF.  The use of other medications for treatment of the index COPD 
exacerbation and any subsequent COPD exacerbation(s), if applicable, is at the 
discretion of the Investigator or medically qualified health care personnel.  Use 
 
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of medication for treatment of subsequent exacerbations does not need to follow 
the SoC requirements for the Index exacerbation. 

In addition, participants are allowed to continue their regular COPD treatments 
(e.g., long-acting bronchodilators, long-acting beta2-agonist/corticosteroid 
combinations, long-acting muscarinic antagonist/long-acting bronchodilator 
combinations, etc.) for the duration of the study (including the 12-Week Double-
Blind Treatment Period and during the 12-Week Post-Treatment Follow-Up 
Period).  However, participants must withhold the morning dose of usual 
scheduled COPD medications (permitted and/or double-blind study treatment) 
on the morning of and prior to the start and during the spirometry assessments, 
with the exception of albuterol [salbutamol] for post-bronchodilator spirometry 
assessment and if the usual scheduled COPD medication is needed for treatment 
of an acute exacerbation of COPD, where possible.
o
Note: Modification(s) of the dosing regimen for the regular COPD 
treatments is(are) permitted as deemed medically appropriate by the 
Investigator/medically qualified designee; the modifications will be 
recorded in source documents and eCRF

Other concomitant COPD medications may be allowed at the discretion of the 
Investigator following consultation with the GSK Clinical Investigation 
Leader/Medical Monitor, with the exception of short-acting anticholinergics for 
use as rescue medication (See Section 7.7.2.1).

Oxygen for intermittent use or PRN therapy ≤15 hours per day is allowed.  
LTOT or nocturnal oxygen therapy required for >15 hours is excluded 
throughout the study.
The study site will supply each randomized participant with albuterol [salbutamol] MDI 
for use in performing the post-bronchodilator FEV1 assessments and as rescue medication 
for use as needed throughout the 12-Week Treatment Period for treatment of acute 
symptoms of COPD.  Albuterol [salbutamol] will be provided locally by GSK. In 
addition, participants may use albuterol [salbutamol] nebules if they have a nebulizer.
Although the use of rescue albuterol [salbutamol] medications is allowable at any time 
during the study, its use should be delayed for at least 4 hours prior to completing the pre-
bronchodilator spirometry assessments, unless required for treatment of an acute 
exacerbation of COPD.  The participants’ use of the study-supplied albuterol 
[salbutamol] will be captured via the clip-on Propeller Sensor for MDI (for countries 
where the Propeller Sensor for MDI is available) or via the eDiary (for countries where
the Propeller Sensor for MDI is not available or for participants who are supplied 
nebulized albuterol [salbutamol]).
For assessment of change from baseline in Clinic Visit FEV1 post-bronchodilator, the 
bronchodilator will be standardized as albuterol [salbutamol], administered as either four
inhalations via the MDI (i.e., 400 mcg) with valved-holding chamber or one nebulized 
treatment.  It is anticipated that participants who are enrolled into the study will receive 
albuterol as part of the routine treatment of AECOPD during visit 2. In this instance 
 
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spirometry should be scheduled to coincide with this treatment to allow post-
bronchodilator recordings to be measured.
7.7.1.2.
Non-COPD Medications and Non-Drug Therapies
All medications for other disorders are permitted as long as the dose remains constant 
wherever possible and their use would not be expected to affect the efficacy (especially 
lung function) or safety assessments.
The use of a continuous positive airway pressure (CPAP) device or non-invasive positive 
pressure ventilation (NIPPV) is permitted during the study, provided that this therapy was 
initiated prior to Screening and the participant is on a stable regimen.  If CPAP or NIPPV 
therapy is initiated during the 12-Week Double-Blind Treatment Period, the participant 
will need to be withdrawn from double-blind study treatment but can continue in the 
study for collection of data.  Patients that require acute use of CPAP or NIPPV may not 
be enrolled.  Use of this therapy is to be recorded in the source document and eCRF. 
Participation in the acute or maintenance phase of a Pulmonary Rehabilitation Program 
during the study (double-blind Treatment Period and/or Post-Treatment Follow-up 
Period) is permitted.  Participation is to be recorded in the source document and eCRF.
7.7.2.
Prohibited Medications and Non-Drug Therapies
7.7.2.1.
COPD Medications and Non-Drug Therapies
Short-acting anticholinergics (e.g., ipratropium bromide) for use as a rescue medication 
are excluded from the Screening Visit through completion of Visit 7, unless required for 
treatment of an acute exacerbation of COPD if albuterol [salbutamol] is not prescribed or 
readily available. If medically appropriate, the use of the rescue anticholinergic up 
through Visit 7 may be replaced with the study-provided albuterol [salbutamol] MDI at 
the discretion of the Investigator/medically qualified designee.
7.7.2.2.
Non-COPD Medications and Non-Drug Therapies
Concomitant use of strong inhibitors of cytochrome P450 3A4 and concomitant use of 
sensitive narrow therapeutic index CYP3A4 substrates is not permitted.  See Section 6.2
Exclusion Criteria 13 for detail.
7.8.
Treatment after the End of the Study
GSK will not provide treatment after the end of the 12-week double-blind treatment 
period.  The Investigator is responsible for ensuring that consideration has been given to 
the care of the participant’s medical condition on completion of 12-week double-blind 
treatment period.
Participants will be prescribed appropriate COPD therapy at the completion of Visit 6 or 
at the Early Withdrawal Visit, which may or may not be the usual COPD daily 
medication that form their maintenance therapy during the 12-week treatment period.
 
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8.
DISCONTINUATION CRITERIA
A participant may voluntarily discontinue participation in this study at any time 
(including during the Screening Period, the 12-Week Double-Blind Treatment Period or 
during the 12-Week Post-Treatment Follow-Up Period).  The Investigator may also at 
his/her discretion discontinue a participant from this study at any time.  Every effort 
should be made by the Investigator to keep the subject in the study.
Participants who are withdrawn from the study will not be replaced and cannot be re-
screened.
The primary reason for subject withdrawal will be recorded in the eCRF (see Section 
8.2). 
8.1.
Discontinuation of Study Treatment
A participant may be discontinued from study treatment but continue in the study for 
collection of data (including efficacy and safety data) and to minimize missing data.  
Participants who discontinue from study treatment will move directly into the 12-Week 
Post Treatment Follow Up Period starting with Visit 7, 28 days following the 
discontinuation date.
If a higher than expected number of participants prematurely discontinues double-blind 
study treatment or prematurely discontinues from the study, additional participants may 
be randomized, at the discretion of the Sponsor.
8.1.1.
Liver Chemistry Stopping and Follow-up Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). These protocol guidelines are in alignment 
with FDA premarketing clinical liver safety guidance: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Discontinuation of study treatment for abnormal liver tests is required when:
a participant meets one of the conditions outlined in the algorithm below
in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study treatment discontinuation is in the 
best interest of the participant. 
 
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Figure 2
Liver Chemistry Stopping and Increased Monitoring Algorithm
Refer to Appendix 7 for required Liver Safety Actions and Follow-Up Assessments.
8.1.2.
QTc Stopping Criteria
In this study, GSK is contracting with an external vendor to provide standardized 12-lead 
ECG equipment and centralized ECG overreads for all participating sites (Section 9.4.3).  
The same QT correction formula (Fridericia’s) must be used throughout the study for all 
participants.  Safety ECGs and other non-protocol specified ECGs are an exception.
The QTc criteria should be based on the averaged QTc value of triplicate ECGs obtained 
over a brief (e.g., 5-10 minute) recording period. 
A participant who meets either bulleted criteria based on the average of triplicate ECG 
readings will be withdrawn from study treatment:

QTc >530 msec (with or without underlying Bundle Branch Block) OR Uncorrected 
QT >600 msec

Change from baseline of QTc > 60 msec
 
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In addition, participants should be excluded (Screening) or be discontinued from study 
treatment if they have an abnormal, clinically significant ECG finding as defined in the 
ECG manual.
8.1.3.
Pneumonia
Presumptive diagnosis or radiographically confirmed (See definition in “COPD 
Exacerbation” Section 9.1.2) requires discontinuation of study treatment.
If a subject is withdrawn due to pneumonia, the AE/SAE section and the pneumonia/
chest X-ray section, if applicable, of the eCRF should be completed and the subject 
should be followed until clinical resolution of the pneumonia.
8.1.4.
Acute respiratory acidosis/invasive mechanical ventilation
A pH < 7.30 or the need for invasive mechanical ventilation requires discontinuation of 
study treatment.
8.1.5.
Other Safety Stopping Criteria
For a study participant, other safety 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 participant at risk (e.g. ECG, vital signs, laboratory test, etc.), as 
judged by the Investigator, in consultation with the Medical Monitor if necessary.
8.1.6.
Pregnancy
A female participant must be discontinued form study treatment if a positive serum 
pregnancy test is obtained.
8.1.7.
Temporary Discontinuation
A participant may be withdrawn from study treatment as discussed in Section 8.1 but 
continue in the follow-up period of the study for collection of efficacy and safety data.
8.1.8.
Rechallenge
8.1.8.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
8.2.
Withdrawal from the Study
A participant may withdraw from the study at any time during the study (including the 
Screening Period, the 12-Week Double-Blind Treatment Period or the 12-Week Post-
Treatment Follow-Up Period) at his/her own request, or may be withdrawn at any time at 
the discretion of the investigator for safety, behavioral, compliance or administrative 
reasons.
 
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If a higher than expected number of participants prematurely discontinues double-blind 
study treatment or prematurely discontinues from the study, additional participants may 
be randomized, at the discretion of the Sponsor.
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records.
Refer to the SoA (Section 2) for data to be collected at the time of study withdrawal and 
follow-up and for any further evaluations that need to be completed.
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.
The primary reason for subject withdrawal will be recorded in the eCRF.  Primary 
reasons for withdrawal will be categorized as:

adverse event

withdrew consent

lost to follow-up

protocol deviation

lack of efficacy

subject reached protocol-defined stopping criteria

study closed/terminated

investigator discretion
Specific regard should be given to distinguishing withdrawals due to an adverse event, 
lack of efficacy and protocol deviation.  Participant compliance with study treatment 
during the 12-Week Double-Blind Treatment Period will be assessed as described in 
Section 7.6.1.
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
 
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the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA (Section 2). 

Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the Medical Monitor
immediately upon occurrence or awareness to determine if the participant should 
continue or discontinue study treatment.

Adherence to the study design requirements, including those specified in the SoA 
(Section 2), is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria.  The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and 
was performed within the time frame defined in the SoA (Section 2).
The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, will not exceed the 
following:

Males: 
o
Main Study: approximately 189 mL (including blood samples for genetic 
research and biomarkers)
o
PK Sub-group: approximately 199 mL (including the above bullet and the 
serial PK samples)

Females
o
Main Study: approximately 214 mL (including blood samples for 
pregnancy testing, genetic research, and biomarkers)
o
PK Sub-group: approximately 224 mL (including the above bullet and the 
serial PK samples)
 
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Repeat or unscheduled blood samples may be taken for safety reasons or for technical 
issues with the samples.
The following procedures must be completed to ensure that the participant is eligible for 
the study:

Obtain informed written consent

Review inclusion/exclusion criteria, including concomitant medications.

