Clinical trial NCT03345407
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: Nemiralisib Dose-Finding GSK2269557 Acute Moderate or Severe Exacerbation of Chronic Obstructive Pulmonary Disease
Sponsor: GlaxoSmithKline
Start date: 2017-11-28; Completion date: 2019-01-10
Enrollment: 943 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Nemiralisib is being developed as an anti-inflammatory drug for the treatment of inflammatory airways disease. This study is designed to assess the dose response, efficacy, safety, and pharmacokinetics of nemiralisib across a range of doses \[up to 750 micrograms (µg)\] compared with placebo. The study consists of a Screening Period, a 12-Week Treatment Period and a 12-Week Post-Treatment Follow-Up Period. Approximately 1,250 subjects with an acute moderate or severe exacerbation of COPD requiring standard of care (SoC) therapy will be randomized in this double-blind study. Subjects will be randomized to receive different doses of nemiralisib or placebo via ELLIPTA® inhaler. The total duration of study participation is approximately 6 months (170 days). ELLIPTA is the registered trademark of GlaxoSmithKline (GSK) group of companies.

Detailed description:

Arms: arm 1: Eligible subjects will receive placebo ELLIPTA dry powder (blended with lactose) for oral inhalation once daily in the morning for 12 weeks. Albuterol (Salbutamol) MDI or nebules will also be provided to all subjects for use as rescue medication as needed. arm 2: Eligible subjects will receive nemiralisib ELLIPTA 50 µg dry powder (blended with lactose and magnesium stearate) for oral inhalation once daily in the morning for 12 weeks. Albuterol (Salbutamol) MDI or nebules will also be provided to all subjects for use as rescue medication as needed. arm 3: Eligible subjects will receive nemiralisib ELLIPTA 100 µg dry powder (blended with lactose and magnesium stearate) for oral inhalation once daily in the morning for 12 weeks. Albuterol (Salbutamol) MDI or nebules will also be provided to all subjects for use as rescue medication as needed. arm 4: Eligible subjects will receive nemiralisib ELLIPTA 250 µg dry powder (blended with lactose and magnesium stearate) for oral inhalation once daily in the morning for 12 weeks. Albuterol (Salbutamol) MDI or nebules will also be provided to all subjects for use as rescue medication as needed. arm 5: Eligible subjects will receive nemiralisib ELLIPTA 500 µg dry powder (blended with lactose and magnesium stearate) for oral inhalation once daily in the morning for 12 weeks. Albuterol (Salbutamol) MDI or nebules will also be provided to all subjects for use as rescue medication as needed. arm 6: Eligible subjects will receive nemiralisib ELLIPTA 750 µg dry powder (blended with lactose and magnesium stearate) for oral inhalation once daily in the morning for 12 weeks. Albuterol (Salbutamol) MDI or nebules will also be provided to all subjects for use as rescue medication as needed.
Interventions: intervention 1: Placebo ELLIPTA intervention 2: Nemiralisib ELLIPTA 50 µg intervention 3: Nemiralisib ELLIPTA 100 µg intervention 4: Nemiralisib ELLIPTA 250 µg intervention 5: Nemiralisib ELLIPTA 500 µg intervention 6: Nemiralisib ELLIPTA 750 µg intervention 7: Albuterol (Salbutamol) MDI or nebules intervention 8: Standard of care therapy
Intervention descriptions: intervention 1: Placebo will be administered via oral inhalation route once daily in the morning. intervention 2: Nemiralisib is a potent and highly selective inhaled PI3Kd inhibitor being developed as an anti-inflammatory for the treatment of inflammatory airways disease. Nemiralisib 50 µg will be administered as a dry powder inhaler via oral inhalation route. In addition, subjects will receive SOC therapy for the index acute moderate or severe exacerbation of COPD. intervention 3: Nemiralisib is a potent and highly selective inhaled PI3Kd inhibitor being developed as an anti-inflammatory for the treatment of inflammatory airways disease. Nemiralisib 100 µg will be administered as a dry powder inhaler via oral inhalation route. In addition, subjects will receive SOC therapy for the index acute moderate or severe exacerbation of COPD. intervention 4: Nemiralisib is a potent and highly selective inhaled PI3Kd inhibitor being developed as an anti-inflammatory for the treatment of inflammatory airways disease. Nemiralisib 250 µg will be administered as a dry powder inhaler via oral inhalation route. In addition, subjects will receive SOC therapy for the index acute moderate or severe exacerbation of COPD. intervention 5: Nemiralisib is a potent and highly selective inhaled PI3Kd inhibitor being developed as an anti-inflammatory for the treatment of inflammatory airways disease. Nemiralisib 500 µg will be administered as a dry powder inhaler via oral inhalation route. In addition, subjects will receive SOC therapy for the index acute moderate or severe exacerbation of COPD. intervention 6: Nemiralisib is a potent and highly selective inhaled PI3Kd inhibitor being developed as an anti-inflammatory for the treatment of inflammatory airways disease. Nemiralisib 750 µg will be administered as a dry powder inhaler via oral inhalation route. In addition, subjects will receive SOC therapy for the index acute moderate or severe exacerbation of COPD. intervention 7: Albuterol (Salbutamol) MDI or nebules will be provided to all subjects as a rescue medication. intervention 8: SoC therapy for the index exacerbation is defined as treatment with oral/systemic corticosteroid (prednisone 40 mg/day or equivalent) for 5 days and antibiotic for 7 days. Subjects will receive SoC as prescribed by the Investigator or medically qualified designee. The dose and/or duration of prednisone and/or the antibiotic can be modified according to the Investigator's/medically qualified designee's judgment or according to local country/institution practice.

Protocol documents:
Prot_000.pdf: 
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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 
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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 
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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 
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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.
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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 
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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 
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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.
REFERENCES
Angulo I, Vadas O, Garçon F, Banham-Hall E, et al. Phosphoinositide 3-kinase δ gene 
mutation predisposes to respiratory infection and airway damage. Science. 
2013;342(6160):866-71.
Barnes PJ. Chronic obstructive pulmonary disease *12: New treatments for COPD. 
Thorax. 2003;58:803–8.
Chapman KR, Mannino DM, Soriano JB, Vermeire PA, Buist AS, Thun MJ, Connell C, 
Jemal A, Lee TA, Miravitlles M, Aldington S, Beasley R. Epidemiology and costs of 
chronic obstructive pulmonary disease. Eur Respir J. 2006;27(1):188-207.
Corral-Gudino L, Jorge-Sánchez RJ, García-Aparicio J, Herrero-Herrero JI, López-
Bernús A, Borao-Cengotita-Bengoa M, Martín-González JI, Moreiro-Barroso MT. Use of 
noninvasive ventilation on internal wards for elderly patients with limitations to 
respiratory care: a cohort study. Eur J Clin Invest. 2011;41(1):59-69.
Darnell K, Dwivedi AK, Weng Z, and Panos RJ. Disproportionate utilization of 
healthcare resources among veterans with COPD: a retrospective analysis of factors 
associated with COPD healthcare cost. Cost Effectiveness and Resource Allocation. 
2013;11(13): 1-10.
Donaldson GC, Wedzicha JA. COPD exacerbations 1: Epidemiology. Thorax. 
2006;61(2):164-8.
Dose Response Information to Support Drug Registration- ICH E4 Harmonised Tripartite 
guideline 1994.
European Medicines Agency, Committee for Medicinal Products for Human Use 
(CHMP). Guideline on the evaluation of medicinal products indicated for treatment of 
bacterial infections. CPMP/EWP/558/95 rev 2, 15 December 2011. 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/
WC500003417.pdf
European Medicines Agency, Committee for Medicinal Products for Human Use 
(CHMP). Addendum to the guideline on the evaluation of medicinal products indicated 
for treatment of bacterial infection. EMA/CHMP/351889/2013, 01 May 2014. 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/11/
WC500153953.pdf
Fallah MP. Role of PI3K-ACT pathway in the age associated decline in TLR mediated 
activation of innate and adaptive immune responses.2011. University of Kentucky 
Doctoral Dissertations. 205. http://uknowledge.uky.edu/gradschool_diss/205.
FDA Guidance for Industry. Exposure-Response relationships- Study Design, Data 
Analysis, and Regulatory Applications. FDA, Rockville, MD, April 2003.
 
2019N398117_00


2017N317218_05
CONFIDENTIAL
200879
97
Food and Drug Administration (FDA). Guidance for industry on acute bacterial 
exacerbations of chronic bronchitis in patients with chronic obstructive pulmonary 
disease: developing antimicrobial drugs for treatment. Silver Spring, MD: Center for 
Drug Evaluation and Research (CDER); 2012. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/ucm070935.pdf
George SN, Garcha DS, Mackay AJ, Patel AR, Singh R, Sapsford RJ, Donaldson GC, 
Wedzicha JA. Human rhinovirus infection during naturally occurring COPD 
exacerbations. Eur Respir J. 2014 Jul;44(1):87-96.
Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and 
Prevention, 2017. Available from: www.ginaasthma.org
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the 
Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, 
(2017 Report). Available from: www.goldcopd.org 
Guidance for Industry:  Population Pharmacokinetics. U.S Department of Health and 
Human Services, FDA, Washington, DC, 1999.
Guidelines on Reporting the Results of Population Pharmacokinetic Analyses –
Committee for Medicinal Products for Human Use - CHMP/EWP/185990/06. Adoption 
By Chmp 21 June 2007, Date For Coming Into Effect 1 January 2008
Hachad H, Raqueneau-Majlessi I, Levy R. A useful tool for drug interaction evaluation: 
The University of Washington Metabolism and Transport Drug Interaction Database. 
Human Genomics. 2010; 5(1): 61-72
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, et al. Contraceptive 
Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc., 2011: 50. Table 3-2.
Hurst JR, Donaldson GC, Quint JK, Goldring JJ, Baghai-Ravary R, Wedzicha JA. 
Temporal clustering of exacerbations in chronic obstructive pulmonary disease. Am J 
Respir Crit Care Med. 2009;179(5):369-74.
Hurst JR, Vestbo J, Anzueto A, Locantore N, Müllerova H, Tal-Singer R, Miller B, 
Lomas DA, Agusti A, MacNee W, Calverley P, Rennard S, D., Wouters EFM, and 
Wedzicha JA, for the Evaluation of COPD Longitudinally to Identify Predictive 
Surrogate Endpoints (ECLIPSE) Investigators. Susceptibility to Exacerbation in Chronic 
Obstructive Pulmonary Disease. N Engl J Med 2010; 363:1128-38.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784..
Jones PW. St George's Respiratory Questionnaire: MCID. Journal of COPD. 2005;2:75-
79.
 
2019N398117_00


2017N317218_05
CONFIDENTIAL
200879
98
Jones, P., Harding, G., Berry, P., Wiklund, I., Chen, W-H., Leidy, N. Development and 
first validation of the COPD Assessment Test (CAT) Eur Respir J. 2009;34:648–654.
Jones, P., Harding, G., Wiklund, I., Berry, P., Tabberer, M., Yu, R., Leidy, N. Tests of 
the Responsiveness of the Chronic Obstructive Pulmonary Disease (COPD) Assessment 
Test (CAT) Following Acute Exacerbation and Pulmonary Rehabilitation. Chest. 
2012;142:134-40
Kim SR, Lee KS, Park HS, Park SJ, Min KH, Moon H, et al. HIF-1inhibition 
ameliorates an allergic airway disease via VEGF suppression in bronchial epithelium. Eur 
J Immunol. 2010;40(10):2858-69.
Leidy, NK, Sexton, CC, Jones PW, et al Measuring respiratory symptoms in clinical trials 
of COPD: reliability and validity of a daily diary. Thorax. 2014; 69:443–49.
Leidy, NK, Wilcox, TK, Jones, PW et al.  Standardizing Measurement of Chronic 
Obstructive Pulmonary Disease Exacerbations Reliability and Validity of a Patient-
reported Diary. Am J Respir Crit Care Med. 2011;183:323–29. 
Lucas CL, Kuehn HS, Zhao F, Niemela JE, et al. Dominant-activating germline 
mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell 
senescence and human immunodeficiency. Nat Immunol. 2014;15(1):88-97.
MacDonald VM and Gibson PG. To define is to limit: perspectives on asthma–COPD 
overlap syndrome and personalised medicine. Eur Respir J. 2017; 49: 1-3.
McGhan R, Radcliff T, Fish R, Sutherland ER, Welsh C, Make B. Predictors of 
rehospitalization and death after a severe exacerbation of COPD. Chest. 
2007;132(6):1748-55.
Meguro M, Barley EA, Spencer S, Jones PW. Development and validation of an 
improved COPD-specific version of the St George's Respiratory Questionnaire. Chest 
2006;132: 456-63.
Miller MR, Hankinson J, Odencrantz J, Brusasco V, Burgos F, Casaburi R, Coates A, 
Crapo R, Enright R, van der Grinten CPM, Gustafsson P, Jensen R, Johnson DC, 
MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J. 
Standarisation of spirometry. Eur Respir J. 2005;26:319-38.
Miravitlles M, Soler-Cataluña JJ, Calle M, Soriano JB. Treatment of COPD by clinical 
phenotypes: putting old evidence into clinical practice. Eur Respir J. 2013;41(6):1252-6.
Morris AC, Brittan M, Wilkinson TS, McAuley DF, et al. C5a-mediated neutrophil 
dysfunction is RhoA-dependent and predicts infection in critically ill patients. Blood. 
2011;12;117(19):5178-88.
National Center for Health Statistics. Health, United States 2015 with Special Feature on 
Racial and Ethnic Health Disparities. Hyattsville, MD: US Dept. Health and Human 
Services; 2016. (http://www.cdc.gov/nchs/hus/).
 
2019N398117_00


2017N317218_05
CONFIDENTIAL
200879
99
Okkenhaug K, Ali K and Vanhaesebroeck B. Antigen receptor signalling: A distinctive 
role for the p110isoform of PI3K. Trends in Immunology, 2007; 28: 80-7.
Papi A, Bellettato CM, Braccioni F, Romagnoli M, Casolari P, Caramori G, Fabbri LM, 
Johnston SL. Infections and airway inflammation in chronic obstructive pulmonary 
disease severe exacerbations. Am J Respir Crit Care Med. 2006;173(10):1114-21.
Pinheiro J, Bretz F, and Branson M. (2006) Analysis of dose-response studies: Modeling 
approaches. In: Dose Finding in Drug Development. Ting, N. (ed.), Springer, New York, 
pp. 146-171.
Public Health England. English surveillance programme for antimicrobial utilisation and 
resistance (ESPAUR). Report 2016.
Sadhu C, Dick K, Tino WT, Staunton DE. Selective role of PI3K delta in neutrophil 
inflammatory responses. Biochem Biophys Res Commun. 2003; 308(4): 764-769.
Sapey E, Greenwood H, Walton G, Mann E, Love A, Aaronson N, Insall RH, Stockley 
RA, and Lord JM. Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in 
the elderly: toward targeted treatments for immunosenescence. Blood. 2014; 123(2): 239-
248.
Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha. Time course and 
recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J 
Respir Crit Care Med. 2000;161(5):1608-13.
Stark AK, Sriskantharajah S, Hessel EM, and Okkenhaug K. PI3K inhibitors in 
inflammation, autoimmunity and cancer. Curr Opin Pharmacol. 2015 Aug; 23: 82–91.
Suissa S, Dell'Aniello S, Ernst P. Long-term natural history of chronic obstructive 
pulmonary disease: severe exacerbations and mortality. Thorax. 2012;67(11):957-63.
The Criteria Committee of the New York Heart Association (NYHA). Nomenclature and 
Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: 
Little, Brown & Co; 1994:253-256.
U.S. Food and Drug Administration (FDA). Combating Antibiotic Resistance, FDA 
Consumer Health Information. Updated November 2011. 
http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm092810.htm FDA
Wedzicha JA, Brill SE, Allinson JP, Donaldson GC. Mechanisms and impact of the 
frequent exacerbator phenotype in chronic obstructive pulmonary disease. BMC Med. 
2013;11(181):1-10.
Weisser SB, McLarren KW, Voglmaier N, van Netten-Thomas CJ, Antov A, Flavell RA, 
Sly LM. Alternative activation of macrophages by IL-4 requires SHIP degradation. Eur J 
Immunol. 2011;41(6):1742-53.
 
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Word Health Organization (WHO) Fact Sheet. November 2016. 
http://www.who.int/mediacentre/factsheets/fs315/en/
 
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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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SAP_001.pdf: 
CONFIDENTIAL
GlaxoSmithKline group of companies
200879
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for 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)
Compound Number 
:
GSK2269557
Effective Date 
:
10-OCT-2018
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 200879 and at the planned interim 
analyses.

This RAP is intended to describe the efficacy, safety and pharmacokinetic analyses 
required for the study. 

This version of the RAP includes amendments to the originally approved RAP.

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
 
Statistics Leader, (Respiratory Clinical Statistics)
Approver
Date
Approval Method
10-OCT-2018
eSignature
TA Director (Respiratory Clinical Statistics)
10-OCT-2018
eSignature
Programming Manager (Respiratory Clinical 
Programming)
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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RAP Team Approvals:
Approver
Date
Approval Method
26-SEP-2018
Email
Principal Programmer (Respiratory Clinical 
Programming)
26-SEP-2018
Email
Clinical Development Director (Respiratory)
24-SEP-2018
Email
Clinical Development Manager (Respiratory)
25-SEP-2018
Email
Medical Director (Global Clinical Safety and 
Pharmacovigilance)
25-SEP-2018
Email
Manager, Clinical Pharmacology (Clinical 
Pharmacology Modelling and Simulation)
01-OCT-2018
Email
Director, Patient Centred Outcomes (Value 
Evidence & Outcomes)
 
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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................8
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................8
2.1.
Study Objective(s) and Endpoint(s)...............................................................8
2.2.
Study Design ..............................................................................................11
3.
PLANNED ANALYSES ..........................................................................................11
3.1.
Interim Analyses .........................................................................................11
3.1.1.
Futility analyses ...........................................................................13
3.1.1.1.
Futility rules ................................................................14
3.2.
Final Analyses ............................................................................................14
4.
ANALYSIS POPULATIONS ...................................................................................15
4.1.
Protocol Deviations.....................................................................................15
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................16
5.1.
Study Treatment & Sub-group Display Descriptors.....................................16
5.2.
Baseline Definitions ....................................................................................16
5.3.
Multicentre Studies .....................................................................................17
5.4.
Examination of Covariates and Subgroups .................................................17
5.4.1.
Covariates ...................................................................................17
5.4.2.
Examination of Subgroups...........................................................18
5.5.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................20
6.
STUDY POPULATION ANALYSES .......................................................................20
6.1.
Overview of Planned Study Population Analyses........................................20
6.1.1.
Concomitant medications.............................................................20
7.
EFFICACY ANALYSES..........................................................................................21
7.1.
Primary Efficacy Analyses ..........................................................................21
7.1.1.
Primary Endpoint .........................................................................21
7.1.2.
Primary Statistical Analyses.........................................................21
7.1.2.1.
Model Checking & Diagnostics ...................................23
7.1.3.
Sensitivity and Supportive Analyses ............................................24
7.1.4.
Subgroup Analyses......................................................................24
7.2.
Secondary Efficacy Analyses......................................................................24
7.2.1.
Rate of exacerbations..................................................................24
7.2.1.1.
Statistical analyses.....................................................25
7.2.1.2.
Subgroup analyses.....................................................26
7.2.1.3.
Exploratory analyses ..................................................26
7.2.2.
Time to next exacerbation............................................................26
7.2.2.1.
Statistical analyses.....................................................27
7.2.2.2.
Subgroup analyses.....................................................27
7.2.3.
Change from baseline in Clinic Visit trough FEV1.........................27
7.2.3.1.
Statistical Analyses.....................................................27
7.2.3.2.
Subgroup analyses.....................................................28
7.2.4.
Change from hospital discharge in clinic visit trough FEV1...........28
 
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7.2.4.1.
Statistical analyses.....................................................28
7.2.5.
EXAcerbations of Chronic Pulmonary Disease Tool -
Patient Reported Outcome (EXACT) ...........................................28
7.2.5.1.
Proportion of participants achieving EXACT-
defined recovery from index exacerbation ..................29
7.2.5.2.
Time to EXACT-defined recovery from index 
exacerbation...............................................................30
7.2.5.3.
Severity of subsequent HCRU-defined 
exacerbation(s) defined by EXACT.............................30
7.2.5.4.
Statistical analyses.....................................................30
7.2.5.5.
Subgroup analyses.....................................................31
7.2.5.6.
Sensitivity and supportive analyses............................31
7.2.6.
COPD Assessment Test (CAT)....................................................31
7.2.6.1.
Proportion of responders using the CAT.....................31
7.2.6.2.
Change from baseline in CAT Total Score..................32
7.2.6.3.
Statistical analyses.....................................................32
7.2.6.4.
Subgroup analyses.....................................................33
7.2.7.
St. George’s Respiratory Questionnaire for COPD 
Patients (SGRQ-C)......................................................................33
7.2.7.1.
Proportion of responders on the SGRQ Total 
Score..........................................................................33
7.2.7.2.
Change from baseline in SGRQ Total Score ..............33
7.2.7.3.
Statistical analyses.....................................................34
7.2.7.4.
Subgroup analyses.....................................................34
7.2.8.
Rescue medication use................................................................34
7.2.8.1.
Rescue medication use via the clip-on 
Propeller Sensor for MDI ............................................35
7.2.8.2.
Statistical analyses.....................................................35
7.3.
Exploratory Efficacy Analyses.....................................................................36
7.3.1.
Change from Day 84 in Clinic Visit trough FEV1...........................36
7.3.1.1.
Statistical analysis ......................................................36
7.3.2.
E-RS:COPD (Evaluating Respiratory Symptoms in COPD) .........36
7.3.3.
Measures of HCRU related to exacerbations...............................36
7.3.3.1.
Re-hospitalisation within 30 days of index 
exacerbation...............................................................37
7.3.3.2.
Time from resolution of index exacerbation to 
next exacerbation .......................................................37
7.3.3.3.
Subsequent exacerbation treatment type ...................37
7.3.4.
Compliance..................................................................................37
7.3.4.1.
Number of actuations of double-blind study 
treatment measured by the clip-on Propeller 
Sensor........................................................................38
7.3.4.2.
Missing EXACT-PRO data..........................................38
7.3.5.
Inflammatory/infective markers in blood and sputum in 
relation to acute exacerbation of COPD.......................................38
7.3.6.
Other spirometry measurements..................................................38
7.3.7.
Other symptoms suggestive of exacerbation ...............................38
7.3.8.
Classification of exacerbating COPD participants and 
prediction of response to nemiralisib using machine 
learning techniques......................................................................38
8.
SAFETY ANALYSES .............................................................................................39
 
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8.1.
Adverse Events Analyses ...........................................................................39
8.1.1.
Adverse Events of Special Interest ..............................................39
8.1.1.1.
Post-inhalation Cough Immediately Following 
Dosing........................................................................39
8.1.1.2.
Paradoxical bronchospasm ........................................39
8.2.
Clinical Laboratory Analyses.......................................................................39
8.3.
Other Safety Analyses ................................................................................39
8.4.
Mortality......................................................................................................40
9.
PHARMACOKINETIC ANALYSES.........................................................................41
9.1.
Population of Interest..................................................................................41
9.2.
Drug Concentration Measures ....................................................................41
10. POPULATION PK ANALYSIS ................................................................................42
10.1.
Derived Pharmacokinetic Parameters.........................................................42
11. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES .................................43
12. REFERENCES.......................................................................................................44
13. APPENDICES........................................................................................................45
13.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................45
13.1.1.
Exclusions from Per Protocol Population .....................................45
13.2.
Appendix 2: Assessment Windows .............................................................46
13.2.1.
Definitions of Assessment Windows for Analyses........................46
13.2.1.1.
Hospital discharge......................................................46
13.2.1.2.
EXACT-Defined Recovery for CAT Trigger.................46
13.3.
Appendix 3: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................47
13.3.1.
Study Periods ..............................................................................47
13.3.1.1.
12-Week Treatment Period.........................................47
13.3.1.2.
12-Week Follow-Up Period.........................................47
13.3.2.
Study Phases ..............................................................................47
13.3.2.1.
Study Phases for Concomitant Medication .................47
13.3.3.
Treatment Emergent Flag for Adverse Events .............................47
13.4.
Appendix 4: Data Display Standards & Handling Conventions....................48
13.4.1.
Reporting Process .......................................................................48
13.4.2.
Reporting Standards....................................................................48
13.4.3.
Reporting Standards for Pharmacokinetic....................................49
13.5.
Appendix 5: Derived and Transformed Data ...............................................50
13.5.1.
General........................................................................................50
13.5.2.
Study Population..........................................................................50
13.5.3.
Safety ..........................................................................................50
13.6.
Appendix 6: Reporting Standards for Missing Data.....................................51
13.6.1.
Premature Withdrawals................................................................51
13.6.2.
Handling of Missing Data.............................................................51
13.6.2.1.
Handling of Missing and Partial Dates ........................51
13.7.
Appendix 7: Values of Potential Clinical Importance ...................................53
13.7.1.
Laboratory Values........................................................................53
13.7.2.
ECG.............................................................................................54
13.7.3.
Vital Signs....................................................................................54
 
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13.8.
Appendix 8: Population Pharmacokinetic (PopPK) Analyses ......................55
13.8.1.
Population Pharmacokinetic (PopPK) Methodology.....................55
13.8.2.
Population Pharmacokinetic (PopPK) Dataset 
Specification ................................................................................55
13.9.
Appendix 9: Pharmacokinetic / Pharmacodynamic Analyses ......................57
13.9.1.
Pharmacokinetic/Pharmacodynamic Methodology.......................57
13.10. Appendix 10: Abbreviations & Trade Marks ................................................58
13.10.1. Abbreviations...............................................................................58
13.10.2. Trademarks .................................................................................59
13.11. Appendix 11: List of Data Displays..............................................................60
13.11.1. Data Display Numbering..............................................................60
13.11.2. Mock Example Shell Referencing ................................................60
13.11.3. Deliverables.................................................................................60
13.11.4. Study Population Tables..............................................................61
13.11.5. Study Population Figures.............................................................63
13.11.6. Efficacy Tables ............................................................................64
13.11.6.1. Efficacy tables for Interim Analysis 1 ..........................64
13.11.6.2. Efficacy tables for Interim Analysis 2 ..........................66
13.11.6.3. Efficacy tables for End of Treatment Interim 
Analysis and SAC.......................................................69
13.11.7. Efficacy Figures ...........................................................................80
13.11.7.1. Efficacy Figures for Interim Analysis 1........................80
13.11.7.2. Efficacy Figures for Interim Analysis 2........................81
13.11.7.3. Efficacy Figures for End of Treatment Interim 
Analysis and SAC.......................................................83
13.11.8. Safety Tables...............................................................................85
13.11.9. Safety Figures .............................................................................89
13.11.10.Pharmacokinetic Tables...............................................................89
13.11.11.ICH Listings .................................................................................90
13.11.12.Non-ICH Listings..........................................................................92
13.12. Appendix 12: Example Mock Shells for Data Displays ................................93
13.12.1. Example shell 1 ...........................................................................93
13.12.2. Example Shell 2...........................................................................94
13.12.3. Example shell 3 ...........................................................................95
13.12.4. Example Shell 4...........................................................................96
13.12.5. Example Shell 5...........................................................................98
13.12.6. Example Shell 6...........................................................................99
13.12.7. Example Shell 7.........................................................................100
13.12.8. Example Shell 8.........................................................................101
13.12.9. Example Shell 9.........................................................................102
13.12.10.Example Shell 10.......................................................................103
13.12.11.Example Shell 11.......................................................................104
13.12.12.Example Shell 12.......................................................................105
13.12.13.Example shell 13 .......................................................................106
13.12.14.Example Shell 14.......................................................................107
13.12.15.Example Shell 15.......................................................................108
13.12.16.Example shell 16 .......................................................................109
13.12.17.Example Shell 17.......................................................................110
13.12.18.Example shell 18 .......................................................................112
13.12.19.Example Shell 19.......................................................................113
13.12.20.Example Shell 20.......................................................................116
13.12.21.Example Shell 21.......................................................................117
 
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13.12.22.Example Shell 22.......................................................................118
13.12.23.Example Shell 23.......................................................................119
13.12.24.Example Shell 24.......................................................................120
13.12.25.Example Shell 25.......................................................................121
13.12.26.Example Shell 26.......................................................................122
13.12.27.Example Shell 27.......................................................................123
13.12.28.Example Shell 28.......................................................................124
13.12.29.Example Shell 29.......................................................................130
13.12.30.Example Shell 30.......................................................................131
13.12.31.Example Shell 31.......................................................................132
13.12.32.Example Shell 32.......................................................................133
13.12.33.Example Shell 33.......................................................................134
13.12.34.Example Shell 34.......................................................................135
13.12.35.Example shell 35 .......................................................................136
13.12.36.Example Shell 36.......................................................................137
 
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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol 200879.
2.
SUMMARY OF KEY PROTOCOL INFORMATION
This study will be undertaken in participants who present with an acute moderate or 
severe exacerbation of COPD requiring Standard of Care (SoC), referred to as the index 
exacerbation.
2.1.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To characterise 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
Secondary Objectives
Secondary Endpoints

To characterise 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 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)

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
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 
 
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Objectives
Endpoints
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

To evaluate the usage of rescue 
medication in patients diagnosed with 
an acute moderate or severe 
exacerbation of COPD

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

To evaluate the population 
pharmacokinetics of nemiralisib in 
participants diagnosed with an acute 
moderate or severe exacerbation of 
COPD

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

To assess the safety and tolerability of 
nemiralisib and placebo in participants 
diagnosed with an acute moderate or 
severe exacerbation of COPD

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 Objectives
Exploratory Endpoints

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 and severe 
combined)
 
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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

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)

To explore the PK/PD relationship for 
nemiralisib

Relationship between drug exposure and 
Pharmacodynamic responses (e.g. efficacy, heart rate, 
clinical laboratory analytes and blood biomarkers) in the 
PK subset of participants (approximately 300) at selected 
sites

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

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.)

To evaluate compliance with study 
treatment

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)

To evaluate inflammatory markers in 
blood in relation to acute exacerbation 
of COPD

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)

To evaluate inflammatory and 
infective markers in sputum in relation 
to acute exacerbation of COPD

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

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 postbronchodilator 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 
 
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Objectives
Endpoints
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
2.2.
Study Design
This is a Phase IIb, multicenter, randomized, stratified (by index COPD exacerbation
severity [moderate or severe] and by whether or not the participant is in the PK
Subgroup), double-blind (Sponsor Open), placebo-controlled, parallel-group study in
participants who present with an acute moderate or severe exacerbation of COPD
requiring Standard of Care (SoC).
This study consists of a Screening Period, a 12-Week Treatment Period and a 12-Week
Post-Treatment Follow-Up Period. 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 
measures, including the EXACT-PRO questionnaire for the day of randomization, and 
FEV1 measurement and no later than 48 hours after the start of SoC.
PK Subgroup: Sparse PK sampling will be conducted in a subgroup of participants 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.
3.
PLANNED ANALYSES
3.1.
Interim Analyses
Ongoing data reviews of unblinded safety data, conducted by an Internal Safety Review 
Committee (iSRC), will be performed throughout the trial. Details will be documented in 
the iSRC charter.  
Interim analyses of the primary endpoint and key secondary endpoints to inform internal 
decision making will be conducted periodically throughout the trial. The first analysis 
(Interim Analysis 1) is planned to occur when approximately 170 participants complete 
28 days of treatment, where approximately 50 of the 170 participants have an index 
exacerbation defined as severe. A change that could arise from this interim analysis is a 
specification of the stratification proportions by index exacerbation severity status 
(moderate or severe). This decision will be based on inspection of all available endpoints 
at the interim analysis. 
Further interim analyses will be performed, depending on the observed recruitment rate. 
At least one interim analysis of the primary endpoint of change from baseline in clinic 
visit trough FEV1 at Day 84 measured post-bronchodilator will be performed to 
 
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determine whether or not any adjustments to the randomization ratio across doses would 
help optimize the characterization of the dose response profile for nemiralisib. This 
analysis (Interim Analysis 2) is planned to occur when approximately 300 participants 
complete 84 days of treatment or when approximately 400 participants remain to be 
randomized, whichever occurs first. Adjustments could include ceasing randomization to 
an existing dose(s) of nemiralisib and/or modification of the allocation ratios for the 
existing nemiralisib doses and/or addition of a 25mcg dose. Other changes may include 
specification of the stratification proportions by index exacerbation severity status. 
An interim analysis of efficacy and safety data collected during the Double-Blind 
Treatment Period will be conducted when the last participant in the study has completed 
the 12-week Double-Blind Treatment Period (End of Treatment Interim Analysis). The 
aim of this analysis is to provide GSK with timely data to inform internal decision 
making, prior to the end of study. 
The following table describes the endpoints that will be analysed/summarised at each 
interim:
Interim
Purpose of interim
Endpoints
Interim Analysis 1
To inform internal decision making 

Change from baseline in FEV1 at Days 
14, 28, and 56 measured pre- and 
post-bronchodilator

Other spirometry measures (percent 
predicted FEV1, Forced Vital Capacity 
(FVC), percent predicted FVC and 
FEV/FVC ratio

On-treatment exacerbations

Proportion of participants achieving 
EXACT-defined recovery by Days 14, 
28, 56 and 84
 
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Interim
Purpose of interim
Endpoints
Interim Analysis 2
To determine if any adjustments to the 
randomization ratio would help 
characterize the dose response profile 
for nemiralisib
Endpoints listed for Interim Analysis 1 and 
also:

Change from baseline in FEV1 at Day 
84 measured pre- and post-
bronchodilator

Rate of (on-treatment) exacerbations 
over the 12-Week Treatment Period

Time to next (on-treatment) 
exacerbation during the 12-Week 
Treatment Period

Proportion of responders using the 
CAT

Change from baseline in CAT Total 
Score

Proportion of responders using the 
SGRQ

Change from baseline in SGRQ Total 
Score

Rescue medication use, as measured 
in eDiary
End of Treatment 
Interim Analysis
To inform internal decision making
Selected Efficacy and Safety endpoints as 
defined in Appendix 11: List of Data 
Displays
The statistical methods of analyses are described in Section 7.
The Respiratory Data Sciences Group will apply machine learning techniques to the 
interim data to determine if identifiable phenotypic sub-population(s) of COPD 
participants are present at baseline, and if they result in different responses to 
Nemiralisib, to predict which participants will respond to Nemiralisib therapy, and to 
identify/quantify relationship(s) between different endpoints and response measures.
Details of these analyses will be described in a separate RAP and results will be reported 
separately to the Clinical Study Report (CSR). 
The following functions will be unblinded to interim analysis data: Clinical Statistics, 
Clinical Programming and Respiratory Data Sciences Group. Other member of GSK will 
be unblinded to group level summary data following the interim analyses (as documented 
internally). 
3.1.1.
Futility analyses
At least one interim analysis for futility will be performed. The first analysis will occur at 
Interim Analysis 2, i.e. when 300 participants complete 84 days of treatment, or when 
approximately 400 participants remain to be randomized, whichever occurs first. 
Futility will be assessed in a sequential manner. 
 