Full source documentation for the above qualifying procedures and related results are 
required.

Any protocol-specified study qualification procedures not already done as part of 
routine care will need to be conducted after the participant signs the ICF and before 
randomization.

The results of all study qualification procedures, whether performed as part of 
routine care or as a study-specific procedure, are required to assess participant 
inclusion/exclusion criteria and should, if possible, be available prior to 
randomization.

For prompt assessment of the participant’s eligibility local laboratory samples should 
be taken at Screening and the results received and reviewed prior to randomisation to 
allow review of exclusion criteria 18.  It is important that a sample for analysis by 
the central laboratory is obtained at the same time and promptly sent to the central 
laboratory.  The local lab results will not be entered into the CRF; however, they will 
be filed in the respective participant’s source documentation.

Samples for Hepatitis B surface antigen, Hepatitis C virus antibody, and HIV 
antibody will be submitted to the central laboratory only for analysis and do not need 
to be submitted to the local laboratory.  Participants who are otherwise eligible may 
be randomized prior to the receipt and review of these results.  If the result for one or 
more of these parameters is positive, then the participant will need to be withdrawn 
from the study. Therefore, it is important that a detailed medical history is 
performed at Screening (Visit 1), in order to minimize the potential for 
randomization of participants who are positive for one or more of these parameters.

Those samples taken prior to or at the time of randomization and sent to the central 
laboratory will serve as the baseline for assessment of potential treatment effect (see 
the Schedule of Activities in Section 2).

The screening process ends when randomization occurs. Randomization and first 
dose of the double-blind study treatment administration should take place as soon as 
possible following diagnosis of acute moderate/severe exacerbation of COPD and 
completion of the EXACT-PRO questionnaire and FEV1 measurement and no later 
than 48hrs after start of SoC.
9.1.
Efficacy Assessments
Efficacy will be assessed via spirometry assessments, subsequent exacerbations of 
COPD, and patient-reported outcomes (PROs).  PRO assessments carried out at study 
 
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visits will be completed as the first assessment in the visit schedule before spirometry or 
any other study procedure.
9.1.1.
Spirometry Testing
Spirometry assessments will be obtained using spirometry equipment that meets or 
exceeds the minimal performance recommendations of the ATS [Miller, 2005].  All 
participating sites will use standardized spirometry equipment provided by an external 
vendor contracted by GSK.  
All participants will perform lung function maneuvers to assess FEV1, and FVC at each 
study visit.  For each testing session, at least 3 valid spirometry efforts should be 
attempted (with no more than 8) using the ATS guidelines [Miller, 2005].  The highest 
FEV1 from the valid forced expiratory curves for each testing session will be used.
Protocol-specified spirometry will be performed in the morning (i.e., initiated between 
6:00AM and 12:00PM) during visits when clinic FEV1 is performed as shown in the SoA 
(Section 2).  In addition, protocol-specified clinic FEV1 must be completed in accordance 
with the lifestyle restrictions as defined in Section 6.3.1- Section 6.3.5.
During Visits 2 through Visit 6, spirometry will be performed prior to administering 
double-blind study medication at two time points: pre-bronchodilator (albuterol 
[salbutamol)] and post-bronchodilator.  Post-bronchodilator FEV1 will be conducted 
approximately 10 to 30 minutes after the participant-administers 4 inhalations of 
albuterol (salbutamol) via MDI (i.e., total of 400 mcg) using a spacer/valved-holding 
chamber or via one nebulized treatment.  It is anticipated that participants who are 
enrolled into the study will receive albuterol as part of the routine treatment of AECOPD 
during visit 2. In this instance, spirometry should be scheduled to coincide with this 
treatment to allow post-bronchodilator recordings to be measured. During Visits 6-9, 
spirometry will be performed prior to administering maintenance COPD medication(s) at 
two time points: pre-bronchodilator (albuterol [salbutamol)] and post-bronchodilator (as 
defined above).
Rescue albuterol [salbutamol] should be withheld for 4hrs prior to spirometry 
measurements, where possible.  Usual daily COPD medications should be withheld on 
the morning of spirometry assessments, where possible.
Baseline Clinic Visit FEV1 is defined as the post-bronchodilator FEV1 performed at Visit 
2.
Spirometry assessments should be made as close to the scheduled time points as possible. 
Where multiple assessments are scheduled at the same time point, the sequence of 
assessments should ideally be as shown below.  However, during the Screening Visit 
(Visit 1) and/or the Randomization Visit (Visit 2), this order may be modified as needed, 
including instances where some or all of these procedures are performed as part of 
routine/urgent/emergency/inpatient hospitalized care.
1. Vital signs
 
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2. 12-lead ECG
3. Blood sampling
4. Spirometry assessment
Details regarding the spirometric procedures are provided in the instruction manual 
provided by the external vendor.
9.1.2.
COPD Exacerbation
Following recovery of the index exacerbation, COPD exacerbation assessments will be 
performed throughout the 12-week treatment period and the 12-week post treatment 
follow up period at study visits and using the eDiary data.  
Additional details on guidelines for COPD exacerbation identification, categorization, 
reporting and treatment are provided in Section 12.9.5.
9.1.3.
Patient-Reported Outcomes (PRO)
Participants will complete the following PROs during this study: 

Exacerbations of Chronic Pulmonary Disease Tool (EXACT-PRO) (which includes
the Evaluating Respiratory Symptoms in COPD [E-RS: COPD] subscales of the 
EXACT-PRO) at randomization and every evening following day of randomization, 

St. George’s Respiratory Questionnaire for COPD Patients (SGRQ-C) as defined in 
the SOA (Section 2).  

COPD Assessment Test (CAT) as defined in the SOA (Section 2).  CAT will also be 
triggered to appear in the e-dairy on the evening following EXACT-defined recovery 
from the index acute moderate or severe exacerbation of COPD.
For participants who are hospitalized, if a participant is too ill to complete the PRO 
questionnaires without assistance on a given day, a member of the study staff may 
verbally recite the questions verbatim to the participant and the staff member may enter 
the participant’s verbal response in the eDiary.  The participant’s confirmation of the 
accuracy of the staff member’s transcription will be documented in the source 
document/eDiary.  Hospitalized participants will be encouraged to complete the eDiary 
personally as soon as possible and will be trained to do so before discharge.
9.1.3.1.
EXAcerbations of Chronic Pulmonary Disease Tool Patient (EXACT-
PRO and Evaluating Respiratory Symptoms in COPD (E-RS: COPD)
The Exacerbations of Chronic Pulmonary Disease Tool (EXACT-PRO) is a 14-item, 
PRO instrument designed to capture information on the occurrence, frequency, severity, 
and duration of exacerbations of disease in patients with COPD.  EXACT-PRO captures 
information on the severity of the respiratory and systemic manifestations of a COPD 
exacerbation as reported by the patient [Leidy, 2011]. 
 
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The instrument is to be completed every evening (typically at bedtime) using an eDiary.  
However, at Visit 2 (Randomization) only, the EXACT-PRO is to be completed as the 
first assessment before randomization and hence will be completed in the morning . 
Participants will be trained to complete the eDiary before completing the first EXACT 
assessment.
The daily recording of information allows an assessment of the underlying day to day 
variability of a patient's symptoms and facilitates the detection of symptom worsening 
indicative of a COPD exacerbation.  The total score for EXACT-PRO ranges from 0 –
100.  The entire instrument is intended to be completed in about 3 minutes or less 
(typically the time required for completion decreases as the patient becomes more 
familiar with the tool and the eDiary).
The Evaluating Respiratory Symptoms in COPD (E-RS: COPD) consists of 11 items 
from the 14-item EXACT-PRO instrument.  E-RS: COPD is intended to capture 
information related to the respiratory symptoms of COPD, i.e., breathlessness, cough, 
sputum production, chest congestion and chest tightness.  The E-RS has a scoring range 
of 0-40 [Leidy, 2014].
Three subscales of the E-RS: COPD are used to describe different symptoms; dyspnoea, 
cough and sputum and chest symptoms.
Additional details are provided in the SRM/vendor manual.
In addition to the collection of EXACT-PRO, subjects will also complete daily diary 
questions to provide the information on other symptoms suggestive of exacerbation: 
sputum purulence (color), wheezing, sore throat, colds (nasal discharge and/or nasal 
congestion) and fever without other cause.
9.1.3.2.
COPD Assessment Test (CAT)
COPD-related health status will be assessed using the CAT at the visits noted in the SoA 
(Section 2).  The CAT will be administered on the eDiary.
Participants will complete the CAT at relevant study visits, prior to performing any other 
study procedures (including concurrent medication assessment, adverse event assessment, 
clinic spirometry, etc.), and prior to completion of the SGRQ-C.
The CAT (www.CATestonline.org) is a validated, short and simple patient-completed 
questionnaire, which has been developed for use in routine clinical practice to measure 
the health status of patients with COPD.  The CAT is designed to measure overall COPD-
related health status for the assessment and long-term follow-up of individual patients.
The CAT is an 8-item questionnaire suitable for completion by all patients diagnosed 
with COPD.  When completing the questionnaire, participants rate their experience on a 
6-point scale, ranging from 0 (no impairment) to 5 (maximum impairment) with a scoring 
range of 0-40 [Jones, 2009; Jones, 2012].
Additional details are provided in the SRM/vendor manual.
 
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9.1.3.3.
St. George’s Respiratory Questionnaire for COPD Patients (SGRQ-C)
Health-related quality of life will be assessed using the SGRQ-C at the visits noted in the 
SoA (Section 2).  The SGRQ-C will be administered on the eDiary.
Participants will complete the SGRQ-C at relevant study visits, prior to performing any 
other study procedures (including concurrent medication assessment, adverse event 
assessment, clinic spirometry, etc.), but after completion of the CAT.
The SGRQ-C is a COPD-specific questionnaire designed to measure the impact of COPD 
and its treatment on the subject’s health-related quality of life [Meguro, 2006].  As well 
as producing an overall summary score, scores for the individual domains of symptoms, 
activity and impacts are also produced.  It has been used in studies of COPD subjects and 
has been translated and validated for use in most major languages.  The SGRQ-C is 
derived from the original SGRQ, and produces scores equivalent to the SGRQ instrument 
[Meguro, 2006].  Research has demonstrated that it is sensitive to change and 
interpretation of the results has been enhanced by determination of the score change 
necessary to achieve a clinically meaningful improvement in quality of life [Jones, 2005].
The SGRQ-C is self-completed by participants.  It is recommended that the SGRQ-C 
should be conducted at the same time during each applicable visit (see the SoA [Section 
2]).  Adequate time (at least 20 minutes) should be allowed, although the participant will 
not be given any stated or implied time limit for completing the questionnaire.  The 
investigator/designee will ask the participant to complete the questionnaire as accurately 
as possible.  If the participant requests help or clarification of any question in the 
questionnaire, the investigator/designee is to instruct the participant to re-read the 
instructions to give the best answer possible.  The investigator/designee will not supply 
the participant with an answer to any question.
Additional details are provided in the SRM/vendor manual.
9.1.3.4.
Rescue Medication Use
Participants’ use of study-supplied rescue medication (albuterol [salbutamol]) will be 
captured via the clip-on Propeller Sensor for MDI (for countries where the Propeller 
Sensor for MDI is available) or via the eDiary (for countries where the Propeller Sensor 
for MDI is not available or for participants who are supplied nebulized albuterol 
[salbutamol]).  For the nebulized formulation, the number of nebulized treatments over 
the previous 24 hours will be recorded daily in the eDiary.
For participants who are hospitalized and the clip-on Propeller Sensor for MDI is not 
available and/or if the participant is too ill to complete the eDiary on his/her own on a 
given day, a member of the study staff may enter the participant’s use of non-nebulized 
rescue medication or the number of nebulized treatments over the previous 24 hours in 
the eDiary as applicable.  The participant’s confirmation of the accuracy of the staff 
member’s transcription will be documented in the eDiary/source document.  Additional 
details are provided in the SRM/vendor manual.
 
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9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study treatment or study (see Section 8). 
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the start of study treatment until Visit 9 in the 
Post-Treatment Follow-Up Period, at the time points specified in the SoA 
(Section 2).  However, any SAEs assessed as related to study participation (e.g., 
study intervention, 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.

All AEs will be collected from the start of double-blind study treatment until 
Visit 9 in the Post-Treatment Follow-Up Period at the time points specified in 
the SoA (Section 2).

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the eCRF not the AE section.

All SAEs will be recorded and reported to the sponsor or designee as soon as 
possible and not more than 24 hours, as indicated in Appendix 4. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of 
it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 4.
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
 
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9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non-serious AEs of special 
interest (as defined in Section 9.2.5), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 8.3). Further information on follow-up procedures is given in Appendix 4.
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information eg, summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
9.2.5.
Adverse Events of Special Interest (AESI) – Post-Inhalation 
Cough Immediately Following Dosing
In the Proof-of-Concept (PoC) study PII116678, which was conducted in 126 randomized 
participants from a population similar to this protocol and a previous formulation of 
nemiralisib (DISKUS formulation blended with only one excipient, lactose), there was a 
higher incidence of treatment-related, mild and moderate adverse events of cough 
(Preferred Term) reported immediately after dosing in exacerbating subjects in the 
GSK2269557 DISKUS 1000 mcg QD group (n=22 [35%] compared exacerbating 
subjects in the placebo DISKUS group (n=2 [3%]).  For the 22 subjects in the 
GSK2269557 1000 mcg group, the events of cough for 20 of the subjects were 
considered by the Investigator to be related to study treatment.  From the review of 
reported events, cough often occurred immediately after dosing and in some subjects it 
seemed to repeat on most of the dosing days.  Cough was reported to be generally mild or 
moderate and resolved after stopping dosing.  Three subjects (all in the GSK2269557 
DISKUS 1000 mcg QD group) discontinued the study due to cough.  Additional details 
are provided in the Nemiralisib (GSK2269557) Investigator’s Brochure.
 
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Therefore, to further evaluate this finding of post-inhalation cough immediately 
following dosing, during study Visits 2-6 in the 12-Week Double-Blind Treatment 
Period, Investigators (or medically qualified designees) will monitor participants for 
potential study treatment tolerability issues, including post-inhalation cough, within 5 
minutes immediately following dosing.  If tolerability issues, including coughing are 
observed, details will be recorded in the source documentation and eCRF.
The iSRC will have study oversight to ensure that it meets the highest standards of ethics 
and participant safety and to carry out the planned interim safety data analyses/data 
reviews as discussed in Appendix 3 and Section 10.3.5.  Data (including adverse event 
reports of post-inhalation cough immediately following study treatment dosing) will be 
reviewed by the iSRC on a periodic basis, as defined in the iSRC Charter.  
9.2.6.
Cardiovascular and Death Events
For any cardiovascular events and all deaths, whether or not they are considered SAEs, 
specific Cardiovascular (CV) and Death sections of the eCRF will be required to be 
completed. These sections include questions regarding cardiovascular (including sudden 
cardiac death) and non-cardiovascular death. 
The CV eCRFs 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 eCRF within one week of receipt of a CV Event data query prompting its completion.
The Death eCRF 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.
9.2.7.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
The following disease related events (DREs) are common in participants with COPD and 
can be serious/life threatening:

exacerbation of COPD
Because these events are typically associated with the disease under study, they will not 
be reported according to the standard process for expedited reporting of SAEs to GSK 
(even though the event may meet the definition of a SAE).  These events will be recorded 
on the DRE page, in this study the exacerbation page in the participant’s eCRF within 72 
hours after the Investigator becomes aware of the event.  These DREs will be monitored 
by a Safety Review Team (SRT) on a routine basis.
NOTE: However, if either of the following conditions apply, then the event must be 
recorded and reported as an SAE (See Section 9.2): 

The event is, in the investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual participant, or
 
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
The investigator considers that there is a reasonable possibility that the event is 
related to study treatment
If an exacerbation is caused by pneumonia this must be recorded as pneumonia in the AE 
or SAE form in the eCRF and the pneumonia form in the eCRF (See Section 9.1.2).
9.2.8.
Pregnancy

Details of all pregnancies in female participants will be collected after the start of 
study treatment and until 14 days after the last dose of study treatment.

Details of pregnancies for female partners of male participants will not be routinely 
collected; however, voluntary reports of such incidents will be captured through the 
GSK standard reporting mechanism.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.2.9.
Medical Device Incidents (Including Malfunctions)
Medical devices, the study-supplied valved-holding chamber and the clip-on Propeller 
Sensors to be attached to the double-blind study treatment ELLIPTA inhalers and the 
study-supplied albuterol [salbutamol] MDIs, are being provided for use in this study for 
the purposes of standardizing the conduct of the post-bronchodilator FEV1 measurements 
and capturing compliance with double-blind study treatment and rescue albuterol 
[salbutamol] use, respectively.  In order to fulfill regulatory reporting obligations 
worldwide, the investigator is responsible for the detection and documentation of events 
meeting the definitions of incident or malfunction that occur during the study with such 
devices. 
The definition of a Medical Device Incident can be found in Appendix 8.
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 9.2 and Appendix 4 of the protocol.
9.2.9.1.
Time Period for Detecting Medical Device Incidents

Medical device incidents or malfunctions of the device that result in an incident 
will be detected, documented, and reported during all periods of the study in 
which the medical device is used. 

If the investigator learns of any incident at any time after a participant has been 
discharged from the study, and such incident is considered reasonably related to 
a medical device provided for the study, the investigator will promptly notify the 
sponsor.

The method of documenting Medical Device Incidents is provided in Appendix 
8.
 
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9.2.9.2.
Follow-up of Medical Device Incidents

All medical device incidents involving an AE will be followed and reported in 
the same manner as other AEs (see Section 9). This applies to all participants, 
including those who discontinue study treatment or the study.

The investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as indicated to elucidate the nature and/or causality 
of the incident.

New or updated information will be recorded on the originally completed form 
with all changes signed and dated by the investigator.
9.2.9.3.
Prompt Reporting of Medical Device Incidents to Sponsor

Medical device incidents will be reported to the sponsor within 24 hours after 
the investigator determines that the event meets the protocol definition of a 
medical device incident.

The Medical Device Incident Report Form will be sent to the sponsor by eCRF. 
If eCRF is unavailable, then completion of the paper Medical Device Incident 
Form should be utilized.

The same individual will be the contact for the receipt of medical device reports 
and SAE.
9.2.9.4.
Regulatory Reporting Requirements for Medical Device Incidents

The investigator will promptly report all incidents occurring with any medical 
device provided for use in the study in order for the sponsor to fulfill the legal 
responsibility to notify appropriate regulatory authorities and other entities about 
certain safety information relating to medical devices being used in clinical 
studies.

The investigator, or responsible person according to local requirements (eg, the 
head of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of incidents to the IRB/IEC.
9.3.
Treatment of Overdose
An overdose is defined as a dose greater than the doses described in Section 7.1 which 
results in clinical signs and symptoms. In event of an overdose the participants should be 
closely monitored for AEs/SAEs and these should be recorded in the eCRF.  
GSK does not recommend specific treatment for an overdose for nemiralisib.
Decisions regarding treating the overdose, and dose interruptions or modifications will be 
made by the investigator in consultation with the Medical Monitor based on the clinical 
evaluation of the participant.
 
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9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 2).
9.4.1.
Physical Examinations

A complete physical examination will be performed at Screening (Visit 1) and 
will include, at a minimum, assessments of the Skin, Cardiovascular, 
Respiratory, Gastrointestinal, and Neurological systems. Height and weight will 
also be measured and recorded as specified in the SoA (Section 2).

A brief physical examination will be performed at all other visits and will
include, at a minimum, assessments of the skin, lungs, cardiovascular system, 
and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
9.4.2.
Vital Signs
Vital signs (pulse rate, blood pressure [systolic and diastolic] and respiratory 
rate) will be performed as specified in the SoA (Section 2), prior to the 
spirometry maneuvers and with the participant in the sitting position.  The 
participant must be seated at least 5 minutes before these measurements are 
performed and a single set of values will be collected.  
Blood pressure and pulse measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device 
is not available.
The vital sign results will be captured in the participant’s clinic notes and in the 
eCRF
9.4.3.
Electrocardiograms
Standardized ECG equipment and centralized overreads of the ECGs will be provided to 
all participating sites by the external provider contracted by GSK.
A 12-lead ECG with a 15-second rhythm strip will be obtained as outlined in the SoA 
(see Section 2) using an ECG machine that automatically calculates the heart rate and 
measures PR, QRS, QT, and QTc intervals.  Refer to Section 8.1.2 for QTc withdrawal 
criteria and additional QTc readings that may be necessary.

For this study, the same QT correction formula (Fridericia’s) must be used 
throughout the study for all participants.  Safety ECGs and other non-protocol 
specified ECGs are an exception.

All ECG measurements will be performed with the participant resting in a supine 
position for approximately 5 minutes before each reading, which should be carried 
out after measurement of vital signs and before spirometry.
 
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
The investigator, a designated sub-investigator, or other appropriately trained site 
personnel, will be responsible for performing the 12-lead ECG recording at each 
applicable study visit (see SoA [Section 2]).

All ECGs will be electronically transmitted to an independent cardiologist 
(contracted by GSK) and evaluated.  The independent cardiologist, blinded to 
treatment assignment, will be responsible for providing measurements of heart rate, 
QT intervals and an interpretation of all ECGs collected in this study.  These results 
will be provided to the investigator.  The investigator is responsible for reviewing 
ECG reports and attesting to his/her review of the independent cardiologist’s 
assessment. 