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1)Futility will first be assessed for the primary endpoint of change from baseline in 
FEV1 at Day 84 by fitting a suitable dose response model, as described in Section 
7.1.2. 
2)If the posterior predictive probability of declaring success for this endpoint is low
across all doses, then futility will be assessed for the rate of (on-treatment) 
exacerbations endpoint.
3)If the posterior predictive probability of declaring success for this endpoint is low, 
then the study may be stopped.
Any decision to stop will be made after a review of all the data summarised/analysed at 
the time of the interim, including the proportion of participants achieving the EXACT-
defined recovery.
3.1.1.1.
Futility rules
The decision rules for futility are defined as follows.
Change from baseline in FEV1 at Day 84
Stop study for futility if the predictive probability of success at the end of the trial, given 
the data at the interim is <20%, across all doses, where success at the end of the trial for 
change from baseline in FEV1 is defined as demonstrating >90% posterior probability 
that the true difference from placebo for any dose of nemiralisib is greater than 0.
Rate of on-treatment (moderate/severe) exacerbations
Stop study for futility if the predictive probability of success at the end of the trial, given 
the data at the interim is <20%, where success at the end of the trial for rate of 
exacerbations is defined as demonstrating >80% posterior probability that the true rate 
reduction on 750 mcg dose versus placebo > 0%.
If a different dose arm appears to be more efficacious than the 750 mcg arm, then futility 
may be assessed using the rate reduction for this arm versus placebo. 
The pre-determined rules will act as guidelines for stopping the study for futility. All of 
the data summarised/analysed at the time of the interim will be reviewed prior to any 
decision to stop the study. 
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All participants have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management.
3.
All criteria for unblinding the randomization codes have been met. 
4.
Randomization codes have been distributed according to RandAll NG procedures.
 
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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Participants 
Enrolled (APE) 
Population

All participants who are screened for eligibility.

Study Population
Modified Intent 
To treat (MITT) 
Population

All randomized participants who receive at least one 
dose of study treatment. 

Participants will be analyzed according to the treatment 
that they were randomized to.

Study Population

Efficacy
Per Protocol (PP) 
Population

All randomized participants who receive at least one 
dose of study treatment, excluding any participants with 
an important protocol deviation.

Participants will be analyzed according to the treatment 
that they were randomized to.

Sensitivity
analyses of 
efficacy
Safety Population

All randomized participants who received at least one 
dose of study treatment.

Participants will be summarised according to the 
treatment that they actually received.
o
If participants receive >1 treatment, then they will 
be summarised according to the most frequently 
dosed treatment. In cases where the frequency is 
equal, the participant will be assigned the lowest 
dose strength of nemiralisib

Safety
Pharmacokinetic
(PK) Population

All participants in the Safety population who had at least 
1 non-missing PK assessment (Non-quantifiable [NQ] 
values will be considered as non-missing values).
Participants will be summarised according to the 
treatment that they actually received

PK
Refer to Appendix 11: List of Data Displays which details the population used for each display.
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
Important deviations which result in exclusion from the analysis population will also be 
summarised and listed. (Please refer to Appendix 1: Protocol Deviation Management and 
Definitions for Per Protocol Population).
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan.
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations and deviations which may lead to exclusion from the 
analysis are captured and categorised on the protocol deviations dataset. 
o This dataset will be the basis for the summaries and listings of protocol 
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A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF.
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG Randomization System
Data Displays for Reporting 
Code
Description
Description
Order in TLF 
A
Placebo
Placebo
1
B
GSK2269557 12.5 mcg
NEMI 12.5 mcg
2
C
GSK2269557 25 mcg*
NEMI 25 mcg
3
D
GSK2269557 50 mcg
NEMI 50 mcg
4
E
GSK2269557 100 mcg
NEMI 100 mcg
5
F
GSK2269557 250 mcg
NEMI 250 mcg
6
G
GSK2269557 500 mcg
NEMI 500 mcg
7
H
GSK2269557 750 mcg
NEMI 750 mcg
8
* The nemiralisib dose of 25 mcg may be added following the results of an un-blinded interim analysis if 
further characterization of the lower end of the dose response curve is required.
Treatment comparisons will be displayed as follows using the descriptors as specified:
1.
NEMI 12.5 mcg vs Placebo
2.
NEMI 25 mcg vs Placebo
3.
NEMI 50 mcg vs Placebo
4.
NEMI 100 mcg vs Placebo
5.
NEMI 250 mcg vs Placebo
6.
NEMI 500 mcg vs Placebo
7.
NEMI 750 mcg vs Placebo
5.2.
Baseline Definitions
For all endpoints, the baseline value will be the latest pre-dose assessment with a non-
missing value, including those from unscheduled visits. If time is not collected, Day 1 
assessments are assumed to be taken prior to first dose and used as baseline.
Post-bronchodilator Baseline FEV1 is defined as the latest FEV1 measured prior to the 
first dose of study treatment and post-bronchodilator.
 
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Pre-bronchodilator Baseline FEV1 is defined as the latest FEV1 measured prior to the first 
dose of study treatment and pre-bronchodilator.
Baseline CAT Total Score is defined as CAT Total Score measured prior to the first dose 
of study treatment on Day 1.
Baseline SGRQ Total Score is defined as SGRQ Total Score measured prior to the first 
dose of study treatment on Day 1.
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing.  
A centred baseline will be derived for each participant by subtracting the mean baseline 
across all participants from each participant’s baseline value. The ‘centred’ baseline may 
be used instead of Baseline in the statistical analyses to aid convergence.
5.3.
Multicentre Studies
In this multicentre global study, enrolment will be presented by investigative site and
country.
5.4.
Examination of Covariates and Subgroups
5.4.1.
Covariates
The list of covariates may be used in descriptive summaries and statistical analyses, some 
of which may also be used for subgroup analyses. The key covariates of interest are Index 
exacerbation severity, Smoking history and Region. Additional covariates of clinical 
interest may also be considered. The decision to include covariates in the model will be 
based on their impact on the model fit and/or convergence and will be detailed in the 
CSR.
A centred covariate will be derived for each participant by subtracting the mean covariate 
across all participants from each participant’s covariate value. The ‘centred’ covariate 
may be used in place of the covariate in the statistical analyses to aid convergence.
 
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Covariate
Details
Index exacerbation severity
Categorical variable (Moderate or Severe) derived using the 
stratification variable from the randomisation system.
Age (at screening)
Continuous variable derived as described in Section 13.6.2.1
BMI
Continuous variable derived using Height and Weight variables 
collected in eCRF:
BMI = Weight (kg) / (Height (m))2
Gender
Categorical variable (Male or Female), collected in eCRF
Country
Categorical variable
Region
Categorical variable derived using Country as: 
Americas: Canada, Mexico, United States
Asia: Australia, Korea
Eastern Europe: Poland, Romania, Russia
Western Europe: France, Germany, Italy, Netherlands, 
Spain, Sweden, U.K.
Smoking history
Categorical variable (Current or Former), collected in eCRF
Baseline COPD maintenance 
therapy type
Categorical variable derived depending on data observed. Possible 
categories of interest are: Monotherapy vs. Dual therapy vs. Triple
therapy
Index exacerbation type
Categorical variable: New or Relapse, derived using the question: 
“Other than the current prescription, for the index exacerbation, has 
the subject received oral/systemic corticosteroids and/or antibiotics 
for a COPD exacerbation within the last 7 days?” in the eCRF:
New = No
Relapse = Yes
Number of exacerbations in the 
previous 12 months
Categorical variable derived from “Total number of COPD 
exacerbations in the last 12 months” in the eCRF. Possible 
categories of interest are: 0 vs. 1 vs. ≥2
Baseline COPD ICS therapy use
Categorical variable (ICS Use or Non-ICS Use) derived from review 
of concomitant medications
Baseline Blood Biomarker Status
Categorical variable derived from Screening time-point for the 
following:
High sensitivity CRP
Bacterial: >10 mg/L
Non-Bacterial: ≤10 mg/L
Procalcitonin
Bacterial: >0.1 µg/L 
Non-Bacterial: ≤ 0.1 µg/L
Eosinophils
High: ≥0.15 GI/L
Low: <0.15 GI/L
5.4.2.
Examination of Subgroups
The list of subgroups may be used in descriptive summaries and statistical analyses.
Additional subgroups of clinical interest may also be considered.
 
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
If the percentage of subjects is small within a particular subgroup, then the subgroup 
categories may be refined.

If the category cannot be refined further, then descriptive rather than statistical 
comparisons may be performed for the particular subgroup.
Subgroup
Categories 
Index exacerbation severity
Moderate vs. Severe  
Baseline COPD maintenance therapy type
Possible categories of interest are: Monotherapy vs. Dual 
therapy vs. Triple therapy
Index exacerbation type
New vs. Relapse
Number of exacerbations in the previous 12 
months
Possible categories of interest are: 0 vs. 1 vs. ≥2
Gender
Male vs. Female
Smoking status
Current vs. Former
Baseline COPD ICS therapy use
ICS Use vs. Non-ICS Use
Baseline Blood Biomarker Status

For High sensitivity CRP: Bacterial vs. Non-Bacterial 

For Procalcitonin: Bacterial vs. Non-Bacterial

For Eosinophils: High vs. Low
 
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5.5.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
Section 13.2
Appendix 2: Assessment Windows
Section 13.3
Appendix 3: Study Phases and Treatment Emergent Adverse Events
Section 13.4
Appendix 4: Data Display Standards & Handling Conventions
Section 13.5
Appendix 5: Derived and Transformed Data
Section 13.6
Appendix 6: Reporting Standards for Missing Data
Section 13.7
Appendix 7: Values of Potential Clinical Importance
6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the “APE” and/or “MITT” populations, 
unless otherwise specified.
Study population analyses including analyses of participant’s disposition, protocol 
deviations, demographic and baseline characteristics, and exposure and treatment 
compliance will be based on GSK Core Data Standards.  Details of the planned displays
are presented in Appendix 11: List of Data Displays.
6.1.1.
Concomitant medications
Concomitant medications will be summarised by treatment group. Separate summaries of
Baseline and On-treatment (Step-up) COPD Maintenance Therapy, and duration of OCS 
use will also be presented. 
Additional summaries or sensitivity analyses of on-treatment COPD maintenance therapy
(step-up therapy) may be performed if the data indicate that further investigation is 
warranted.
 
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7.
EFFICACY ANALYSES
Details of the outputs are provided in Appendix 11: List of Data Displays and will be 
based on GSK data standards and statistical principles.
Further details for use in the endpoint derivations below can be found in Appendix 5: 
Derived and Transformed Data.
7.1.
Primary Efficacy Analyses
7.1.1.
Primary Endpoint
The primary endpoint of change from baseline in clinic visit trough FEV1 at Day 84 
measured post-bronchodilator is defined as:
FEV1 measured prior to dosing and post-bronchodilator on Day 84 – Post-bronchodilator 
Baseline FEV1
7.1.2.
Primary Statistical Analyses
The primary endpoint will be analysed by fitting a suitable dose response model. The 
following models will be fitted, and the one that gives the best fit to the data will be 
selected: Bayesian 4-parameter Emax dose response model, 3-parameter Emax model and 
a Log-linear model.
The 4-parameter Emax dose response model will take the form:
Change from baseline FEV1 =



Dose
ED
Dose
baseline
b
E
baseline
a
E




50
*
)
*
(
)
*
0
(
1
max
1
The 3-parameter Emax dose response model will take the form:
Change from baseline FEV1 =
Dose
ED
Dose
baseline
b
E
baseline
a
E




50
*
)
*
(
)
*
0
(
1
max
1
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
a1, b1, are covariates for explanatory parameters
Initially, normal non-informative priors will be used for the E0, a1, a2, and Emax
parameters with mean 0 and standard deviation 1E6 L. A functional uniform prior will be 
used for the ED50 and slope parameters (Bornkamp, 2014), where the prior density for 
the functional uniform prior is based on all the parameters in the model. An inverse -
 
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gamma prior with shape of 0.001 and scale of 0.001 will be used for the residual 
variance. However, if a prior distribution appears not to be truly non-informative then 
alternative prior distributions may be used.
Parameters will be blocked such that the MCMC procedure samples from E0, a1, b1, and 
Emax, first, then the ED50 and slope parameters and then finally the residual variance 
parameter. For the functional uniform priors, the density will be calculated for values of 
dose from 0.0001 to 750 in steps of 50 (i.e. 0.0001, 50.0001, 100.0001,…, 750.0001). For
the continuous covariates, the density will be calculated from the minimum to the 
maximum in 10 equal steps.  For binary covariates the density will be calculated for 
values 0 and 1.  If the model does not converge including covariates, the model may be 
fitted with covariates removed. 
If the log-linear model is fitted an offset of 1 will be used. 
The posterior median change from baseline with 95% Highest Posterior Density (HPD) 
Credible Intervals, will be presented for each dose along with the adjusted median 
difference from placebo with 95% HPD, calculated at the mean baseline value across the 
treatment arms. Posterior probabilities that the true improvement is greater than 0 mL and 
75 mL will also be presented. 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. 
For the futility analysis: 
The predictive probability of success at the end of the study will be calculated (assuming 
the randomisation ratios remain the same after the interim) for each dose using the 
formula suggested by Spiegelhalter, 2004 as follows:
Where n1 is the number of subjects with Day 84 data in the active arm of interest, m1 is 
the number of subjects yet to be observed in the active arm of interest, yn is the posterior 
mean difference from placebo from the fitted model, and σ is the standard deviation of 
the posterior mean difference from placebo.
For the possible adaptations at Interim Analysis 2:
If the study is not deemed futile, and either the 4 parameter or 3 parameter Emax dose 
response curves has successfully been fitted to the data then adaptation of the 
randomisation schedule will be considered, to drop, add or amend doses from the 
randomisation scheme. 
The adaptation will be done by comparing the relative information from alternative 
randomisation schemes with the original randomisation schemes, such to find the design 
 
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that provides the most information about the dose response relationship.  The efficiency 
ratio (ER) for an alternative scheme comparted to the original, will be calculated as:
, i=1,…,1000
Where 
is the information matrix for the design and model parameters = (e0, 
emax, ed50, , a1, b1)T,
is the alternative design one and 
is the fixed original design, 
and p is the number of parameters (Dette, 2008).  In order to ensure any adaptation is 
robust to the variability in the parameter estimates at the interim analysis, 1000 samples 
will be generated from the posterior distribution of the parameters 
and the 
ER calculated for each set of parameter.  Adaptation will then only take place if the 
median ER is >1.05 and the 10th percentile of the ER is >1. The efficiency ratio will be 
estimated using the mean baseline value across the population. 
The alternative designs that will be considered will depend on the dose response model 
fitted but could include:
1.Add 25mcg dose
2.Add 25mcg dose, drop 500mcg dose
3.Add 25mcg dose, drop 250 mcg and 500 mcg doses
4.Drop 12.5mcg dose
5.Drop 12.5 mcg and 50mcg doses
The potential adaption may also be verified in the moderate and severe subgroups to 
ensure the adaption is beneficial across both groups. 
7.1.2.1.
Model Checking & Diagnostics
The following list of convergence diagnostics will be applied for each parameter: 
The Monte Carlo Standard Errors (MCSE) should be compared with the standard 
deviation (SD) of the posterior distribution to ensure that only a fraction of the 
posterior variability is due to the simulation. The number of samples generated 
and/or the thinning may be increased to reduce the ratio of the MCSE/SD as 
deemed necessary.
The Geweke diagnostic test will be used to assess whether the mean estimates have 
converged by comparing means from the early and latter part of the Markov chain 
using a z-score t-test. Large absolute values of the z-score statistic indicate 
rejection of the null hypothesis of no difference between the mean estimates 
obtained from the early and latter parts of the chain.
Trace plots of samples versus the simulation index will be visually inspected to 
assess some aspects of convergence. The centre of the chain should appear stable 
with very small fluctuations, i.e., the distribution of points should not change as 
the chain progresses and the posterior mean and variance are relatively constant.
Autocorrelation plots will be visually inspected to assess degree of autocorrelation 
(should decline rapidly and show no oscillation patterns).
 
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7.1.3.
Sensitivity and Supportive Analyses
If there are greater than 20% of participants with an important protocol deviation that 
results in exclusion from the Per Protocol Population, the primary analysis may be 
repeated using the Per Protocol Population. 
Change from baseline in clinic visit trough FEV1 at Day 84 will also be compared 
between treatment groups using a Bayesian Repeated Measures analysis with covariates 
for baseline-by-Day interaction and treatment-by-Day interaction. Day will be fitted as a 
repeated effect within each participant. All post-baseline scheduled visits will be included 
in the analysis using Day. Non-informative priors will be used for all modelling 
parameters. Wherever possible conjugate priors will be utilised. An unstructured 
covariance matrix will be used to model the within-subject error.
A further sensitivity analysis may be performed where Baseline FEV1 is replaced with 
the FEV1 measured post-bronchodilator and prior to dosing on day of hospital discharge 
for participants who were hospitalised for their index exacerbation, i.e. who were 
randomized with a Severe index exacerbation but kept as Baseline FEV1 for participants 
who were randomized with a Moderate index exacerbation.
7.1.4.
Subgroup Analyses
A subgroup analysis of change from baseline in clinic visit trough FEV1 by index 
exacerbation severitywill be performed by fitting separate models to each level of the 
severity subgroup. 
A subgroup analysis of change from baseline in clinic visit trough FEV1 by index 
exacerbation severity will also be performed by including a treatment-by-severity-by-Day
interaction term in the Bayesian Repeated Measures model. 
7.2.
Secondary Efficacy Analyses
7.2.1.
Rate of exacerbations
Rate of exacerbation is defined as the frequency of exacerbations (subsequent to the 
index exacerbation) within the specified time period, for example, the 12-Week 
Treatment Period or the 24-Week Study Period.
The length of time on treatment or in study, depending on the specified time-period, for 
each participant will be calculated for each endpoint as follows:
Endpoint
Time period
Length of time derivation
Rate of (on-treatment) 
exacerbations, summarised by:

Moderate/severe 
exacerbations

Moderate exacerbations

Severe exacerbations

All (mild, moderate and 
12-Week Treatment Period
Time from date of randomisation 
to date of last dose of study 
treatment 
 
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Endpoint
Time period
Length of time derivation
severe) exacerbations
Rate of (on-or off-treatment) 
exacerbations, summarised by:

Moderate/severe 
exacerbations

All exacerbations
12-Week Treatment Period
Time from date of randomisation 
to Day 84 (Visit 6) Visit Date. 
For participants who withdraw 
early from the study: Time from
date of randomisation to date of 
study withdrawal
Rate of (off-treatment) 
exacerbations, summarised by:

Moderate/severe 
exacerbations

Moderate exacerbations

Severe exacerbations
12-Week Follow Up Period
Time from date of last dose of 
study treatment to date of study 
withdrawal/completion
Rate of (on- and off- treatment)
exacerbations, summarised by:

Moderate/severe 
exacerbations

Moderate exacerbations

Severe exacerbations
Full 24-Week Study Period
Time from date of randomisation 
to date of study 
withdrawal/completion
Refer to Section 13.5 for further details regarding the length of time derivation
7.2.1.1.
Statistical analyses
The rate of exacerbations will be analysed using a Bayesian generalized linear model 
assuming a negative binomial distribution for the underlying exacerbation rate with a log 
link function. An offset to account for the length of time on treatment or in study, 
depending on the specified time-period, for each participant (as described above) will be 
included in the model as loge (length of time). 
Non-informative priors will be used for all modelling parameters. Wherever possible 
conjugate priors will be utilised.
The median exacerbation rates for each dose arm per 12 weeks, along with the median 
ratio in exacerbation rates (nemiralisib/placebo) per 12 weeks for each dose, will be 
estimated and corresponding 95% HPD credible intervals presented. The probability that 
the true exacerbation rate ratio is less than 1, in addition to other values appropriately 
selected based on the data, will be presented.
Based on pharmacological predictions, the 500 mcg and 750 mcg doses are expected to 
result in similar levels of target inhibition and thus potentially translate to similar clinical 
benefit, therefore estimates of the exacerbation rates for pooled data from 500 mcg plus 
750 mcg will also be presented.
 
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7.2.1.2.
Subgroup analyses
A subgroup analysis of exacerbation rate by Index exacerbation severity will be 
performed by including a treatment-by-severity term in the model.
7.2.1.3.
Exploratory analyses
A summary of exacerbation rate by the following groups will be presented and, if 
feasible, a subgroup analyses may be performed:
Index exacerbation type (New or Relapse)
Number of exacerbations in previous 12 months (0, 1 or ≥2). 
7.2.2.
Time to next exacerbation
Time to next (on-treatment) exacerbation following index exacerbation during the 12-
Week Treatment Period is defined as time from the date of randomisation until the date 
of onset of the first exacerbation whilst on study treatment. Participants who did not have 
an exacerbation whilst on study treatment will be censored at the date of their last dose of 
study treatment. 
Time to next (on-or off-treatment) exacerbation during the 12-Week Treatment Period is 
defined as time from the date of randomisation until the date of onset of the first 
exacerbation occurring up to Day 84. Participants who have not had an exacerbation 
during the 12-Week Treatment Period will be censored at Day 84 or the date of study 
withdrawal, for participants who withdrew from the study prior to Day 84.
Time to next exacerbation following cessation of study treatment is defined as time from 
the date of last dose of study treatment until the date of onset of the next exacerbation 
whilst off study treatment during the 12-Week Follow Up Period. Participants who have 
not had an exacerbation off-treatment will be censored at the date of their last follow up 
assessment.
Time to next exacerbation will be analysed by severity, as follows: 
Endpoint
Time period
Time to next (on-treatment) exacerbation, 
summarised by:

Moderate/severe exacerbations

All (mild, moderate and severe) exacerbations
12-Week Treatment Period
Time to next (on-or off-treatment) exacerbation, 
summarised by:

Moderate/severe exacerbations

All exacerbations
12-Week Treatment Period
Time to next exacerbation following cessation of 
treatment, summarised by:

Moderate/severe exacerbations
12-Week Follow Up Period
 
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Refer to Section 13.5 for further details regarding the length of time derivation
7.2.2.1.
Statistical analyses
Time to next exacerbation will be analysed using a Bayesian Cox proportional hazards 
model with the “Efron” method for handling ties.
Kaplan-Meier (KM) estimates of the probability of exacerbation will also be presented.
Non-informative priors will be used for all modelling parameters. Wherever possible 
conjugate priors will be utilised.
The hazard ratio and corresponding 95% HPD credible intervals for each nemiralisib 
dose versus placebo will be presented. The probability that the true hazard ratio is less 
than 1, in addition to other values appropriately selected based on the data, will be 
presented.
Based on pharmacological predictions, the 500 mcg and 750 mcg doses are expected to 
result in similar levels of target inhibition and thus potentially translate to similar clinical 
benefit, therefore an estimate of hazard ratio for pooled data from 500 mcg plus 750 mcg 
nemiralisib doses versus placebo will also be presented.
7.2.2.2.
Subgroup analyses
A subgroup analysis of time to exacerbation by Index exacerbation severity will be 
performed by including a treatment-by-severity term in the model.
7.2.3.
Change from baseline in Clinic Visit trough FEV1
Change from baseline in clinic visit trough FEV1 at Day 14, 28, 56 measured post-
bronchodilator is defined as:
FEV1 measured prior to dosing and post-bronchodilator on Day X – Post-bronchodilator 
Baseline FEV1
Where Day X is Day 14, 28, and 56.
Change from baseline in clinic visit trough FEV1 at Day 14, 28, 56, 84 measured pre-
bronchodilator is defined as:
FEV1 measured prior to dosing and pre-bronchodilator on Day X – Pre-bronchodilator 
Baseline FEV1
Where Day X is Day 14, 28, 56, and 84.
7.2.3.1.
Statistical Analyses
Change from baseline in Clinic Visit trough FEV1 measured post-bronchodilator will be 
analysed using a dose response model and repeated measures analysis as described for 
the primary endpoint in Section 7.1.2.
 
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Change from baseline in Clinic Visit trough FEV1 measured pre-bronchodilator will be 
analysed using a repeated measures analysis as described in Section 7.1.2
7.2.3.2.
Subgroup analyses
A subgroup analysis of change from baseline in clinic visit trough FEV1 by index 
exacerbation severitywill be performed. 
7.2.4.
Change from hospital discharge in clinic visit trough FEV1
Change from hospital discharge in clinic visit trough FEV1 will be derived only for 
participants who were hospitalised for their index exacerbation and who have been 
subsequently discharged. 
Change from hospital discharge in clinic visit trough FEV1 measured post-bronchodilator 
is defined as:
FEV1 measured prior to dosing and post-bronchodilator on Day X – FEV1 measured post-
bronchodilator and prior to dosing on day of hospital discharge.
Where Day X is 14, 28, 56 and 84.
Change from hospital discharge in clinic visit trough FEV1 measured pre-bronchodilator 
is defined as:
FEV1 measured prior to dosing and pre-bronchodilator on Day X – FEV1 measured prior 
to dosing and post-bronchodilator on day of hospital discharge.
Where Day X is 14, 28, 56 and 84.
Note, as per Section 5.1 of the Protocol, if discharge takes place between Day 11 and Day 
17 (inclusive), the assessments planned for Day 14 may be completed on the day of 
discharge. In these cases, for this endpoint only, the FEV1 assessment will be assigned 
the hospital discharge assessment and the Day 14 assessment will be missing. Refer to 
Section 13.2.1.1 for further details. 
In addition, if discharge takes place after Day 14, the Day 14 assessment will be missing 
for this analysis. 
7.2.4.1.
Statistical analyses
Change from hospital discharge in clinic visit trough FEV1 will be analysed using a 
repeated measures analysis as described in Section 7.1.2 if there are a sufficient number 
of participants to provide a meaningful analysis, otherwise the data will be summarised.
7.2.5.
EXAcerbations of Chronic Pulmonary Disease Tool - Patient 
Reported Outcome (EXACT)
The EXACT is a 14-item daily diary designed to provide a measure of patient-reported 
symptoms of COPD exacerbation. An EXACT Total Score, ranging from 0 to 100, where 
 
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higher scores indicate a more severe condition, will be derived for each day of diary 
collection according to the instructions in the EXACT User Manual (Version 8.0, 
Evidera, 2016).
The electronic EXACT diary does not allow a study patient to skip individual items, 
therefore no missing data are expected for individual items. However, if missing values 
occur for individual items, the Total Score that contains the item will be set to missing for 
that day. Moderate-to-severe COPD patients are expected to experience symptom(s) each 
day, and a score of zero on all 14 EXACT items is likely to represent a situation where in 
order to complete the diary quickly, the respondent did not accurately report their daily 
symptom(s), therefore if the EXACT Total Score is 0, it will be set to missing.
A 3-day Rolling Average EXACT Total Score will be calculated for each day, X, as:
(EXACT Total Score on Day X-1 + EXACT Total Score on Day X + EXACT 
Total Score on Day X+1) / (Number of days with non-missing values)
Note, for Day 1, the Rolling Average EXACT Total Score will be calculated as the 
average of EXACT Total Score on Days 1 (Randomisation) and 2 only, since no EXACT 
data is collected prior to randomisation. Similarly, the Rolling Average EXACT Total 
Score for the last study day will be calculated as the average of EXACT Total Score on 
the last day and on the day before the last day.
The Rolling Average EXACT Total Score will be calculated for each day as long as at 
least 1 EXACT total score in the sequence is present. Therefore, only in the case where 
EXACT total scores are missing for 3 consecutive days in a row (or 2 consecutive days in 
the case of the first and last day rolling average calculation), will the rolling average 
score be missing.
The Maximum Observed Value (MOV) is defined as the highest Rolling Average 
EXACT Total Score observed within the first 14 days of randomisation. Note: this 
definition differs from the definition in the EXACT User Manual of "the highest rolling 
average EXACT score observed in the context of an EXACT exacerbation within the first 
14 days of the exacerbation", since the date of the index exacerbation is likely to be prior 
to randomisation.
7.2.5.1.
Proportion of participants achieving EXACT-defined recovery from 
index exacerbation
EXACT-defined recovery from the index exacerbation is defined as a decrease in the 
Rolling Average EXACT Total Score ≥9 points from the Maximum Observed Value, 
sustained for ≥7 days, with the first of the 7 days defined as the recovery day.
The proportion of participants achieving EXACT-defined recovery from the index 
exacerbation by Days 14, 28, 56, and 84 will be calculated as:
(Number of participants who experience an EXACT-defined recovery on or 
before Day X) / (Total number of participants in the MITT population) 
 
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Where Day X is 14, 28, 56, and 84.
7.2.5.2.
Time to EXACT-defined recovery from index exacerbation
Time to EXACT-defined recovery from index exacerbation is defined as time from the 
date of randomisation until date of the first EXACT-defined recovery day during the 12-
Week Treatment Period, where EXACT-defined recovery is described in Section 7.2.5.1. 
Participants who did not experience EXACT-defined recovery during the 12-Week 
Treatment Period will be censored at the date of their last dose of study treatment.
7.2.5.3.
Severity of subsequent HCRU-defined exacerbation(s) defined by 
EXACT 
Severity of subsequent HCRU-defined exacerbation(s) defined by EXACT is defined as 
the highest EXACT Total Score (not using the 3-day Rolling Average) during the period 
from date of onset of the subsequent HCRU-exacerbation until date of EXACT-defined 
recovery of subsequent exacerbation. 
Note, in this case, the Maximum Observed Value and EXACT-defined recovery are 
derived using the date of onset of the subsequent HCRU-exacerbation.
Severity of subsequent HCRU-defined exacerbation(s) defined by EXACT will only be 
derived for participants who have had a subsequent exacerbation. If a participant has 
more than one subsequent exacerbation, severity will be calculated for each subsequent 
exacerbation.
7.2.5.4.
Statistical analyses
The proportion of participants achieving EXACT-defined recovery from the index 
exacerbation will be analysed using a Bayesian logistic regression model. Separate 
models will be fitted for each time-point. 
Non-informative priors will be used for all modelling parameters. Wherever possible 
conjugate priors will be utilised.
The results of the analysis will be presented in terms of odds ratios together with its 
associated 95% HPD credible interval. The probability that the true odds ratio is greater 
than 1, in addition to other values appropriately selected based on the data, will be 
presented.
Time to EXACT-defined recovery from index exacerbation will be analysed using the 
same techniques as described in Section 7.2.2.1.
Severity of subsequent HCRU-defined exacerbation(s) defined by EXACT will be 
summarised for each treatment group and reported by study period. The severity of 
subsequent HCRU-defined exacerbation(s) occurring whilst a participant is on treatment 
will be reported as during the 12-Week Treatment Period and the severity of subsequent 
HCRU-defined exacerbation(s) occurring after the last dose of study treatment will be 
reported as during the 12-Week Follow-up Period.
 
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7.2.5.5.
Subgroup analyses
A subgroup analysis of the proportion of participants achieving EXACT-defined recovery 
from the index exacerbation by Index Exacerbation Severity will be performed by 
including a treatment-by-severity term in the model.
7.2.5.6.
Sensitivity and supportive analyses
Sensitivity analyses exploring the impact of any missing data, and changes to the 
definition of EXACT-defined recovery may be conducted and may be performed post-
SAC. 
7.2.6.
COPD Assessment Test (CAT)
The COPD Assessment Test (CAT) is a patient completed questionnaire developed to 
measure the health status of patients with COPD. The CAT consists of eight items, each 
on a six-point scale: 0 (no impact) to 5 (high impact). The CAT Score will be calculated 
for each study day of collection by summing the scores for all questions. The CAT Score 
ranges from 0 to 40, where higher scores indicate a more severe condition.
7.2.6.1.
Proportion of responders using the CAT
The proportion of responders using the CAT will only be derived for participants with a 
baseline CAT Total Score ≥2.
The Proportion of responders using the CAT is defined as:
(Number of participants with a decrease from baseline in CAT Total Score ≥2 on 
or before Day X)/(Total number of participants in the MITT population)
Where Day X is 28, 56, and 84 and the study day following EXACT-defined recovery 
from the index exacerbation. See Section 13.2.1.2 for details for cases where the study 
day following EXACT-defined recovery occurs within a scheduled assessment window.
Note: due to software limitations of the electronic PRO device, the study day following 
EXACT-defined recovery is not derived according to the EXACT User Manual, see 
Section 13.2.1.2 for further details.
Exploratory – Follow-Up Period
The Proportion of responders using the CAT at Day 112 and 168 is defined as:
(Number of participants with a decrease from baseline in CAT Total Score ≥2 on 
or before Day X)/(Total number of participants in the MITT population)
Where Day X is Day 112 and Day 168 and the study day following EXACT defined 
recovery, if it occurs during the Follow-up period. 
 
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7.2.6.2.
Change from baseline in CAT Total Score
Change from baseline in CAT Total Score is defined as:
CAT Total Score on Day X – Baseline CAT Total Score
Where Day X is 28, 56, 84 and the study day following EXACT defined recovery from 
the index exacerbation. See Section 13.2.1.2 for details for cases where the study day 
following EXACT-defined recovery occurs within a scheduled assessment window.
Note: due to software limitations of the electronic PRO device, the study day following 
EXACT-defined recovery is not derived according to the EXACT User Manual, see
Section 13.2.1.2 for further details.
Exploratory – Follow-Up Period
The Change from baseline in CAT Total Score at Day 112 and 168 is defined as:
CAT Total Score on Day X – Baseline CAT Total Score
Where Day X is Day 112 and Day 168. 
The Change from end of treatment in CAT Total Score at Day 112 and 168 is defined as:
CAT Total Score on Day X – CAT Total Score on Day 84
Where Day X is Day 112 and Day 168. 
7.2.6.3.
Statistical analyses
The proportion of responders using CAT will be analysed using the same techniques as 
described in Section 7.2.5.4.
Change from baseline/end of treatment in CAT Total Score will be compared between 
treatment groups using a Bayesian Repeated Measures analysis with covariates for 
baseline-by-Day interaction and treatment-by-Day interaction. Day will be fitted as a 
repeated effect within each participant. 
All post-baseline scheduled visits will be included in the analysis using Day.
Non-informative priors will be used for all modelling parameters. Wherever possible 
conjugate priors will be utilised. An unstructured covariance matrix will be used to model 
the within-subject error.
Adjusted posterior median change from baseline and corresponding 95% HPD credible 
intervals will be summarised for each treatment by time-point, together with estimated 
treatment differences (GSK – Placebo) and corresponding 95% HPD credible intervals. 
The posterior probability that the true treatment difference is less than 0, in addition to 
other values appropriately selected based on the data, will also be presented.
 