A local ECG may be used to assess eligibility criteria however an ECG for central 
review should also be performed at screening/randomisation.  If the central review 
indicates that the patient is ineligible the patient will be withdrawn from the study.  

Participants with an abnormal ECG reading(s) (exclusionary and non-exclusionary) 
will be followed/referred to a specialist according to the discretion of the 
Investigator.

Details of all cardiac monitoring procedures will be provided by the centralized 
cardiology service provider.
9.4.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of routine, non-fasting clinical laboratory tests to 
be performed and to the SoA (Section 2) for the timing and frequency.  At the 
discretion of the investigator, additional samples may be taken for safety 
reasons.

Approximately 40 mL (approximately 8 teaspoons [4 teaspoons each for local 
laboratory and central laboratory assessment]) of whole blood will be collected 
at Screening and then approximately 10 mL (approximately 2 teaspoons) of 
whole blood will be collected at each of the other assessment visits for a total of 
approximately 100 mL (20 teaspoons) over the course of the study 

All protocol-required clinical laboratory samples will be analyzed by a central 
laboratory contracted by GSK.

At screening, for prompt assessment of the participant’s eligibility local 
laboratory samples, with the exception of hepatitis B, hepatitis C, and HIV,
should be taken and the results received and reviwed prior to randomisation to
allow review of exclusion 18.  It is important that a sample for analysis by the 
central laboratory is obtained at the same time and promptly sent to the central 
laboratory.  The local lab results will not be entered into the CRF; however, they 
will be filed in the respective participant’s source documentation.

The investigator must review the laboratory report (local [as applicable] and 
central), document this review, and record any clinically relevant changes 
occurring during the study in the AE section of the CRF.  The laboratory reports 
must be filed with the source documents.  Clinically significant abnormal 
 
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laboratory findings are those which are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 28 days after the last dose of double-
blind study treatment should be repeated until the values return to normal or 
baseline or are no longer considered significantly abnormal by the investigator 
or medical monitor.  If such values do not return to normal/baseline within a 
period of time judged reasonable by the investigator, the etiology should be 
identified and the sponsor notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA (Section 2).

If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator, then this 
should be documented in the source notes, and in the eCRF where applicable 
(eg, SAE or AE or dose modification).
9.4.5.
Medical Problems and Concomitant Medications
Participants will be instructed to record any medical problems they may have experienced 
and any medications used to treat those problems over the previous 24 hours in the 
eDiary.  These entries will be reviewed by the Investigator/study coordinator at each 
study visit and recorded in the eCRF as adverse events and concomitant medications as 
appropriate.  Signs and symptoms of COPD should be evaluated according to Section 
9.1.2 and Section 12.9.5.
9.5.
Pharmacokinetics

During the 12-Week Double-Blind Treatment Period approximately 2 mL of 
whole blood samples for measurement of plasma concentrations of nemiralisib 
will be collected in a subset of randomized participants (approximately 300) at 
selected sites on days 14 and 28 (total of 12mL) as below: 
o
pre-dose (trough)
o
approximately 0-1 hour post dose
o
approximately >1 hour to 6 hours post dose

Plasma samples will be analyzed to determine plasma pharmacokinetics. 
Instructions for the collection and handling of biological samples will be provided 
by the central laboratory.  The actual date and time (24-hour clock time) of each 
sample will be recorded.

Samples will be used to evaluate the PK of nemiralisib.  Samples collected for 
analyses of nemiralisib plasma concentration may also be used to evaluate safety 
or efficacy aspects related to concerns arising during or after the study.
 
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
Plasma analysis for nemiralisib will be performed under the control Bioanalysis, 
Immunogenicity, Biomarkers, BIB /Third Party Resourcing, TPR, 
GlaxoSmithKline
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has completed and the database 
has been unblinded.
9.6.
Pharmacodynamics
See Section 9.8, Section 9.9, and Section 10.3.4 for details of pharmacodynamics.
9.7.
Genetics
A 6 mL blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Participation is 
optional. Participants who do not wish to participate in the genetic research may still 
participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
See Appendix 6 for information regarding genetic research.  Details on processes for 
collection and shipment and destruction of these samples can be found in the Central 
Laboratory Instruction Manual.
9.8.
Biomarkers

For exploratory research, blood samples will be collected for analysis of selected 
blood inflammatory biomarkers (including but not limited to high sensitivity C-
reactive protein [hs-CRP], chemokine interferon-inducible protein 10 kDa 
(CXCL10)], and procalcitonin) in relation to acute exacerbations of COPD. 

Approximately 20 mL (4 teaspoons) of blood will be collected for all 
participants at each visit noted in the SoA (Section 2).  At Visit 1 (Screening), 
the sample should be collected as soon as possible after the participant has 
completed the informed consent, PRO assessments and ECG.

All biomarker samples will be shipped to the central laboratory contracted by 
GSK/BIB/TPR, GlaxoSmithKline for analysis and reporting.

All biomarker assessments must be conducted in accordance with the central 
laboratory manual.
9.9.
Spontaneous Sputum
At Screening and Day 56 only, a spontaneous sputum sample will be collected for all 
participants who are willing and able to provide spontaneous sputum.  Sample collection 
kits and instructions will be provided by the central laboratory contracted by GSK.
 
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9.10.
Health Care Resource Utilization (HCRU) and Health 
Economics
Participants will record (Yes or No) in the eDiary each day whether or not they have had 
any Unscheduled Health Care Contacts (HCRU) contacts/visits for any reason (including 
COPD-related and non-COPD-related) other than a scheduled visit to the Investigator’s 
site (this includes contacts/visits with/to a physician’s office, visits to urgent care, visits 
to an emergency department, hospitalizations, and inpatient hospitalization days).  For 
any “Yes” response, participants will be prompted to contact the Investigator to promptly 
report further details regarding the HCRU and the Investigator will receive an e-mail 
notification as well.  The investigator (or designee) will enter the HCRU details in the 
eCRF.  The investigator (or designee) will ask the participant if any of the health care 
contacts were due to a COPD exacerbation.  The investigator (or designee) could refer to 
his/her records to verify or supplement information given by the participant, if necessary.
Also, at Visits 2-9 or the Early Withdrawal Visit, the resource utilization data reported by 
the participant for all health care contacts experienced since the last visit will be reviewed 
by the investigator (or designee).
All confirmed mild, moderate or severe COPD exacerbations will be recorded in the 
source document and on the COPD Exacerbation form in the eCRF and on the SAE form 
in the eCRF (if applicable).
The data collected may be used to conduct exploratory analyses of HCRU and other 
economic analyses and could include:

Number of medical care encounters 

Hospitalizations

Duration of hospitalization (total days or length of stay)

Re-hospitalization within 30 days

Number of Emergency Room [ER] visits
9.11.
Smoking Cessation Counseling
During Visits 1 through 9 or Early Withdrawal, participants will be given smoking 
cessation counselling, which includes advice regarding the following:

the health effects that smoking may cause

the health benefits that may result if they stop smoking

if they do not feel capable of discontinuing smoking that their primary care 
physician may be able to discuss anti-smoking strategies with them

that they may discontinue smoking at any time during the study and will not have 
to be withdrawn from the study if they do so.
 
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The specific information to be discussed with each subject is provided in the SRM.
10.
STATISTICAL CONSIDERATIONS
The primary objective of this study is to characterize the dose response of nemiralisib 
when administered in addition to SoC on change from baseline in Clinic Visit FEV1 at 
Day 84 (measured at trough and post-bronchodilator), in participants diagnosed with an 
acute exacerbation of COPD requiring treatment with oral/systemic corticosteroid(s) 
(prednisone 40 mg/day or equivalent) for 5 days and antibiotic(s) for 7 days; the dose 
and/or duration of prednisone (40 mg/day or equivalent) and/or the antibiotic can be 
modified according to the Investigator’s/medically qualified designee’s judgement or 
according to local country/institution practice.  There are initially six doses of nemiralisib 
to be investigated in this study; however, one additional dose may be included during the 
course of the study.
A key secondary objective is to evaluate treatment effect of nemiralisib compared with 
placebo on the rate of subsequent exacerbation(s) (moderate and severe) over the 12-
Week Treatment Period.  In order to increase precision around the estimate of the 
treatment effect from a pair-wise comparison of the rate of subsequent exacerbation(s) of 
COPD, the sample size will be increased for the 750 mcg dose of nemiralisib and 
placebo.
10.1.
Sample Size Determination
The sample size has been determined by considering the probability of achieving the end 
of study success criteria for both the primary and key secondary objectives.
Assuming a 20% withdrawal rate, approximately 1,250 participants will be randomized 
in total into the study to ensure approximately 1,000 participants complete the 12-Week 
Treatment Period.
Initially, the randomization ratio between placebo and the the six doses (12.5 mcg, 50 
mcg, 100 mcg, 250 mcg, 500 mcg, and 750mcg) of nemiralisib will be 3:1:1:1:1:1:3.
Randomization will be stratified by index COPD exacerbation severity (moderate or 
severe) and whether or not the participant will provide PK samples, to ensure a balance 
across treatments. Table 2 shows the expected sample sizes allocated to the six doses of 
nemiralisib and placebo at the end of study.  These figures are approximate and assume 
that no further adjustments to the randomization ratio are made.  The actual sample sizes 
at the end of the study may be different, depending upon whether changes are made 
following the results of the unblinded interim analysis of change from baseline in clinic 
visit FEV1.
 
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Table 2
Expected Sample Sizes Allocated to the Five Doses of Nemiralisib 
and Placebo at the End of the Study
Dose
Number 
randomized
Number who complete dosing period and 
provide clinic visit FEV1 at Day 84
Placebo
340 
272 
12.5 mcg
114
91
50 mcg
114 
91 
100 mcg
114 
91 
250 mcg
114 
91 
500 mcg
114 
91 
750 mcg
340  
272 
10.1.1.
Sample Size for Primary Objective: To Characterize the Dose 
Response of Nemiralisib when Administered in Addition to SoC 
on Change from Baseline in Clinic Visit FEV1 at Day 84
Simulations of change from baseline FEV1 data have been performed to evaluate the 
probability of achieving end of study success criteria given the estimated sample size for 
each dose for various assumed scenarios.  Three scenarios were considered, each based 
on different assumptions of the change from baseline FEV1 for each of the treatment 
arms.  The scenarios are described in Table 3. The estimate of the dose response profile 
were obtained from fitting a 3-parameter Emax dose response model to simulated change 
from baseline FEV1 data for the expected end of study sample size given these assumed 
true scenarios.  A 3 parameter model was used rather than a 4 parameter model to 
improve the model convergence under simulation conditions.  For the purpose of 
simulations, a frequentist analysis technique was used which should provide analogous 
results to fitting non-informative prior distributions for all modelling parameters using a 
Bayesian framework.  A baseline and a single post dose observation were simulated for 
each subject using the bivariate normal distribution, assuming the between participant 
standard deviation of 300 mL for both time points, and a correlation of 0.7 between them. 
The average baseline was considered to be 1.383 L. These values were obtained from the 
PoC Study PII1116678 (a randomised, double-blind, placebo-controlled, parallel-group, 
study to evaluate the efficacy and safety of GSK2269557 administered in addition to 
standard of care in 126 participants diagnosed with an acute exacerbation of COPD). For 
each simulation, the appropriate number of participants was simulated using the expected 
sample size completing Day 84 as described in Table 2. For each scenario, 5,000 
iterations of simulations were run with each simulation analyzed using proc nlmixed in 
SAS.
 
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Table 3
Change from Baseline in FEV1 Assumptions for Three Assumed 
Scenarios
Dose
Scenario 1
Scenario 2
Scenario 3
Placebo
-20 mL
-20 mL
-20 mL
12.5 mcg
-15 mL
-15 mL
-20 mL
50 mcg
-15 mL
-10 mL
-20 mL
100 mcg
20 mL
10 mL
-15 mL
250 mcg
50 mL
30 mL
-10 mL
500 mcg
80 mL
40 mL
0 mL
750 mcg
80 mL
50 mL
0 mL
Table 4 shows the probability of achieving various criteria under the three assumed 
scenarios:
Table 4
Probability of Achieving Various Criteria under the Three Assumed 
Scenarios
Criteria
Scenario 
1
Scenario 
2
Scenario 
3
Observed lowest dose difference from placebo <25 mL1
53% 
62% 
88% 
Observing >90% posterior probability that the true difference 
from placebo for any dose is >0
100%
100%
64% 
Observing >90% posterior probability that the true difference 
from placebo for any dose is >0 with an observed difference 
from placebo >75 mL2
97% 
44% 
0%
1.
25 mL chosen to represent a ‘non efficacious’ difference from placebo
2.
75 mL chosen to represent a minimum clinically meaningful difference from placebo
The results of the simulations indicate that the proposed sample size and participant 
allocation to each dose is adequate to achieve the key end of study success criterion for 
change from baseline FEV1, where this success is defined as demonstrating >90% 
posterior probability that the true difference from placebo for any dose of nemiralisib is 
greater than 0 for the assumptions used and the true response scenarios considered.  
Although the probability of achieving the key end of success criterion for the primary 
endpoint is high for scenarios 1 and 2, the true nature of the dose response profile is 
 
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currently unknown.  In addition to these simulations, consideration of the probability of 
achieving the end of study success for the secondary endpoint of reduction in 
exacerbation rate has also been given. 
10.1.2.
Sample Size for Key Secondary Objective: To Evaluate Treatment 
Effect of Nemiralisib Compared with Placebo on the Rate of 
Exacerbations
The key secondary endpoint of number of exacerbations over the 12-Week treatment 
period will be analysed using a Bayesian generalized linear model assuming a negative 
binomial distribution for the underlying exacerbation rate. Non-informative prior 
distributions will be used for all modelling parameters.
The probability of achieving the end of study success criterion for this secondary 
endpoint was calculated assuming a placebo exacerbation rate of 0.51 per 12 weeks and 
dispersion parameter of 3.5, observed in the PoC Study PII116678.  With 340 participants 
in the selected exacerbation dose arm versus 340 participants in the placebo arm, the 
probability of declaring success (assuming that the true rate reduction over placebo is 
25%) is 76%, where success is defined as demonstrating >80% posterior probability that 
the true rate reduction over placebo is greater than 0%.
Estimates of the variability (dispersion parameter) and placebo exacerbation rate have 
been taken from PoC Study PII116678, however have large associated uncertainty. The 
probability of achieving the end of study success criterion has therefore also been 
calculated using different assumptions for the dispersion and placebo exacerbation rate 
and are presented in Table 5. The table shows that the probability of achieving the end of 
study success criteria for the secondary endpoint varies substantially depending on these 
assumptions. These assumptions will be assessed during the course of the study.
Table 5
Probability of Achieving the End of Study Success Criterion, 
Assuming a True Rate Reduction over Placebo of 25% under 
Different Placebo Exacerbation and Dispersion Assumptions
Placebo Rate
Dispersion Parameter 
3.5
2
1
0.25
68%  
73% 
77% 
0.51
76% 
83% 
89% 
1.00
81% 
90% 
96% 
 
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10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
All Participants Enrolled 
(APE) Population
All participants who are screened for eligibility 
Modified Intent-to-Treat 
(MITT)
All randomized participants who receive at least one dose of study 
treatment.  Participants will be analyzed according to the 
treatment that they were randomised to.
The MITT Population will be used for all efficacy summaries.
Per-Protocol (PP) 
Population
The PP population is comprised of the MITT population, excluding 
any participants with an important protocol deviation.
The PP population will be used to present sensitivity analyses for 
the primary and key secondary efficacy endpoints.
Safety Population
All randomized participants who receive at least one dose of study 
treatment. Participants will be analyzed according to the treatment 
they actually received.
The Safety Population will be used for all safety summaries.
Pharmacokinetic (PK) 
Population
All participants in the MITT Population for whom a 
pharmacokinetic sample was obtained and analyzed.
The PK population will be used for all PK summaries.
In the event one or more investigators are withdrawn from the trial due to concerns over 
protocol deviations, then a further population will be defined, which will consist of all 
participants in the MITT population excluding participants from those investigators. This 
population will be used to perform additional sensitivity analysis for the primary and key 
secondary efficacy endpoints.
10.3.
Statistical Analyses
10.3.1.
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
The primary efficacy endpoint is the change from baseline in trough and 
post-bronchodilator Clinic Visit FEV1 at Day 84.  The primary intent will be to 
analyze this data by fitting a Bayesian dose response model.  The 4-
parameter Emax model will be fitted by first intent; however, should the data 
not allow for a suitable model fit, then other models may be attempted such 
 
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Endpoint
Statistical Analysis Methods
as the 3-parameter Emax, Log-linear model or similar.
The primary model will take the form:
Change from baseline FEV1 = E0 + (Emax*Doseγ)/(ED50γ+Doseγ)
Where: E0 = the response at dose = 0 (placebo)
Emax = the maximal response
ED50 = the dose that yields 50% of the maximal response
γ = the slope parameter
Non-informative prior distributions will be fitted to all modeling parameters, 
ensuring that they are non-informative within the parameter space. 
Functional uniform priors will be attempted to be fitted by first intent however 
other prior distributions may be considered. Full details of the specification of 
prior distributions will be documented in the RAP.
The posterior mean change from baseline, along with 95% Credible 
Intervals, will be presented for each of the studied doses along with the 
placebo corrected results obtained from the non-linear model. Graphical 
representation of the dose response across the full dose range will also be 
produced to allow inference to be made for the non-studied doses based 
upon the model fit. Posterior probabilities that the true improvement is 
greater than 0 mL, 50 mL and 100 mL will also be presented.
Full details of the statistical analysis will be documented in the RAP.
Secondary
The key secondary endpoint of number of exacerbations (moderate and 
severe) over the 12-Week treatment period will be analysed using a 
Bayesian generalized linear model assuming a negative binomial distribution 
for the underlying exacerbation rate with a log link and an offset to account 
for the length of time in study for each participant. Non-informative priors will 
be used for all modelling assumptions. The exacerbation rates for the 
selected nemiralisib dose and placebo arms, along with the ratio in 
exacerbation rates nemiralisib/placebo, will be estimated and corresponding 
95% credible intervals produced.
Exploratory
Will be described in the RAP
10.3.2.
Safety Analyses
Safety endpoints will be summarized by treatment group and all safety analyses will be 
performed on the Safety Population.  Further details will be described in the RAP.
 
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10.3.3.
Population PK
A population non-linear mixed effects analysis or other appropriate method(s) will be 
performed on the sparse plasma samples using an optimal population PK model to 
describe the time course of systemic exposure of nemiralisib in this target subject 
population and associated inter- and residual variability.  A covariate analysis will be 
undertaken to evaluate any subject factors (including demographic, physiological, co-
medication, pharmacogenetic markers) likely to influence the systemic exposure to 
nemiralisib in this participant population.  Appropriate validation of this population 
analysis will be performed in line with the European and US regulatory guidance 
documents on population PK analysis [EMEA- CHMP/EWP/185990/06, 2008 and the 
FDA, 1999].  Full details of analysis will be provided in the RAP.
10.3.4.
Pharmacokinetic/Pharmacodynamic Analyses
A longitudinal population dose-FEV1 response analysis will be undertaken using trough 
FEV1 at all measured time points over the duration of the study.  Quantification of dose–
response relationship, covariate effects, and time courses such as placebo effect onset, 
disease progression, and dose-related effect onset and offset will be characterized if data 
are amenable.  This analysis may provide additional support for dose selection in future 
studies.
In addition, an exposure-driven clinical safety analysis will be performed using 
participant-specific exposure data and corresponding systemic safety signals, if data 
allow.  If data are amenable, any relationship between steady state individual average 
drug levels (Css) with corresponding PROs will be assessed. 
The above analysis will be conducted in alignment with the FDA and ICH E4 guidance 
documents [FDA Guidance for Industry. Exposure-Response relationships- Study 
Design, Data Analysis, and Regulatory Applications. FDA, Rockville, MD, April 2003
(FDA, 2003), Dose Response Information to Support Drug Registration- ICH E4, 1994]. 
Full details of analysis will be provided in the Reporting and Analysis Plan (RAP).
10.3.5.
Interim Analyses
Interim analyses will be performed during the course of the study.
Interim analyses of the primary endpoint of change from baseline in clinic visit FEV1 at 
Day 84 will be performed to determine whether or not any adjustments to the 
randomization ratio across the nemiralisib doses would help optimize the characterization 
of the dose response profile.  Adjustments could include starting randomization to a 
nemiralisib dose of 25 mcg QD and/or ceasing randomization to an existing dose(s) of
nemiralisib and/or modification of the allocation ratios for the existing nemiralisib doses.  
Change from baseline in clinic visit FEV1 will be analyzed by fitting a Baysesian Emax 
dose response model, as described in Section 10.3.1.  The timing of interim analyses of 
FEV1 will be pre-specified in the RAP, prior to any unblinding taking place.
In addition, interim analyses will be used to assess the study for futility, to amend the 
stratification proportions by index exacerbation severity status (moderate or severe) and 
 
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to assess the study endpoint assumptions made prior to the study.  The specific details 
regarding the interim analyses will be documented, prior to any un-blinding taking place, 
in the RAP.  The timing of these analyses will depend upon recruitment and may be 
performed at the same time as the interim analyses of change from baseline FEV1. 
Additionally, an unblinded interim analysis will be conducted at the end of the 12-week 
treatment period to inform internal program-related decision making.
All interim analyses will be based on un-blinded data and will be performed by the study 
statistics and programming team (see Section 7.4). The randomization schedules and 
unblinded datasets will be stored on internal restricted drives. The GSK study team, with 
the exception of the statistics and programming team, will not have access to an un-
blinded copy of the randomization schedule during the course of the trial.
The full details of the interim analyses will be pre-defined in the RAP.
 