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7.2.6.4.
Subgroup analyses
A subgroup analysis of the proportion of responders using CAT and the change from 
baseline in CAT Total Score by Index exacerbation severity will be performed by 
including a treatment-by-severity term and a treatment-by-severity-by-Day term in the 
Bayesian logistic regression and Bayesian Repeated Measures models, respectively.
7.2.7.
St. George’s Respiratory Questionnaire for COPD Patients 
(SGRQ-C)
St. George’s Respiratory Questionnaire for COPD Patients (SGRQ-C) is a 40-item 
questionnaire designed specifically to focus on COPD patients. SGRQ-C will be scored 
to be equivalent to the SGRQ Total Score, ranging from 0 to 100, where higher scores 
reflect worse health-related quality of life. SGRQ Total Scores will be calculated for each 
day of collection according to the instructions in SGRQ-C Manual (Version 1.3, March 
2016). 
7.2.7.1.
Proportion of responders on the SGRQ Total Score
The proportion of responders on the SGRQ Total Score will only be derived for 
participants with a baseline SGRQ Total Score ≥4.
Proportion of responders on the SGRQ Total Score is defined as:
(Number of participants with a decrease from baseline in SGRQ Total Score ≥4 
on or before Day X)/(Total number of participants in the MITT population)
Where Day X is 28, 56, and 84.
Exploratory – Follow-Up Period
The Proportion of responders on the SGRQ Total Score at Day 112 and 168 is defined as:
(Number of participants with a decrease from baseline in SGRQ Total Score ≥4 
on or before Day X)/(Total number of participants in the MITT population)
Where Day X is Day 112 and Day 168 and the study day following EXACT defined 
recovery, if it occurs during the Follow-up period. 
7.2.7.2.
Change from baseline in SGRQ Total Score
Change from baseline in SGRQ Total Score is defined as:
SGRQ Total Score on Day X – Baseline SGRQ Total Score
Where Day X is Day 28, 56, and 84.
Exploratory – Follow-Up Period
The Change from baseline in SGRQ Total Score at Day 112 and 168 is defined as:
 
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SGRQ Total Score on Day X – Baseline SGRQ Total Score
Where Day X is Day 112 and Day 168. 
The Change from end of treatment in SGRQ Total Score at Day 112 and 168 is defined 
as:
SGRQ Total Score on Day X – SGRQ Total Score on Day 84
Where Day X is Day 112 and Day 168. 
7.2.7.3.
Statistical analyses
Change from baseline/end of treatment in SGRQ Total Score and the proportion of 
responders on the SGRQ Total Score will be analysed using the same techniques as 
described in Section 7.2.6.3.
7.2.7.4.
Subgroup analyses
Subgroup analyses of change from baseline in SGRQ Total Score and the proportion of 
responders on the SGRQ Total Score by Index exacerbation severity will be conducted as 
described in Section 7.2.6.4.
7.2.8.
Rescue medication use
All participants will record rescue medication use in the eDiary. Rescue medication use 
will be recorded as the number of occasions of rescue medication use each day. 
The Mean Number of Occasions of Rescue Medication Use Per Day is defined as:
(Sum of the number of occasions of rescue medication use each day within the 
time-period) / (Total number of days with non-missing values within the time-
period)
The Percentage of  Rescue-Free Days is defined as:
(Sum of the number of days where the number of occasions of rescue medication 
use is zero within the time-period) / (Total number of days with non-missing 
values within the time-period)*100
Where the time-period is defined as follows:
Week 1 of the 12-Week Treatment Period: Day 1 to Day 7
Week 2 of the 12-Week Treatment Period: Day 8 to Day 14
Week 3 of the 12-Week Treatment Period: Day 15 to Day 21
Week 4 of the 12-Week Treatment Period: Day 22 to Day 28
Week 5 of the 12-Week Treatment Period: Day 29 to Day 35
 
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Week 6 of the 12-Week Treatment Period: Day 36 to Day 42
Week 7 of the 12-Week Treatment Period: Day 43 to Day 49
Week 8 of the 12-Week Treatment Period: Day 50 to Day 56
Week 9 of the 12-Week Treatment Period: Day 57 to Day 63
Week 10 of the 12-Week Treatment Period: Day 64 to Day 70
Week 11 of the 12-Week Treatment Period: Day 71 to Day 77
Week 12 of the 12-Week Treatment Period: Day 78 to Day of last dose
Over the 12-Week Treatment Period: Day 1 to Day of last dose. 
Exploratory – Follow-Up Period
Rescue medication use up to Day 112 will also be summarised by including the time-
periods:
Week 13 (Follow-up Period): (Day of last dose + 1)  to (Day of last dose + 1) + 6 days
Week 14 (Follow-up Period): (Day of last dose + 7)  to (Day of last dose + 1) + 13 days
Week 15 (Follow-up Period): (Day of last dose + 14)  to (Day of last dose + 1) + 20 days
Week 16 (Follow-up Period): (Day of last dose + 21)  to (Day of last dose + 1) + 27 days
For a subject to be counted in the time periods for rescue medication use, they must have 
at least one eDiary entry recorded during that time period.
7.2.8.1.
Rescue medication use via the clip-on Propeller Sensor for MDI
A subset of participants from countries where the Propeller Sensor for MDI is available 
will also record rescue medication use via the clip-on Propeller Sensor for MDI. A 
supportive summary of rescue medication use via the clip-on Propeller Sensor for MDI 
for these participants will be presented. 
Rescue medication use via the clip-on Propeller Sensor for MDI is defined in the same 
way as rescue medication use via the eDiary, except that the number of actuations will be 
used instead of the number of occasions in accordance with the way the data is captured. 
7.2.8.2.
Statistical analyses
The Mean Number of (on-treatment) Occasions of Rescue Medication Use Per Day will 
be summarised between each treatment group using means, standard deviations, medians, 
minimum and maximum.
The Percentage of (on-treatment) Rescue-Free Days will be summarised between each 
treatment group using means, standard deviations, medians, minimum and maximum.
 
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Rescue medication use via the clip-on Propeller Sensor for MDI will be summarised in 
the same way as rescue medication use via the eDiary.
7.3.
Exploratory Efficacy Analyses
7.3.1.
Change from Day 84 in Clinic Visit trough FEV1
Change from Day 84 in clinic visit trough FEV1 measured post-bronchodilator is defined 
as:
FEV1 measured prior to dosing and post-bronchodilator on Day X – Day 84 post-
bronchodilator FEV1
Where Day X is Day112, Day  140 and  Day 168.
Change from Day 84 in clinic visit trough FEV1 measured pre-bronchodilator is defined 
as:
FEV1 measured prior to dosing and pre-bronchodilator on Day X – Day 84 pre-
bronchodilator FEV1
Where Day X is Day 112, Day 140 and  Day 168.
Participants who discontinue study treatment prior to Day 84 will be excluded from this 
analysis. 
7.3.1.1.
Statistical analysis
Change from Day 84 in Clinic Visit trough FEV1 will be analysed using the same 
techniques as described for Change from baseline in CAT Total Score in Section 7.2.6.3.
A subgroup analysis of change from Day 84 in FEV1 will be performed by including a 
treatment-by-severity-by-Day term in the Bayesian Repeated Measures model.
7.3.2.
E-RS:COPD (Evaluating Respiratory Symptoms in COPD)
Change from baseline in E-RS: COPD and subscales will be summarised by treatment 
group. Exploratory analyses related to E-RS: COPD and subscales may be performed 
post SAC.
7.3.3.
Measures of HCRU related to exacerbations
Unscheduled Healthcare Utilisation will be summarised separately for exacerbation-
related, COPD-related or non-COPD related; each summary will be presented by all 
patients (i.e. moderate and severe index exacerbation combined), and separately by index 
exacerbation severity. 
The number of days of hospital admission for the index and subsequent exacerbations 
will also be summarised by treatment group.
 
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7.3.3.1.
Re-hospitalisation within 30 days of index exacerbation
Re-hospitalisation within 30 days of index exacerbation is defined as 30 days from the 
date of hospital discharge until the date of next hospital admission (+ 1 day, to account 
for study day derivation), for participants who were hospitalised for their index 
exacerbation. 
Exacerbation-related, COPD-related and Non-COPD-related hospital admissions are 
collected in separate eCRFs. The date of hospital admission is not collected in the COPD-
related eCRF, therefore the date of next hospital admission will be estimated using the 
earliest of:
Date of hospital admission for exacerbation-related hospitalisations
Date of contact for COPD-related hospitalisations, where the number of inpatient 
hospitalisation days >0
Date of hospital admission for non-COPD-related hospitalisations.
The proportion of participants who were re-hospitalised within 30 days of the index 
exacerbation will be summarised by each treatment arm.
7.3.3.2.
Time from resolution of index exacerbation to next exacerbation
Time from resolution of index exacerbation to next exacerbation is defined as time from 
the date of (Investigator-defined) resolution of index exacerbation until the date of onset 
of the subsequent exacerbation. 
A summary of time from resolution of index exacerbation to next exacerbation will be 
presented. Participants who did not have a subsequent exacerbation or for whom the 
index exacerbation was not resolved will be excluded from the summary. 
Time from resolution of index exacerbation to next exacerbation will only be derived for 
the first subsequent exacerbation following the index exacerbation. 
7.3.3.3.
Subsequent exacerbation treatment type 
A summary of the type of treatment for subsequent exacerbations (OCS, antibiotics, or 
both) may also be presented.
7.3.4.
Compliance
Compliance with study treatment for all participants is captured from the dose counter on 
the ELLIPTA and the overall percentage compliance will be summarised by each 
treatment group.
Reported compliance with study treatment is also captured daily in the eDiary from the 
question "Did you take this morning’s dose of study medication”? 
The percentage of reported compliance for each participant is calculated as:
 
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(Sum of the number of days where the question was answered with ‘Y’) / (Number of 
days from first dose of study treatment to last dose of study treatment) x 100
Overall percentage of reported compliance will also be summarised by each treatment 
group.
7.3.4.1.
Number of actuations of double-blind study treatment measured by the 
clip-on Propeller Sensor
Percentage compliance via the clip-on Propeller Sensor for ELLIPTA in the subset of 
participants from countries where the Propeller Sensor for ELLIPTA is available is 
calculated as:
(Sum of the number of days with actuation > 0) / (Number of days from first dose of 
study treatment to last dose of study treatment) x 100
Overall percentage compliance will be summarised by each treatment group.
7.3.4.2.
Missing EXACT-PRO data
Missing EXACT-PRO data will be summarised by treatment group.
7.3.5.
Inflammatory/infective markers in blood and sputum in relation to 
acute exacerbation of COPD
Results of the analysis of blood/spontaneous sputum samples of eosinophil counts and 
inflammatory/infective mediators/markers will be summarised by treatment group.
Further analyses of inflammatory/infective markers may be performed, for example split 
by CRP high, CRP low, Procalcitonin high, etc. categories.
7.3.6.
Other spirometry measurements
Percent predicted FEV1, Forced Vital Capacity (FVC), percent predicted FVC and 
FEV/FVC ratio will be summarised by treatment group. 
7.3.7.
Other symptoms suggestive of exacerbation
Responses to questions in the eDiary related to symptoms of sputum purulence (colour), 
fever, sore throat, wheezing and colds collected in the eDiary will be listed by treatment 
group.
7.3.8.
Classification of exacerbating COPD participants and prediction 
of response to nemiralisib using machine learning techniques
Exploratory analysis of endpoints using machine learning techniques will be performed 
which will include classification of COPD participants, identification of parameters 
which describe a responder, and prediction of response to nemiralisib using baseline data. 
Details of these analyses will be described in a separate RAP and results may be reported 
separately to the CSR.
 
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8.
SAFETY ANALYSES
The safety analyses will be based on the Safety population, unless otherwise specified.
The details of the planned displays will be provided in Appendix 11: List of Data 
Displays.
8.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs) and Serious
(SAEs) will be based on GSK Core Data Standards. 
8.1.1.
Adverse Events of Special Interest
Adverse events of special interest (AESI) are significant identified or potential risks 
identified in the nemiralisib clinical development programme.
8.1.1.1.
Post-inhalation Cough Immediately Following Dosing
Post-inhalation cough immediately following dosing is an AESI and will be evaluated 
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.
The percentage of patients experiencing post-inhalation cough following dosing, 
regardless of whether it was also reported as an AE, overall and by each visit will be 
summarised for each treatment group. The type of cough, time to onset and duration of 
cough, and severity will also be summarised.
In addition, any post-inhalation cough immediately following dosing reported as an
adverse event during the clinic visit observation or during the course of the study will be 
summarised by treatment group.  
8.1.1.2.
Paradoxical bronchospasm
Paradoxical bronchospasm is an AESI, defined using the Preferred Terms Bronchospasm 
and Bronchospasm paradoxical and will be summarised by treatment group.
8.2.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, 
Haematology laboratory tests and liver function tests will be based on GSK Core Data 
Standards.
8.3.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. 
 
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8.4.
Mortality
A summary of all-cause mortality by treatment will be presented. 
 
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9.
PHARMACOKINETIC ANALYSES
9.1.
Population of Interest 
The primary pharmacokinetic analyses will be based on the “Pharmacokinetic” 
population, unless otherwise specified.
9.2.
Drug Concentration Measures
Plasma nemiralisib concentrations of GSK2269557 will be listed and summarised by 
dose, day and time. Drug levels will be summarised by day (14, 28), dose and time 
intervals (trough, 0-<1h, 1-6h).
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 13.4.3
Reporting Standards for Pharmacokinetic).
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
 
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10.
POPULATION PK ANALYSIS
A dataset for population PK analysis will be provided by Statistics and Programming
based on the NONMEM data specifications in Section 13.8.2.
Conduct of the population PK analyses will be based on the current guidance which 
contains specific recommendations for working practices, processes and standards for 
population PK and PK/PD analysis conducted by Clinical Pharmacology Modelling and 
Simulation (CPMS) [Analysis & Reporting, 2017].
The sparse PK samples will be subjected to a validated population PK model for 
nemiralisib currently under development.
Details of these analyses will be described in a separate CPMS RAP and results will be 
reported separately to the CSR. Analyses and reporting of the population PK model will 
be in accordance with the FDA and EMEA guidance on population PK, PK-PD analyses.
10.1.
Derived Pharmacokinetic Parameters
The exposure parameters (e.g. AUC, Cmax) will be derived from the individual post-hoc 
estimates from the POP PK model. These will be summarized across dose treatments, 
subgroups (e.g., gender, race) or as a function of a continuous variable (e.g., age).
 
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11.
PHARMACOKINETIC / PHARMACODYNAMIC 
ANALYSES
If statistical analyses suggest an effect of nemiralisib on primary and other key clinical 
endpoints, an integrated longitudinal population dose/exposure versus clinical response 
on analysis key parameters including FEV1 and exacerbation rate will be undertaken. 
Participant characteristics influencing the relationship will be evaluated. 
Details of these analyses will be described in a separate CPMS RAP and results will be 
reported separately to the CSR.
 
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12.
REFERENCES
Bornkamp, B. (2014). Practical considerations for using functional uniform prior 
distributions for dose-response estimation in clinical trials. Biometrical Journal, 56(6), 
947-962. doi: 10.1002/bimj.201300138.
Dette, H., Bretz, F., Pepelyshev, A. & Pinheiro, J., (2008). Optimal Designs for Dose-
Finding Studies. Journal of the American Statistical Association, 103:483, 1255-1237. 
doi: 10.1198/016214508000000427.
Evidera. (2016). The Exacerbations of Chronic Pulmonary Disease Tool (EXACT)
Patient-Reported Outcome (PRO) USER MANUAL (Version 8.0). 
Spiegelhalter, D.J., Abrams, K.R. & Myles, J.P., (2004). Bayesian Approaches to Clinical 
Trials and Health-Care Evaluation. John Wiley & Sons, Ltd.
 
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13.
APPENDICES
13.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
13.1.1.
Exclusions from Per Protocol Population
Protocol deviations will be reviewed regularly throughout the course of the study, as 
described in Protocol Deviation Management Plan (PDMP). Deviations which will result 
in exclusion from the Per Protocol population will be assigned on a case-by-case basis
prior to database freeze (DBF).  
Decisions on whether or not the subject should be excluded from the PP population 
because the incorrect treatment was taken, due to the incorrect container being dispensed, 
will be identified after unblinding (i.e. post DBF). A PD of “incorrect treatment” will be 
added to the reporting dataset. 
 
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13.2.
Appendix 2: Assessment Windows
13.2.1.
Definitions of Assessment Windows for Analyses
13.2.1.1.
Hospital discharge
As per Section 5.1 of the Protocol, if discharge takes place between Day 11 and Day 17 
(inclusive), the assessments planned for Day 14 may be completed on the day of 
discharge. In these cases, for this endpoint only, the FEV1 assessment will be assigned 
the hospital discharge FEV1 assessment and the Day 14 assessment will be missing. 
For all other analyses and summaries that include participants who were hospitalised for 
their index exacerbation, an additional Analysis Timepoint of “HOSPTIAL 
DISCHARGE” will be derived. However, in the cases where discharge takes place 
between Day 11 and Day 17 (inclusive), participants will be summarised under DAY 14 
and a footnote to say that participants who were discharged at Day 14 are summarised 
under DAY 14 will be included.
13.2.1.2.
EXACT-Defined Recovery for CAT Trigger
If the study day following EXACT-defined recovery for a participant occurs within a 
scheduled assessment window, an additional analysis time-point will be 
programmatically created for that scheduled visit. For example, if EXACT-defined 
recovery occurred on Day 56, then a Day 56 Visit will be programmatically created with 
the data from the Recovery visit so that it can be summarised/analysed in both the Visit 
and Recovery categories.
Due to software limitations of the electronic PRO device, the study day following 
EXACT-defined recovery from the index exacerbation is not derived according to the 
EXACT User Manual. Instead, it has been derived using a 3-day Rolling Average that is 
calculated as the mean EXACT score [Day X-2, Day X-1, Day X].
 
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13.3.
Appendix 3: Study Phases and Treatment Emergent 
Adverse Events
13.3.1.
Study Periods
13.3.1.1.
12-Week Treatment Period 
The 12-Week Treatment Period is assigned from Study Day 1 to Study Day 84.
13.3.1.2.
12-Week Follow-Up Period
The 12-Week Follow-up Period is assigned from Study Day 85 to Study Day 168.
13.3.2.
Study Phases
Exacerbation events during the 12-Week Treatment Period will be classified according to 
their occurrence from randomisation until treatment discontinuation/study withdrawal 
days, as detailed below.
Study Phase
Occurring from randomisation until
On-Treatment during the 12-Week Treatment Period
Treatment Stop Day
On- or Off-Treatment during the 12-Week Treatment 
Period
Day 84 or Study Withdrawal Day if Treatment Stop 
Day is < Day 84
13.3.2.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before Randomisation Date
Concomitant
Any medication that is not a prior
NOTES: 

Please refer to Appendix 6: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.
13.3.3.
Treatment Emergent Flag for Adverse Events
Flag
Definition
Treatment 
Emergent

If AE onset date is on or after treatment start date & on or before treatment stop 
date plus 10 days.
NOTES: 

If the study treatment stop date is missing, then the AE will be considered to be On-Treatment.

Time of study treatment dosing and start/stop time of AEs should be considered, if collected.
 
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13.4.
Appendix 4: Data Display Standards & Handling 
Conventions
13.4.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: uk1salx00175
HARP Compound
: \arprod\gsk2269557\mid200879
Analysis Datasets 

For all interim analyses, except for the End of Treatment Interim Analysis, datasets will be created 
according to Legacy GSK A&R dataset standards.

For the End of Treatment Interim Analysis and the final reporting effort, datasets will be created 
according to current CDISC standards
Generation of RTF Files

RTF files will be generated for the final reporting effort.
13.4.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):
4.03 to 4.23: General Principles
5.01 to 5.08: Principles Related to Data Listings
6.01 to 6.11: Principles Related to Summary Tables
7.01 to 7.13: Principles Related to Graphics 
Figures will be produced using PROC SGPLOT in SAS 
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places will be adopted for reporting of data 
based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may be
adjusted to a clinically interpretable number of decimal places. 

For lab parameters results that contain a character value of ‘<’, or ‘>’, e.g. ‘<X’ or ‘>X’, the parameter 
value will be imputed with X.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:
Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.
The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 
Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).
Unscheduled or unplanned readings will be presented within the subject’s listings. 
 
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Unscheduled Visits

Unscheduled visits will be included in summary tables of the worst-case results by potential clinical 
importance criteria only.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principles 7.01 to 7.13.
13.4.3.
Reporting Standards for Pharmacokinetic
Pharmacokinetic Concentration Data
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
NONMEM/Pop PK 
File
Pop-PK file (CSV format) for the POP-PK analysis by Clinical Pharmacology
Modelling and Simulation function will be created according to the data specification 
detailed in Section 13.8.2 Population Pharmacokinetic (PopPK) Dataset 
Specification.
NONMEM/PK/PD 
File
PK/PD file (CSV format) for the PK/PD analysis by Clinical Pharmacology Modelling 
and Simulation function will be created according to the data specification detailed 
in the CPMS RAP.
 
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13.5.
Appendix 5: Derived and Transformed Data
13.5.1.
General
Multiple Measurements at One Analysis Time Point

Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables.
Study Day

Calculated as the number of days from Randomisation Date:
Ref Date = Missing              → Study Day = Missing 
Ref Date < Randomisation Date → Study Day = Ref Date – Randomisation Date
Ref Data ≥ Randomisation Date → Study Day = Ref Date – (Randomisation Date) + 1    
Time from date of randomisation and time from date of last dose of study treatment

For endpoints that use the time from the date of randomisation to a reference date, time will be 
calculated as
(Ref Date – Randomisation Date) + 1

For endpoints that use the time from the date of last dose of study treatment to a reference date, time 
will be calculated as
(Ref Date – (Last Dose Date + 1)) +1
13.5.2.
Study Population
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1
13.5.3.
Safety
Adverse Events
AE’S of Special Interest

Post-inhalation cough: Lower level term (LLT) to be included is “coughing after drug inhalation”

Paradoxical bronchospasm: Preferred Terms to be included are “Bronchospasm paradoxical” and 
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13.6.
Appendix 6: Reporting Standards for Missing Data
13.6.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) is defined as completing all 
phases of the study including the last scheduled study visit

A participant is considered to have completed the Treatment Period, if he/she has 
completed the last on-treatment study visit (Visit 6) 

Withdrawn subjects were not replaced in the study.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.

Withdrawal visits will not be summarised (and will be listed only).
13.6.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:
These data will be indicated by the use of a “blank” in subject listing displays. Unless 
all data for a specific visit are missing in which case the data is excluded from the 
table. 
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
13.6.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to 
be recorded for AE start and end dates; that is, the day of the month may be 
missing. In such a case, the following conventions will be applied for calculating 
the time to onset and the duration of the event:
Missing Start Day: First of the month will be used unless this is before 
the start date of study treatment; in this case the study treatment start 
date will be used and hence the event is considered On-treatment as 
per Appendix 3: Study Phases and Treatment Emergent Adverse 
Events.
Missing Stop Day: Last day of the month will be used, unless this is after the 
stop date of study treatment; in this case the study treatment stop date will 
be used.

Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be 
missing.
 
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Element
Reporting Detail
Concomitant 
Medications/Medical 
History

Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:
If the partial date is a start date, a '01' will be used for the day and 'Jan' 
will be used for the month
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.
Age

The eCRF collects year of birth only. Day and Month will be imputed by 
Data Management using a 
 for the day and '
 for the month

Age will then be derived referenced to the Screening Date

A footnote to say that age has been imputed will be included in any outputs 
containing age.
 
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13.7.
Appendix 7: Values of Potential Clinical Importance
13.7.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Haemoglobin 
G/DL
Male 18-64 years
7.1
19.9
Male 65+ years
7.1
19.9
Female 18-64 years
7.1
19.9
Female 65+ years
7.1
19.9
Lymphocytes 
GI/L
0.85
4.1
Total Absolute Neutrophil Count 
GI/L
1.5
8
Platelet Count 
GI/L
31
1499
White Blood Cell count
GI/L
18-64 years
1.1
10.8
65+ years
1.1
10.8
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Albumin
g/L
32
50
Calcium
mmol/L
1.5
3.24
Creatinine
Male 40-49 years
69
160
Male 50-59 years
67.2
160
Male 60-69 years
67.2
160
Male 70+ years
59.2
160
Female 40-49 years
52.2
160
Female 50-59 years
53
160
Female 60-69 years
53
160
Female 70+ years
55.7
160
Glucose
mmol/L
13-49 years
2.2
27.8
50+ years
2.2
27.8
Potassium
mmol/L
2.8
6.5
Sodium
mmol/L
120
160
Urea/BUN
mmol/L
13-64 years
2.5
15
65+ years
2.5
15
 
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Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
≥ 2x ULN
AST/SGOT 
U/L
High
≥ 2x ULN
AlkPhos 
U/L
High
≥ 2x ULN
T Bilirubin 
µmol/L
High
≥ 2x ULN
T. Bilirubin + ALT
µmol/L
High
2xULN T.Bilirubin + ≥ 3x ULN ALT
U/L
Direct Bilirubin
µmol/L
0 – 6
13.7.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 530
Absolute PR Interval
msec
< 110
> 240
Absolute QRS Interval
msec
< 75
> 110
Change from Baseline
Increase from Baseline QTc
msec
> 60
13.7.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 95
> 160 
Diastolic Blood Pressure
mmHg
< 55
> 100
Heart Rate
bpm
< 40 
> 110 
 
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13.8.
Appendix 8: Population Pharmacokinetic (PopPK) Analyses
13.8.1.
Population Pharmacokinetic (PopPK) Methodology
All analysis will be performed in the validated Modelling and Analysis Platform (MAP). 
MAP consists of a Linux desktop containing various modelling applications, including 
NONMEM, PsN, Pirana, R and RStudio. All software versions used will be documented.
The population PK analysis will be performed in the following sequence of steps:
1.Exploratory data analysis/data check out.
2.Base structural model development.
3.Covariate analysis.
4.Model refinement.
5.Model evaluation.
6.Model application using simulation
The above analysis and reporting steps follow EMEA 
(http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/
WC500003067.pdf) and FDA population PK guidances 
(https://www.fda.gov/downloads/drugs/guidances/UCM072137.pdf ) 
Key components of these regulatory guidelines on population PK are also included in the 
Global CPMS guidance for pop pk RAP
(https://connect.gsk.com/sites/cpms/TandD/Guidances).
13.8.2.
Population Pharmacokinetic (PopPK) Dataset Specification
Statistics & Programming, in discussion with CPMS, will provide a NONMEM dataset.  
Column headings in NONMEM-ready datasets and specifications should be consistent to 
minimise the programming process, and facilitate a smooth transfer of projects between 
users as needed. IDSL standards will be followed where possible.
A list of most common standardised variable names for NONMEM datasets can be found 
in Table below.
 
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List of Variable Names for NONMEM-Ready Datasets for PopPK Analysis
Variable
Label (Variable description)
C
NONMEM line exclusion identifier
ID
NONMEM subject identifier
STUD
Study ID
SUBJID
Subject identifier for study
SITEID
Unique identifier for a study site
AMT
NONMEM Amount of drug administered then EVID =1- dose event record
UAMT
Unit of AMT (mg)
ADDL
NONMEM Additional dose
CONC
Drug Concentration 
UCONC
Unit of CONC (ng/mL)
LNCONC
Natural log of CONC column 
ANALYTE
Drug label e.g 557
LLQ
Lower Limit of quantification
LNLLQ
Natural log of LLQ column
DAY
Study day number of record or of dosing
TIME
Plasma sample time after last dose
UTIME
Unit of TIME (h)
DOSE
Dose amount
EVID
NONMEM Event ID If row has dose then EVID=1 else EVID =0  
If EVID=1 then this is a dose event record
If EVID = 0 then this is an observation record 
II
NONMEM Inter-dose interval II=24 – dose every day
SS
Steady state item SS= 1 refers to steady state
MDV
NONMEM Missing data value then MDV=1 else MDV=0
AGE
Subject Age (yrs)
SEX
Subject gender 0 = Male 1 =Female
SEXTEXT
Subject gender text Male or Female
BMI
Baseline Body Mass Index
WT
Baseline Subject weight
CONMED1
Identifier for inhibitor CYP3A4 1 =Yes, 0 = No
CONMED1TXT
Inhibitor Name
CONMED2
Identifier for inducer CYP3A4 1 =Yes, 0 = No
CONMED2TXT
Inducer Name
If observation record e.g CONC  has “NA” or “NS” then assign CONC cell as  “.”
If observation record e.g CONC  has “NQ” or “BQL” then assign CONC cell as  “.” and MDV = 1 -this means 
value can be estimated by model
Missing covariate data should be imputed as “-99. 
 
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13.9.
Appendix 9: Pharmacokinetic / Pharmacodynamic Analyses
13.9.1.
Pharmacokinetic/Pharmacodynamic Methodology
PK-PD analysis of Nemiralisib will be guided by the results of the formal statistical 
analyses on the key clinical endpoints. The aims of the PK-PD analyses will contribute 
towards the dose selection in future studies using an integrated longitudinal analysis 
framework.
The objective is to explore an integrated modelling framework to characterise the 
longitudinal FEV1 response versus dose (average systemic exposure) during on- & off-  
treatment phases
A longitudinal nonlinear mixed-effects model will be used to describe the FEV1 response 
over time measured for each patient (i) at each visit (tij) with ɛ denoting the normal 
distributed residual variability with mean 0 and variance σ2. The function f() describes the
relative change from observed FEV1 at baseline (FEV1,base) and any influence of patient 
characteristics on FEV1 response will be assessed.
Joint relationship between time to first exacerbation and FEV1 change as function of 
dose/exposure and patient covariates will be assessed.
Details of these analyses will be described in a separate CPMS RAP and results will be 
reported separately to the CSR.
 
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13.10.
Appendix 10: Abbreviations & Trade Marks
13.10.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AESI
Adverse Event of Special Interest
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
APE
All Participants Enrolled
AUC
Area Under the Curve
BMI
Body Mass Index
CAT
COPD Assessment Test
CDISC
Clinical Data Interchange Standards Consortium
COPD
Chronic Obstructive Pulmonary Disease
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CSV
Comma Separated Values
CTR
Clinical Trial Register
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
ECG
Electrocardiogram
eCRF
Electronic Case Record Form
EMA
European Medicines Agency
ERS
Evaluating Respiratory Symptoms
EXACT
Exacerbations of Chronic Pulmonary Disease Tool
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
FEV1
Forced Expiratory Volume in one second
FVC
Forced Vital Capacity
GSK
GlaxoSmithKline
HCRU
Health Care Resource Use
HPD
Highest Posterior Density
IA
Interim Analysis
ICH
International Conference on Harmonization
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
iSRC
Independent Safety Review Committee
KM
Kaplan-Meier
 
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LLT
Lower Level Term
MCMC
Markov Chain Monte Carlo
MCSE
Monte Carlo Standard Errors
MDI
Metered Dose Inhaler
MITT
Modified Intent To Treat
OCS
Oral Corticosteroids
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
PRO
Patient Reported Outcomes
PT
Preferred Term
QC
Quality Control
QTcF
Fridericia’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
SAS
Statistical Analysis Software
SD
Standard Deviation
SDTM
Study Data Tabulation Model
SGRQ
St. George’s Respiratory Questionnaire
SGRQ-C
St. George’s Respiratory Questionnaire for COPD Patients
SoC
Standard of Care
SOP
Standard Operation Procedure
TFL
Tables, Figures & Listings 
13.10.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
COPD Assessment Test (CAT)
E-RS: COPD
ELLIPTA
EXACT-PRO
HARP
NONMEM
Propeller Sensor
SAS
SGRQ
 
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13.11.
Appendix 11: List of Data Displays
13.11.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays for SAC:
Section
Tables
Figures
Study Population
1.1 to 1.31
1.3
Efficacy
2.1 to 2.107
2.1 to 2.20
Safety
3.1 to 3.33
3.1 to 3.4
Pharmacokinetic
4.1 to 4.2
Not applicable
Section
Listings
ICH Listings
1 to 27
Other Listings
28 to 30
13.11.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 12: Example Mock Shells for Data Displays.
13.11.3.
Deliverables
Delivery
Description
IA
Interim Analysis (except the End of treatment Phase Interim Analysis)
EOT
End of Treatment Phase Interim Analysis
SAC
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13.11.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
MITT
ES8
Summary of Subject Status and Reason for Study Withdrawal
EOT, SAC
1.2.
MITT
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
EOT, SAC
1.3.
APE
ES6
Summary of Screening Status and Reasons for Screen Failure
SAC
1.4.
APE
NS1
Summary of Number of Participants by Country and Site ID
For EOT, use MITT population and 
summarise country only: Summary of 
Number of Participants by Country
EOT, SAC
Protocol Deviation
1.5.
MITT
DV1
Summary of Important Protocol Deviations
SAC
1.6.
MITT
IE1
Summary of Inclusion/Exclusion Criteria Deviations
SAC
Population Analysed
1.7.
MITT
SP1
Summary of Study Populations 
SAC
1.8.
MITT
SP2
Summary of Exclusions from the Per Protocol/Safety Population
SAC
Demographic and Baseline Characteristics
1.9.
MITT
DM1
Summary of Demographic Characteristics
Use the following ranges for the Age 
Group row: ≤64; 65-74; ≥75
EOT, SAC
1.10.
APE
DM11
Summary of Age Ranges
SAC
1.11.
MITT
DM5
Summary of Race and Racial Combinations
SAC
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.12.
MITT
MH4
Summary of Past Medical Conditions
SAC
1.13.
MITT
MH4
Summary of Current Medical Conditions
SAC
1.14.
MITT
FH1
Summary of Family History of Cardiovascular Risk Factors
SAC
1.15.
MITT
SU1
Summary of Smoking History at Screening
EOT, SAC
1.16.
MITT
SU1
Summary of Smoking Status Over the 12-Week Treatment 
Period
SAC
1.17.
MITT
SU1
Summary of Smoking Status Over the 12-Week Follow-Up 
Period
SAC
1.18.
MITT
Example 7
Summary of COPD Duration at Screening
SAC
1.19.
MITT
Example 1
Summary of COPD Exacerbation History at Screening
Use categories 0;1;2;3;≥3. Summarise 
moderate/severe, moderate; severe
Include 7-Day History of COPD 
Exacerbations
EOT, SAC
1.20.
MITT
Example 1
Summary of COPD Exacerbation History at Screening by 
Country
SAC
Concomitant Medications
1.21.
MITT
Example 14
Summary of Baseline COPD Maintenance Therapy
For EOT use categories: Triple, 
Non-triple
EOT, SAC
1.22.
MITT
Example 14
Summary of Baseline ICS Therapy
For EOT use categories: Yes, No
EOT, SAC
1.23.
MITT
Example 15
Summary of On-Treatment COPD Maintenance (Step-up) 
Therapy 
SAC
1.24.
MITT
CM1
Summary of Concomitant Medications During 12-Week 
Treatment Period
SAC
1.25.
MITT
Example 16
Summary of Duration of On-Treatment OCS 
EOT, SAC
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.26.
MITT
Example 16
Summary of Duration of On-Treatment OCS Excluding Non-
COPD medications
EOT, SAC
1.27.
MITT
CM1
Summary of Concomitant Medications During 12-Week Follow-
Up Period
SAC
Exposure and Treatment Compliance
1.28.
MITT
Example 36
Summary of Exposure to Study Treatment
EOT, SAC
1.29.
MITT
Example 2
Summary of Overall Treatment Compliance Measured by the 
Dose Counter on the ELLIPTA
EOT, SAC
1.30.
MITT
Example 2
Summary of Reported Treatment Compliance from the Daily 
eDiary
SAC
1.31.
MITT
Example 2
Summary of Overall Treatment Compliance Measured by the 
Clip-on Propeller Sensor for ELLIPTA
SAC
13.11.5.
Study Population Figures
Study Population Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
MITT
Example 4
Plot of COPD Exacerbation History at Screening (Moderate)
EOT
1.2.
MITT
Example 4
Plot of COPD Exacerbation History at Screening (Severe)
EOT
1.3.
MITT
Example 4
Plot of COPD Exacerbation History at Screening 
(Moderate/Severe)
EOT
 
 
 