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11.
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
AB
Antibiotic
AE
Adverse Event
ALT
Alanine Aminotransferase
APDS
Activated Phosphoinositide 3-kinase Delta Syndrome, also 
referred to as p110delta-Activating mutation causing 
senescent T cells, Lymphadenopathy and 
Immunodeficiency (PASLI)
AST
Aspartate Aminotransferase
ATS
American Thoracic Society
AUC
Area Under the Plasma Drug Concentration versus Time 
Curve
BIB
Bioanalysis, Immunogenicity, Biomarkers
BMI
Body Mass Index
BP
Blood Pressure
BUN
Blood Urea Nitrogen
CAT
COPD Assessment Test
CXCL10
Chemokine interferon-inducible protein 10 kDa
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences 
Cmax
Maximum Observed Plasma Drug Concentration
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
CPAP
Continuous Positive Airway Pressure
CRF
Case Report Form
cRNA
Complimentary Ribonucleic Acid
CSR
Clinical Study Report
CT
Computed Tomography
CV
Cardiovascular
DRE
Disease Related Event
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
E-RS: COPD
Evaluating Respiratory Symptoms in COPD
ERS
European Respiratory Society
EU
European Union
EXACT-PRO
EXAcerbations of Chronic Pulmonary Disease Tool –
Patient-Reported Outcome
FDA
Food and Drug Administration
FEV1
Forced Expiratory Volume in One Second
FRC
Functional Residual Capacity
 
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FRI
Functional Respiratory Imaging
FSH
Follicle Stimulating Hormone
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GGT
Gamma Glutamyl Transferase
GSK
GlaxoSmithKline
HBcAb
Hepatitis B core antibody
HBsAg
Hepatitis B Surface Antigen
hcCRP
High-Sensitivity C-Reactive Protein
HCRU
Health Care Resource Utilization 
HPLC
High-Performance Liquid Chromatography
HRT
Hormonal Replacement Therapy
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IL-1
Interleukin-1
IND
Investigational New Drug Application
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
iSRC
Internal Safety Review Committee
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
Kg
Kilogram
Kg/m2
Kilogram/square meter
LTOT
Long-Term Oxygen Therapy
mcg
Microgram
MDI
Metered-Dose Inhaler
MedDRA
Medical Dictionary for Regulatory Activities
MgST
Magnesium Stearate
mL
Milliter
MITT
Modified Intent to Treat
MSDS
Material Safety Data Sheet
NIPPV
Non-Invasive Positive Pressure Ventilation
OCS
Oral Corticosteroid
PI3Kd
Phosphoinositide 3-Kinase Delta
PGx
Pharmacogenetics
PK
Pharmacokinetic
PP
Per Protocol
PRO
Patient-Reported Outcome
QD
Once daily
 
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QTc
Corrected QT Interval
QTcF
QT interval corrected for heart rate according to Fridericia's 
formula
RAP
Reporting and Analysis Plan
SAE
Serious Adverse Event
SCS
Systemic Corticosteroid
SDA
Source Document Agreement
SGOT 
Serum Glutamic-Oxaloacetic Transaminase
SGPT 
Serum Glutamic-Pyruvic Transaminase
siVaw
Specific Imaging Airway Volume
siRaw
Specific imaging Airway Resistance
SoA
Schedule of Activities
SoC
Standard of Care (in this protocol this refers to SoC for the 
index lesion)
SGRQ-C
St. George’s Respiratory Questionnaire for COPD Patients
SRDP
Study Results Dissemination Plan
SRM
Study Reference Manual
SRT
Safety Review Team
SUSAR
Suspected Unexpected Serious Adverse Reaction
T1/2
Terminal half-life
TLC
Total Lung Capacity
Tmax
Time at Maximum Plasma Concentration
TNF
Tumor Necrosis Factor
TPR
Third Party Resourcing
ULN
Upper Limit of Normal
US
United States of America
WBC
While Blood Cell
WHO
World Health Organization
WOCBP
Women of Childbearing Potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
COPD Assessment Test (CAT)
E-RS: COPD
DISKUS
EXACT-PRO
ELLIPTA
Propeller Sensor
SAS
SGRQ-C
 
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12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 6 will be performed by the central laboratory (Q2 
Solutions) for all time points as shown in the SoA (Section 2). 

At Screening, for prompt assessment of the participant’s eligibility local 
laboratory samples, with the exception of Hepatitis B, C and HIV,should be 
taken and the results received and reviewed prior to randomisation to allow for 
review of exclusion 18.  It is important that a sample for analysis by the central 
laboratory is obtained at the same time and promptly sent to the central 
laboratory.  The local lab results will not be entered into the CRF; however, they
will be filed in the respective participant’s source documentation

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 6
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
BUN
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose 
(nonfasting)
Calcium
Alkaline 
phosphatase
Albumin
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

Serum human chorionic gonadotropin (hCG) pregnancy test (as needed for 
women of childbearing potential)2 at Screening and to confirm any positive 
 
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Laboratory 
Assessments
Parameters
urine pregnancy test

Urine  pregnancy test (as needed for women of childbearing potential) at 
visits as shown in the SoA

Hepatitis B surface antigen [HBsAg] and hepatitis C virus antibody 3

HIV antibody 3
The results of each local laboratory test will not be entered into the CRF; 
however, they will be filed in the respective participant’s source documentation.
NOTES :
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 8.1.1 and Appendix 7 All events of ALT 3 × upper limit of normal (ULN) 
and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if 
INR measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis).
2.
Serum testing
3.
Hepatitis B surface antigen [HBsAg], hepatitis C virus antibody and HIV antibody will be assessed by the central 
laboratory only and will not be assessed at the local lab.
Laboratory/analyte results for the PK and biomarker anslyses that could unblind the study 
will not be reported to investigative sites or other blinded personnel until the study has 
been unblinded.
 
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12.3.
Appendix 3: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
 
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informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
Committees Structure
An iSRC will have study oversight to ensure that it meets the highest standards of ethics 
and participant safety and to carry out the planned interim safety data analyses/data 
reviews.  Data will be reviewed by the iSRC on a periodic basis, as defined in the iSRC 
Charter.  The iSRC, which will comprise a minimum of 3 people (including an 
independent statistician, an independent clinician with experience in respiratory and 
general medicine ), will be authorized to review unblinded interim safety analyses/data 
during the study.  .
The unblinded interim analysis and periodic safety updates will be performed and 
delivered to the iSRC by an independent statistician/statistical team.  Following review of 
the interim results for safety, the iSRC will give a recommendation to the pre-specified 
GSK personnel as to whether or not any adjustments in the study design or conduct 
should be made, including any adjustments in the treatment allocations.  The designated 
GSK personnel will decide whether or not to act on this recommendation.
 
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Membership, functions and operating procedures of the iSRC for this study will be 
defined in the iSRC Charter, which is available upon request.  Operating procedures for 
the iSRC will be established before the first review of unblinded data.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
Dissemination of Clinical Study Data
Study information from this protocol will be posted on publicly accessible clinical trial 
registers (e.g., www.clinicaltrials.gov; www.clinicaltrialsregister.eu) before enrollment of 
subjects begins.
The results summary will be posted to the publicly accessible GSK Clinical Study 
Register and other publicly available clinical trials registers (e.g.,www.clinicaltrials.gov; 
www.clinicaltrialsregister.eu) in accordance with GSK policy and SOPs.
In addition, a manuscript will be submitted to a peer-reviewed journal for publication in 
accordance with GSK policy and SOPs; see also Publication Policy section in this 
protocol.
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 each participating investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the study 
participants, as appropriate.
GSK will provide each participating investigator with the randomization codes for his/her 
site only after completion of the full statistical analysis.
 
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Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. 
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in the Source Document 
Agreement (SDA).
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
 
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The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development
 
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12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE.
 
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Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
 
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normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
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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Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
 
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Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
 
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Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper SAE data collection tool (see next section).

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in the SRM.
 
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12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1.
Premenarchal
2.
Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3.
Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 7.
 
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Table 7
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulationb

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.) 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies. 
b.
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case two highly effective methods of contraception should be utilized during the 
treatment period and for at least 10 days, corresponding to time needed to eliminate study treatment (5 half-lives), 
after the last dose of study treatment 
Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a 
negative highly sensitive serum pregnancy test conducted at Screening (Visit 1). 

Additional pregnancy testing should be performed at Visit 4 (Day 28), Visit 5 
(Day 56), and Visit 6 (Day 84; 24 hours after the last dose of double-blind study 
 
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treatment) or Early Withdrawal during the 12-Week Double-Blind Treatment 
Period and at Study Day 112 (Day 28 in the Post-Treatment Follow-Up Period), 
corresponding to time needed to eliminate study treatment (5 half-lives = 10 days) 
after the last dose of study treatment and as required locally.

Pregnancy testing will be performed whenever a menstrual cycle is missed or 
when pregnancy is otherwise suspected 

Pregnancy testing, with a sensitivity of 25 mIU/mL will be performed and 
assayed in the central laboratory 
Collection of Pregnancy Information
Male participants with partners who become pregnant

Investigator will not routinely attempt to collect pregnancy information on any male 
participant’s female partner(s) who becomes pregnant while the male participant is 
participating in this study; however, voluntary reports of such incidents will be 
captured through the GSK standard reporting mechanism.  This applies only to male
participants who receive double-blind study treatment.

If pregnancy information for a male participant’s female partner(s) is voluntarily 
reported, after obtaining the necessary signed informed consent from the pregnant 
female partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy. 

Partner will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded to GSK

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

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. 
 
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
A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 5. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
Any female participant who becomes pregnant while participating  

will discontinue study treatment and will be withdrawn from the study.
 
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12.6.
Appendix 6: Genetics
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis.

DNA samples will be used for research related to nemiralisib or COPD and related 
diseases. They may also be used to develop tests/assays including diagnostic tests) 
related to nemiralisib or study treatments of this drug class, and COPD. Genetic 
research may consist of the analysis of one or more candidate genes (including but 
not limited to: PIK3CD, PIK3CA, IL10, CHRNA3, CHRNA5, DNAH5, SUMF1, and 
CELSR1) or the analysis of genetic markers throughout the genome [or analysis of 
the entire genome] (as appropriate)

DNA samples may be analyzed to help understand the clinical data. 

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to nemiralisib or study treatments of this class. The results 
of genetic analyses may be reported in the clinical study report or in a separate study 
summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained while research on nemiralisib (or study treatments of 
this class) or COPD continues but no longer than 15 years after the last subject last 
visit or other period as per local requirements.
 
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12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments 
12.7.1.
Phase II Liver Chemistry Stopping Criteria
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 
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING below) 

Do not restart/rechallenge participant with study 
treatment unless allowed per protocol and GSK 
Medical Governance approval is granted (refer 
to Section 8.1.8.1 Section 12.7)

If restart/rechallenge not allowed per protocol or 
not granted, permanently discontinue study 
treatment and may continue participant in the 
study for any protocol specified follow up 
assessments (may include if applicable details 
on required follow up assessments 

Viral hepatitis serology4

Obtain INR and recheck with each liver chemistry 
assessment until the transaminases values show 
downward trend 

Blood sample for pharmacokinetic (PK) analysis, 
obtained within 14 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 form including 
acetaminophen, herbal remedies, other over the counter 
medications.