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13.11.6.
Efficacy Tables
13.11.6.1. Efficacy tables for Interim Analysis 1
Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in Clinic Visit trough FEV1
2.1.
MITT
Example 3
Summary of FEV1 (L) 
Include pre- and post-bronchodilator
IA1
2.2.
MITT
Example 3
Summary of FEV1 (L) by Index Exacerbation Severity
Include pre- and post-bronchodilator 
Include additional row for hospital 
discharge visit for Severe group
IA1
2.3.
MITT
Example 3
Summary of Change from Baseline in FEV1 (L)
Include pre- and post-bronchodilator
IA1
2.4.
MITT
Example 3
Summary of Change from Baseline in FEV1 (L) by Index 
Exacerbation Severity
Include pre- and post-bronchodilator. 
Include additional row for hospital 
discharge visit for Severe group
IA1
2.5.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 at Day 14 
Measured Post-bronchodilator (Dose Response Model)
IA1
2.6.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 at Day 28 
Measured Post-bronchodilator (Dose Response Model) 
IA1
2.7.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
14 Measured Post-bronchodilator by Index Exacerbation 
Severity (Dose Response Model)
IA1
2.8.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
28 Measured Post-bronchodilator by Index Exacerbation 
Severity (Dose Response Model)
IA1
2.9.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
Measured Post-bronchodilator (Repeated Measures Model)
IA1
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.10.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
Measured Pre-bronchodilator (Repeated Measures Model)
IA1
2.11.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
Measured Post-bronchodilator by Index Exacerbation Severity
(Repeated Measures Model)
IA1
2.12.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
Measured Pre-bronchodilator by Index Exacerbation Severity
(Repeated Measures Model)
IA1
Rate of Exacerbations
2.13.
MITT
Example 5
Summary of On-treatment Exacerbations
IA1
2.14.
MITT
Example 5
Summary of On-treatment Exacerbations by Index Exacerbation 
Severity
IA1
EXAcerbations of Chronic Pulmonary Disease Tool - Patient Reported Outcome (EXACT)
2.15.
MITT
Example 9
Summary of Proportion of Participants Achieving the EXACT-
definition of Recovery by Visit
Exclude statistical analysis 
information (summary only)
IA1
2.16.
MITT
Example 9
Summary of Proportion of Participants Achieving the EXACT-
definition of Recovery by Index Exacerbation Severity
Exclude statistical analysis 
information (summary only)
IA1
Other Spirometry Measures
2.17.
MITT
Example 3
Summary of Spirometry Measurements
IA1
2.18.
MITT
Example 3
Summary of Change from Baseline in Spirometry Measurements
IA1
 
 
 
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13.11.6.2. Efficacy tables for Interim Analysis 2
Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in Clinic Visit trough FEV1
2.1.
MITT
Example 3
Summary of FEV1 (L) 
Include pre- and post-bronchodilator
IA2
2.2.
MITT
Example 3
Summary of FEV1 (L) by Index Exacerbation Severity
Include pre- and post-bronchodilator 
Include additional row for hospital 
discharge visit for Severe group
IA2
2.3.
MITT
Example 3
Summary of Change from Baseline in FEV1 (L)
Include pre- and post-bronchodilator
IA2
2.4.
MITT
Example 3
Summary of Change from Baseline in FEV1 (L) by Index 
Exacerbation Severity
Include pre- and post-bronchodilator. 
Include additional row for hospital 
discharge visit for Severe group
IA2
2.5.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
14 Measured Post-bronchodilator (Dose Response Model)
IA2
2.6.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
28 Measured Post-bronchodilator (Dose Response Model)
IA2
2.7.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
56 Measured Post-bronchodilator (Dose Response Model)
IA2
2.8.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
84 Measured Post-bronchodilator (Dose Response Model)
IA2
2.9.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
14 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate (Dose Response Model)
IA2
2.10.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
14 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe (Dose Response Model)
IA2
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.11.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
28 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate (Dose Response Model)
IA2
2.12.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
28 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe (Dose Response Model)
IA2
2.13.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
56 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate (Dose Response Model)
IA2
2.14.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
56 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe (Dose Response Model)
IA2
2.15.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
84 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate (Dose Response Model)
IA2
2.16.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
84 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe (Dose Response Model)
IA2
2.17.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
Measured Post-bronchodilator (Repeated Measures Model)
IA2
2.18.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
Measured Pre-bronchodilator (Repeated Measures Model)
IA2
2.19.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
Measured Post-bronchodilator by Index Exacerbation Severity 
(Repeated Measures Model)
IA2
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.20.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
Measured Pre-bronchodilator by Index Exacerbation Severity 
(Repeated Measures Model)
IA2
2.21.
MITT
Example 32
Summary of Efficiency Ratio for Possible Adaptions to 
Randomization Ratio
IA2
Rate of Exacerbations
2.22.
MITT
Example 5
Summary of On-treatment (Moderate/Severe) Subsequent
Exacerbations
IA2
2.23.
MITT
Example 5
Summary of On-treatment (Moderate/Severe) Subsequent
Exacerbations by Index Exacerbation Severity
IA2
2.24.
MITT
Example 6
Statistical Analysis of On-treatment (Moderate/Severe) 
Subsequent Exacerbations
IA2
2.25.
MITT
Example 6
Subgroup Analysis of On-treatment (Moderate/Severe) 
Subsequent Exacerbations by Index Exacerbation Severity
IA2
EXAcerbations of Chronic Pulmonary Disease Tool - Patient Reported Outcome (EXACT)
2.26.
MITT
Example 9
Statistical Analysis of Proportion of Participants Achieving the 
EXACT-definition of Recovery by Visit
IA2
2.27.
MITT
Example 9
Subgroup Analysis of Proportion of Participants Achieving the 
EXACT-definition of Recovery by Index Exacerbation Severity
IA2
COPD Assessment Test (CAT)
2.28. )
MITT
Example 3
Summary of Change from Baseline in CAT Total Score
IA2
2.29.
MITT
Example 9
Statistical Analysis of Proportion of Responders Using the CAT 
Total Score by Visit
IA2
2.30.
MITT
Example 11
Statistical Analysis of Change from Baseline in CAT Total Score 
(Repeated Measures Model)
IA2
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
St. George’s Respiratory Questionnaire (SGRQ)
2.31.
MITT
Example 3
Summary of Change from Baseline in SGRQ Total Score
IA2
2.32.
MITT
Example 9
Statistical Analysis of Proportion of Responders Using the 
SGRQ Total Score by Visit
IA2
2.33.
MITT
Example 11
Statistical Analysis of Change from Baseline in SGRQ Total 
Score (Repeated Measures Model)
IA2
Rescue Medication Use
2.34.
MITT
RM1
Summary of Mean Number of Occasions of Rescue Medication 
Use Per Day
IA2
2.35.
MITT
RM1
Summary of Percentage of Rescue-Free Days
IA2
Other Spirometry Measures
2.36.
MITT
Example 3
Summary of Spirometry Measurements
IA2
2.37.
MITT
Example 3
Summary of Change from Baseline in Spirometry Measurements
IA2
13.11.6.3. Efficacy tables for End of Treatment Interim Analysis and SAC
Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in Clinic Visit trough FEV1
2.1.
MITT
Example 3
Summary of FEV1 (L)
Include pre- and post-bronchodilator
EOT, SAC
2.2.
MITT
Example 3
Summary of FEV1 (L) by Index Exacerbation Severity
Include pre- and post-bronchodilator 
Include additional row for hospital 
discharge visit for Severe group
EOT, SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.3.
MITT
Example 3
Summary of Change from Baseline in FEV1 (L)
Include pre- and post-bronchodilator
EOT, SAC
2.4.
MITT
Example 3
Summary of Change from Baseline in FEV1 (L) by Index 
Exacerbation Severity
Include pre- and post-bronchodilator. 
Include additional row for hospital 
discharge visit for Severe group
EOT, SAC
2.5.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
14 Measured Post-bronchodilator (Dose Response Model)
SAC
2.6.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
28 Measured Post-bronchodilator (Dose Response Model)
SAC
2.7.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
56 Measured Post-bronchodilator (Dose Response Model)
SAC
2.8.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
84 Measured Post-bronchodilator (Dose Response Model)
SAC
2.9.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
14 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate (Dose Response Model)
SAC
2.10.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
14 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe (Dose Response Model)
SAC
2.11.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
28 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate (Dose Response Model)
SAC
2.12.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
28 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe (Dose Response Model)
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.13.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
56 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate (Dose Response Model)
SAC
2.14.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
56 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe (Dose Response Model)
SAC
2.15.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
84 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate (Dose Response Model)
SAC
2.16.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
84 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe (Dose Response Model)
SAC
2.17.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
Measured Post-bronchodilator (Repeated Measures Model)
EOT, SAC
2.18.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
Measured Post-bronchodilator by Index Exacerbation Severity 
(Repeated Measures Model)
EOT, SAC
Change from Hospital Discharge in Clinic Visit trough FEV1
2.19.
MITT
Example 3
Summary of Change from Hospital Discharge in FEV1 (L)
Include pre- and post-bronchodilator
SAC
2.20.
MITT
Example 11
Statistical Analysis of Change from Hospital Discharge in FEV1
(L) Measured Post-bronchodilator (Repeated Measures Model)
SAC
2.21.
MITT
Example 11
Statistical Analysis of Change from Hospital Discharge in FEV1
(L) Measured Pre-bronchodilator (Repeated Measures Model)
SAC
Change from Day 84 in Clinic Visit trough FEV1
2.22.
MITT
Example 3
Summary of Change from Day 84 in FEV1 (L) 
Include pre- and post-bronchodilator
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.23.
MITT
Example 11
Statistical Analysis of Change from Day 84 in FEV1 (L) 
Measured Post-bronchodilator (Repeated Measures Model)
SAC
2.24.
MITT
Example 11
Statistical Analysis of Change from Day 84 in FEV1 (L) 
Measured Pre-bronchodilator (Repeated Measures Model)
SAC
2.25.
MITT
Example 11
Subgroup Analysis of Change from Day 84 in FEV1 (L) 
Measured Post-bronchodilator by Index Exacerbation Severity 
(Repeated Measures Model)
SAC
2.26.
MITT
Example 11
Subgroup Analysis of Change from Day 84 in FEV1 (L) 
Measured Pre-bronchodilator by Index Exacerbation Severity 
(Repeated Measures Model)
SAC
Rate of Exacerbations
2.27.
MITT
Example 5
Summary of On-treatment (Moderate/Severe) Subsequent
Exacerbations
EOT, SAC
2.28.
MITT
Example 5
Summary of On-treatment (Mild/Moderate/Severe) Subsequent
Exacerbations
SAC
2.29.
MITT
Example 5
Summary of On-treatment (Moderate/Severe) Subsequent
Exacerbations by Index Exacerbation Severity
EOT, SAC
2.30.
MITT
Example 6
Statistical Analysis of On-treatment (Moderate/Severe) 
Subsequent Exacerbations
EOT, SAC
2.31.
MITT
Example 6
Statistical Analysis of On-treatment (Mild/Moderate/Severe) 
Subsequent Exacerbations
SAC
2.32.
MITT
Example 6
Subgroup Analysis of On-treatment (Moderate/Severe) 
Subsequent Exacerbations by Index Exacerbation Severity
EOT, SAC
2.33.
MITT
Example 5
Summary of On-treatment Subsequent Exacerbations by Index 
Exacerbation Type
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.34.
MITT
Example 5
Summary of On-treatment Subsequent Exacerbations by 
Number of Exacerbations in Previous 12 Months
SAC
2.35.
MITT
Example 5
Summary of On-treatment (Moderate/Severe) Subsequent 
Exacerbations by Baseline Maintenance Therapy  
EOT, SAC
2.36.
MITT
Example 6
Subgroup Analysis of On-treatment (Moderate/Severe) 
Subsequent Exacerbations by Baseline Maintenance Therapy
EOT, SAC
2.37.
MITT
Example 5
Summary of On-treatment (Moderate/Severe) Subsequent 
Exacerbations by Baseline ICS Therapy  
EOT, SAC
2.38.
MITT
Example 6
Subgroup Analysis of On-treatment (Moderate/Severe) 
Subsequent Exacerbations by Baseline ICS Therapy
EOT, SAC
2.39.
MITT
Example 6
Subgroup Analysis of On-treatment (Moderate/Severe) 
Subsequent Exacerbations by EXACT Recovery Status at Day 
14
EOT, SAC
2.40.
MITT
Example 12
Summary of Number of On-treatment Subsequent 
(Moderate/Severe) Exacerbations Treated with 
Steroids/Antibiotics
EOT, SAC
2.41.
MITT
Example 6
Subgroup Analysis of On-treatment (Moderate/Severe) 
Subsequent Exacerbations by Baseline Blood Biomarker Status
EOT, SAC
2.42.
MITT
Example 5
Summary of On-or Off-treatment (Moderate/Severe) Subsequent
Exacerbations During the 12-Week Treatment Period
SAC
2.43.
MITT
Example 5
Summary of On-or Off-treatment (Mild/Moderate/Severe) 
Subsequent Exacerbations During the 12-Week Treatment 
Period
SAC
2.44.
MITT
Example 5
Summary of On-or Off-treatment (Moderate/Severe) Subsequent
Exacerbations During the 12-Week Treatment Period by Index 
Exacerbation Severity
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.45.
MITT
Example 6
Statistical Analysis of On- or Off-treatment (Moderate/Severe) 
Subsequent Exacerbations During the 12-Week Treatment 
Period
EOT, SAC
2.46.
MITT
Example 6
Statistical Analysis of On- or Off-treatment 
(Mild/Moderate/Severe) Subsequent Exacerbations During the 
12-Week Treatment Period
SAC
2.47.
MITT
Example 6
Subgroup Analysis of On- or Off-treatment (Moderate/Severe) 
Subsequent Exacerbations During the 12-Week Treatment 
Period by Index Exacerbation Severity
SAC
2.48.
MITT
Example 5
Summary of Off-treatment (Moderate/Severe) Subsequent
Exacerbations 
EOT, SAC
2.49.
MITT
Example 5
Summary of Off-treatment (Moderate/Severe) Subsequent
Exacerbations by Index Exacerbation Severity
SAC
2.50.
MITT
Example 6
Statistical Analysis of Off-treatment (Moderate/Severe) 
Subsequent Exacerbations
EOT, SAC
2.51.
MITT
Example 6
Subgroup Analysis of Off-treatment (Moderate/Severe) 
Subsequent Exacerbations by Index Exacerbation Severity
SAC
2.52.
MITT
Example 5
Summary of On- and Off-treatment (Moderate/Severe) 
Subsequent Exacerbations During the 24-Week Study Period
SAC
2.53.
MITT
Example 5
Summary of On- and Off-treatment (Moderate/Severe) 
Subsequent Exacerbations During the 24-Week Study Period by 
Index Exacerbation Severity
SAC
2.54.
MITT
Example 6
Statistical Analysis of On- and Off-treatment (Moderate/Severe) 
Subsequent Exacerbations During the 24-Week Study Period
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.55.
MITT
Example 6
Subgroup Analysis of On- and Off-treatment (Moderate/Severe) 
Subsequent Exacerbations During the 24-Week Study Period by 
Index Exacerbation Severity
SAC
Time to Next Exacerbation
2.56.
MITT
Example 8
Statistical Analysis of Time to next On-treatment Exacerbation 
EOT, SAC
2.57.
MITT
Example 8
Subgroup Analysis of Time to next On-treatment Exacerbation 
by Index Exacerbation Severity
EOT, SAC
2.58.
MITT
Example 8
Statistical Analysis of Time to next On- or Off-treatment 
Exacerbation During the 12-Week Treatment Period
SAC
2.59.
MITT
Example 8
Statistical Analysis of Time to next On- or Off-treatment 
Exacerbation During the 12-Week Treatment Period by Index 
Exacerbation Severity
SAC
2.60.
MITT
Example 8
Statistical Analysis of Time to Next Exacerbation Following 
Cessation of Study Treatment
SAC
2.61.
MITT
Example 8
Statistical Analysis of Time to Next Exacerbation Following 
Cessation of Study Treatment by Index Exacerbation Severity
SAC
EXAcerbations of Chronic Pulmonary Disease Tool - Patient Reported Outcome (EXACT)
2.62.
MITT
Example 9
Statistical Analysis of Proportion of Participants Achieving the 
EXACT-definition of Recovery by Visit
EOT, SAC
2.63.
MITT
Example 9
Subgroup Analysis of Proportion of Participants Achieving the 
EXACT-definition of Recovery by Index Exacerbation Severity
EOT, SAC
2.64.
MITT
Example 8
Summary and Statistical Analysis of Time to EXACT-defined 
Recovery
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.65.
MITT
Example 10
Summary of Severity of Subsequent HCRU-defined 
Exacerbation During 12-Week Treatment Period
Also split by moderate and severe
SAC
2.66.
MITT
Example 10
Summary of Severity of Subsequent HCRU-Defined 
Exacerbation During 12-Week Follow-up Period
Also split by moderate and severe
SAC
2.67.
MITT
Example 35
Summary of Missing On-treatment EXACT-PRO data
EOT, SAC
2.68.
MITT
Example 35
Summary of Missing Off-treatment EXACT-PRO data
SAC
COPD Assessment Test (CAT)
2.69.
MITT
Example 3
Summary of Change from Baseline in CAT Total Score
EOT, SAC
2.70.
MITT
Example 3
Summary of Change from Baseline in CAT Total Score by Index 
Exacerbation Severity
SAC
2.71.
MITT
Example 9
Statistical Analysis of Proportion of Responders Using the CAT 
Total Score by Visit
EOT, SAC
2.72.
MITT
Example 9
Subgroup Analysis of Proportion of Responders Using the CAT 
Total Score by Visit by Index Exacerbation Severity
SAC
2.73.
MITT
Example 11
Statistical Analysis of Change from Baseline in CAT Total Score 
(Repeated Measures Model)
EOT, SAC
2.74.
MITT
Example 11
Subgroup Analysis of Change from Baseline in CAT Total Score 
(Repeated Measures Model) by Index Exacerbation Severity
SAC
2.75.
MITT
Example 3
Summary of Change from End of Treatment in CAT Total Score
SAC
2.76.
MITT
Example 3
Summary of Change from End of Treatment in CAT Total Score 
by Index Exacerbation Severity
SAC
2.77.
MITT
Example 11
Statistical Analysis of Change from End of Treatment in CAT 
Total Score (Repeated Measures Model)
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.78.
MITT
Example 11
Subgroup Analysis of Change from End of Treatment in CAT 
Total Score (Repeated Measures Model) by Index Exacerbation 
Severity
SAC
St. George’s Respiratory Questionnaire (SGRQ)
2.79.
MITT
Example 3
Summary of Change from Baseline in SGRQ Total Score
EOT, SAC
2.80.
MITT
Example 3
Summary of Change from Baseline in SGRQ Total Score by 
Index Exacerbation Severity
SAC
2.81.
MITT
Example 9
Statistical Analysis of Proportion of Responders on the SGRQ 
Total Score by Visit
EOT, SAC
2.82.
MITT
Example 9
Subgroup Analysis of Proportion of Responders on the SGRQ 
Total Score by Index Exacerbation Severity
SAC
2.83.
MITT
Example 11
Statistical Analysis of Change from Baseline SGRQ Total Score 
(Repeated Measures Model)
EOT, SAC
2.84.
MITT
Example 11
Subgroup Analysis of Change from Baseline SGRQ Total Score 
(Repeated Measures Model) by Index Exacerbation Severity
SAC
2.85.
MITT
Example 3
Summary of Change from End of Treatment in SGRQ Total 
Score
SAC
2.86.
MITT
Example 3
Summary of Change from End of Treatment in SGRQ Total 
Score by Index Exacerbation Severity
SAC
2.87.
MITT
Example 11
Statistical Analysis of Change from End of Treatment in SGRQ 
Total Score (Repeated Measures Model)
SAC
2.88.
MITT
Example 11
Subgroup Analysis of Change from End of Treatment in SGRQ 
Total Score (Repeated Measures Model) by Index Exacerbation 
Severity
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
E-RS: COPD
2.89.
MITT
Example 3
Summary of Change from Baseline in E-RS: COPD and 
Subscales
SAC
Rescue Medication Use
2.90.
MITT
RM1
Summary of Mean Number of Occasions of Rescue Medication 
Use Per Day
EOT, SAC
2.91.
MITT
RM1
Summary of Percentage of Rescue-Free Days
EOT, SAC
2.92.
MITT
RM1
Summary of Mean Number of Actuations of Rescue Medication 
Use Per Day Via the Clip-on Propeller Sensor for MDI
SAC
2.93.
MITT
RM1
Summary of Percentage of Rescue-Free Days Via the Clip-on 
Propeller Sensor for MDI
SAC
Healthcare Resource Utilisation
2.94.
MITT
Example 19
Summary of Exacerbation Related Unscheduled Healthcare 
Resource Utilisation 
SAC
2.95.
MITT
Example 19
Summary of Exacerbation Related Unscheduled Healthcare 
Resource Utilization by Index Exacerbation Severity
SAC
2.96.
MITT
Example 21
Summary of Exacerbation Related Hospitalizations
SAC
2.97.
MITT
Example 19
Summary of COPD Related Unscheduled Healthcare Resource 
Utilisation 
SAC
2.98.
MITT
Example 19
Summary of COPD Related Unscheduled Healthcare Resource 
Utilisation by Index Exacerbation Severity
SAC
2.99.
MITT
Example 20
Summary of Non-COPD Related Unscheduled Healthcare 
Resource Utilisation 
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.100.
MITT
Example 20
Summary of Non-COPD Related Unscheduled Healthcare 
Resource Utilisation by Index Exacerbation Severity
SAC
2.101.
MITT 
Example 22
Summary of Re-hospitalization Within 30 days of Index 
Exacerbation
SAC
2.102.
MITT
Example 24
Summary of Time from Resolution of Index Exacerbation to Next 
Exacerbation
SAC
2.103.
MITT
Example 23
Summary of Subsequent Exacerbation Treatment
SAC
Other Spirometry Measures
2.104.
MITT
Example 3
Summary of Spirometry Measurements
EOT, SAC
2.105.
MITT
Example 3
Summary of Change from Baseline in Spirometry Measurements
EOT, SAC
Inflammatory/infective Markers in Blood and Sputum
2.106.
MITT
Example 3
Summary of Inflammatory Markers in Blood
For EOT only include Screening 
timepoint
EOT, SAC
2.107.
MITT
Example 3
Summary of Inflammatory Markers in Sputum
SAC
 
 
 
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13.11.7.
Efficacy Figures
13.11.7.1. Efficacy Figures for Interim Analysis 1
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in Clinic Visit trough FEV1
2.1.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 14 Measured Post-bronchodilator
IA1
2.2.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 28 Measured Post-bronchodilator 
IA1
2.3.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 56 measured post-bronchodilator 
IA1
2.4.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 14 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate
IA1
2.5.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 14 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe
IA1
2.6.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 28 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate
IA1
2.7.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 28 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe
IA1
 
 
 
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13.11.7.2. Efficacy Figures for Interim Analysis 2
Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in Clinic Visit trough FEV1
2.1.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 14 Measured Post-bronchodilator
IA2
2.2.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 28 Measured Post-bronchodilator 
IA2
2.3.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 56 Measured Post-bronchodilator
IA2
2.4.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 84 Measured Post-bronchodilator
IA2
2.5.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 14 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate
IA2
2.6.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 14 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe
IA2
2.7.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 28 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate
IA2
2.8.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 28 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe
IA2
2.9.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 56 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate
IA2
 
 
 
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.10.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 56 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe
IA2
2.11.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 84 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate
IA2
2.12.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 84 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe
IA2
2.13.
MITT
Example 31
Plot of Repeated Measures Model of Change from Baseline in 
FEV1 Measured Post-bronchodilator
IA2
2.14.
MITT
Example 31
Plot of Repeated Measures Model of Change from Baseline in 
FEV1 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate
IA2
2.15.
MITT
Example 31
Plot of Repeated Measures Model of Change from Baseline in 
FEV1 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe
IA2
Time to Next Exacerbation 
2.16.
MITT
Example 30
Kaplan-Meier Plot of Time to Next On-treatment 
(Moderate/Severe) Exacerbation
IA2
2.17.
MITT
Example 30
Kaplan-Meier Plot of Time to Next On-treatment 
(Mild/Moderate/Severe) Exacerbation
IA2
 
 
 
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13.11.7.3. Efficacy Figures for End of Treatment Interim Analysis and SAC
Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in Clinic Visit trough FEV1
2.1.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 14 Measured Post-bronchodilator
SAC
2.2.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 28 Measured Post-bronchodilator 
SAC
2.3.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 56 Measured Post-bronchodilator
SAC
2.4.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 84 Measured Post-bronchodilator
SAC
2.5.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 14 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate
SAC
2.6.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 14 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe
SAC
2.7.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 28 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate
SAC
2.8.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 28 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe
SAC
2.9.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 56 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate
SAC
 
 
 
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.10.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 56 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe
SAC
2.11.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 84 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate
SAC
2.12.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 84 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe
SAC
2.13.
MITT
Example 31
Plot of Adjusted Posterior Medians (95% HPD Crl) of Change 
from Baseline in FEV1 Measured Post-bronchodilator
EOT, SAC
2.14.
MITT
Example 31
Plot of Adjusted Posterior Medians (95% HPD Crl) of Change 
from Baseline in FEV1 Measured Post-bronchodilator by Index 
Exacerbation Severity: Moderate
EOT, SAC
2.15.
MITT
Example 31
Plot of Adjusted Posterior Medians (95% HPD Crl) of Change 
from Baseline in FEV1 Measured Post-bronchodilator by Index 
Exacerbation Severity: Severe
EOT, SAC
Time to Next Exacerbation
2.16.
MITT
Example 30
Kaplan-Meier Plot of Time to Next On-treatment 
(Moderate/Severe) Exacerbation
EOT, SAC
2.17.
MITT
Example 30
Kaplan-Meier Plot of Time to Next On-treatment 
(Mild/Moderate/Severe) Exacerbation
SAC
2.18.
MITT
Example 30
Kaplan-Meier Plot of Time to Next On-or Off-treatment 
(Moderate/Severe) Exacerbation During the 12-Week Treatment 
Period
SAC
 
 
 
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.19.
MITT
Example 30
Kaplan-Meier Plot of Time to Next On-or Off-treatment 
(Mild/Moderate/Severe) Exacerbation During the 12-Week 
Treatment Period
SAC
2.20.
MITT
Example 30
Kaplan-Meier Plot of Time to Next (Moderate/Severe) 
Exacerbation Following Cessation of Study Treatment
SAC
13.11.8.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.1.
Safety
AE1
Summary of Treatment Emergent Adverse Events by System 
Organ Class and Preferred Term
EOT, SAC
3.2.
Safety
AE1
Summary of Post-Treatment Adverse Events by System Organ 
Class and Preferred Term
SAC
3.3.
Safety
AE3
Summary of Common (>=5%) Treatment Emergent Adverse 
Events by Overall Frequency
EOT, SAC
3.4.
Safety
AE1
Summary of Drug-Related Treatment Emergent Adverse Events 
by System Organ Class and Preferred Term
EOT, SAC
3.5.
Safety
AE15
Summary of Common (>=5%) Non-serious Treatment Emergent 
Adverse Events by System Organ Class and Preferred Term 
(Number of Participant and Occurrences)
SAC
3.6.
Safety
AE5A
Summary of All Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term
SAC
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.7.
Safety
AE1
Summary of Treatment Emergent Adverse Events for 
Participants with Absolute Neutrophil Count Below Lower Value 
of PCI
SAC
Serious and Other Significant Adverse Events
3.8.
Safety
AE16
Summary of Serious Treatment Emergent Adverse Events by 
System Organ Class and Preferred Term (Number of 
Participants and Occurrences)
EOT, SAC
3.9.
Safety
AE16
Summary of Fatal Serious Treatment Emergent Adverse Events 
by System Organ Class and Preferred Term (Number of 
Participants and Occurrences)
Only with subcategory: Number of Fatal 
SAEs
EOT, SAC
3.10.
Safety
AE1
Summary of Serious Treatment Emergent Drug-related Adverse 
Events by System Organ Class and Preferred Term
SAC
3.11.
Safety
AE1 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term
EOT, SAC
3.12.
Safety
AE1
Summary of Post-treatment Serious Adverse Events by System 
Organ Class and Preferred Term
SAC
3.13.
Safety
AE1
Summary of Treatment Emergent Adverse Events of Special 
Interest by Lower Level Term
EOT, SAC
3.14.
Safety
AE1
Summary of Treatment Emergent Adverse Events of Special 
Interest by System Organ Class and Preferred Term
EOT, SAC
3.15.
Safety
Example 17
Summary of Post-Inhalation Cough by Visit
EOT, SAC
3.16.
Safety
Example 28
Summary of Post-Inhalation Cough by Visit and Cough Type
EOT, SAC
3.17.
Safety
Example 33
Summary of Post-Inhalation (PI) Cough at Any Visit
EOT, SAC
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory: Chemistry 
3.18.
Safety
LB1
Summary of Chemistry Data 
For EOT summarise Alkaline 
Phosphates at Screening only
EOT, SAC
3.19.
Safety
LB17
Summary of Worst Case Chemistry Results by PCI Criteria 
Post-Baseline Relative to Baseline
EOT, SAC
Laboratory: Hematology
3.20.
Safety
LB1
Summary of Hematology Data
For EOT summarise Eosinophils, 
Monocytes, Lymphocytes at Screening 
only
EOT, SAC
3.21.
Safety
LB1
Summary of Change from Baseline in Hematology
Only for WBC, lymphocytes, neutrophils
SAC
3.22.
Safety
LB17
Summary of Worst Case Hematology Results by PCI Criteria 
Post-Baseline Relative to Baseline
EOT, SAC
Laboratory: Hepatobiliary (Liver)
3.23.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting
SAC
3.24.
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities
SAC
ECG
3.25.
Safety
EG1
Summary of ECG Findings 
Include Worst Case 
Post-Baseline row
EOT, SAC
3.26.
Safety
EG2
Summary of ECG Values by Visit
For the following parameters: QTcF, 
QTcB, PR, Heart rate 
EOT, SAC
3.27.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit
For the following parameters: QTcF, 
QTcB, PR, Heart rate
SAC
3.28.
Safety
Example 27
Summary of QTcF Categories
SAC
3.29.
Safety
Example 27
Summary of QTcB Categories
SAC
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.30.
Safety
EG10
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category
SAC
3.31.
Safety
EG11
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category
SAC
3.32.
Safety
Example 25
Summary of ECG Abnormalities for Participants with Any 
Abnormal ECG Interpretation
EOT, SAC
Vital Signs
3.33.
Safety
VS1
Summary of Vital Signs
SAC
3.34.
Safety
VS7
Summary of Worst Case Vital Signs Results by PCI Criteria 
Post-Baseline Relative to Baseline
EOT, SAC
 
 
 
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13.11.9.
Safety Figures
Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory
3.1.
Safety
LB7
LFT Shift from Baseline to Maximum
EOT, SAC
3.2.
Safety
Example 34
Plot of Laboratory Data at Screening
EOT, SAC
3.3.
Safety
Example 13
Median (range) Absolute Neutrophil Count by Time and 
Treatment
SAC
ECG
3.4.
Safety
EG8
Distribution of QTcF Change by Time and Treatment
SAC
13.11.10. Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetic Concentration-Time Data
4.1.
PK
PK01
Summary of Plasma GSK2269557 Pharmacokinetic 
Concentration-Time Data
SAC
4.2.
PK
PK05
Summary of Log-Transformed Plasma GSK2269557 
Pharmacokinetic Concentration-Time Data
SAC
 
 
 
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13.11.11. ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
APE
ES7
Listing of Reasons for Screen Failure
SAC
2.
MITT
ES2
Listing of Reasons for Study Withdrawal
SAC
3.
MITT
SD2
Listing of Reasons for Study Treatment Discontinuation
SAC
4.
MITT
BL1
Listing of Participants for Whom the Treatment Blind was Broken
SAC
5.
MITT
TA1
Listing of Planned and Actual Treatments
SAC
Protocol Deviations
6.
MITT
DV2
Listing of Important Protocol Deviations 
SAC
7.
MITT
IE3
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations
SAC
Populations Analysed
8.
MITT
SP3
Listing of Participants Excluded from Per Protocol Population
For participants excluded from MITT 
population (i.e. participants in the MITT 
but not in PP)
SAC
Demographic and Baseline Characteristics
9.
MITT
DM2
Listing of Demographic Characteristics
SAC
10.
MITT
DM9
Listing of Race
SAC
Prior and Concomitant Medications
11.
MITT
CP_CM3
Listing of Concomitant Medications
SAC
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Exposure and Treatment Compliance
12.
Safety
EX3
Listing of Exposure Data
SAC
Adverse Events
13.
Safety
AE8
Listing of All Adverse Events
SAC
14.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
SAC
15.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
SAC
Serious and Other Significant Adverse Events
16.
Safety
AE8
Listing of Fatal Serious Adverse Events
SAC
17.
Safety
AE8
Listing of Non-Fatal Serious Adverse Events
SAC 
18.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse Event
SAC
19.
Safety
AE8
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
SAC
Hepatobiliary (Liver)
20.
Safety
MH2
Listing of Medical Conditions for Participants with Liver Stopping 
Events
SAC
21.
Safety
SU2
Listing of Substance Use for Participants with Liver Stopping 
Events
SAC
All Laboratory
22.
Safety
LB5
Listing of All Chemistry Data for Participants with Any Value of 
Potential Clinical Importance
SAC
23.
Safety
LB14
Listing of Chemistry Data with Character Results
SAC
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
24.
Safety
LB5
Listing of All Hematology Data for Participants with Any Value of 
Potential Clinical Importance
SAC
25.
Safety
LB14
Listing of all Hematology Data with Character Results
SAC
ECG
26.
Safety
EG3
Listing of All ECG Values for Participants with Any Value of 
Potential Clinical Importance
SAC
27.
Safety
EG5
Listing of All ECG Findings for Participants with an Abnormal 
Finding
SAC
13.11.12. Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
28.
MITT
Example 29
Listing of Subjects who Received Incorrect Medication
SAC
29.
PK
PK07
Listing of Plasma Pharmacokinetic Concentration-Time Data
SAC
30.
Safety
EG5
Listing of All ECG Findings for Subjects with an Abnormal 
Finding
SAC
 
 
 
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13.12.
Appendix 12: Example Mock Shells for Data Displays
13.12.1.
Example shell 1
Example Shell X
Protocol: XYZ100001                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
                             Summary of COPD Exacerbation History at Screening
                                                                  Treatment A  Treatment B   Total
                                                                  (N=100)      (N=100)      (N=200)
   -----------------------------------------------------------------------------------------------------
   Moderate COPD exacerbations
     n                                                            X            X             X
     0                                                            xx (x%)      xx (x%)       xx (x%)    
     1                                                            xx (x%)      xx (x%)       xx (x%)  
     >=2                                                          xx (x%)      xx (x%)       xx (x%)    
   Severe COPD exacerbations
     n                                                            X            X             X
     0                                                            xx (x%)      xx (x%)       xx (x%)
     1                                                            xx (x%)      xx (x%)       xx (x%)
     >=2                                                          xx (x%)      xx (x%)       xx (x%)
   Total number of moderate/severe COPD exacerbations
     n                                                            911          899          1810
     0                                                            313 (34%)    317 (35%)     630 (35%)
     1                                                            252 (28%)    253 (28%)     505 (28%)
     >=2                                                          346 (38%)    329 (37%)     675 (37%)
Note: Number of COPD exacerbations reported in the 12 months prior to the Screening Visit.
 
 
 
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13.12.2.
Example Shell 2
Protocol: XYZ100001                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
Summary of Treatment Compliance
                                                                  Treatment A  Treatment B   Total
                                                                  (N=100)      (N=100)      (N=200)
   -----------------------------------------------------------------------------------------------------
   Overall compliance (%)
     n                                                            xx           xx            xx
     Mean                                                         xx           xx            xx 
     SD                                                           xx           xx            xx 
     Median                                                       xx           xx            xx
     Min.                                                         xx           xx            xx
     Max.                                                         xx           xx            xx
   Compliance interval
     < 80%                                                         xx (x%)      xx (x%)       xx (x%)
     80% - < 100%                                                  xx (x%)      xx (x%)       xx (x%)
     100% - < 120%                                                 xx (x%)      xx (x%)       xx (x%)
     >=120%                                                        xx (x%)      xx (x%)       xx (x%)
 
 
 
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13.12.3.
Example shell 3
Example Shell X
Protocol: ABC123456                                                                            Page 1 of n
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
                             Summary of Change from Baseline in FEV1 (L)
Measured post-bronchodilator
                                              
Visit             N      Treatment Arm       n    Mean    SD      Median  Min.   Max.
----------------------------------------------------------------------------------------------------------
Day 1
200    Placebo             200   0.111  0.1111   0.100  -0.11  1.11
                   200    GSK2269557 12.5 mcg 190   0.222  0.2222   0.200  -0.22  1.22
                   200    GSK2269557   50 mcg 195   0.333  0.3333   0.300  -0.33  1.33
                   200    GSK2269557  100 mcg 195   0.444  0.4444   0.400  -0.44  1.44
                   200    GSK2269557  250 mcg 190   0.555  0.5555   0.500  -0.55  1.55
                   200    GSK2269557  500 mcg 190   0.555  0.5555   0.500  -0.55  1.55
                   200    GSK2269557  750 mcg 190   0.555  0.5555   0.500  -0.55  1.55
Day 14
200    Placebo             200   0.111  0.1111   0.100  -0.11  1.11
                   200    GSK2269557 12.5 mcg 190   0.222  0.2222   0.200  -0.22  1.22
                   200    GSK2269557   50 mcg 195   0.333  0.3333   0.300  -0.33  1.33
                   200    GSK2269557  250 mcg 195   0.444  0.4444   0.400  -0.44  1.44
                   200    GSK2269557  500 mcg 190   0.555  0.5555   0.500  -0.55  1.55
200    GSK2269557  750 mcg 190   0.555  0.5555   0.500  -0.55  1.55
                                              
 
 
 
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13.12.4.
Example Shell 4
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Figure X
                        Plot of Number of Exacerbations in Previous 12 Months
(Moderate/Severe)
 
 
 
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Protocol: ABC123456                                                                             Page 2 of 2
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
                        Statistical Analysis of Change from Baseline in FEV1 (ml)
Measured post-bronchodilator
Visit
Treatment Comparison
Adjusted
Median
Difference
Std Dev
95% Credible 
Interval
Prob Treat. 
Diff >0 (%)
Day 14
GSK2269557 12.5 mg vs
x.xx
x.xx
(x.xx, x.xx)
x.xx
Placebo
GSK2269557   50 mg vs
x.xx
x.xx
(x.xx, x.xx)
x.xx
Placebo
GSK2269557 100 mg vs
x.xx
x.xx
(x.xx, x.xx)
x.xx
Placebo
GSK2269557 250 mg vs
x.xx
x.xx
(x.xx, x.xx)
x.xx
Placebo
GSK2269557 500 mg vs
x.xx
x.xx
(x.xx, x.xx)
x.xx
Placebo
GSK2269557 750 mg vs
x.xx
x.xx
(x.xx, x.xx)
x.xx
Placebo
Day 28
GSK2269557 12.5 mg vs
x.xx
x.xx
(x.xx, x.xx)
x.xx
Placebo
GSK2269557   50 mg vs
x.xx
x.xx
(x.xx, x.xx)
x.xx
Placebo
GSK2269557 100 mg vs
x.xx
x.xx
(x.xx, x.xx)
x.xx
Placebo
 
 
 
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13.12.5.
Example Shell 5
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
                                  Summary of On-treatment Exacerbations
                                                                      
                                                               Treatment A       Treatment B
                                                                  (N=100)         (N=100)
        -------------------------------------------------------------------------------------------
        Number of moderate/severe exacerbations per subject                      
         0                                                      50 (50%)       98 (98%)
         1                                                       6  (6%)       15 (15%)
         2                                                       6  (6%)        9  (9%)
         3                                                       1  (1%)        1  (1%)
         4                                                       0              2  (2%)
         5                                                       0              1  (1%)
   >5                                                      0              1  (1%)
        Subjects with >=1 moderate/severe exacerbation         13 (13%)       28 (28%)
        Total Number of moderate/severe exacerbations          21             49
        Number of moderate exacerbations per Subject                      
         0                                                      50 (50%)       98 (98%)
         1                                                       6  (6%)       15 (15%)
         2                                                       6  (6%)        9  (9%)
         3                                                       1  (1%)        1  (1%)
        
 
 
 
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13.12.6.
Example Shell 6
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
                           Statistical Analysis of On-treatment Exacerbations
                                                                      
                                                               Treatment A       Treatment B
                                                                  (N=100)         (N=100)
        -------------------------------------------------------------------------------------------
        Moderate/severe exacerbations
        Annual exacerbation rate (95% CrI)                  0.35 (x.xx, x.xx)   0.30 (x.xx, x.xx)                     
        Active vs. Placebo
          Ratio                                                                 0.85 (x.xx, x.xx)   
          Pr Diff <1                                                            x.xx   
        Percent reduction in rate (95% CrI)                                     15% (x.xx, x.xx)
  Predictive probability (%) [1]  
  xx%
        [only when required] 
        Moderate exacerbations
        Annual exacerbation rate (95% CrI)                  0.35 (x.xx, x.xx)   0.30 (x.xx, x.xx)                     
        Active vs. Placebo
          Ratio                                                                 0.85 (x.xx, x.xx)   
          Pr Diff <1                                                            x.xx   
        Percent reduction in rate (95% CrI)                                     15% (x.xx, x.xx)                          
[1] Predictive posterior probability of success at end of study, where success is Pr(Reduction>0%)>80%
 
 
 
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13.12.7.
Example Shell 7
Protocol: ABC123456                                                                           Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
                                   Summary of COPD Duration at Screening
                                                   
                                                   Treatment A   Treatment B    Total
                                                   (N=100)       (N=100)       (N=200)
                 --------------------------------------------------------------------------
                 Duration of COPD:
                   n                                 100            99          199
                   <1 year                            XX   (x%)     XX   (x%)     XX   (x%)
                   >=1 to <5 years                    XX   (x%)    XX   (x%)     XX   (x%)
                   >=5 to <10 years                   XX   (x%)     XX   (x%)     XX   (x%)
                   >=10 to <15 years                  XX   (x%)     XX   (x%)     XX   (x%)
                   >=15 to <20 years                  XX   (x%)     XX   (x%)     XX   (x%)
                   >=20 to <25 years                  XX   (x%)     XX   (x%)     XX   (x%)
                   >=25 years                         XX   (x%)     XX   (x%)     XX   (x%)
 
 
 
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13.12.8.
Example Shell 8
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
         Summary and Analysis of Time to Next On-treatment Moderate/Severe Exacerbation (days)
                                               up to Day 84
                                                                  Treatment A      Treatment B
                                                                  (N=100)          (N=100)
            ------------------------------------------------------------------------------------
            Number of Subjects with Event                           10  (10%)        14  (14%)
            Number of Subjects Censored                             90  (90%)        86  (86%)
            
            
            Treatment A vs. Placebo
              Hazard Ratio                                           X.XX
              95% Credible Interval                                 (x.xx, x.xx)
              
Note: Hazard ratio and 95% Credible Interval are from a Bayesian Cox proportional hazards model 
 
 
 
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13.12.9.
Example Shell 9
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
             Statistical Analysis of Proportion of Participants Achieving EXACT-definition of Response
                                                                      
                                                               Treatment A       Treatment B
                                                                  (N=100)         (N=100)
        -------------------------------------------------------------------------------------------
        Day 14
          n                                                   x.xx                x.xx                    
          Responder          
  x.xx (x%)           x.xx (x%)                     
          Non-responder                                       x.xx (x%)           x.xx (x%)                    
          Active vs. Placebo
           Odds Ratio (OR) (95% CrI)                              x.xx (x.xx, x.xx)   x.xx (x.xx, x.xx)
           Pr OR >1   
                     x.xx               x.xx
        Day 28
          n                                                   x.xx                x.xx                    
          Responder          
  x.xx (x%)           x.xx (x%)                     
          Non-responder                                       x.xx (x%)           x.xx (x%)                     
          Active vs. Placebo
           Odds Ratio (95% CrI)                                x.xx (x.xx, x.xx)   x.xx (x.xx, x.xx)
           Pr Diff >1   
                     x.xx               x.xx
        
        
        
 
 
 
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13.12.10. Example Shell 10
Protocol: XYZ100001                                                                    Page 1 of n
Population: Intent-to-Treat/Safety/Other study specific
Table X
Summary of severity of subsequent HCRU-defined exacerbation during 12-Week Treatment Period
Treatment
N
n
Mean
SD
Median
Min.
Max.
Placebo
30
30
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Trt A
30
30
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Trt B
30
30
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
 
 
 
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13.12.11. Example Shell 11
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
                        Mixed Model Repeated Measures Analysis of CAT Total Score
                                                                      
                                                               Treatment A       Treatment B
                                                                  (N=100)         (N=100)
        -------------------------------------------------------------------------------------------
        Day 28
          n                                                   x.xx               x.xx                    
          Adjusted mean score change (SE)                     x.xx (x)           x.xx (x)                     
          Active - Placebo
           Difference (SE)                                    x.xx (x.xx)        x.xx (x.xx)
           95% (CrI)                                          x.xx               x.xx
           Pr Diff >0  
                          x.xx               x.xx
        Day 56
          n                                                   x.xx                x.xx                    
          Adjusted mean score change (SE)                     x.xx (x)           x.xx (x)                     
          Active - Placebo
           Difference (SE)                                    x.xx (x.xx)        x.xx (x.xx)
           95% (CrI)                                          x.xx               x.xx
           Pr Diff >0  
                          x.xx               x.xx
        
           
 
 
 
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13.12.12. Example Shell 12
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
Table X
Summary of the Number of Subsequent (On-treatment) Exacerbations Treated with Steroids/Antibiotics
                                                                        
                                                                        Treatment A    Treatment B
                                                                       (N=100)        (N=100)
        --------------------------------------------------------------------------------------------
          Total exacerbations                                            50  
        51
                                                            
Treatment
            Antibiotics
                     30            40
            Steroids
                     50            40
           Both
                     30            30
 
 
 
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13.12.13. Example shell 13
Protocol: XYZ100001                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific 
       
Figure X
Median (range) Absolute Neutrophil Count by Time and Treatment
 
 
 
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13.12.14. Example Shell 14
Protocol: XYZ100001                                                                             Page 1 of n
Population: Intent-to-Treat/Safety/Other study specific
Table X
Summary of Baseline COPD Maintenance Therapy
Therapy category
Treatment A
(N=81)
Treatment B
(N=79)
Any medication at baseline
70 (86%)
50 (63%)
Monotherapy
X (x%)
X (x%)
  LAMA only
x  (x%)
x  (x%)
Dual therapy                          
x (x%)
x (x%)
  ICS/LABA
x  (x%)
x  (x%)
  Dual bronchodilator
xx (xx%)
xx (xx%)
Triple therapy
X (x%)
    X (x%)
  LAMA/ICS/LABA
x  (x%)
   0
 
 
 
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13.12.15. Example Shell 15
Protocol: XYZ100001                                                                             Page 1 of n
Population: Intent-to-Treat/Safety/Other study specific
Table X
Summary of On-Treatment COPD Maintenance (Step-up) Therapy
Therapy category
Treatment A
(N=81)
Treatment B
(N=79)
Any Step-up Therapy
70 (86%)
50 (63%)
 
 
 
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13.12.16. Example shell 16
Protocol: XYZ100001                                                                             Page 1 of n
Population: Intent-to-Treat/Safety/Other study specific
Table X
Summary of OCS use 
Treatment A
(N=81)
Treatment B
(N=79)
OCS use for index exacerbation
81 (100%)
79 (100%)
  Total number of Days of OCS use
   Mean
Xx
xx
    SD
Xx
xx
    Median
Xx
xx
    Min.
Xx
xx
    Max.
Xx
xx
On-treatment OCS use
xx (xx%)
xx (xx%)
  Total number of Days of OCS use
   Mean
Xx
xx
    SD
Xx
xx
    Median
Xx
xx
    Min.
Xx
xx
    Max.
Xx
xx
 
 
 
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13.12.17. Example Shell 17
Protocol: ABC123456                                                                               Page 1 of x
Population: Safety
                                                 Table X
                                 Summary of Post-Inhalation Cough by Visit
Visit: VISIT 2 (RANDOMISATION)
                                                     GSK2269557 GSK2269557 GSK2269557 GSK2269557 GSK2269557
                                          Placebo    50 mcg     100 mcg    250 mcg    500 mcg    750 mcg
                                          (N=43)     (N=14)     (N=15)     (N=16)     (N=14)     (N=42)
----------------------------------------------------------------------------------------------------------
Did subject experience PI cough? [1]       
  n                                      20         10          12         15          12         35
  Yes                                     7  (35%)   4  (40%)    6  (50%)   3  (20%)    6  (50%)  12  (34%)
  No                                     13  (65%)   6   (60%)   6  (50%)  12  (80%)    6  (50%)  23  (66%)
Type of cough
   Single cough                           4  (57%)   2  (50%)   1  (17%)   1  (33%)   1  (17%)    2  (17%)
   Intermittent cough                     2  (29%)   2  (50%)   5  (83%)   1  (33%)   4  (67%)    5  (42%)
   Continuous cough                       1  (14%)   0          0          1  (33%)   1  (17%)    5  (42%)
Severity of cough
   Mild                                   5  (71%)   3  (75%)   3  (50%)   2  (67%)   1  (17%)    6  (50%)
   Moderate                               2  (29%)   1  (25%)   2  (33%)   1  (33%)   5  (83%)    4  (33%)
   Severe                                 0          0          1  (17%)   0          0           2  (17%)
Time to onset of PI cough (minutes)
   0-1                                    6  (86%)   3  (75%)   6 (100%)   3 (100%)   6 (100%)   12 (100%)
   >1-2                                   1  (14%)   1  (25%)   0          0          0           0
   >2-3                                   0          0          0          0          0           0
   >3-4                                   0          0          0          0          0           0
   >4-5                                   0          0          0          0          0           0
   >5                                     0          0          0          0          0           0
Duration of PI cough (minutes)
   <=1                                    6  (86%)   3  (75%)   5  (83%)   3 (100%)   5  (83%)   11  (92%)
   >1-2                                   1  (14%)   1  (25%)   1  (17%)   0          1  (17%)    1   (8%)
   >2-3                                   0          0          0          0          0           0
   >3-4                                   0          0          0          0          0           0
   >4-5                                   0          0          0          0          0           0
 
 
 
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   >5-10                                  x          x
   >10-30                                 x          x
   >30                                    x          x
Number of subjects reporting cough as
AE/SAE                                   2  (29%)   1  (25%)   4  (67%)   0          2  (33%)    3  (25%)
   Mild                                   x  (x%)    x
   Moderate                               x  (x%)    x
   Severe                                 x  (x%)    x
[1] Percentages are calculated using the number of subjects evaluated at visit as the denominator.
All other percentages are calculated using the number of subjects with a PI cough at visit as the denominator.
 
 
 
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13.12.18. Example shell 18
Protocol: ABC123456                                                                             Page 1 of x
Population: Intent-to-Treat/Safety/Other study specific
                                                 Figure X
Plot of Dose Response Model of Change from Baseline in FEV1 
[Footnote to describe the fitted model]
 
 
 
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13.12.19. Example Shell 19
Protocol: ABC123456                                                                             Page 1 of 3
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
             Summary of COPD Related Unscheduled Healthcare Resource Utilization
                                                                        
                                                                        Treatment A    Treatment B
                                                                        (N=100)        (N=100)
        --------------------------------------------------------------------------------------------
          Unscheduled Healthcare Utilisation                Yes          97  (97%)      19  (19%)
                                                            No            3  ( 3%)      81  (81%)
          Number of Home Visits (day)                       n           100            100
                                                            0            90  (90%)      92  (92%)
                                                            1             4   (4%)       4   (4%)
                                                            2             0              0  
                                                            3             0              0
                                                            >3            0              2  (<1%)
                                                            Total [1]     4              4
          Number of Home Visits (night)                     n           100            100
                                                            0           100 (100%)     100 (100%)
                                                            1             0              0  
                                                            2             0              0
                                                            3             0              0
                                                            >3            0              0
                                                            Total [1]     0              0
[1] Total number of contacts across all subjects.
[2] Total number of days across all subjects.
 
 
 
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Protocol: ABC123456                                                                             Page 2 of 3
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
             Summary of COPD Related Unscheduled Healthcare Resource Utilization 
                                                                        
                                                                        Treatment A    Treatment B
                                                                        (N=100)        (N=100)
        --------------------------------------------------------------------------------------------
          Number of Office/Practice Visits                  n           911            899
                                                            0           846  (93%)     808  (90%)
                                                            1            42   (5%)      58   (6%)
                                                            2            13   (1%)      23   (3%)
                                                            3             7  (<1%)       8  (<1%)
                                                            >3            3  (<1%)       2  (<1%)
                                                            Total [1]   103            140
          Number of Urgent Care/Outpatient Visits           n           911            899
                                                            0           886  (97%)     882  (98%)
                                                            1            15   (2%)      10   (1%)
                                                            2             3  (<1%)       2  (<1%)
                                                            3             3  (<1%)       3  (<1%)
                                                            >3            4  (<1%)       2  (<1%)
                                                           Total [1]    54             37
          Number of Emergency Room Visits                   n           911            899
                                                            0           906 (>99%)     893 (>99%)
                                                            1             5  (<1%)       5  (<1%)
                                                            2             0              1  (<1%)
                                                            3             0              0
                                                            >3            0              0
                                                            Total [1]     5              7
[1] Total number of contacts across all subjects.
[2] Total number of days across all subjects.
 
 
 
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Protocol: ABC123456                                                                             Page 3 of 3
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
             Summary of COPD Related Unscheduled Healthcare Resource Utilization
                                                                        
                                                                        Treatment A    Treatment B
                                                                        (N=100)        (N=100)
        --------------------------------------------------------------------------------------------
          Number of Days in Intensive Care                  n           911            899
                                                            0           910 (>99%)     894 (>99%)
                                                            1             0              0
                                                            2             0              1  (<1%)
                                                            3             0              0
                                                            >3            1  (<1%)       4  (<1%)
                                                            Total [2]    12             40
          Number of Days in General Ward                    n           911            899
                                                            0           896  (98%)     878  (98%)
                                                            1             0              2  (<1%)
                                                            2             1  (<1%)       1  (<1%)
                                                            3             0              0
                                                            >3           14   (2%)      18   (2%)
                                                            Total [2]   119            258
[1] Total number of contacts across all subjects.
[2] Total number of days across all subjects.
 
 
 
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13.12.20. Example Shell 20
Protocol: ABC123456                                                                             Page 1 of x
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
             Summary of Non-COPD Related Unscheduled Healthcare Resource Utilization
                                                                        
                                                                        Treatment A    Treatment B
                                                                        (N=100)        (N=100)
        --------------------------------------------------------------------------------------------
          Unscheduled Healthcare Utilisation                Yes          97  (97%)      19  (19%)
                                                            No            3  ( 3%)      81  (81%)
          Number of Days in Accident and emergency          n           100            100
                                                            0            90  (90%)      92  (92%)
                                                            1             4   (4%)       4   (4%)
                                                            2             0              0  
                                                            3             0              0
                                                            >3            0              2  (<1%)
                                                            Total         4              4
          Number of Days in General Ward                    n           100            100
                                                            0           100 (100%)     100 (100%)
                                                            1             0              0  
                                                            2             0              0
                                                            3             0              0
                                                            >3            0              0
                                                            Total         0              0
 
 
 
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13.12.21. Example Shell 21
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
Summary of Exacerbation Related Hospitalizations
                                                                      
                                                               Treatment A       Treatment B
                                                                  (N=100)         (N=100)
        -------------------------------------------------------------------------------------------
        Index exacerbation
          Participants with hospitalization                   x.xx               x.xx                    
          Number of hospitalizations          
  x.xx               x.xx                      
          Mean duration (days)                                x.xx               x.xx                      
          SD                                                  x.xx               x.xx
          Median duration (days)                              x.xx               x.xx
          Minimum duration (days)                             x.xx               x.xx
          Maximum duration (days)                             x.xx               x.xx                      
        Subsequent exacerbations
          Participants with hospitalization                   x.xx               x.xx                    
          Number of hospitalizations          
  x.xx               x.xx                      
          Mean duration (days)                                x.xx               x.xx                      
          SD                                                  x.xx               x.xx
          Median duration (days)                              x.xx               x.xx
          Minimum duration (days)                             x.xx               x.xx
          Maximum duration (days)                             x.xx               x.xx                              
        
      
 
 
 
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13.12.22. Example Shell 22
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
Summary of Re-hospitalization Within 30 days of Index Exacerbation
                                                                        
                                                                        Treatment A    Treatment B
                                                                        (N=100)        (N=100)
        --------------------------------------------------------------------------------------------
          Re-hospitalization Within 30 days                 Yes          97  (97%)      19  (19%)
                                                            No            3  ( 3%)      81  (81%)
          
 
 
 
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13.12.23. Example Shell 23
Protocol: XYZ100001                                                                             Page 1 of n
Population: Intent-to-Treat/Safety/Other study specific
Table X
Summary of Subsequent Exacerbation Treatment
Treatment A
(N=81)
Treatment B
(N=79)
Subsequent exacerbation
70 (86%)
50 (63%)
OCS
X (x%)
X (x%)
Antibiotics                           
x (x%)
x (x%)
OCS and antibiotics
X (x%)
    X (x%)
 
 
 
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13.12.24. Example Shell 24
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
Summary of Time from Resolution of Index Exacerbation to Next Exacerbation
                                                                      
                                                               Treatment A       Treatment B
                                                                  (N=100)         (N=100)
        -------------------------------------------------------------------------------------------
          Subsequent exacerbation                             x.xx               x.xx                    
          
          Mean duration (days)                                x.xx               x.xx                      
          SD                                                  x.xx               x.xx
          Median duration (days)                              x.xx               x.xx
          Minimum duration (days)                             x.xx               x.xx
          Maximum duration (days)                             x.xx               x.xx                      
        
        
        
 
 
 
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13.12.25. Example Shell 25
Protocol: ABC123456                                                                             Page 1 of x
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
Summary of ECG Abnormalities for Participants with Any Abnormal Clinically Significant ECG Interpretation
                                                                      
                                                               Treatment A       Treatment B
                                                                 (N=100)         (N=100)
        -------------------------------------------------------------------------------------------
        Visit 2 (Day 1)
         Abnormal – Clinically significant                        10 (10%)       15 (15%)
           Any finding                                             5 (50%)        5 (33%)
           ST depression                                           5 (50%)        5 (33%)
           Short PR Interval                                       0              5 (33%)
           T wave inversion                                        0              5 (33%)
           …….
Includes Scheduled, unscheduled and Early Withdrawal visits.
Participants may have more than one abnormality at each visit. 
 
 
 
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13.12.26. Example Shell 26
Protocol: ABC123456   
Page 1 of n
Population: Intent-to-Treat/Safety/Other study specific
Table X
Statistical Analysis of Change from Baseline in FEV1 (mL) (Dose Response Model)
Measured post-bronchodilator
Placebo
(N=xx)
DNX 5mg
(N=xx)
DNX 10mg
(N=xx)
DNX 25mg
(N=xx)
DNX 35mg
(N=xx)
DNX 50mg
(N=xx)
n [1]
xx
xx
xx
xx
xx
xx
Posterior Adj. Median Change
x.xx
x.xx
x.xx
x.xx
x.xx
x.xx 
95% HPD Credible Interval 
(x.xx,x.xx)
(x.xx,x.xx)
(x.xx,x.xx)
(x.xx,x.xx)
(x.xx,x.xx)
(x.xx,x.xx)
Active - Placebo  
  Posterior Adj. Median 
Difference
x.xx
x.xx
x.xx
x.xx
x.xx
  95% HPD Credible Interval
(x.xx, 
x.xx)
(x.xx, 
x.xx)
(x.xx, 
x.xx)
(x.xx, 
x.xx)
(x.xx, 
x.xx)
  Prob(Difference>0) 
xx%
xx%
xx%
xx%
xx%
  Predictive probability (%) [2] 
[only if required]
xx%
xx%
xx%
xx%
xx%
[1] Number of subjects with data contributing to the analysis.
[2] Predictive posterior probability of success at end of study, where success is Pr(Difference>0)>90%.
Note: Model fitted was a…..[insert as appropriate]. 
 
 
 
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13.12.27. Example Shell 27
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
Summary of QTc(F) (msec) Categories
                                                                  Treatment A      Treatment B
                                                                  (N=100)          (N=100)
            ------------------------------------------------------------------------------------
            Screening                                           
              n                                                    xx               xx   
              <=450                                                xx  (xx%)        xx  (xx%) 
              >450 to <=480                                        xx  (xx%)        xx  (xx%)
              >480 to <=500                                        xx  (xx%)        xx  (xx%)
              >500                                                 xx  (xx%)        xx  (xx%)
            
            Day 1 (Baseline)                                          
              n                                                    xx               xx   
              <=450                                                xx  (xx%)        xx  (xx%) 
              >450 to <=480                                        xx  (xx%)        xx  (xx%)
              >480 to <=500                                        xx  (xx%)        xx  (xx%)
              >500                                                 xx  (xx%)        xx  (xx%)
             Day 14                                          
              n                                                    xx               xx   
              <=450                                                xx  (xx%)        xx  (xx%) 
              >450 to <=480                                        xx  (xx%)        xx  (xx%)
              >480 to <=500                                        xx  (xx%)        xx  (xx%)
              >500                                                 xx  (xx%)        xx  (xx%)
 
 
 
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13.12.28. Example Shell 28
Protocol: ABC123456                                                                             Page 1 of x
Population: Safety
                                                 Table X
                         Summary of Post-Inhalation Cough by Visit and Cough Type
                                                                      
          Visit 2 (Day 1)                             
          Type of cough: Single cough                        Treatment A       
                                                                (N=100)         
        -------------------------------------------------------------------------------------------
         
           Did subject experience event [1]?                           12 (24%)        
           Cough severity              
             Mild                                                    6 (50%)       
             Moderate                                                5 (42%)        
             Severe                                                  1 (8%)             
           Time to onset of PI cough (minutes)                      
             0-1                                                     2(17%)          
             >1-2                                                    3(25%)          
             >2-3                                                    4(33%)          
             >3-4                                                    3(25%)          
             >4-5                                                    0          
             >5                                                      0  
       
           Duration of PI cough (minutes)                      
             <=1                                                     7(58%)          
             >1  - 2                                                 2(17%)          
             >2  - 3                                                 3(25%)          
             >3  - 4                                                 0          
             >4  - 5                                                 0          
             >5  - 10                                                0          
             >10 - 30                                                0          
             >30                                                     0         
[1] Percentages are calculated using the number of subjects evaluated at visit as the denominator.
 
 
 
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All other percentages are calculated using the number of subjects with particular cough type at visit as the 
denominator.
Protocol: ABC123456                                                                             Page 2 of x
Population: Safety
                                                 Table X
                         Summary of Post-Inhalation Cough by Visit and Cough Type
                                                                      
          Visit 2 (Day 1)                                           
          Type of cough: Single cough                        Treatment A            
                                                              (N=100)         
        -------------------------------------------------------------------------------------------
   Number of subjects reporting cough as AE/SAE              4 (33%)  
      Mild                                                   2 (17%)
      Moderate                                               2 (17%)
      Severe                                                 0
 
 
 
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Protocol: ABC123456                                                                             Page 3 of x
Population: Safety
                                                Table X
                           Summary of Post-Inhalation Cough by Visit and Cough Type
                                                                      
          Visit 2 (Day 1)                                           
          Type of cough: Intermittent cough                        Treatment A     
                                                                    (N=100)         
        -------------------------------------------------------------------------------------------
                      
           Did subject experience event [1]?                           11 (22%)        
           Cough severity              
             Mild                                                    2 (18%)       
             Moderate                                                6 (55%)        
             Severe                                                  3 (27%)             
           Time to onset of PI cough (minutes)                      
             0-1                                                     1(9%)          
             >1-2                                                    4(36%)          
             >2-3                                                    6(55%)          
             >3-4                                                    0          
             >4-5                                                    0          
             >5                                                      0    
     
           Duration of PI cough (minutes)                      
             <=1                                                     0          
             >1  - 2                                                 3(27%)          
             >2  - 3                                                 6(55%)          
             >3  - 4                                                 1(9%)          
             >4  - 5                                                 0          
             >5  - 10                                                0          
             >10 - 30                                                1(9%)      
             >30                                                     0         
   
 
 
 
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Protocol: ABC123456                                                                             Page 4 of x
Population: Safety
                                                 Table X
                      Summary of Post-Inhalation Cough by Visit and Cough Type
                                                                      
         Visit 2 (Day 1)                                              
          Type of cough: Intermittent cough                      Treatment A              
                                                                  (N=100)         
        -------------------------------------------------------------------------------------------
   Number of subjects reporting cough as AE/SAE              5 (45%)  
      Mild                                                   1 (9%)
      Moderate                                               2 (18%)
      Severe                                                 2 (18%)
 
 
 
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Protocol: ABC123456                                                                             Page 5 of x
Population: Safety
                                                 Table X
                      Summary of Post-Inhalation Cough by Visit and Cough Type
                                                                      
          Visit 2 (Day 1)                                       
          Type of cough: Continuous cough                      Treatment A                   
                                                                  (N=100)         
        -------------------------------------------------------------------------------------------
                    
           Did subject experience event [1]?                            4 (8%)        
           Cough severity              
             Mild                                                    1 (25%)       
             Moderate                                                2 (50%)        
             Severe                                                  1 (25%)             
           Time to onset of PI cough (minutes)                      
             0-1                                                     3(75%)          
             >1-2                                                    1(25%)          
             >2-3                                                    0          
             >3-4                                                    0          
             >4-5                                                    0          
             >5                                                      0   
      
           Duration of PI cough (minutes)                      
             <=1                                                     0         
             >1  - 2                                                 0          
             >2  - 3                                                 0 
             >3  - 4                                                 1 (25%)                    
             >4  - 5                                                 1 (25%)                   
             >5  - 10                                                0          
             >10 - 30                                                1 (25%)                   
             >30                                                     1 (25%)                   
   
 
 
 
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Protocol: ABC123456                                                                             Page 6 of x
Population: Safety
                                                 Table X
                        Summary of Post-Inhalation Cough by Visit and Cough Type
                                                                      
          Visit 2 (Day 1)                                      
          Type of cough: Continuous cough                      Treatment A                         
                                                                  (N=100)         
        -------------------------------------------------------------------------------------------
   Number of subjects reporting cough as AE/SAE              2 (50%)  
      Mild                                                   1 (25%)
      Moderate                                               1 (25%)
      Severe                                                 0
REPEAT FOR EACH VISIT
 
 
 
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13.12.29. Example Shell 29
Protocol: MID200879                                                                              Page 1 of 1
Population: Intent-to-Treat
                                                Listing X
                           Listing of Subjects who Received Incorrect Medication
                             Start      End                                              Actual
Randomized         Centre/   Date of    Date of    Duration                   Dispense   Treatment
Treatment          Subj      Dosing     Dosing     (Days)   Dispense Visit    Date       Dispensed
------------------------------------------------------------------------------------------------------------
GSK2269557 500 mcg 
   XXXXXXXXX  XXXXXXXXX    XX     Visit 3 (Week 0)  XXFEB2013  GSK2269557 500 mcg
                   
                                                               
                             XXXXXXXXX  XXXXXXXXX    XX     Visit 5 (Week 4)  XXMAR2013  GSK2269557 100 mcg
                             XXXXXXXXX  XXXXXXXXX    XX     Visit 6 (Week 8)  XXAPR2013  GSK2269557 500 mcg
 
 
 
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13.12.30. Example Shell 30
Protocol: ABC123456                                                                             Page 1 of x
Population: Intent-to-Treat/Safety/Other study specific
                                                 
Figure X
Kaplan-Meier Plot of Time to Next On-treatment Exacerbation During the 12-Week Treatment Period
 
 
 
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13.12.31. Example Shell 31
Protocol: ABC123456                                                                             Page 1 of x
Population: Intent-to-Treat/Safety/Other study specific
                                                 
Figure X
Plot of Repeated Measures Model of Change from Baseline in FEV1 Measured Post-bronchodilator
 
 
 
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13.12.32. Example Shell 32
Protocol: XYZ100001                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
                             Summary of Efficiency Ratio for Possible Adaptions to Randomization Ratio 
                                                                  
                                                                  Median      10th Percentile
   -----------------------------------------------------------------------------------------------------
   
     Design 1: Add 25mcg dose                                     xx           xx
     Design 2: Add 25mcg dose, drop 500mcg dose                   xx           xx    
     Design 3: Add 25mcg dose, drop 250 mcg and 500 mcg doses     xx           xx
    Design 4: Drop 12.5mcg dose                                  xx           xx
     Design 5: Drop 12.5mcg and 50mcg doses                       xx           xx
   
 
 
 
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13.12.33. Example Shell 33
Protocol: ABC123456                                                                               Page 1 of x
Population: Safety
                                                 Table X
                                   Summary of Post-Inhalation (PI) Cough at Any Visit
                                                     GSK2269557 GSK2269557 GSK2269557 GSK2269557 GSK2269557
                                          Placebo    50 mcg     100 mcg    250 mcg    500 mcg    750 mcg
                                          (N=43)     (N=14)     (N=15)     (N=16)     (N=14)     (N=42)
----------------------------------------------------------------------------------------------------------
Did subject experience PI cough at any visit?        
  Yes                                     X  (xx%)   X  (xx%)   X  (xx%)   X  (xx%)    X  (xx%)  X  (xx%)
  No                                      X  (xx%)   X  (xx%)   X  (xx%)  X  (xx%)    X  (xx%)  X  (xx%)
Maximum Severity of cough
   Mild                                   X  (xx%)   X  (xx%)   X  (xx%)   X  (xx%)   X  (xx%)    X  (xx%)
   Moderate                               X  (xx%)   X  (xx%)   X  (xx%)   X  (xx)   X  (xx%)    X  (xx%)
   Severe                                 0          0          X  (xx%)   0          0           X  (xx%)
Maximum Duration of PI cough (minutes)[1]
   Mean                                    x         x          x          x          x           x
   SD                                      x         x          x          x          x           x   
   Median                                  x         x          x
        x          x           x
   Minimum                                 x         x          x          x          x           x
   Maximum                                 x         x          x          x          x           x
   
Number of occurrences of PI cough
   0                                       x         x          x          x          x           x
   1                                       x         x          x          x          x           x   
   2                                       x         x          x          x          x           x
   3                                       x         x          x          x          x           x
   4                                       x         x          x          x          x           x
   
[1] Duration from the maximum severity cough
 
 
 
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13.12.34. Example Shell 34
Protocol: ABC123456                                                                               Page 1 of x
Population: Safety
Figure X
Plot of Laboratory Data at Screening
 
 
 
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13.12.35. Example shell 35
Protocol: ABC123456                                                                               Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
                                   Summary of Missing On-treatment EXACT-PRO data
                                                     GSK2269557 GSK2269557 GSK2269557 GSK2269557 GSK2269557
                                          Placebo    50 mcg     100 mcg    250 mcg    500 mcg    750 mcg
                                          (N=300)    (N=100)    (N=100)    (N=100)    (N=100)    (N=300)
----------------------------------------------------------------------------------------------------------
No. subjects missing >4 consecutive days  X (xx%)   X (xx%)   X (xx%)   X (xx%)    X (xx%)    X (xx%)
Number of missing days                
  Mean
X.xx       X.xx  
  X.xx        X.xx       X.xx       X.xx
  Median                 
X.xx       X.xx      X.xx        X.xx       X.xx       X.xx
   Minimum
X.xx       X.xx      X.xx        X.xx       X.xx       X.xx
   Maximum
X.xx       X.xx      X.xx        X.xx       X.xx       X.xx
   
 
 
 
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13.12.36. Example Shell 36
Example EX1
Protocol: XYZ100001                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
Table X
Summary of Exposure to Study Treatment
                          Treatment A
(N=100)
Treatment B
(N=100)
Time on Study Treatment(days)
n
   97
  100
Mean
   15.6
   11.2
SD
   13.23
    9.46
Median
  11.5
    8.0
Min.
    1
    1
Max.
   64
   50
< 28 days
20 (21%)
20 (20%)
28 days to 42 days
50 (52%)
50 (50%)
43 days to 56 days
10 (10%)
10 (10%)
57 days to 70 days
>70 days 
xx (xx%)
Xx (xx%)
xx (xx%)
Xx (xx%)
 
 
 
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CONFIDENTIAL
The GlaxoSmithKline group of companies
200879
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for 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)
Compound Number 
:
GSK2269557
Effective Date 
:
08-MAY-2018
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 200879 and at the planned interim 
analyses.