Record alcohol use on the liver event alcohol intake case 
report form
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 participants twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 
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 
 
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
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 participants weekly until liver chemistries 
resolve, stabilize or return to within baseline 
potential acetaminophen contribution to liver injury in 
participants with definite or likely acetaminophen use in 
the preceding week [James, 2009]). NOTE: not required 
in China 

Liver imaging (ultrasound, magnetic resonance, or 
computerised tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms. 
1.
Serum bilirubin fractionation should be performed if testing is available If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT 3xULN and bilirubin 2xULN.. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold 
value stated will not apply to participants receiving anticoagulants 
3.
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 participants known to be receiving placebo or non-GSK comparator 
treatments.) Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample 
cannot be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample 
handling and shipping are in the SRM.
 
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12.7.2.
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 participant safety. 

Participant can continue study treatment 

Participant 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 participant meets the liver chemistry 
stopping criteria, proceed as described above 

If, after 4 weeks of monitoring, ALT <3xULN and bilirubin 
<2xULN, monitor participants twice monthly until liver 
chemistries normalize or return to within baseline
 
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12.8.
Appendix 8: Medical Device Incidents: Definition and 
Procedures for Recording, Evaluating, Follow-up, and 
Reporting
Definition and Documentation of Medical Device Incidents
Definitions of a Medical Device Incident
The detection and documentation procedures described in this protocol apply to all GSK 
medical devices provided for use in the study (see Section 9.2.9 for the list of GSK 
medical devices). 
Medical Device Incident Definition

A medical device incident is any malfunction or deterioration in the characteristics 
and/or performance of a device as well as any inadequacy in the labeling or the 
instructions for use which, directly or indirectly, might lead to or might have led to 
the death of a participant/user/other person or to a serious deterioration in his/her 
state of health.

Not all incidents lead to death or serious deterioration in health. The nonoccurrence 
of such a result might have been due to other fortunate circumstances or to the 
intervention of health care personnel.
It is sufficient that:

An incident associated with a device happened and

The incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.
A serious deterioration in state of health can include any of the following:

Life-threatening illness

Permanent impairment of body function or permanent damage to body structure

Condition necessitating medical or surgical intervention to prevent one of the 
above 

Fetal distress, fetal death, or any congenital abnormality or birth defects
 
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Examples of incidents

A participant, user, caregiver, or healthcare professional is injured as a result of a 
medical device failure or its misuse.

A participant’s study treatment is interrupted or compromised by a medical device 
failure.

A misdiagnosis due to medical device failure leads to inappropriate treatment.

A participant’s health deteriorates due to medical device failure.
Documenting Medical Device Incidents
Medical Device Incident Documenting

Any medical device incident occurring during the study will be documented in the 
participant’s medical records, in accordance with the investigator’s normal clinical 
practice, and on the appropriate form.

For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE 
CRF page will be completed as described in Appendix 4.

The form will be completed as thoroughly as possible and signed by the investigator 
before transmittal to the GSK.

It is very important that the investigator provides his/her assessment of causality 
(relationship to the medical device provided by GSK) at the time of the initial report 
and describes any corrective or remedial actions taken to prevent recurrence of the 
incident.

A remedial action is any action other than routine maintenance or servicing of a 
medical device where such action is necessary to prevent recurrence of an incident. 
This includes any amendment to the device design to prevent recurrence.
 
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12.9.
Appendix 9:  Guidelines for COPD Exacerbation 
Identification, Categorization, Reporting, and Treatment
12.9.1.
Guidelines for Identifying an Acute Exacerbation of COPD
For this protocol, eligible participants must have an acute exacerbation of COPD 
requiring an escalation in therapy to include oral/systemic corticosteroid(s) and
antibiotic(s) as defined in Inclusion Criterion 4.
Acute exacerbation is to be confirmed by an experienced physician and to represent a 
recent worsening in at least two major and one minor symptoms, one major and two 
minor symptoms, or all 3 major symptoms.
a.
Major symptoms:
i.
Subjective increase in dyspnea
ii.
Increase in sputum volume
iii.
Change in sputum color
b. Minor symptoms:
i
Increased cough
ii.
Increased wheeze
iii.
Sore throat
iv.
Colds (nasal discharge and/or nasal congestion)
v.
Fever (oral temperature >37.5 C) without other cause
12.9.2.
COPD Exacerbation Severity
For the purposes of this study, each COPD exacerbation (including the index 
exacerbation at Screening and subsequent exacerbation[s]) will be categorized based 
upon the GOLD [GOLD, 2017] classification of severity as follows:

Mild COPD exacerbation: Worsening symptoms of COPD treated with short-
acting bronchodilators (SABDs) only

Moderate COPD exacerbation: worsening symptoms of COPD treated with 
SABDs plus antibiotics and/or oral/systemic corticosteroids

Severe COPD exacerbation: worsening symptoms of COPD that require 
hospitalization or visit to the emergency room.  Severe exacerbation may also be 
associated with acute respiratory failure.
 
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For this study, mild, moderate and severe exacerbations of COPD will be captured in the 
eCRF (See Section 12.9.4.).
Note: Use of oral/systemic corticosteroids and antibiotics for the treatment of upper or 
lower respiratory tract infections will not be considered a COPD exacerbation unless the 
participant experiences worsening symptoms of COPD, which match the definition of an 
exacerbation as given above.
12.9.3.
Subsequent COPD Exacerbation(s)
After the index exacerbation of COPD at Screening (Visit 1) has resolved, any 
randomized participant who experiences worsening of COPD for >48 hours should:

Contact his/her study investigator and/or research coordinator immediately, and 
report to the study clinic as required

If the participant is unable to contact his/her study investigator and/or research 
coordinator, he/she should contact his/her primary care physician (or other health 
care practitioner as required) and contact their study site as soon as possible

Continue to complete the eDiary

If the participant seeks emergent/acute care for worsening respiratory symptoms, 
he/she should inform the caring Health Care Provider (HCP) to contact the 
investigator as soon as possible.
Participants with presence of worsening respiratory symptoms will be classified by the 
Investigator as having:

A mild/moderate/severe COPD exacerbation and/or pneumonia

A lower respiratory tract infection (LRTI) [i.e., other than pneumonia]

Background variability of COPD

A non-respiratory-related disease

Other respiratory-related disease
Investigators and site/hospital staff should remain vigilant for the possible development 
of pneumonia in patients with COPD, as the clinical features of such infections overlap 
with the symptoms of COPD exacerbations (See Section 12.9.7).
If, based upon these criteria, a participant’s symptoms do not fulfil the diagnosis of a 
COPD exacerbation and/or pneumonia, then the investigator should use his/her clinical 
judgment to assess the participant’s symptoms (including increased volume of sputum 
production and/or change in the sputum color) for a diagnosis of LRTI (e.g., acute 
bronchitis), background variability of COPD, a non-respiratory-related disease or other 
 
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respiratory-related disease.  Investigator judgment should be used in deciding whether to 
report the signs and symptoms (and/or determined diagnosis) as an AE/SAE in the eCRF.
12.9.4.
Collection of COPD Exacerbation Data
COPD exacerbations (mild, moderate, severe) will be collected for all participants who 
are randomized and receive at least one dose of double-blind study treatment (Visit 2).  
The time period for collection of exacerbations will begin with the index exacerbation at 
Visit 1 (Screening) and will end when Visit 9 (last study visit) has been completed.
COPD exacerbations are considered DREs (see Section 9.2.7).  Because these events are 
typically associated with the disease under study, they will not be reported according to 
the standard process for expedited reporting of SAEs to GSK (even though the event may 
meet the definition of a SAE).  These events will be recorded on the DRE page, in this 
study the exacerbation page in the participant’s eCRF within 72 hours after the 
Investigator becomes aware of the event.  These DREs will be monitored by a Safety 
Review Team (SRT) on a routine basis
NOTE: However, if either of the following conditions apply, then the event must be 
recorded and reported as an SAE (See Section 9.2): 

The event is, in the investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual participant, or

The investigator considers that there is a reasonable possibility that the event is 
related to study treatment
If an exacerbation is caused by pneumonia then pneumonia should be considered the 
event and must be recorded in the AE or SAE form in the eCRF and on the pneumonia 
form in the eCRF (See Section 9.1.2)
12.9.4.1.
Guideline for Determining Exacerbation Onset and Resolution Dates
The date of onset of the exacerbation is the first day (of at least 2 consecutive days) of 
worsening symptoms of COPD as described in Section 12.9.1.
The date of resolution of the exacerbation should be based upon when the 
Investigator/treating physician and/or participant determines that the COPD symptoms 
have returned to pre-exacerbation levels or to a new baseline.  In determining this 
resolution date, consideration should be given to eDiary recordings and/or participant 
evaluation.
12.9.4.2.
Guideline for Assessing Multiple Mild Exacerbations
Two mild exacerbations can be combined into one, per the Investigator’s judgement, if a 
participant’s diary reveals that the two mild COPD exacerbations are separated by no 
more than three exacerbation-free days.
 
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12.9.4.3.
Guideline for Assessing Exacerbations that Increase in Severity
If an exacerbation begins as mild, but becomes moderate or severe or begins as moderate 
and becomes severe, the exacerbation should be captured as one exacerbation and 
classified by its highest level of severity.
12.9.5.
Treatment of COPD Exacerbations
To be eligible for this protocol, at Visit 1 (Screening), participants must present with a 
moderate or severe (requires hospitalization) acute exacerbation of COPD requiring 
treatment with SoC (defined for this protocol as treatment with oral/systemic 
corticosteroid[s] and antibiotic[s]) to be confirmed by an experienced physician (referred 
to as the ‘index COPD exacerbation;’ See Inclusion Criterion 4).  SoC must be 
documented in the participant’s source documentation and in the eCRF.
For the index COPD exacerbation at Screening and any subsequent COPD 
exacerbation(s) during the study (Screening, 12-Week Double-Blind Treatment Period, 
and the 12-Week Post-Treatment Follow-Up Period), the Investigator/medically qualified 
health care personnel should treat the participant’s COPD exacerbation as deemed 
medically appropriate.  If medically necessary, the Principal Investigator or other 
medically qualified health care personnel may stop the participant’s double-blind study 
treatment temporarily in order to treat the COPD exacerbation.
All medications (COPD and non-COPD) used for the treatment of an exacerbation(s) 
must be recorded in the source documents and in the COPD Exacerbation form in the 
eCRF.
12.9.6.
Guidelines for Distinguishing Between Continuation of an 
Existing Exacerbation versus a Subsequent New Exacerbation

Any course of oral/systemic corticosteroids started within 7 days of finishing a 
previous course will be considered as treatment for a single exacerbation

Any course of antibiotics started within 7 days of finishing a previous course will 
be considered as treatment for a single exacerbation
12.9.7.
Pneumonia
Participants who develop pneumonia during the 12-Week Double-Blind Treatment 
Period should discontinue study treatment.
For the purpose of this study, pneumonia is defined as new auscultatory findings 
compatible with parenchymal lung infection and/or radiographic evidence of 
parenchymal/air space disease.  All suspected cases of pneumonia are encouraged to be 
confirmed radiographically within 48 hours of diagnosis.  All diagnoses of pneumonia 
(radiographically confirmed or unconfirmed) must be reported as an AE or SAE (if 
applicable).  Information regarding chest X-ray-confirmed cases of pneumonia will be 
recorded in the eCRF.  Details regarding the information to be captured for pneumonias 
will be provided in the SRM.
 
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All medications used to treat the pneumonia are to be recorded in the source 
documentation and in the eCRF.
 
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12.10.
Appendix 10: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
Amendment 01 – Country Amendment – Korea
(Document Number 2017N317218_04)
26-SEPTEMBER-2017
Amendment 01 – Global Amendment
(Non-tracked changes version: document number 2017N317218_03 –
to re-insert the missing text shown in bold that was present in the 
tracked changes version of Amendment 1 (document number 
2017N317218_01), but inadvertently missing from the non-tracked 
changes version of Amendment 1(document number 
2017N317218_02) for Exclusion Criterion #6: “6. Other respiratory 
disorders: A diagnosis of 1-antitrypsin deficiency as the underlying cause of 
COPD, active tuberculosis, lung cancer, clinically overt bronchiectasis 
(Note: focal bronchiectasis is not exclusionary), sarcoidosis, pulmonary 
fibrosis (Note: focal fibrotic pulmonary lesions are not exclusionary), primary 
pulmonary hypertension, interstitial lung diseases, 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.” 
26-SEPTEMBER-2017
Amendment 01 – Global Amendment
(Non-tracked changes version: document number 2017N317218_02)
15-SEPTEMBER-2017
Amendment 01 – Global Amendment
(Tracked changes version: document number 2017N317218_01)
24-AUGUST-2017
Original Protocol
(document number 2017N317218_00)
15-JUNE-2017
Amendment 1 Country Specific Amendment – South Korea (26Sep17)
Overall Rationale for the Amendment:  The rationale for this country-specific 
Amendment 1 for participating Investigators in South Korea only (Amendment 1/SKO-1) 
is to include a new Appendix (Appendix  11) to provide information regarding the name, 
model number and manufacturer for the standardized equipment that is being provided 
for capturing the electrocardiogram (ECG) data and spirometry data (MasterScope CT) 
and the sensors for capturing compliance with study-provided, double-blind study 
treatment (Propeller Sensor for ELLIPTA) and the use of study-provided, rescue 
medication (Propeller Sensor for MDI) to support importation of these devices into South 
Korea.  This information is also provided in the study documentation provided to all 
participating Investigators globally by the respective vendor.
This protocol amendment applies to all participating Investigators in South Korea only.
Section # and 
Name
Description of Change
Brief Rationale
Appendix 11 – new 
country-specific 
Appendix for South 
New country-specific Appendix 
(Appendix 11) added for 
Investigators participating in 
To support importation of these devices 
into South Korea.
 
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Section # and 
Name
Description of Change
Brief Rationale
Korea only added
South Korea to provide 
information regarding the name, 
model number and manufacturer 
for the standardized equipment 
that is being provided for 
capturing the electrocardiogram 
(ECG) data and spirometry data 
(MasterScope CT) and the 
sensors for capturing compliance 
with study-provided, double-blind 
study treatment (Propeller 
Sensor for ELLIPTA) and the 
use of study-provided, rescue 
medication (Propeller Sensor for 
MDI).
Appendix 12: 
Protocol Amendment 
History
Appendix number revised from 
11 to 12.
Appendix number revised in light of the 
addition of the new Appendix 11: 
Country-Specific Amendment 1 for 
South Korea (SKO-1).
Table of Contents
The Table of Contents was 
revised to account for the 
addition of the new Appendix 11: 
Country-Specific Amendment 1 
for South Korea (SKO-1) and the 
resulting change in appendix 
number for the Protocol 
Amendment History from 
Appendix number 11 to 
Appendix number12.
Table of Contents revised in light of the 
addition of the new Appendix 11: 
Country-Specific Amendment 1 for 
South Korea (SKO-1).
Appendix 1: 
Abbreviations and 
Trademarks
MasterScope added to the list of 
trademarks not owned by the 
GlaxoSmithKline group of 
companies in the country-
specific amendment for South 
Korea.
MasterScope appears in the new 
country-specific Appendix 11.
Amendment 1 – Global Amendment (26Sep17):  
Overall Rationale for the Amendment:  The rationale for Amendment 01 was to 
incorporate the following revisions to the protocol in response to the Grounds for Non-
Acceptance (GNA) issued during the Voluntary Harmonisation Procedure (VHP) in the 
European Union (EU) as well as other clarifications as summarized in the table below.
 
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This protocol amendment applied to all participating Investigators globally.
Section # and 
Name
Description of Change
Brief Rationale
Section 2 Schedule 
of Activities (SOA) 
12-Week Double-
Blind Treatment 
Period
Addition of the row titled, 
“Dispense eDiary and initiate 
training module within,” during 
Visit 2.
To ensure clarity that the eDiary (which 
includes the EXACT, CAT and SGRQ 
questionnaires, etc., already noted in 
the SOA) is dispensed during Visit 2.
Section 2 Schedule 
of Activities (SOA) 
12-Week Double-
Blind Treatment 
Period and 12-Week 
Post-Treatment 
Follow-Up Period
Addition of the rows titled, 
“Review eDiary” and “Collect 
eDiary)
To ensure clarity that the eDiary (which 
includes the EXACT, CAT and SGRQ 
questionnaires, etc., already noted in 
the SOA) is to be reviewed during the 
12-Week Double-Blind Treatment 
Period and the 12-Week Post-
Treatment Follow-Up Period and 
collected during Visit 9 or the Early 
Withdrawal Visit (if Early Withdrawal 
from the study occurs during either the 
12-Week Double-Blind Treatment 
Period or during the 12-Week Post-
Treatment Follow-Up Period)
Section 2 Schedule 
of Activities (SOA) 
12-Week Double-
Blind Treatment 
Period and Section 
6.2 Exclusion 
Criteria, Criterion 22 
HIV antibody
Addition of the requirement for 
HIV testing at Screening;
Since subjects with HIV infection are 
excluded from the study, it was 
requested that a specific test to assess 
the seronegativity to the virus should be 
performed at Screening.
Section 2 Schedule 
of Activities (SOA) 
12-Week Double-
Blind Treatment 
Period, Early 
Withdrawal Visit
Addition of “X19”in the row titled,” 
Assessment of study treatment 
compliance”
To correct an inadvertent typographical 
error.  
Section 2 Schedule 
of Activities (SoA): 
12-Week Post-
Treatment Follow-Up 
Period, row for 
EXACT
Extension of the width of the 
bidirectional arrow
To ensure clarity that EXACT is 
completed daily in the evening during 
the 12-Week Post-Treatment Follow-Up 
Period.
 
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Section # and 
Name
Description of Change
Brief Rationale
Section 2 Schedule 
of Activities (SOA) 
12-Week Double-
Blind Treatment 
Period and 12-Week 
Post-Treatment 
Follow-Up Period 
and Section 9.10 
Health Care 
Research Utlization 
(HCRU) and Health 
Economics 
Revision of text to clarify that 
participants will record a “Yes” or 
“No” response in the eDiary each 
day regarding whether or not 
they have had any HCRU 
contacts/visits for any reason 
(including COPD-related and 
non-COPD-related) other than a 
scheduled visit to the 
Investigator’s site.  For any “Yes” 
response, participants will be 
prompted to contact the 
Investigator to promptly report 
further details regarding the 
HCRU and the Investigator will 
receive an e-mail notification as 
well.  The investigator (or 
designee) will enter the HCRU 
details in the eCRF.
Addition of the row titled, “Health 
Care Resource Utilization 
(HCRU) Review” during the 12-
Week Double-Blind Treatment 
Period and the Post-Treatment 
Follow-Up Period, including 
Early Withdrawal (if applicable).
To clarify that the participant will enter a 
“Yes” or “No” response in the eDiary 
and contact the Investigator to report 
the details, which will be recorded in 
the eCRF.
Section 3.2 
Background and
Section 11 
References
Addition of a brief summary 
regarding the reported rate of 
moderate and severe 
exacerbations, the prevalence of 
‘frequent exacerbators’ and 
addition of the corresponding 
references.
To provide information regarding the 
estimated frequency of moderate or 
severe acute exacerbation in patients 
with COPD, the prevalence of “frequent 
exacerbators” and the annual rate of 
rehospitalisation in patients with COPD
Section 6.1 Inclusion 
Criteria,  Criterion 1 
Age 
Addition of an upper age limit (80 
years of age)
To provide an upper age limit for 
eligible participants, since the safety 
and efficacy of nemiralisib has not been 
investigated in the very elderly to date.
Section 6.2 
Exclusion Criteria, 
Criterion 6 Other 
respiratory disorders
Deletion of inadvertent duplicate 
text, “active tuberculosis, lung 
cancer, bronchiectasis (Note: 
focal bronchiectasis is not 
exclusionary)”
To delete inadvertent typographical 
error of duplicated text
 
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Section # and 
Name
Description of Change
Brief Rationale
Section 6.2 
Exclusion Criteria, 
Criterion 13
Addition of information to provide 
clarification regarding 
allowed/excluded strong 
inhibitors and sensitive narrow 
therapeutic index substrates of 
CYP3A4
To provide information about the 
absence of in vivo elimination 
information and that the role of CYP3A 
as an important drug metabolising 
enzyme is based upon in vitro data and 
to revise Exclusion Criterion 13 to more 
clearly explain which strong inhibitors 
and sensitive narrow therapeutic index 
substrates of  CYP3A are 
allowed/excluded.   Strong inhibitor 
inclusion/ exclusion criteria based on 
GSK2269557 safety margin.
Section 6.4 Screen 
Failures
Correction of the text regarding 
re-screened participants will 
retain the same participant 
number to must be assigned a 
new participant number and will 
be entered into the eCRF again.
To correct an inadvertent typographical 
error.
Section 7.4 Blinding
Deletion of text regarding 
Investigator encouraged to 
contact the GSK Medical Monitor 
or appropriate GSK study 
personnel before the treatment 
blind is broken and replacing 
with guidance that GSK must be 
notified of the decision to 
unblind.
The  text encouraging the Investigators 
to contact/consult with the GSK Medical 
Monitor or appropriate GSK personnel 
before making a decision to break the 
treatment blind was deleted, since 
breaking of the treatment blind is the 
responsibility of the Investigator or 
treating physician in the case of an 
emergency, or if, in the opinion of the 
Investigator, it is in the participant’s 
best interest for the Investigator to 
know the study treatment assignment 
(consistent with the Declaration of 
Helsinki and ICH GCP).  The deleted 
text was replaced with text stating that 
GSK must be notified of the decision to 
unblind.
 
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