This RAP is intended to describe the efficacy, safety and pharmacokinetic analyses 
required for the study. 

This version of the RAP includes amendments to the originally approved RAP.

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
 
Statistics Leader, (Respiratory Clinical Statistics)
Approver
Date
Approval Method
08-MAY-2018
Email
TA Director (Respiratory Clinical Statistics)
03-MAY-2018
Email
Programming Manager (Respiratory Clinical 
Programming)
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
 
 
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The GlaxoSmithKline group of companies
200879
2
RAP Team Approvals:
Approver
Date
Approval Method
02-MAY-2018
Email
Principal Programmer (Respiratory Clinical 
Programming)
03-MAY-2018
Email
Clinical Development Director (Respiratory)
01-MAY-2018
Email
Clinical Development Manager (Respiratory)
01-MAY-2018
Email
Medical Director (Global Clinical Safety and 
Pharmacovigilance)
01-MAY-2018
Email
Manager, Clinical Pharmacology (Clinical 
Pharmacology Modelling and Simulation)
03-MAY-2018
Email
Director, Patient Centred Outcomes (Value 
Evidence & Outcomes)
 
 
 
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CONFIDENTIAL
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3
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................8
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................8
2.1.
Study Objective(s) and Endpoint(s)...............................................................8
2.2.
Study Design ..............................................................................................11
3.
PLANNED ANALYSES ..........................................................................................11
3.1.
Interim Analyses .........................................................................................11
3.1.1.
Futility analyses ...........................................................................13
3.1.1.1.
Futility rules ................................................................13
3.2.
Final Analyses ............................................................................................14
4.
ANALYSIS POPULATIONS ...................................................................................15
4.1.
Protocol Deviations.....................................................................................15
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................16
5.1.
Study Treatment & Sub-group Display Descriptors.....................................16
5.2.
Baseline Definitions ....................................................................................16
5.3.
Multicentre Studies .....................................................................................17
5.4.
Examination of Covariates and Subgroups .................................................17
5.4.1.
Covariates ...................................................................................17
5.4.2.
Examination of Subgroups...........................................................18
5.5.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................19
6.
STUDY POPULATION ANALYSES .......................................................................19
6.1.
Overview of Planned Study Population Analyses........................................19
6.1.1.
Concomitant medications.............................................................19
7.
EFFICACY ANALYSES..........................................................................................20
7.1.
Primary Efficacy Analyses ..........................................................................20
7.1.1.
Primary Endpoint .........................................................................20
7.1.2.
Primary Statistical Analyses.........................................................20
7.1.2.1.
Model Checking & Diagnostics ...................................22
7.1.3.
Sensitivity and Supportive Analyses ............................................23
7.1.4.
Subgroup Analyses......................................................................23
7.2.
Secondary Efficacy Analyses......................................................................23
7.2.1.
Rate of exacerbations..................................................................23
7.2.1.1.
Statistical analyses.....................................................24
7.2.1.2.
Subgroup analyses.....................................................25
7.2.1.3.
Exploratory analyses ..................................................25
7.2.2.
Time to next exacerbation............................................................25
7.2.2.1.
Statistical analyses.....................................................26
7.2.2.2.
Subgroup analyses.....................................................26
7.2.3.
Change from baseline in Clinic Visit trough FEV1.........................26
7.2.3.1.
Statistical Analyses.....................................................26
7.2.3.2.
Subgroup analyses.....................................................27
7.2.4.
Change from hospital discharge in clinic visit trough FEV1...........27
 
 
 
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7.2.4.1.
Statistical analyses.....................................................27
7.2.5.
EXAcerbations of Chronic Pulmonary Disease Tool -
Patient Reported Outcome (EXACT) ...........................................27
7.2.5.1.
Proportion of participants achieving EXACT-
defined recovery from index exacerbation ..................28
7.2.5.2.
Time to EXACT-defined recovery from index 
exacerbation...............................................................29
7.2.5.3.
Severity of subsequent HCRU-defined 
exacerbation(s) defined by EXACT.............................29
7.2.5.4.
Statistical analyses.....................................................29
7.2.5.5.
Subgroup analyses.....................................................30
7.2.5.6.
Sensitivity and supportive analyses............................30
7.2.6.
COPD Assessment Test (CAT)....................................................30
7.2.6.1.
Proportion of responders using the CAT.....................30
7.2.6.2.
Change from baseline in CAT Total Score..................30
7.2.6.3.
Statistical analyses.....................................................31
7.2.6.4.
Subgroup analyses.....................................................31
7.2.7.
St. George’s Respiratory Questionnaire for COPD 
Patients (SGRQ-C)......................................................................32
7.2.7.1.
Proportion of responders on the SGRQ Total 
Score..........................................................................32
7.2.7.2.
Change from baseline in SGRQ Total Score ..............32
7.2.7.3.
Statistical analyses.....................................................33
7.2.7.4.
Subgroup analyses.....................................................33
7.2.8.
Rescue medication use................................................................33
7.2.8.1.
Rescue medication use via the clip-on 
Propeller Sensor for MDI ............................................34
7.2.8.2.
Statistical analyses.....................................................34
7.3.
Exploratory Efficacy Analyses.....................................................................35
7.3.1.
Change from Day 84 in Clinic Visit trough FEV1...........................35
7.3.1.1.
Statistical analysis ......................................................35
7.3.2.
E-RS:COPD (Evaluating Respiratory Symptoms in COPD) .........35
7.3.3.
Measures of HCRU related to exacerbations...............................35
7.3.3.1.
Re-hospitalisation within 30 days of index 
exacerbation...............................................................36
7.3.3.2.
Time from resolution of index exacerbation to 
next exacerbation .......................................................36
7.3.3.3.
Subsequent exacerbation treatment type ...................36
7.3.4.
Compliance..................................................................................36
7.3.4.1.
Number of actuations of double-blind study 
treatment measured by the clip-on Propeller 
Sensor........................................................................37
7.3.5.
Inflammatory/infective markers in blood and sputum in 
relation to acute exacerbation of COPD.......................................37
7.3.6.
Other spirometry measurements..................................................37
7.3.7.
Other symptoms suggestive of exacerbation ...............................37
7.3.8.
Classification of exacerbating COPD participants and 
prediction of response to nemiralisib using machine 
learning techniques......................................................................37
8.
SAFETY ANALYSES .............................................................................................37
8.1.
Adverse Events Analyses ...........................................................................38
 
 
 
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8.1.1.
Adverse Events of Special Interest ..............................................38
8.1.1.1.
Post-inhalation Cough Immediately Following 
Dosing........................................................................38
8.2.
Clinical Laboratory Analyses.......................................................................38
8.3.
Other Safety Analyses ................................................................................38
8.4.
Mortality......................................................................................................38
9.
PHARMACOKINETIC ANALYSES.........................................................................38
9.1.
Population of Interest..................................................................................38
9.2.
Drug Concentration Measures ....................................................................39
10. POPULATION PK ANALYSIS ................................................................................39
10.1.
Derived Pharmacokinetic Parameters.........................................................39
11. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES .................................39
12. REFERENCES.......................................................................................................40
13. APPENDICES........................................................................................................41
13.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................41
13.1.1.
Exclusions from Per Protocol Population .....................................41
13.2.
Appendix 2: Assessment Windows .............................................................42
13.2.1.
Definitions of Assessment Windows for Analyses........................42
13.2.1.1.
Hospital discharge......................................................42
13.2.1.2.
EXACT-Defined Recovery for CAT Trigger.................42
13.3.
Appendix 3: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................43
13.3.1.
Study Periods ..............................................................................43
13.3.1.1.
12-Week Treatment Period.........................................43
13.3.1.2.
12-Week Follow-Up Period.........................................43
13.3.2.
Study Phases ..............................................................................43
13.3.2.1.
Study Phases for Concomitant Medication .................43
13.3.3.
Treatment Emergent Flag for Adverse Events .............................43
13.4.
Appendix 4: Data Display Standards & Handling Conventions....................44
13.4.1.
Reporting Process .......................................................................44
13.4.2.
Reporting Standards....................................................................44
13.4.3.
Reporting Standards for Pharmacokinetic....................................45
13.5.
Appendix 5: Derived and Transformed Data ...............................................46
13.5.1.
General........................................................................................46
13.5.2.
Study Population..........................................................................46
13.5.3.
Safety ..........................................................................................46
13.6.
Appendix 6: Reporting Standards for Missing Data.....................................47
13.6.1.
Premature Withdrawals................................................................47
13.6.2.
Handling of Missing Data.............................................................47
13.6.2.1.
Handling of Missing and Partial Dates ........................47
13.7.
Appendix 7: Values of Potential Clinical Importance ...................................49
13.7.1.
Laboratory Values........................................................................49
13.7.2.
ECG.............................................................................................50
13.7.3.
Vital Signs....................................................................................50
13.8.
Appendix 8: Population Pharmacokinetic (PopPK) Analyses ......................51
13.8.1.
Population Pharmacokinetic (PopPK) Methodology.....................51
 
 
 
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13.8.2.
Population Pharmacokinetic (PopPK) Dataset 
Specification ................................................................................51
13.9.
Appendix 9: Pharmacokinetic / Pharmacodynamic Analyses ......................53
13.9.1.
Pharmacokinetic/Pharmacodynamic Methodology.......................53
13.10. Appendix 10: Abbreviations & Trade Marks ................................................54
13.10.1. Abbreviations...............................................................................54
13.10.2. Trademarks .................................................................................55
13.11. Appendix 11: List of Data Displays..............................................................56
13.11.1. Data Display Numbering..............................................................56
13.11.2. Mock Example Shell Referencing ................................................56
13.11.3. Deliverables.................................................................................56
13.11.4. Study Population Tables..............................................................57
13.11.5. Efficacy Tables ............................................................................59
13.11.5.1. Efficacy tables for Interim Analysis 1 ..........................59
13.11.5.2. Efficacy tables for Interim Analysis 2 ..........................62
13.11.5.3. Efficacy tables for End of Treatment Interim 
Analysis and SAC.......................................................65
13.11.6. Efficacy Figures ...........................................................................76
13.11.6.1. Efficacy Figures for Interim Analysis 1........................76
13.11.6.2. Efficacy Figures for Interim Analysis 2........................77
13.11.6.3. Efficacy Figures for End of Treatment Interim 
Analysis and SAC.......................................................79
13.11.7. Safety Tables...............................................................................81
13.11.8. Safety Figures .............................................................................85
13.11.9. Pharmacokinetic Tables...............................................................85
13.11.10.ICH Listings .................................................................................86
13.11.11.Non-ICH Listings..........................................................................88
13.12. Appendix 12: Example Mock Shells for Data Displays ................................89
13.12.1. Example shell 1 ...........................................................................89
13.12.2. Example Shell 2...........................................................................90
13.12.3. Example shell 3 ...........................................................................91
13.12.4. Example Shell 4...........................................................................92
13.12.5. Example Shell 5...........................................................................94
13.12.6. Example Shell 6...........................................................................95
13.12.7. Example Shell 7...........................................................................96
13.12.8. Example Shell 8...........................................................................97
13.12.9. Example Shell 9...........................................................................98
13.12.10.Example Shell 10.........................................................................99
13.12.11.Example Shell 11.......................................................................100
13.12.12.Example Shell 12.......................................................................101
13.12.13.Example shell 13 .......................................................................104
13.12.14.Example Shell 14.......................................................................105
13.12.15.Example Shell 15.......................................................................106
13.12.16.Example shell 16 .......................................................................107
13.12.17.Example Shell 17.......................................................................108
13.12.18.Example shell 18 .......................................................................110
13.12.19.Example Shell 19.......................................................................111
13.12.20.Example Shell 20.......................................................................114
13.12.21.Example Shell 21.......................................................................115
13.12.22.Example Shell 22.......................................................................116
13.12.23.Example Shell 23.......................................................................117
13.12.24.Example Shell 24.......................................................................118
 
 
 
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13.12.25.Example Shell 25.......................................................................119
13.12.26.Example Shell 26.......................................................................120
13.12.27.Example Shell 27.......................................................................121
13.12.28.Example Shell 28.......................................................................122
13.12.29.Example Shell 29.......................................................................128
13.12.30.Example Shell 30.......................................................................129
13.12.31.Example Shell 31.......................................................................130
13.12.32.Example Shell 32.......................................................................131
13.12.33.Example Shell 33.......................................................................132
 
 
 
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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol 200879.
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To characterise 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
Secondary Objectives
Secondary Endpoints

To characterise 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 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)

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
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 
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Objectives
Endpoints
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

To evaluate the usage of rescue 
medication in patients diagnosed with 
an acute moderate or severe 
exacerbation of COPD

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

To evaluate the population 
pharmacokinetics of nemiralisib in 
participants diagnosed with an acute 
moderate or severe exacerbation of 
COPD

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

To assess the safety and tolerability of 
nemiralisib and placebo in participants 
diagnosed with an acute moderate or 
severe exacerbation of COPD

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 Objectives
Exploratory Endpoints

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 and severe 
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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

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)

To explore the PK/PD relationship for 
nemiralisib

Relationship between drug exposure and 
Pharmacodynamic responses (e.g. efficacy, heart rate, 
clinical laboratory analytes and blood biomarkers) in the 
PK subset of participants (approximately 300) at selected 
sites

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

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.)

To evaluate compliance with study 
treatment

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)

To evaluate inflammatory markers in 
blood in relation to acute exacerbation 
of COPD

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)

To evaluate inflammatory and 
infective markers in sputum in relation 
to acute exacerbation of COPD

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

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 postbronchodilator 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 
 
 
 
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Objectives
Endpoints
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
2.2.
Study Design
This is a Phase IIb, multicenter, randomized, stratified (by index COPD exacerbation
severity [moderate or severe] and by whether or not the participant is in the PK
Subgroup), double-blind (Sponsor Open), placebo-controlled, parallel-group study in
participants who present with an acute moderate or severe exacerbation of COPD
requiring Standard of Care (SoC).
This study consists of a Screening Period, a 12-Week Treatment Period and a 12-Week
Post-Treatment Follow-Up Period. 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 
measures, including the EXACT-PRO questionnaire for the day of randomization, and 
FEV1 measurement and no later than 48 hours after the start of SoC.
PK Subgroup: Sparse PK sampling will be conducted in a subgroup of participants 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.
3.
PLANNED ANALYSES
3.1.
Interim Analyses
Ongoing data reviews of unblinded safety data, conducted by an Internal Safety Review 
Committee (iSRC), will be performed throughout the trial. Details will be documented in 
the iSRC charter.  
Interim analyses of the primary endpoint and key secondary endpoints to inform internal 
decision making will be conducted periodically throughout the trial. The first analysis 
(Interim Analysis 1) is planned to occur when approximately 170 participants complete 
28 days of treatment, where approximately 50 of the 170 participants have an index 
exacerbation defined as severe. A change that could arise from this interim analysis is a 
specification of the stratification proportions by index exacerbation severity status 
(moderate or severe). This decision will be based on inspection of all available endpoints 
at the interim analysis. 
Further interim analyses will be performed, depending on the observed recruitment rate. 
At least one interim analysis of the primary endpoint of change from baseline in clinic 
visit trough FEV1 at Day 84 measured post-bronchodilator will be performed to 
determine whether or not any adjustments to the randomization ratio across doses would 
help optimize the characterization of the dose response profile for nemiralisib. This 
analysis (Interim Analysis 2) is planned to occur when approximately 300 participants 
 
 
 
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complete 84 days of treatment or when approximately 400 participants remain to be 
randomized, whichever occurs first. Adjustments could include ceasing randomization to 
an existing dose(s) of nemiralisib and/or modification of the allocation ratios for the 
existing nemiralisib doses and/or addition of a 25mcg dose. Other changes may include 
specification of the stratification proportions by index exacerbation severity status. 
An interim analysis of efficacy data collected during the Double-Blind Treatment Period 
will be conducted when the last participant in the study has completed the 12-week 
Double-Blind Treatment Period (End of Treatment Interim Analysis). The aim of this 
analysis is to provide GSK with timely data to inform internal decision making, prior to 
the end of study. 
The following table describes the endpoints that will be analysed/summarised at each 
interim:
Interim
Purpose of interim
Endpoints
Interim Analysis 1
To inform internal decision making 

Change from baseline in FEV1 at Days 
14, 28, and 56 measured pre- and 
post-bronchodilator

Other spirometry measures (percent 
predicted FEV1, Forced Vital Capacity 
(FVC), percent predicted FVC and 
FEV/FVC ratio

On-treatment exacerbations

Proportion of participants achieving 
EXACT-defined recovery by Days 14, 
28, 56 and 84
Interim Analysis 2
To determine if any adjustments to the 
randomization ratio would help 
characterize the dose response profile 
for nemiralisib
Endpoints listed for Interim Analysis 1 and 
also:

Change from baseline in FEV1 at Day 
84 measured pre- and post-
bronchodilator

Rate of (on-treatment) exacerbations 
over the 12-Week Treatment Period

Time to next (on-treatment) 
exacerbation during the 12-Week 
Treatment Period

Proportion of responders using the 
CAT

Change from baseline in CAT Total 
Score

Proportion of responders using the
SGRQ

Change from baseline in SGRQ Total 
Score

Rescue medication use, as measured 
in eDiary
End of Treatment 
Interim Analysis
To inform internal decision making
Selected Efficacy and Safety endpoints as 
defined in Appendix 11: List of Data 
Displays
The statistical methods of analyses are described in Section 7.
 
 
 
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The Respiratory Data Sciences Group will apply machine learning techniques to the 
interim data to determine if identifiable phenotypic sub-population(s) of COPD 
participants are present at baseline, and if they result in different responses to 
Nemiralisib, to predict which participants will respond to Nemiralisib therapy, and to 
identify/quantify relationship(s) between different endpoints and response measures.
Details of these analyses will be described in a separate RAP and results will be reported 
separately to the Clinical Study Report (CSR). 
The following functions will be unblinded to interim analysis data: Clinical Statistics, 
Clinical Programming and Respiratory Data Sciences Group. Other member of GSK will 
be unblinded to group level summary data following the interim analyses (as documented 
internally). 
3.1.1.
Futility analyses
At least one interim analysis for futility will be performed. The first analysis will occur at 
Interim Analysis 2, i.e. when 300 participants complete 84 days of treatment, or when 
approximately 400 participants remain to be randomized, whichever occurs first. 
Futility will be assessed in a sequential manner. 
1) Futility will first be assessed for the primary endpoint of change from baseline in 
FEV1 at Day 84 by fitting a suitable dose response model, as described in Section 
7.1.2. 
2) If the posterior predictive probability of declaring success for this endpoint is low
across all doses, then futility will be assessed for the rate of (on-treatment) 
exacerbations endpoint.
3) If the posterior predictive probability of declaring success for this endpoint is low, 
then the study may be stopped.
Any decision to stop will be made after a review of all the data summarised/analysed at 
the time of the interim, including the proportion of participants achieving the EXACT-
defined recovery.
3.1.1.1.
Futility rules
The decision rules for futility are defined as follows.
Change from baseline in FEV1 at Day 84
Stop study for futility if the predictive probability of success at the end of the trial, given 
the data at the interim is <20%, across all doses, where success at the end of the trial for 
change from baseline in FEV1 is defined as demonstrating >90% posterior probability 
that the true difference from placebo for any dose of nemiralisib is greater than 0.
 
 
 
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Rate of on-treatment (moderate/severe) exacerbations
Stop study for futility if the predictive probability of success at the end of the trial, given 
the data at the interim is <20%, where success at the end of the trial for rate of 
exacerbations is defined as demonstrating >80% posterior probability that the true rate 
reduction on 750 mcg dose versus placebo > 0%.
If a different dose arm appears to be more efficacious than the 750 mcg arm, then futility 
may be assessed using the rate reduction for this arm versus placebo. 
The pre-determined rules will act as guidelines for stopping the study for futility. All of 
the data summarised/analysed at the time of the interim will be reviewed prior to any 
decision to stop the study. 
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All participants have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management.
3.
All criteria for unblinding the randomization codes have been met. 
4.
Randomization codes have been distributed according to RandAll NG procedures.
 
 
 
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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Participants 
Enrolled (APE) 
Population

All participants who are screened for eligibility.

Study Population
Modified Intent 
To treat (MITT) 
Population

All randomized participants who receive at least one 
dose of study treatment. 

Participants will be analyzed according to the treatment 
that they were randomized to.

Study Population

Efficacy
Per Protocol (PP) 
Population

All randomized participants who receive at least one 
dose of study treatment, excluding any participants with 
an important protocol deviation.

Participants will be analyzed according to the treatment 
that they were randomized to.

Sensitivity
analyses of 
efficacy
Safety Population

All randomized participants who received at least one 
dose of study treatment.

Participants will be summarised according to the 
treatment that they actually received.
o If participants receive >1 treatment, then they will 
be summarised according to the most frequently 
dosed treatment. In cases where the frequency is 
equal, the participant will be assigned the lowest 
dose strength of nemiralisib

Safety
Pharmacokinetic
(PK) Population

All participants in the Safety population who had at least 
1 non-missing PK assessment (Non-quantifiable [NQ] 
values will be considered as non-missing values).

Participants will be summarised according to the 
treatment that they actually received

PK
Refer to Appendix 11: List of Data Displays which details the population used for each display.
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
Important deviations which result in exclusion from the analysis population will also be 
summarised and listed. (Please refer to Appendix 1: Protocol Deviation Management and 
Definitions for Per Protocol Population).
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan.
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations and deviations which may lead to exclusion from the 
analysis are captured and categorised on the protocol deviations dataset. 
o This dataset will be the basis for the summaries and listings of protocol 
deviations.
 
 
 
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A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF.
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG Randomization System
Data Displays for Reporting 
Code
Description
Description
Order in TLF 
A
Placebo
Placebo
1
B
GSK2269557 12.5 mcg
NEMI 12.5 mcg
2
C
GSK2269557 25 mcg*
NEMI 25 mcg
3
D
GSK2269557 50 mcg
NEMI 50 mcg
4
E
GSK2269557 100 mcg
NEMI 100 mcg
5
F
GSK2269557 250 mcg
NEMI 250 mcg
6
G
GSK2269557 500 mcg
NEMI 500 mcg
7
H
GSK2269557 750 mcg
NEMI 750 mcg
8
* The nemiralisib dose of 25 mcg may be added following the results of an un-blinded interim analysis if 
further characterization of the lower end of the dose response curve is required.
Treatment comparisons will be displayed as follows using the descriptors as specified:
1.
NEMI 12.5 mcg vs Placebo
2.
NEMI 25 mcg vs Placebo
3.
NEMI 50 mcg vs Placebo
4.
NEMI 100 mcg vs Placebo
5.
NEMI 250 mcg vs Placebo
6.
NEMI 500 mcg vs Placebo
7.
NEMI 750 mcg vs Placebo
5.2.
Baseline Definitions
For all endpoints, the baseline value will be the latest pre-dose assessment with a non-
missing value, including those from unscheduled visits. If time is not collected, Day 1 
assessments are assumed to be taken prior to first dose and used as baseline.
Post-bronchodilator Baseline FEV1 is defined as the latest FEV1 measured prior to the 
first dose of study treatment and post-bronchodilator.
 
 
 
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Pre-bronchodilator Baseline FEV1 is defined as the latest FEV1 measured prior to the first 
dose of study treatment and pre-bronchodilator.
Baseline CAT Total Score is defined as CAT Total Score measured prior to the first dose 
of study treatment on Day 1.
Baseline SGRQ Total Score is defined as SGRQ Total Score measured prior to the first 
dose of study treatment on Day 1.
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing.  
A centred baseline will be derived for each participant by subtracting the mean baseline 
across all participants from each participant’s baseline value. The ‘centred’ baseline may 
be used instead of Baseline in the statistical analyses to aid convergence.
5.3.
Multicentre Studies
In this multicentre global study, enrolment will be presented by investigative site and
country.
5.4.
Examination of Covariates and Subgroups
5.4.1.
Covariates
The list of covariates may be used in descriptive summaries and statistical analyses, some 
of which may also be used for subgroup analyses. Additional covariates of clinical 
interest may also be considered. The decision to include covariates in the model will be 
based on their impact on the model fit and will be detailed in the CSR.
A centred covariate will be derived for each participant by subtracting the mean covariate 
across all participants from each participant’s covariate value. The ‘centred’ covariate 
may be used in place of the covariate in the statistical analyses to aid convergence.
 
 
 
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Covariate
Details
Index exacerbation severity
Categorical variable (Moderate or Severe) derived using the 
stratification variable from the randomisation system.
Age (at screening)
Continuous variable derived as described in Section 13.6.2.1
BMI
Continuous variable derived using Height and Weight variables 
collected in eCRF:
BMI = Weight (kg) / (Height (m))2
Gender
Categorical variable (Male or Female), collected in eCRF
Country
Categorical variable
Smoking status
Categorical variable (Current or Former), collected in eCRF
Baseline COPD maintenance 
therapy type
Categorical variable derived depending on data observed. Possible 
categories of interest are: Monotherapy vs. Dual therapy vs. Triple
therapy
Index exacerbation type
Categorical variable: New or Relapse, derived using the question: 
“Other than the current prescription, for the index exacerbation, has 
the subject received oral/systemic corticosteroids and/or antibiotics 
for a COPD exacerbation within the last 7 days?” in the eCRF:
New = No
Relapse = Yes
Number of exacerbations in the 
previous 12 months
Categorical variable derived from “Total number of COPD 
exacerbations in the last 12 months” in the eCRF. Possible 
categories of interest are: 0 vs. 1 vs. ≥2
5.4.2.
Examination of Subgroups
The list of subgroups may be used in descriptive summaries and statistical analyses.
Additional subgroups of clinical interest may also be considered.

If the percentage of subjects is small within a particular subgroup, then the subgroup 
categories may be refined.

If the category cannot be refined further, then descriptive rather than statistical 
comparisons may be performed for the particular subgroup.
Subgroup
Categories 
Index exacerbation severity
Moderate vs. Severe  
Baseline COPD maintenance therapy type
Possible categories of interest are: Monotherapy vs. Dual 
therapy vs. Triple therapy
Index exacerbation type
New vs. Relapse
Number of exacerbations in the previous 12 
months
Possible categories of interest are: 0 vs. 1 vs. ≥2
Gender
Male vs. Female
Smoking status
Current vs. Former
 
 
 
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5.5.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
Section 13.2
Appendix 2: Assessment Windows
Section 13.3
Appendix 3: Study Phases and Treatment Emergent Adverse Events
Section 13.4
Appendix 4: Data Display Standards & Handling Conventions
Section 13.5
Appendix 5: Derived and Transformed Data
Section 13.6
Appendix 6: Reporting Standards for Missing Data
Section 13.7
Appendix 7: Values of Potential Clinical Importance
6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the “APE” and/or “MITT” populations, 
unless otherwise specified.
Study population analyses including analyses of participant’s disposition, protocol 
deviations, demographic and baseline characteristics, and exposure and treatment 
compliance will be based on GSK Core Data Standards.  Details of the planned displays
are presented in Appendix 11: List of Data Displays.
6.1.1.
Concomitant medications
Concomitant medications will be summarised by treatment group. Separate summaries of
Baseline and On-treatment (Step-up) COPD Maintenance Therapy, and duration of OCS 
use will also be presented. 
Additional summaries or sensitivity analyses of on-treatment COPD maintenance therapy
(step-up therapy) may be performed if the data indicate that further investigation is 
warranted.
 
 
 
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7.
EFFICACY ANALYSES
Details of the outputs are provided in Appendix 11: List of Data Displays and will be
based on GSK data standards and statistical principles.
Further details for use in the endpoint derivations below can be found in Appendix 5: 
Derived and Transformed Data. 
7.1.
Primary Efficacy Analyses
7.1.1.
Primary Endpoint
The primary endpoint of change from baseline in clinic visit trough FEV1 at Day 84 
measured post-bronchodilator is defined as:
FEV1 measured prior to dosing and post-bronchodilator on Day 84 – Post-bronchodilator 
Baseline FEV1
7.1.2.
Primary Statistical Analyses
The primary endpoint will be analysed by fitting a suitable dose response model. The 
following models will be fitted, and the one that gives the best fit to the data will be 
selected: Bayesian 4-parameter Emax dose response model, 3-parameter Emax model and 
a Log-linear model.
The 4-parameter Emax dose response model will take the form:
Change from baseline FEV1 =



Dose
ED
Dose
baseline
b
E
baseline
a
E




50
*
)
*
(
)
*
0
(
1
max
1
The 3-parameter Emax dose response model will take the form:
Change from baseline FEV1 =
Dose
ED
Dose
baseline
b
E
baseline
a
E




50
*
)
*
(
)
*
0
(
1
max
1
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
a1, b1, are covariates for explanatory parameters
Initially, normal non-informative priors will be used for the E0, a1, a2, and Emax
parameters with mean 0 and standard deviation 1E6 L. A functional uniform prior will be 
used for the ED50 and slope parameters (Bornkamp, 2014), where the prior density for 
the functional uniform prior is based on all the parameters in the model. An inverse -
 
 
 
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gamma prior with shape of 0.001 and scale of 0.001 will be used for the residual 
variance. However, if a prior distribution appears not to be truly non-informative then 
alternative prior distributions may be used.
Parameters will be blocked such that the MCMC procedure samples from E0, a1, b1, and 
Emax, first, then the ED50 and slope parameters and then finally the residual variance 
parameter. For the functional uniform priors, the density will be calculated for values of 
dose from 0.0001 to 750 in steps of 50 (i.e. 0.0001, 50.0001, 100.0001,…, 750.0001). For 
the continuous covariates, the density will be calculated from the minimum to the 
maximum in 10 equal steps.  For binary covariates the density will be calculated for 
values 0 and 1.  If the model does not converge including covariates, the model may be 
fitted with covariates removed. 
If the log-linear model is fitted an offset of 1 will be used. 
The posterior median change from baseline with 95% Highest Posterior Density (HPD) 
Credible Intervals, will be presented for each dose along with the adjusted median 
difference from placebo with 95% HPD, calculated at the mean baseline value across the 
treatment arms. Posterior probabilities that the true improvement is greater than 0 mL and 
75 mL will also be presented. 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. 
For the futility analysis: 
The predictive probability of success at the end of the study will be calculated (assuming 
the randomisation ratios remain the same after the interim) for each dose using the 
formula suggested by Spiegelhalter et al., 2004 as follows:
Where n1 is the number of subjects with Day 84 data in the active arm of interest, m1 is 
the number of subjects yet to be observed in the active arm of interest, yn is the posterior 
mean difference from placebo from the fitted model, and σ is the standard deviation of 
the posterior mean difference from placebo.
For the possible adaptations at Interim Analysis 2:
If the study is not deemed futile, and either the 4 parameter or 3 parameter Emax dose 
response curves has successfully been fitted to the data then adaptation of the 
randomisation schedule will be considered, to drop, add or amend doses from the 
randomisation scheme. 
The adaptation will be done by comparing the relative information from alternative 
randomisation schemes with the original randomisation schemes, such to find the design 
that provides the most information about the dose response relationship.  The efficiency 
ratio (ER) for an alternative scheme comparted to the original, will be calculated as:
 
 
 
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, i=1,…,1000
Where 
is the information matrix for the design and model parameters = (e0, 
emax, ed50, , a1, b1)T,
is the alternative design one and 
is the fixed original design, 
and p is the number of parameters (Dette et al 2008).  In order to ensure any adaptation is 
robust to the variability in the parameter estimates at the interim analysis, 1000 samples 
will be generated from the posterior distribution of the parameters 
and the 
ER calculated for each set of parameter.  Adaptation will then only take place if the 
median ER is >1.05 and the 10th percentile of the ER is >1. The efficiency ratio will be 
estimated using the mean baseline value across the population. 
The alternative designs that will be considered will depend on the dose response model 
fitted but could include:
1. Add 25mcg dose
2. Add 25mcg dose, drop 500mcg dose
3. Add 25mcg dose, drop 250 mcg and 500 mcg doses
4. Drop 12.5mcg dose
5. Drop 12.5 mcg and 50mcg doses
The potential adaption may also be verified in the moderate and severe subgroups to 
ensure the adaption is beneficial across both groups. 
7.1.2.1.
Model Checking & Diagnostics
The following list of convergence diagnostics will be applied for each parameter: 

The Monte Carlo Standard Errors (MCSE) should be compared with the standard 
deviation of the posterior distribution (SD) to ensure that only a fraction of the 
posterior variability is due to the simulation. The number of samples generated 
and/or the thinning may be increased to reduce the ratio of the MCSE/SD as 
deemed necessary.

The Geweke diagnostic test will be used to assess whether the mean estimates 
have converged by comparing means from the early and latter part of the Markov 
chain using a z-score t-test. Large absolute values of the z-score statistic indicate 
rejection of the null hypothesis of no difference between the mean estimates 
obtained from the early and latter parts of the chain.

Trace plots of samples versus the simulation index will be visually inspected to 
assess some aspects of convergence. The centre of the chain should appear stable 
with very small fluctuations, i.e., the distribution of points should not change as 
the chain progresses and the posterior mean and variance are relatively constant.

Autocorrelation plots will be visually inspected to assess degree of autocorrelation 
(should decline rapidly and show no oscillation patterns).
 
 
 
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7.1.3.
Sensitivity and Supportive Analyses
If there are greater than 20% of participants with an important protocol deviation that 
results in exclusion from the Per Protocol Population, the primary analysis may be 
repeated using the Per Protocol Population. 
Change from baseline in clinic visit trough FEV1 at Day 84 will also be compared 
between treatment groups using a Bayesian Repeated Measures analysis with covariates 
for baseline-by-Day interaction and treatment-by-Day interaction. Day will be fitted as a 
repeated effect within each participant. All post-baseline scheduled visits will be included 
in the analysis using Day. Non-informative priors will be used for all modelling 
parameters. Wherever possible conjugate priors will be utilised. An unstructured 
covariance matrix will be used to model the within-subject error.
A further sensitivity analysis may be performed where Baseline FEV1 is replaced with 
the FEV1 measured post-bronchodilator and prior to dosing on day of hospital discharge 
for participants who were hospitalised for their index exacerbation, i.e. who were 
randomized with a Severe index exacerbation but kept as Baseline FEV1 for participants 
who were randomized with a Moderate index exacerbation.
7.1.4.
Subgroup Analyses
A subgroup analysis of change from baseline in clinic visit trough FEV1 by index 
exacerbation severity will be performed by fitting separate models to each level of the 
severity subgroup. 
A subgroup analysis of change from baseline in clinic visit trough FEV1 by index 
exacerbation severity will also be performed by including a treatment-by-severity-by-Day
interaction term in the Bayesian Repeated Measures model. 
7.2.
Secondary Efficacy Analyses
7.2.1.
Rate of exacerbations
Rate of exacerbation is defined as the frequency of exacerbations (subsequent to the 
index exacerbation) within the specified time period, for example, the 12-Week 
Treatment Period or the 24-Week Study Period.
The length of time on treatment or in study, depending on the specified time-period, for 
each participant will be calculated for each endpoint as follows:
Endpoint
Time period
Length of time derivation
Rate of (on-treatment) 
exacerbations, summarised by:

Moderate/severe 
exacerbations

Moderate exacerbations

Severe exacerbations

All (mild, moderate and 
12-Week Treatment Period
Time from date of randomisation 
to date of last dose of study 
treatment 
 
 
 
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Endpoint
Time period
Length of time derivation
severe) exacerbations
Rate of (on-or off-treatment) 
exacerbations, summarised by:

Moderate/severe 
exacerbations

All exacerbations
12-Week Treatment Period
Time from date of randomisation 
to Day 84 (Visit 6) Visit Date. 
For participants who withdraw 
early from the study: Time from
date of randomisation to date of 
study withdrawal
Rate of (off-treatment) 
exacerbations, summarised by:

Moderate/severe 
exacerbations

Moderate exacerbations

Severe exacerbations
12-Week Follow Up Period
Time from date of last dose of 
study treatment to date of study 
withdrawal/completion
Rate of (on- and off- treatment)
exacerbations, summarised by:

Moderate/severe 
exacerbations

Moderate exacerbations

Severe exacerbations
Full 24-Week Study Period
Time from date of randomisation 
to date of study 
withdrawal/completion
Refer to Section 13.5 for further details regarding the length of time derivation
7.2.1.1.
Statistical analyses
The rate of exacerbations will be analysed using a Bayesian generalized linear model 
assuming a negative binomial distribution for the underlying exacerbation rate with a log 
link function. An offset to account for the length of time on treatment or in study, 
depending on the specified time-period, for each participant (as described above) will be 
included in the model as loge (length of time). 
Non-informative priors will be used for all modelling parameters. Wherever possible 
conjugate priors will be utilised.
The median exacerbation rates for each dose arm per 12 weeks, along with the median 
ratio in exacerbation rates (nemiralisib/placebo) per 12 weeks for each dose, will be 
estimated and corresponding 95% HPD credible intervals presented. The probability that 
the true exacerbation rate ratio is less than 1, in addition to other values appropriately 
selected based on the data, will be presented.
Based on pharmacological predictions, the 500 mcg and 750 mcg doses are expected to 
result in similar levels of target inhibition and thus potentially translate to similar clinical 
benefit, therefore estimates of the exacerbation rates for pooled data from 500 mcg plus 
750 mcg will also be presented.
 
 
 
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7.2.1.2.
Subgroup analyses
A subgroup analysis of exacerbation rate by Index exacerbation severity will be 
performed by including a treatment-by-severity term in the model.
7.2.1.3.
Exploratory analyses
A summary of exacerbation rate by the following groups will be presented and, if 
feasible, a subgroup analyses may be performed:

Index exacerbation type (New or Relapse)

Number of exacerbations in previous 12 months (0, 1 or ≥2). 
7.2.2.
Time to next exacerbation
Time to next (on-treatment) exacerbation following index exacerbation during the 12-
Week Treatment Period is defined as time from the date of randomisation until the date 
of onset of the first exacerbation whilst on study treatment. Participants who did not have 
an exacerbation whilst on study treatment will be censored at the date of their last dose of 
study treatment. 
Time to next (on-or off-treatment) exacerbation during the 12-Week Treatment Period is 
defined as time from the date of randomisation until the date of onset of the first 
exacerbation occurring up to Day 84. Participants who have not had an exacerbation 
during the 12-Week Treatment Period will be censored at Day 84 or the date of study 
withdrawal, for participants who withdrew from the study prior to Day 84.
Time to next exacerbation following cessation of study treatment is defined as time from 
the date of last dose of study treatment until the date of onset of the next exacerbation 
whilst off study treatment during the 12-Week Follow Up Period. Participants who have 
not had an exacerbation off-treatment will be censored at the date of their last follow up 
assessment.
Time to next exacerbation will be analysed by severity, as follows: 
Endpoint
Time period
Time to next (on-treatment) exacerbation, 
summarised by:

Moderate/severe exacerbations

All (mild, moderate and severe) exacerbations
12-Week Treatment Period
Time to next (on-or off-treatment) exacerbation, 
summarised by:

Moderate/severe exacerbations

All exacerbations
12-Week Treatment Period
Time to next exacerbation following cessation of 
treatment, summarised by:

Moderate/severe exacerbations
12-Week Follow Up Period
Refer to Section 13.5 for further details regarding the length of time derivation
 
 
 
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7.2.2.1.
Statistical analyses
Time to next exacerbation will be analysed using a Bayesian Cox proportional hazards 
model with the “Efron” method for handling ties.
Kaplan-Meier (KM) estimates of the probability of exacerbation will also be presented.
Non-informative priors will be used for all modelling parameters. Wherever possible 
conjugate priors will be utilised.
The hazard ratio and corresponding 95% HPD credible intervals for each nemiralisib 
dose versus placebo will be presented. The probability that the true hazard ratio is less 
than 1, in addition to other values appropriately selected based on the data, will be 
presented.
Based on pharmacological predictions, the 500 mcg and 750 mcg doses are expected to 
result in similar levels of target inhibition and thus potentially translate to similar clinical 
benefit, therefore an estimate of hazard ratio for pooled data from 500 mcg plus 750 mcg 
nemiralisib doses versus placebo will also be presented.
7.2.2.2.
Subgroup analyses
A subgroup analysis of time to exacerbation by Index exacerbation severity will be 
performed by including a treatment-by-severity term in the model.
7.2.3.
Change from baseline in Clinic Visit trough FEV1
Change from baseline in clinic visit trough FEV1 at Day 14, 28, 56 measured post-
bronchodilator is defined as:
FEV1 measured prior to dosing and post-bronchodilator on Day X – Post-bronchodilator 
Baseline FEV1
Where Day X is Day 14, 28, and 56.
Change from baseline in clinic visit trough FEV1 at Day 14, 28, 56, 84 measured pre-
bronchodilator is defined as:
FEV1 measured prior to dosing and pre-bronchodilator on Day X – Pre-bronchodilator 
Baseline FEV1
Where Day X is Day 14, 28, 56, and 84.
7.2.3.1.
Statistical Analyses
Change from baseline in Clinic Visit trough FEV1 measured post-bronchodilator will be 
analysed using a dose response model and repeated measures analysis as described for 
the primary endpoint in Section 7.1.2.
 
 
 
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Change from baseline in Clinic Visit trough FEV1 measured pre-bronchodilator will be 
analysed using a repeated measures analysis as described in Section 7.1.2
7.2.3.2.
Subgroup analyses
A subgroup analysis of change from baseline in clinic visit trough FEV1 by index 
exacerbation severity will be performed. 
7.2.4.
Change from hospital discharge in clinic visit trough FEV1
Change from hospital discharge in clinic visit trough FEV1 will be derived only for 
participants who were hospitalised for their index exacerbation and who have been 
subsequently discharged. 
Change from hospital discharge in clinic visit trough FEV1 measured post-bronchodilator 
is defined as:
FEV1 measured prior to dosing and post-bronchodilator on Day X – FEV1 measured post-
bronchodilator and prior to dosing on day of hospital discharge.
Where Day X is 14, 28, 56 and 84.
Change from hospital discharge in clinic visit trough FEV1 measured pre-bronchodilator 
is defined as:
FEV1 measured prior to dosing and pre-bronchodilator on Day X – FEV1 measured prior 
to dosing and post-bronchodilator on day of hospital discharge.
Where Day X is 14, 28, 56 and 84.
Note, as per Section 5.1 of the Protocol, if discharge takes place between Day 11 and Day 
17 (inclusive), the assessments planned for Day 14 may be completed on the day of 
discharge. In these cases, for this endpoint only, the FEV1 assessment will be assigned 
the hospital discharge assessment and the Day 14 assessment will be missing. Refer to 
Section 13.2.1.1 for further details. 
In addition, if discharge takes place after Day 14, the Day 14 assessment will be missing 
for this analysis. 
7.2.4.1.
Statistical analyses
Change from hospital discharge in clinic visit trough FEV1 will be analysed using a 
repeated measures analysis as described in Section 7.1.2 if there are a sufficient number 
of participants to provide a meaningful analysis, otherwise the data will be summarised.
7.2.5.
EXAcerbations of Chronic Pulmonary Disease Tool - Patient 
Reported Outcome (EXACT)
The EXACT is a 14-item daily diary designed to provide a measure of patient-reported 
symptoms of COPD exacerbation. An EXACT Total Score, ranging from 0 to 100, where 
 
 
 
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higher scores indicate a more severe condition, will be derived for each day of diary 
collection according to the instructions in the EXACT User Manual (Version 8.0, 
Evidera, 2016).
The electronic EXACT diary does not allow a study patient to skip individual items, 
therefore no missing data are expected for individual items. However, if missing values 
occur for individual items, the Total Score that contains the item will be set to missing for 
that day. Moderate-to-severe COPD patients are expected to experience symptom(s) each 
day, and a score of zero on all 14 EXACT items is likely to represent a situation where in 
order to complete the diary quickly, the respondent did not accurately report their daily 
symptom(s), therefore if the EXACT Total Score is 0, it will be set to missing.
A 3-day Rolling Average EXACT Total Score will be calculated for each day, X, as:
(EXACT Total Score on Day X-1 + EXACT Total Score on Day X + EXACT 
Total Score on Day X+1) / (Number of days with non-missing values)
Note, for Day 1, the Rolling Average EXACT Total Score will be calculated as the 
average of EXACT Total Score on Days 1 (Randomisation) and 2 only, since no EXACT 
data is collected prior to randomisation. Similarly, the Rolling Average EXACT Total 
Score for the last study day will be calculated as the average of EXACT Total Score on
the last day and on the day before the last day.
The Rolling Average EXACT Total Score will be calculated for each day as long as at 
least 1 EXACT total score in the sequence is present. Therefore, only in the case where 
EXACT total scores are missing for 3 consecutive days in a row (or 2 consecutive days in 
the case of the first and last day rolling average calculation), will the rolling average 
score be missing.
The Maximum Observed Value (MOV) is defined as the highest Rolling Average 
EXACT Total Score observed within the first 14 days of randomisation. Note: this 
definition differs from the definition in the EXACT User Manual of "the highest rolling 
average EXACT score observed in the context of an EXACT exacerbation within the first 
14 days of the exacerbation", since the date of the index exacerbation is likely to be prior 
to randomisation.
7.2.5.1.
Proportion of participants achieving EXACT-defined recovery from 
index exacerbation
EXACT-defined recovery from the index exacerbation is defined as a decrease in the 
Rolling Average EXACT Total Score ≥9 points from the Maximum Observed Value, 
sustained for ≥7 days, with the first of the 7 days defined as the recovery day.
The proportion of participants achieving EXACT-defined recovery from the index 
exacerbation by Days 14, 28, 56, and 84 will be calculated as:
(Number of participants who experience an EXACT-defined recovery on or 
before Day X) / (Total number of participants in the MITT population) 
 
 
 
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Where Day X is 14, 28, 56, and 84.
7.2.5.2.
Time to EXACT-defined recovery from index exacerbation
Time to EXACT-defined recovery from index exacerbation is defined as time from the 
date of randomisation until date of the first EXACT-defined recovery day during the 12-
Week Treatment Period, where EXACT-defined recovery is described in Section 7.2.5.1. 
Participants who did not experience EXACT-defined recovery during the 12-Week 
Treatment Period will be censored at the date of their last dose of study treatment.
7.2.5.3.
Severity of subsequent HCRU-defined exacerbation(s) defined by 
EXACT 
Severity of subsequent HCRU-defined exacerbation(s) defined by EXACT is defined as 
the highest EXACT Total Score (not using the 3-day Rolling Average) during the period 
from date of onset of the subsequent HCRU-exacerbation until date of EXACT-defined 
recovery of subsequent exacerbation. 
Note, in this case, the Maximum Observed Value and EXACT-defined recovery are 
derived using the date of onset of the subsequent HCRU-exacerbation.
Severity of subsequent HCRU-defined exacerbation(s) defined by EXACT will only be 
derived for participants who have had a subsequent exacerbation. If a participant has 
more than one subsequent exacerbation, severity will be calculated for each subsequent 
exacerbation.
7.2.5.4.
Statistical analyses
The proportion of participants achieving EXACT-defined recovery from the index 
exacerbation will be analysed using a Bayesian logistic regression model. Separate 
models will be fitted for each time-point. 
Non-informative priors will be used for all modelling parameters. Wherever possible 
conjugate priors will be utilised.
The results of the analysis will be presented in terms of odds ratios together with its 
associated 95% HPD credible interval. The probability that the true odds ratio is greater 
than 1, in addition to other values appropriately selected based on the data, will be 
presented.
Time to EXACT-defined recovery from index exacerbation will be analysed using the 
same techniques as described in Section 7.2.2.1.
Severity of subsequent HCRU-defined exacerbation(s) defined by EXACT will be 
summarised for each treatment group and reported by study period. The severity of 
subsequent HCRU-defined exacerbation(s) occurring whilst a participant is on treatment 
will be reported as during the 12-Week Treatment Period and the severity of subsequent 
HCRU-defined exacerbation(s) occurring after the last dose of study treatment will be 
reported as during the 12-Week Follow-up Period.
 
 
 
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7.2.5.5.
Subgroup analyses
A subgroup analysis of the proportion of participants achieving EXACT-defined recovery 
from the index exacerbation by Index Exacerbation Severity will be performed by 
including a treatment-by-severity term in the model.
7.2.5.6.
Sensitivity and supportive analyses
Sensitivity analyses exploring the impact of any missing data, and changes to the 
definition of EXACT-defined recovery may be conducted and may be performed post-
SAC. 
7.2.6.
COPD Assessment Test (CAT)
The COPD Assessment Test (CAT) is a patient completed questionnaire developed to 
measure the health status of patients with COPD. The CAT consists of eight items, each 
on a six-point scale: 0 (no impact) to 5 (high impact). The CAT Score will be calculated 
for each study day of collection by summing the scores for all questions. The CAT Score 
ranges from 0 to 40, where higher scores indicate a more severe condition.
7.2.6.1.
Proportion of responders using the CAT
The proportion of responders using the CAT will only be derived for participants with a 
baseline CAT Total Score ≥2.
The Proportion of responders using the CAT is defined as:
(Number of participants with a decrease from baseline in CAT Total Score ≥2 on 
or before Day X)/(Total number of participants in the MITT population)
Where Day X is 28, 56, and 84 and the study day following EXACT-defined recovery
from the index exacerbation.
Note: due to software limitations of the electronic PRO device, the study day following 
EXACT-defined recovery is not derived according to the EXACT User Manual, see 
Section 13.2.1.2 for further details.
Exploratory – Follow-Up Period
The Proportion of responders using the CAT at Day 112 and 168 is defined as:
(Number of participants with a decrease from baseline in CAT Total Score ≥2 on 
or before Day X)/(Total number of participants in the MITT population)
Where Day X is Day 112 and Day 168 and the study day following EXACT defined 
recovery, if it occurs during the Follow-up period. 
7.2.6.2.
Change from baseline in CAT Total Score
Change from baseline in CAT Total Score is defined as:
 
 
 
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CAT Total Score on Day X – Baseline CAT Total Score
Where Day X is 28, 56, 84 and the study day following EXACT defined recovery from 
the index exacerbation.
Note: due to software limitations of the electronic PRO device, the study day following 
EXACT-defined recovery is not derived according to the EXACT User Manual, see
Section 13.2.1.2 for further details.
Exploratory – Follow-Up Period
The Change from baseline in CAT Total Score at Day 112 and 168 is defined as:
CAT Total Score on Day X – Baseline CAT Total Score
Where Day X is Day 112 and Day 168. 
The Change from end of treatment in CAT Total Score at Day 112 and 168 is defined as:
CAT Total Score on Day X – CAT Total Score on Day 84
Where Day X is Day 112 and Day 168. 
7.2.6.3.
Statistical analyses
The proportion of responders using CAT will be analysed using the same techniques as 
described in Section 7.2.5.4.
Change from baseline/end of treatment in CAT Total Score will be compared between 
treatment groups using a Bayesian Repeated Measures analysis with covariates for 
baseline-by-Day interaction and treatment-by-Day interaction. Day will be fitted as a 
repeated effect within each participant. 
All post-baseline scheduled visits will be included in the analysis using Day.
Non-informative priors will be used for all modelling parameters. Wherever possible 
conjugate priors will be utilised. An unstructured covariance matrix will be used to model 
the within-subject error.
Adjusted posterior median change from baseline and corresponding 95% HPD credible 
intervals will be summarised for each treatment by time-point, together with estimated 
treatment differences (GSK – Placebo) and corresponding 95% HPD credible intervals. 
The posterior probability that the true treatment difference is less than 0, in addition to 
other values appropriately selected based on the data, will also be presented.
7.2.6.4.
Subgroup analyses
A subgroup analysis of the proportion of responders using CAT and the change from 
baseline in CAT Total Score by Index exacerbation severity will be performed by 
 
 
 
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including a treatment-by-severity term and a treatment-by-severity-by-Day term in the 
Bayesian logistic regression and Bayesian Repeated Measures models, respectively.
7.2.7.
St. George’s Respiratory Questionnaire for COPD Patients 
(SGRQ-C)
St. George’s Respiratory Questionnaire for COPD Patients (SGRQ-C) is a 40-item 
questionnaire designed specifically to focus on COPD patients. SGRQ-C will be scored 
to be equivalent to the SGRQ Total Score, ranging from 0 to 100, where higher scores 
reflect worse health-related quality of life. SGRQ Total Scores will be calculated for each 
day of collection according to the instructions in SGRQ-C Manual (SGRQ, March 2016). 
7.2.7.1.
Proportion of responders on the SGRQ Total Score
The proportion of responders on the SGRQ Total Score will only be derived for 
participants with a baseline SGRQ Total Score ≥4.
Proportion of responders on the SGRQ Total Score is defined as:
(Number of participants with a decrease from baseline in SGRQ Total Score ≥4 
on or before Day X)/(Total number of participants in the MITT population)
Where Day X is 28, 56, and 84.
Exploratory – Follow-Up Period
The Proportion of responders on the SGRQ Total Score at Day 112 and 168 is defined as:
(Number of participants with a decrease from baseline in SGRQ Total Score ≥4 
on or before Day X)/(Total number of participants in the MITT population)
Where Day X is Day 112 and Day 168 and the study day following EXACT defined 
recovery, if it occurs during the Follow-up period. 
7.2.7.2.
Change from baseline in SGRQ Total Score
Change from baseline in SGRQ Total Score is defined as:
SGRQ Total Score on Day X – Baseline SGRQ Total Score
Where Day X is Day 28, 56, and 84.
Exploratory – Follow-Up Period
The Change from baseline in SGRQ Total Score at Day 112 and 168 is defined as:
SGRQ Total Score on Day X – Baseline SGRQ Total Score
Where Day X is Day 112 and Day 168. 
 
 
 
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The Change from end of treatment in SGRQ Total Score at Day 112 and 168 is defined 
as:
SGRQ Total Score on Day X – SGRQ Total Score on Day 84
Where Day X is Day 112 and Day 168. 
7.2.7.3.
Statistical analyses
Change from baseline/end of treatment in SGRQ Total Score and the proportion of 
responders on the SGRQ Total Score will be analysed using the same techniques as 
described in Section 7.2.6.3.
7.2.7.4.
Subgroup analyses
Subgroup analyses of change from baseline in SGRQ Total Score and the proportion of 
responders on the SGRQ Total Score by Index exacerbation severity will be conducted as 
described in Section 7.2.6.4.
7.2.8.
Rescue medication use
All participants will record rescue medication use in the eDiary. Rescue medication use 
will be recorded as the number of occasions of rescue medication use each day. 
The Mean Number of Occasions of Rescue Medication Use Per Day is defined as:
(Sum of the number of occasions of rescue medication use each day within the 
time-period) / (Total number of days with non-missing values within the time-
period)
The Percentage of  Rescue-Free Days is defined as:
(Sum of the number of days where the number of occasions of rescue medication 
use is zero within the time-period) / (Total number of days with non-missing 
values within the time-period)*100
Where the time-period is defined as follows:
Week 1 of the 12-Week Treatment Period: Day 1 to Day 7
Week 2 of the 12-Week Treatment Period: Day 8 to Day 14
Week 3 of the 12-Week Treatment Period: Day 15 to Day 21
Week 4 of the 12-Week Treatment Period: Day 22 to Day 28
Week 5 of the 12-Week Treatment Period: Day 29 to Day 35
Week 6 of the 12-Week Treatment Period: Day 36 to Day 42
Week 7 of the 12-Week Treatment Period: Day 43 to Day 49
 
 
 
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Week 8 of the 12-Week Treatment Period: Day 50 to Day 56
Week 9 of the 12-Week Treatment Period: Day 57 to Day 63
Week 10 of the 12-Week Treatment Period: Day 64 to Day 70
Week 11 of the 12-Week Treatment Period: Day 71 to Day 77
Week 12 of the 12-Week Treatment Period: Day 78 to Day of last dose
Over the 12-Week Treatment Period: Day 1 to Day of last dose. 
Exploratory – Follow-Up Period
Rescue medication use up to Day 112 will also be summarised by including the time-
periods:
Week 13 (Follow-up Period): (Day of last dose + 1)  to (Day of last dose + 1) + 6 days
Week 14 (Follow-up Period): (Day of last dose + 7)  to (Day of last dose + 1) + 13 days
Week 15 (Follow-up Period): (Day of last dose + 14)  to (Day of last dose + 1) + 20 days
Week 16 (Follow-up Period): (Day of last dose + 21)  to (Day of last dose + 1) + 27 days
For a subject to be counted in the time periods for rescue medication use, they must have 
at least one eDiary entry recorded during that time period.
7.2.8.1.
Rescue medication use via the clip-on Propeller Sensor for MDI
A subset of participants from countries where the Propeller Sensor for MDI is available 
will also record rescue medication use via the clip-on Propeller Sensor for MDI. A 
supportive summary of rescue medication use via the clip-on Propeller Sensor for MDI 
for these participants will be presented. 
Rescue medication use via the clip-on Propeller Sensor for MDI is defined in the same 
way as rescue medication use via the eDiary, except that the number of actuations will be 
used instead of the number of occasions in accordance with the way the data is captured. 
7.2.8.2.
Statistical analyses
The Mean Number of (on-treatment) Occasions of Rescue Medication Use Per Day will 
be summarised between each treatment group using means, standard deviations, medians, 
minimum and maximum.
The Percentage of (on-treatment) Rescue-Free Days will be summarised between each 
treatment group using means, standard deviations, medians, minimum and maximum.
Rescue medication use via the clip-on Propeller Sensor for MDI will be summarised in 
the same way as rescue medication use via the eDiary.
 
 
 
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7.3.
Exploratory Efficacy Analyses
7.3.1.
Change from Day 84 in Clinic Visit trough FEV1
Change from Day 84 in clinic visit trough FEV1 measured post-bronchodilator is defined 
as:
FEV1 measured prior to dosing and post-bronchodilator on Day X – Day 84 post-
bronchodilator FEV1
Where Day X is Day112, Day  140 and  Day 168.
Change from Day 84 in clinic visit trough FEV1 measured pre-bronchodilator is defined 
as:
FEV1 measured prior to dosing and pre-bronchodilator on Day X – Day 84 pre-
bronchodilator FEV1
Where Day X is Day 112, Day 140 and  Day 168.
Participants who discontinue study treatment prior to Day 84 will be excluded from this 
analysis. 
7.3.1.1.
Statistical analysis
Change from Day 84 in Clinic Visit trough FEV1 will be analysed using the same 
techniques as described for Change from baseline in CAT Total Score in Section 7.2.6.3.
A subgroup analysis of change from Day 84 in FEV1 will be performed by including a 
treatment-by-severity-by-Day term in the Bayesian Repeated Measures model.
7.3.2.
E-RS:COPD (Evaluating Respiratory Symptoms in COPD)
Change from baseline in E-RS: COPD and subscales will be summarised by treatment 
group. Exploratory analyses related to E-RS: COPD and subscales may be performed 
post SAC.
7.3.3.
Measures of HCRU related to exacerbations
Unscheduled Healthcare Utilisation will be summarised separately for exacerbation-
related, COPD-related or non-COPD related; each summary will be presented by all 
patients (i.e. moderate and severe index exacerbation combined), and separately by index 
exacerbation severity. 
The number of days of hospital admission for the index and subsequent exacerbations 
will also be summarised by treatment group.
 
 
 
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7.3.3.1.
Re-hospitalisation within 30 days of index exacerbation
Re-hospitalisation within 30 days of index exacerbation is defined as 30 days from the 
date of hospital discharge until the date of next hospital admission (+ 1 day, to account 
for study day derivation), for participants who were hospitalised for their index 
exacerbation. 
Exacerbation-related, COPD-related and Non-COPD-related hospital admissions are 
collected in separate eCRFs. The date of hospital admission is not collected in the COPD-
related eCRF, therefore the date of next hospital admission will be estimated using the 
earliest of:

Date of hospital admission for exacerbation-related hospitalisations

Date of contact for COPD-related hospitalisations, where the number of inpatient 
hospitalisation days >0

Date of hospital admission for non-COPD-related hospitalisations.
The proportion of participants who were re-hospitalised within 30 days of the index 
exacerbation will be summarised by each treatment arm.
7.3.3.2.
Time from resolution of index exacerbation to next exacerbation
Time from resolution of index exacerbation to next exacerbation is defined as time from 
the date of (Investigator-defined) resolution of index exacerbation until the date of onset 
of the subsequent exacerbation. 
A summary of time from resolution of index exacerbation to next exacerbation will be 
presented. Participants who did not have a subsequent exacerbation or for whom the 
index exacerbation was not resolved will be excluded from the summary. 
Time from resolution of index exacerbation to next exacerbation will only be derived for 
the first subsequent exacerbation following the index exacerbation. 
7.3.3.3.
Subsequent exacerbation treatment type 
A summary of the type of treatment for subsequent exacerbations (OCS, antibiotics, or 
both) may also be presented.
7.3.4.
Compliance
Reported compliance for all participants is captured daily in the eDiary from the question
"Did you take this morning’s dose of study medication”? 
Percentage compliance for each participant is calculated as:
(Sum of the number of days where the question was answered with ‘Y’) / (Number of 
days from first dose of study treatment to last dose of study treatment) x 100
Overall percentage compliance will be summarised by each treatment group.
 
 
 
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7.3.4.1.
Number of actuations of double-blind study treatment measured by the 
clip-on Propeller Sensor
Percentage compliance via the clip-on Propeller Sensor for ELLIPTA in the subset of 
participants from countries where the Propeller Sensor for ELLIPTA is available is 
calculated as:
(Sum of the number of days with actuation > 0) / (Number of days from first dose of 
study treatment to last dose of study treatment) x 100
Overall percentage compliance will be summarised by each treatment group.
7.3.5.
Inflammatory/infective markers in blood and sputum in relation to 
acute exacerbation of COPD
Results of the analysis of blood/spontaneous sputum samples of eosinophil counts and 
inflammatory/infective mediators/markers will be summarised by treatment group.
Further analyses of inflammatory/infective markers may be performed, for example split 
by CRP high, CRP low, Procalcitonin high, etc. categories.
7.3.6.
Other spirometry measurements
Percent predicted FEV1, Forced Vital Capacity (FVC), percent predicted FVC and 
FEV/FVC ratio will be summarised by treatment group. 
7.3.7.
Other symptoms suggestive of exacerbation
Responses to questions in the eDiary related to symptoms of sputum purulence (colour), 
fever, sore throat, wheezing and colds collected in the eDiary will be listed by treatment 
group.
7.3.8.
Classification of exacerbating COPD participants and prediction 
of response to nemiralisib using machine learning techniques
Exploratory analysis of endpoints using machine learning techniques will be performed 
which will include classification of COPD participants, identification of parameters 
which describe a responder, and prediction of response to nemiralisib using baseline data. 
Details of these analyses will be described in a separate RAP and results may be reported 
separately to the CSR.
8.
SAFETY ANALYSES
The safety analyses will be based on the Safety population, unless otherwise specified.
The details of the planned displays will be provided in Appendix 11: List of Data 
Displays.
 
 
 
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8.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs) and Serious
(SAEs) will be based on GSK Core Data Standards. 
8.1.1.
Adverse Events of Special Interest
8.1.1.1.
Post-inhalation Cough Immediately Following Dosing
Post-inhalation cough immediately following dosing is an Adverse Event of Special 
Interest (AESI).
Post-inhalation cough immediately following dosing will be evaluated 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.
The percentage of patients experiencing post-inhalation cough following dosing, 
regardless of whether it was also reported as an AE, overall and by each visit will be 
summarised for each treatment group. The type of cough, time to onset and duration of 
cough, and severity will also be summarised.
In addition, any post-inhalation cough immediately following dosing reported as an
adverse event during the clinic visit observation or during the course of the study will be 
summarised by treatment group.  
8.2.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, 
Haematology laboratory tests and liver function tests will be based on GSK Core Data 
Standards.
8.3.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. 
8.4.
Mortality
A summary of all-cause mortality by treatment will be presented. 
9.
PHARMACOKINETIC ANALYSES
9.1.
Population of Interest 
The primary pharmacokinetic analyses will be based on the “Pharmacokinetic” 
population, unless otherwise specified.
 
 
 
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9.2.
Drug Concentration Measures
Plasma nemiralisib concentrations of GSK2269557 will be listed and summarised by 
dose, day and time. Drug levels will be summarised by day (14, 28), dose and time 
intervals (trough, 0-<1h, 1-6h).
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 13.4.3
Reporting Standards for Pharmacokinetic).
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
10.
POPULATION PK ANALYSIS
A dataset for population PK analysis will be provided by Statistics and Programming
based on the NONMEM data specifications in Section 13.8.2.
Conduct of the population PK analyses will be based on the current guidance which 
contains specific recommendations for working practices, processes and standards for 
population PK and PK/PD analysis conducted by Clinical Pharmacology Modelling and 
Simulation (CPMS) [Analysis & Reporting, 2017].
The sparse PK samples will be subjected to a validated population PK model for 
nemiralisib currently under development.
Details of these analyses will be described in a separate CPMS RAP and results will be 
reported separately to the CSR. Analyses and reporting of the population PK model will 
be in accordance with the FDA and EMEA guidance on population PK, PK-PD analyses.
10.1.
Derived Pharmacokinetic Parameters
The exposure parameters (e.g. AUC, Cmax) will be derived from the individual post-hoc 
estimates from the POP PK model. These will be summarized across dose treatments, 
subgroups (e.g., gender, race) or as a function of a continuous variable (e.g., age).
11.
PHARMACOKINETIC / PHARMACODYNAMIC 
ANALYSES
If statistical analyses suggest an effect of nemiralisib on primary and other key clinical 
endpoints, an integrated longitudinal population dose/exposure versus clinical response 
on analysis key parameters including FEV1 and exacerbation rate will be undertaken. 
Participant characteristics influencing the relationship will be evaluated. 
Details of these analyses will be described in a separate CPMS RAP and results will be 
reported separately to the CSR.
 
 
 
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12.
REFERENCES
Bornkamp, B. (2014). Practical considerations for using functional uniform prior 
distributions for dose-response estimation in clinical trials. Biometrical Journal, 56(6), 
947-962. doi: 10.1002/bimj.201300138.
Dette, H., Bretz, F., Pepelyshev, A. & Pinheiro, J., (2008). Optimal Designs for Dose-
Finding Studies. Journal of the American Statistical Association, 103:483, 1255-1237. 
doi: 10.1198/016214508000000427.
Evidera. (2016). The Exacerbations of Chronic Pulmonary Disease Tool (EXACT®) 
Patient-Reported Outcome (PRO) USER MANUAL (Version 8.0). 
SGRQ-C Manual (2016). St George’s Respiratory Questionnaire for COPD Patients 
(SGRQ-C) Manual (Version 1.3).
Spiegelhalter, D.J., Abrams, K.R. & Myles, J.P., (2004). Bayesian Approaches to Clinical 
Trials and Health-Care Evaluation. John Wiley & Sons, Ltd.
 
 
 
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13.
APPENDICES
13.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
13.1.1.
Exclusions from Per Protocol Population
Protocol deviations will be reviewed regularly throughout the course of the study, as 
described in Protocol Deviation Management Plan (PDMP). Deviations which will result 
in exclusion from the Per Protocol population will be assigned on a case-by-case basis
prior to database freeze (DBF).  
Decisions on whether or not the subject should be excluded from the PP population 
because the incorrect treatment was taken, due to the incorrect container being dispensed, 
will be identified after unblinding (i.e. post DBF). A PD of “incorrect treatment” will be 
added to the reporting dataset. 
 
 
 
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13.2.
Appendix 2: Assessment Windows
13.2.1.
Definitions of Assessment Windows for Analyses
13.2.1.1.
Hospital discharge
As per Section 5.1 of the Protocol, if discharge takes place between Day 11 and Day 17 
(inclusive), the assessments planned for Day 14 may be completed on the day of 
discharge. In these cases, for this endpoint only, the FEV1 assessment will be assigned 
the hospital discharge FEV1 assessment and the Day 14 assessment will be missing. 
For all other analyses and summaries that include participants who were hospitalised for 
their index exacerbation, an additional Analysis Timepoint of “HOSPTIAL 
DISCHARGE” will be derived. However, in the cases where discharge takes place 
between Day 11 and Day 17 (inclusive), participants will be summarised under DAY 14 
and a footnote to say that participants who were discharged at Day 14 are summarised 
under DAY 14 will be included.
13.2.1.2.
EXACT-Defined Recovery for CAT Trigger
Due to software limitations of the electronic PRO device, the study day following 
EXACT-defined recovery from the index exacerbation is not derived according to the 
EXACT User Manual. Instead, it has been derived using a 3-day Rolling Average that is 
calculated as the mean EXACT score [Day X-2, Day X-1, Day X].
 
 
 
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13.3.
Appendix 3: Study Phases and Treatment Emergent 
Adverse Events
13.3.1.
Study Periods
13.3.1.1.
12-Week Treatment Period 
The 12-Week Treatment Period is assigned from Study Day 1 to Study Day 84.
13.3.1.2.
12-Week Follow-Up Period
The 12-Week Follow-up Period is assigned from Study Day 85 to Study Day 168.
13.3.2.
Study Phases
Exacerbation events during the 12-Week Treatment Period will be classified according to 
their occurrence from randomisation until treatment discontinuation/study withdrawal 
days, as detailed below.
Study Phase
Occurring from randomisation until
On-Treatment during the 12-Week Treatment Period
Treatment Stop Day
On- or Off-Treatment during the 12-Week Treatment 
Period
Day 84 or Study Withdrawal Day if Treatment Stop 
Day is < Day 84
13.3.2.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before Randomisation Date
Concomitant
Any medication that is not a prior
NOTES: 

Please refer to Appendix 6: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.
13.3.3.
Treatment Emergent Flag for Adverse Events
Flag
Definition
Treatment 
Emergent

If AE onset date is on or after treatment start date & on or before treatment stop 
date plus 10 days.
NOTES: 

If the study treatment stop date is missing, then the AE will be considered to be On-Treatment.

Time of study treatment dosing and start/stop time of AEs should be considered, if collected.
 
 
 
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13.4.
Appendix 4: Data Display Standards & Handling 
Conventions
13.4.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: uk1salx00175
HARP Compound
: \arprod\gsk2269557\mid200879
Analysis Datasets 

For all interim analyses, except for the End of Treatment Interim Analysis, datasets will be created 
according to Legacy GSK A&R dataset standards.

For the End of Treatment Interim Analysis and the final reporting effort, datasets will be created 
according to current CDISC standards
Generation of RTF Files

RTF files will be generated for the final reporting effort.
13.4.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 

Figures will be produced using PROC SGPLOT in SAS 
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may be
adjusted to a clinically interpretable number of DP’s. 

For lab parameters results that contain a character value of ‘<’, or ‘>’, e.g. ‘<X’ or ‘>X’, the parameter 
value will be imputed with X.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 
 
 
 
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Unscheduled Visits

Unscheduled visits will be included in summary tables of the worst-case results by potential clinical 
importance criteria only.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principles 7.01 to 7.13.
13.4.3.
Reporting Standards for Pharmacokinetic
Pharmacokinetic Concentration Data
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
NONMEM/Pop PK 
File
Pop-PK file (CSV format) for the POP-PK analysis by Clinical Pharmacology 
Modelling and Simulation function will be created according to the data specification 
detailed in Section 13.8.2 Population Pharmacokinetic (PopPK) Dataset 
Specification.
NONMEM/PK/PD 
File
PK/PD file (CSV format) for the PK/PD analysis by Clinical Pharmacology Modelling 
and Simulation function will be created according to the data specification detailed 
in the CPMS RAP.
 
 
 
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13.5.
Appendix 5: Derived and Transformed Data
13.5.1.
General
Multiple Measurements at One Analysis Time Point

Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables.
Study Day

Calculated as the number of days from Randomisation Date:

Ref Date = Missing              → Study Day = Missing 

Ref Date < Randomisation Date → Study Day = Ref Date – Randomisation Date

Ref Data ≥ Randomisation Date → Study Day = Ref Date – (Randomisation Date) + 1    
Time from date of randomisation and time from date of last dose of study treatment

For endpoints that use the time from the date of randomisation to a reference date, time will be 
calculated as

(Ref Date – Randomisation Date) + 1

For endpoints that use the time from the date of last dose of study treatment to a reference date, time 
will be calculated as

(Ref Date – (Last Dose Date + 1)) +1
13.5.2.
Study Population
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1

The cumulative dose will be based on the formula:
Cumulative Dose = Sum of (Number of Days x Total Daily Dose)
13.5.3.
Safety
Adverse Events
AE’S of Special Interest

Post-inhalation cough is an AE of special interest. The lower level term (LLT) to be included is 
“coughing after drug inhalation”
 
 
 
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13.6.
Appendix 6: Reporting Standards for Missing Data
13.6.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) is defined as completing all 
phases of the study including the last scheduled study visit

A participant is considered to have completed the Treatment Period, if he/she has 
completed the last on-treatment study visit (Visit 6) 

Withdrawn subjects were not replaced in the study.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.

Withdrawal visits will not be summarised (and will be listed only).
13.6.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:

These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 

Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
13.6.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to be 
recorded for AE start and end dates; that is, the day of the month may be missing. In 
such a case, the following conventions will be applied for calculating the time to onset 
and the duration of the event:

Missing Start Day: First of the month will be used unless this is before the start 
date of study treatment; in this case the study treatment start date will be used and 
hence the event is considered On-treatment as per Appendix 3: Study Phases and 
Treatment Emergent Adverse Events.

Missing Stop Day: Last day of the month will be used, unless this is after the stop 
date of study treatment; in this case the study treatment stop date will be used.

Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing.
 
 
 
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Element
Reporting Detail
Concomitant 
Medications/
Medical 
History

Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention:

If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month

If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.
Age

The eCRF collects year of birth only. Day and Month will be imputed by Data 
Management using a 
 for the day and 
 for the month

Age will then be derived referenced to the Screening Date

A footnote to say that age has been imputed will be included in any outputs containing 
age.
 
 
 
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13.7.
Appendix 7: Values of Potential Clinical Importance
13.7.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Haemoglobin 
G/DL
Male 18-64 years
7.1
19.9
Male 65+ years
7.1
19.9
Female 18-64 years
7.1
19.9
Female 65+ years
7.1
19.9
Lymphocytes 
GI/L
0.85
4.1
Total Absolute Neutrophil Count 
GI/L
1.5
8
Platelet Count 
GI/L
31
1499
White Blood Cell count
GI/L
18-64 years
1.1
10.8
65+ years
1.1
10.8
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Albumin
g/L
32
50
Calcium
mmol/L
1.5
3.24
Creatinine
Male 40-49 years
69
160
Male 50-59 years
67.2
160
Male 60-69 years
67.2
160
Male 70+ years
59.2
160
Female 40-49 years
52.2
160
Female 50-59 years
53
160
Female 60-69 years
53
160
Female 70+ years
55.7
160
Glucose
mmol/L
13-49 years
2.2
27.8
50+ years
2.2
27.8
Potassium
mmol/L
2.8
6.5
Sodium
mmol/L
120
160
Urea/BUN
mmol/L
13-64 years
2.5
15
65+ years
2.5
15
 
 
 
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Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
≥ 2x ULN
AST/SGOT 
U/L
High
≥ 2x ULN
AlkPhos 
U/L
High
≥ 2x ULN
T Bilirubin 
µmol/L
High
≥ 2x ULN
T. Bilirubin + ALT
µmol/L
High
2xULN T.Bilirubin + ≥ 3x ULN ALT
U/L
Direct Bilirubin
µmol/L
0 – 6
13.7.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 530
Absolute PR Interval
msec
< 110
> 240
Absolute QRS Interval
msec
< 75
> 110
Change from Baseline
Increase from Baseline QTc
msec
> 60
13.7.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 90
> 140 
Diastolic Blood Pressure
mmHg
< 60
> 90
Heart Rate
bpm
< 40 
> 110 
 
 
 
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13.8.
Appendix 8: Population Pharmacokinetic (PopPK) Analyses
13.8.1.
Population Pharmacokinetic (PopPK) Methodology
All analysis will be performed in the validated Modelling and Analysis Platform (MAP). 
MAP consists of a Linux desktop containing various modelling applications, including 
NONMEM, PsN, Pirana, R and RStudio. All software versions used will be documented.
The population PK analysis will be performed in the following sequence of steps:
1. Exploratory data analysis/data check out.
2. Base structural model development.
3. Covariate analysis.
4. Model refinement.
5. Model evaluation.
6. Model application using simulation
The above analysis and reporting steps follow EMEA 
(http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/
WC500003067.pdf) and FDA population PK guidances 
(https://www.fda.gov/downloads/drugs/guidances/UCM072137.pdf ) 
Key components of these regulatory guidelines on population PK are also included in the 
Global CPMS guidance for pop pk RAP
(https://connect.gsk.com/sites/cpms/TandD/Guidances).
13.8.2.
Population Pharmacokinetic (PopPK) Dataset Specification
Statistics & Programming, in discussion with CPMS, will provide a NONMEM dataset.  
Column headings in NONMEM-ready datasets and specifications should be consistent to 
minimise the programming process, and facilitate a smooth transfer of projects between 
users as needed. IDSL standards will be followed where possible.
A list of most common standardised variable names for NONMEM datasets can be found 
in Table below.
 
 
 
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List of Variable Names for NONMEM-Ready Datasets for PopPK Analysis
Variable
Label (Variable description)
C
NONMEM line exclusion identifier
ID
NONMEM subject identifier
STUD
Study ID
SUBJID
Subject identifier for study
SITEID
Unique identifier for a study site
AMT
NONMEM Amount of drug administered then EVID =1- dose event record
UAMT
Unit of AMT (mg)
ADDL
NONMEM Additional dose
CONC
Drug Concentration 
UCONC
Unit of CONC (ng/mL)
LNCONC
Natural log of CONC column 
ANALYTE
Drug label e.g 557
LLQ
Lower Limit of quantification
LNLLQ
Natural log of LLQ column
DAY
Study day number of record or of dosing
TIME
Plasma sample time after last dose
UTIME
Unit of TIME (h)
DOSE
Dose amount
EVID
NONMEM Event ID If row has dose then EVID=1 else EVID =0  
If EVID=1 then this is a dose event record
If EVID = 0 then this is an observation record 
II
NONMEM Inter-dose interval II=24 – dose every day
SS
Steady state item SS= 1 refers to steady state
MDV
NONMEM Missing data value then MDV=1 else MDV=0
AGE
Subject Age (yrs)
SEX
Subject gender 0 = Male 1 =Female
SEXTEXT
Subject gender text Male or Female
BMI
Baseline Body Mass Index
WT
Baseline Subject weight
CONMED1
Identifier for inhibitor CYP3A4 1 =Yes, 0 = No
CONMED1TXT
Inhibitor Name
CONMED2
Identifier for inducer CYP3A4 1 =Yes, 0 = No
CONMED2TXT
Inducer Name
If observation record e.g CONC  has “NA” or “NS” then assign CONC cell as  “.”
If observation record e.g CONC  has “NQ” or “BQL” then assign CONC cell as  “.” and MDV = 1 -this means 
value can be estimated by model
Missing covariate data should be imputed as “-99. 
 
 
 
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13.9.
Appendix 9: Pharmacokinetic / Pharmacodynamic Analyses
13.9.1.
Pharmacokinetic/Pharmacodynamic Methodology
PK-PD analysis of Nemiralisib will be guided by the results of the formal statistical 
analyses on the key clinical endpoints. The aims of the PK-PD analyses will contribute 
towards the dose selection in future studies using an integrated longitudinal analysis 
framework.
The objective is to explore an integrated modelling framework to characterise the 
longitudinal FEV1 response versus dose (average systemic exposure) during on- & off-  
treatment phases
FEV1i (ti j ) = FEV1i,base · (1 + f (ti j , dosei , xi ) + εi j with εi j ∼N(0, σ2)
A longitudinal nonlinear mixed-effects model will be used to describe the FEV1 response 
over time measured for each patient (i) at each visit (tij) with ɛ denoting the normal 
distributed residual variability with mean 0 and variance σ2. The function f() describes 
the relative change from observed FEV1 at baseline (FEV1,base) and any influence of 
patient characteristics on FEV1 response will be assessed.
Joint relationship between time to first exacerbation and FEV1 change as function of 
dose/exposure and patient covariates will be assessed.
Details of these analyses will be described in a separate CPMS RAP and results will be 
reported separately to the CSR.
 
 
 
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13.10.
Appendix 10: Abbreviations & Trade Marks
13.10.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GSK
GlaxoSmithKline
IA
Interim Analysis
ICH
International Conference on Harmonization
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
QC
Quality Control
QTcF
Fridericia’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SDTM
Study Data Tabulation Model
SGRQ
St. George’s Respiratory Questionnaire
SGRQ-C
St. George’s Respiratory Questionnaire for COPD Patients
SOP
Standard Operation Procedure
 
 
 
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TFL
Tables, Figures & Listings 
13.10.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
COPD Assessment Test (CAT)
E-RS: COPD
ELLIPTA
EXACT-PRO
HARP
NONMEM
Propeller Sensor
SAS
SGRQ
 
 
 
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13.11.
Appendix 11: List of Data Displays
13.11.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays for SAC:
Section
Tables
Figures
Study Population
1.1 to 1.28
Not applicable 
Efficacy
2.1 to 2.100
2.1 to 2.20
Safety
3.1 to 3.31
3.1 to 3.3
Pharmacokinetic
4.1 to 4.2
Not applicable
Section
Listings
ICH Listings
1 to 27
Other Listings
28 to 30
13.11.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 12: Example Mock Shells for Data Displays.
13.11.3.
Deliverables
Delivery
Description
IA
Interim Analysis (except the End of treatment Phase Interim Analysis)
EOT
End of Treatment Phase Interim Analysis
SAC
Statistical Analysis Complete
 
 
 
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13.11.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
MITT
ES8
Summary of Subject Status and Reason for Study Withdrawal
EOT, SAC
1.2.
MITT
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
EOT, SAC
1.3.
APE
ES6
Summary of Screening Status and Reasons for Screen Failure
SAC
1.4.
APE
NS1
Summary of Number of Participants by Country and Site ID
SAC
Protocol Deviation
1.5.
MITT
DV1
Summary of Important Protocol Deviations
SAC
1.6.
MITT
IE1
Summary of Inclusion/Exclusion Criteria Deviations
SAC
Population Analysed
1.7.
MITT
SP1
Summary of Study Populations 
SAC
1.8.
MITT
SP2
Summary of Exclusions from the Per Protocol/Safety Population
SAC
Demographic and Baseline Characteristics
1.9.
MITT
DM1
Summary of Demographic Characteristics
Use the following ranges for the Age 
Group row: ≤64; 65-74; ≥75
EOT, SAC
1.10.
APE
DM11
Summary of Age Ranges
SAC
1.11.
MITT
DM5
Summary of Race and Racial Combinations
SAC
1.12.
MITT
MH4
Summary of Past Medical Conditions
EOT, SAC
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.13.
MITT
MH4
Summary of Current Medical Conditions
EOT, SAC
1.14.
MITT
FH1
Summary of Family History of Cardiovascular Risk Factors
EOT, SAC
1.15.
MITT
SU1
Summary of Smoking History at Screening
EOT, SAC
1.16.
MITT
SU1
Summary of Smoking Status Over the 12-Week Treatment 
Period
EOT, SAC
1.17.
MITT
SU1
Summary of Smoking Status Over the 12-Week Follow-Up 
Period
SAC
1.18.
MITT
Example 7
Summary of COPD Duration at Screening
EOT, SAC
1.19.
MITT
Example 1
Summary of COPD Exacerbation History at Screening
Use categories 0;1;2;3;≥3. Summarise 
moderate/severe, moderate; severe
Include 7-Day History of COPD 
Exacerbations
EOT, SAC
1.20.
MITT
Example 1
Summary of COPD Exacerbation History at Screening by 
Country
EOT, SAC
Concomitant Medications
1.21.
MITT
Example 14
Summary of Baseline COPD Maintenance Therapy
EOT, SAC
1.22.
MITT
Example 15
Summary of On-Treatment COPD Maintenance (Step-up) 
Therapy 
EOT, SAC
1.23.
MITT
CM1
Summary of Concomitant Medications During 12-Week 
Treatment Period
EOT, SAC
1.24.
MITT
Example 16
Summary of OCS Use
EOT, SAC
1.25.
MITT
CM1
Summary of Concomitant Medications During 12-Week Follow-
Up Period
SAC
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Exposure and Treatment Compliance
1.26.
MITT
EX1
Summary of Exposure to Study Treatment
EOT, SAC
1.27.
MITT
Example 2
Summary of Treatment Compliance
EOT, SAC
1.28.
MITT
Example 2
Summary of Actuations of Study Treatment Measured by the 
Clip-on Propeller Sensor
SAC
13.11.5.
Efficacy Tables
13.11.5.1. Efficacy tables for Interim Analysis 1
Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in Clinic Visit trough FEV1
2.1.
MITT
Example 3
Summary of FEV1 (L) 
Include pre- and post-bronchodilator
IA1
2.2.
MITT
Example 3
Summary of FEV1 (L) by Index Exacerbation Severity
Include pre- and post-bronchodilator 
Include additional row for hospital 
discharge visit for Severe group
IA1
2.3.
MITT
Example 3
Summary of Change from Baseline in FEV1 (L)
Include pre- and post-bronchodilator
IA1
2.4.
MITT
Example 3
Summary of Change from Baseline in FEV1 (L) by Index 
Exacerbation Severity
Include pre- and post-bronchodilator. 
Include additional row for hospital 
discharge visit for Severe group
IA1
2.5.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 at Day 14 
Measured Post-bronchodilator (Dose Response Model)
IA1
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.6.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 at Day 28 
Measured Post-bronchodilator (Dose Response Model) 
IA1
2.7.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
14 Measured Post-bronchodilator by Index Exacerbation 
Severity (Dose Response Model)
IA1
2.8.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
28 Measured Post-bronchodilator by Index Exacerbation 
Severity (Dose Response Model)
IA1
2.9.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
Measured Post-bronchodilator (Repeated Measures Model)
IA1
2.10.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
Measured Pre-bronchodilator (Repeated Measures Model)
IA1
2.11.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
Measured Post-bronchodilator by Index Exacerbation Severity
(Repeated Measures Model)
IA1
2.12.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
Measured Pre-bronchodilator by Index Exacerbation Severity
(Repeated Measures Model)
IA1
Rate of Exacerbations
2.13.
MITT
Example 5
Summary of On-treatment Exacerbations
IA1
2.14.
MITT
Example 5
Summary of On-treatment Exacerbations by Index Exacerbation 
Severity
IA1
EXAcerbations of Chronic Pulmonary Disease Tool - Patient Reported Outcome (EXACT)
2.15.
MITT
Example 9
Summary of Proportion of Participants Achieving the EXACT-
definition of Recovery by Visit
Exclude statistical analysis 
information (summary only)
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.16.
MITT
Example 9
Summary of Proportion of Participants Achieving the EXACT-
definition of Recovery by Index Exacerbation Severity
Exclude statistical analysis 
information (summary only)
IA1
Other Spirometry Measures
2.17.
MITT
Example 3
Summary of Spirometry Measurements
IA1
2.18.
MITT
Example 3
Summary of Change from Baseline in Spirometry Measurements
IA1
 
 
 
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13.11.5.2. Efficacy tables for Interim Analysis 2
Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in Clinic Visit trough FEV1
2.1.
MITT
Example 3
Summary of FEV1 (L) 
Include pre- and post-bronchodilator
IA2
2.2.
MITT
Example 3
Summary of FEV1 (L) by Index Exacerbation Severity
Include pre- and post-bronchodilator 
Include additional row for hospital 
discharge visit for Severe group
IA2
2.3.
MITT
Example 3
Summary of Change from Baseline in FEV1 (L)
Include pre- and post-bronchodilator
IA2
2.4.
MITT
Example 3
Summary of Change from Baseline in FEV1 (L) by Index 
Exacerbation Severity
Include pre- and post-bronchodilator. 
Include additional row for hospital 
discharge visit for Severe group
IA2
2.5.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
14 Measured Post-bronchodilator (Dose Response Model)
IA2
2.6.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
28 Measured Post-bronchodilator (Dose Response Model)
IA2
2.7.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
56 Measured Post-bronchodilator (Dose Response Model)
IA2
2.8.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
84 Measured Post-bronchodilator (Dose Response Model)
IA2
2.9.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
14 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate (Dose Response Model)
IA2
2.10.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
14 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe (Dose Response Model)
IA2
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.11.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
28 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate (Dose Response Model)
IA2
2.12.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
28 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe (Dose Response Model)
IA2
2.13.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
56 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate (Dose Response Model)
IA2
2.14.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
56 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe (Dose Response Model)
IA2
2.15.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
84 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate (Dose Response Model)
IA2
2.16.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
84 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe (Dose Response Model)
IA2
2.17.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
Measured Post-bronchodilator (Repeated Measures Model)
IA2
2.18.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
Measured Pre-bronchodilator (Repeated Measures Model)
IA2
2.19.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
Measured Post-bronchodilator by Index Exacerbation Severity 
(Repeated Measures Model)
IA2
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.20.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
Measured Pre-bronchodilator by Index Exacerbation Severity 
(Repeated Measures Model)
IA2
2.21.
MITT
Example 32
Summary of Efficiency Ratio for Possible Adaptions to 
Randomization Ratio
IA2
Rate of Exacerbations
2.22.
MITT
Example 5
Summary of On-treatment (Moderate/Severe) Subsequent
Exacerbations
IA2
2.23.
MITT
Example 5
Summary of On-treatment (Moderate/Severe) Subsequent
Exacerbations by Index Exacerbation Severity
IA2
2.24.
MITT
Example 6
Statistical Analysis of On-treatment (Moderate/Severe) 
Subsequent Exacerbations
IA2
2.25.
MITT
Example 6
Subgroup Analysis of On-treatment (Moderate/Severe) 
Subsequent Exacerbations by Index Exacerbation Severity
IA2
EXAcerbations of Chronic Pulmonary Disease Tool - Patient Reported Outcome (EXACT)
2.26.
MITT
Example 9
Statistical Analysis of Proportion of Participants Achieving the 
EXACT-definition of Recovery by Visit
IA2
2.27.
MITT
Example 9
Subgroup Analysis of Proportion of Participants Achieving the 
EXACT-definition of Recovery by Index Exacerbation Severity
IA2
COPD Assessment Test (CAT)
2.28.
MITT
Example 3
Summary of Change from Baseline in CAT Total Score
IA2
2.29.
MITT
Example 9
Statistical Analysis of Proportion of Responders Using the CAT 
Total Score by Visit
IA2
2.30.
MITT
Example 11
Statistical Analysis of Change from Baseline in CAT Total Score 
(Repeated Measures Model)
IA2
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
St. George’s Respiratory Questionnaire (SGRQ)
2.31.
MITT
Example 3
Summary of Change from Baseline in SGRQ Total Score
IA2
2.32.
MITT
Example 9
Statistical Analysis of Proportion of Responders Using the 
SGRQ Total Score by Visit
IA2
2.33.
MITT
Example 11
Statistical Analysis of Change from Baseline in SGRQ Total 
Score (Repeated Measures Model)
IA2
Rescue Medication Use
2.34.
MITT
RM1
Summary of Mean Number of Occasions of Rescue Medication 
Use Per Day
IA2
2.35.
MITT
RM1
Summary of Percentage of Rescue-Free Days
IA2
Other Spirometry Measures
2.36.
MITT
Example 3
Summary of Spirometry Measurements
IA2
2.37.
MITT
Example 3
Summary of Change from Baseline in Spirometry Measurements
IA2
13.11.5.3. Efficacy tables for End of Treatment Interim Analysis and SAC
Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in Clinic Visit trough FEV1
2.1.
MITT
Example 3
Summary of FEV1 (L) 
Include pre- and post-bronchodilator
EOT, SAC
2.2.
MITT
Example 3
Summary of FEV1 (L) by Index Exacerbation Severity
Include pre- and post-bronchodilator 
Include additional row for hospital 
discharge visit for Severe group
EOT, SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.3.
MITT
Example 3
Summary of Change from Baseline in FEV1 (L)
Include pre- and post-bronchodilator
EOT, SAC
2.4.
MITT
Example 3
Summary of Change from Baseline in FEV1 (L) by Index 
Exacerbation Severity
Include pre- and post-bronchodilator. 
Include additional row for hospital 
discharge visit for Severe group
EOT, SAC
2.5.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
14 Measured Post-bronchodilator (Dose Response Model)
EOT, SAC
2.6.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
28 Measured Post-bronchodilator (Dose Response Model)
EOT, SAC
2.7.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
56 Measured Post-bronchodilator (Dose Response Model)
EOT, SAC
2.8.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
84 Measured Post-bronchodilator (Dose Response Model)
EOT, SAC
2.9.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
14 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate (Dose Response Model)
EOT, SAC
2.10.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
14 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe (Dose Response Model)
EOT, SAC
2.11.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
28 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate (Dose Response Model)
EOT, SAC
2.12.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
28 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe (Dose Response Model)
EOT, SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.13.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
56 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate (Dose Response Model)
EOT, SAC
2.14.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
56 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe (Dose Response Model)
EOT, SAC
2.15.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
84 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate (Dose Response Model)
EOT, SAC
2.16.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
84 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe (Dose Response Model)
EOT, SAC
2.17.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
Measured Post-bronchodilator (Repeated Measures Model)
EOT, SAC
2.18.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
Measured Post-bronchodilator by Index Exacerbation Severity 
(Repeated Measures Model)
EOT, SAC
Change from Hospital Discharge in Clinic Visit trough FEV1
2.19.
MITT
Example 3
Summary of Change from Hospital Discharge in FEV1 (L)
Include pre- and post-bronchodilator
EOT, SAC
2.20.
MITT
Example 11
Statistical Analysis of Change from Hospital Discharge in FEV1
(L) Measured Post-bronchodilator (Repeated Measures Model)
EOT, SAC
2.21.
MITT
Example 11
Statistical Analysis of Change from Hospital Discharge in FEV1
(L) Measured Pre-bronchodilator (Repeated Measures Model)
EOT, SAC
Change from Day 84 in Clinic Visit trough FEV1
2.22.
MITT
Example 3
Summary of Change from Day 84 in FEV1 (L) 
Include pre- and post-bronchodilator
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.23.
MITT
Example 11
Statistical Analysis of Change from Day 84 in FEV1 (L) 
Measured Post-bronchodilator (Repeated Measures Model)
SAC
2.24.
MITT
Example 11
Statistical Analysis of Change from Day 84 in FEV1 (L) 
Measured Pre-bronchodilator (Repeated Measures Model)
SAC
2.25.
MITT
Example 11
Subgroup Analysis of Change from Day 84 in FEV1 (L) 
Measured Post-bronchodilator by Index Exacerbation Severity 
(Repeated Measures Model)
SAC
2.26.
MITT
Example 11
Subgroup Analysis of Change from Day 84 in FEV1 (L) 
Measured Pre-bronchodilator by Index Exacerbation Severity 
(Repeated Measures Model)
SAC
Rate of Exacerbations
2.27.
MITT
Example 5
Summary of On-treatment (Moderate/Severe) Subsequent
Exacerbations
EOT, SAC
2.28.
MITT
Example 5
Summary of On-treatment (Mild/Moderate/Severe) Subsequent
Exacerbations
EOT, SAC
2.29.
MITT
Example 5
Summary of On-treatment (Moderate/Severe) Subsequent
Exacerbations by Index Exacerbation Severity
EOT, SAC
2.30.
MITT
Example 6
Statistical Analysis of On-treatment (Moderate/Severe) 
Subsequent Exacerbations
EOT, SAC
2.31.
MITT
Example 6
Statistical Analysis of On-treatment (Mild/Moderate/Severe) 
Subsequent Exacerbations
EOT, SAC
2.32.
MITT
Example 6
Subgroup Analysis of On-treatment (Moderate/Severe) 
Subsequent Exacerbations by Index Exacerbation Severity
EOT, SAC
2.33.
MITT
Example 5
Summary of On-treatment Subsequent Exacerbations by Index 
Exacerbation Type
EOT, SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.34.
MITT
Example 5
Summary of On-treatment Subsequent Exacerbations by 
Number of Exacerbations in Previous 12 Months
EOT, SAC
2.35.
MITT
Example 5
Summary of On-or Off-treatment (Moderate/Severe) Subsequent
Exacerbations During the 12-Week Treatment Period
EOT, SAC
2.36.
MITT
Example 5
Summary of On-or Off-treatment (Mild/Moderate/Severe) 
Subsequent Exacerbations During the 12-Week Treatment 
Period
EOT, SAC
2.37.
MITT
Example 5
Summary of On-or Off-treatment (Moderate/Severe) Subsequent
Exacerbations During the 12-Week Treatment Period by Index 
Exacerbation Severity
EOT, SAC
2.38.
MITT
Example 6
Statistical Analysis of On- or Off-treatment (Moderate/Severe) 
Subsequent Exacerbations During the 12-Week Treatment 
Period
EOT, SAC
2.39.
MITT
Example 6
Statistical Analysis of On- or Off-treatment 
(Mild/Moderate/Severe) Subsequent Exacerbations During the 
12-Week Treatment Period
EOT, SAC
2.40.
MITT
Example 6
Subgroup Analysis of On- or Off-treatment (Moderate/Severe) 
Subsequent Exacerbations During the 12-Week Treatment 
Period by Index Exacerbation Severity
EOT, SAC
2.41.
MITT
Example 5
Summary of Off-treatment (Moderate/Severe) Subsequent
Exacerbations 
EOT, SAC
2.42.
MITT
Example 5
Summary of Off-treatment (Moderate/Severe) Subsequent
Exacerbations by Index Exacerbation Severity
EOT, SAC
2.43.
MITT
Example 6
Statistical Analysis of Off-treatment (Moderate/Severe) 
Subsequent Exacerbations
EOT, SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.44.
MITT
Example 6
Subgroup Analysis of Off-treatment (Moderate/Severe) 
Subsequent Exacerbations by Index Exacerbation Severity
EOT, SAC
2.45.
MITT
Example 5
Summary of On- and Off-treatment (Moderate/Severe) 
Subsequent Exacerbations During the 24-Week Study Period
EOT, SAC
2.46.
MITT
Example 5
Summary of On- and Off-treatment (Moderate/Severe) 
Subsequent Exacerbations During the 24-Week Study Period by 
Index Exacerbation Severity
EOT, SAC
2.47.
MITT
Example 6
Statistical Analysis of On- and Off-treatment (Moderate/Severe) 
Subsequent Exacerbations During the 24-Week Study Period
EOT, SAC
2.48.
MITT
Example 6
Subgroup Analysis of On- and Off-treatment (Moderate/Severe) 
Subsequent Exacerbations During the 24-Week Study Period by 
Index Exacerbation Severity
EOT, SAC
Time to Next Exacerbation
2.49.
MITT
Example 8
Statistical Analysis of Time to next On-treatment Exacerbation 
EOT, SAC
2.50.
MITT
Example 8
Subgroup Analysis of Time to next On-treatment Exacerbation  
by Index Exacerbation Severity
EOT, SAC
2.51.
MITT
Example 8
Statistical Analysis of Time to next On- or Off-treatment 
Exacerbation During the 12-Week Treatment Period
EOT, SAC
2.52.
MITT
Example 8
Statistical Analysis of Time to next On- or Off-treatment 
Exacerbation During the 12-Week Treatment Period by Index 
Exacerbation Severity
EOT, SAC
2.53.
MITT
Example 8
Statistical Analysis of Time to Next Exacerbation Following 
Cessation of Study Treatment
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.54.
MITT
Example 8
Statistical Analysis of Time to Next Exacerbation Following 
Cessation of Study Treatment by Index Exacerbation Severity
SAC
EXAcerbations of Chronic Pulmonary Disease Tool - Patient Reported Outcome (EXACT)
2.55.
MITT
Example 9
Statistical Analysis of Proportion of Participants Achieving the 
EXACT-definition of Recovery by Visit
EOT, SAC
2.56.
MITT
Example 9
Subgroup Analysis of Proportion of Participants Achieving the 
EXACT-definition of Recovery by Index Exacerbation Severity
EOT, SAC
2.57.
MITT
Example 8
Summary and Statistical Analysis of Time to EXACT-defined 
Recovery
EOT, SAC
2.58.
MITT
Example 10
Summary of Severity of Subsequent HCRU-defined 
Exacerbation During 12-Week Treatment Period
Also split by moderate and severe
EOT, SAC
2.59.
MITT
Example 10
Summary of Severity of Subsequent HCRU-Defined 
Exacerbation During 12-Week Follow-up Period
Also split by moderate and severe
EOT, SAC
COPD Assessment Test (CAT)
2.60.
MITT
Example 3
Summary of Change from Baseline in CAT Total Score
EOT, SAC
2.61.
MITT
Example 3
Summary of Change from Baseline in CAT Total Score by Index 
Exacerbation Severity
EOT, SAC
2.62.
MITT
Example 9
Statistical Analysis of Proportion of Responders Using the CAT 
Total Score by Visit
EOT, SAC
2.63.
MITT
Example 9
Subgroup Analysis of Proportion of Responders Using the CAT 
Total Score by Visit by Index Exacerbation Severity
EOT, SAC
2.64.
MITT
Example 11
Statistical Analysis of Change from Baseline in CAT Total Score 
(Repeated Measures Model)
EOT, SAC
2.65.
MITT
Example 11
Subgroup Analysis of Change from Baseline in CAT Total Score 
(Repeated Measures Model) by Index Exacerbation Severity
EOT, SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.66.
MITT
Example 3
Summary of Change from End of Treatment in CAT Total Score
EOT, SAC
2.67.
MITT
Example 3
Summary of Change from End of Treatment in CAT Total Score 
by Index Exacerbation Severity
EOT, SAC
2.68.
MITT
Example 11
Statistical Analysis of Change from End of Treatment in CAT 
Total Score (Repeated Measures Model)
EOT, SAC
2.69.
MITT
Example 11
Subgroup Analysis of Change from End of Treatment in CAT 
Total Score (Repeated Measures Model) by Index Exacerbation 
Severity
EOT, SAC
St. George’s Respiratory Questionnaire (SGRQ)
2.70.
MITT
Example 3
Summary of Change from Baseline in SGRQ Total Score
EOT, SAC
2.71.
MITT
Example 3
Summary of Change from Baseline in SGRQ Total Score by 
Index Exacerbation Severity
EOT, SAC
2.72.
MITT
Example 9
Statistical Analysis of Proportion of Responders on the SGRQ 
Total Score by Visit
EOT, SAC
2.73.
MITT
Example 9
Subgroup Analysis of Proportion of Responders on the SGRQ 
Total Score by Index Exacerbation Severity
EOT, SAC
2.74.
MITT
Example 11
Statistical Analysis of Change from Baseline SGRQ Total Score 
(Repeated Measures Model)
EOT, SAC
2.75.
MITT
Example 11
Subgroup Analysis of Change from Baseline SGRQ Total Score 
(Repeated Measures Model) by Index Exacerbation Severity
EOT, SAC
2.76.
MITT
Example 3
Summary of Change from End of Treatment in SGRQ Total 
Score
EOT, SAC
2.77.
MITT
Example 3
Summary of Change from End of Treatment in SGRQ Total 
Score by Index Exacerbation Severity
EOT, SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.78.
MITT
Example 11
Statistical Analysis of Change from End of Treatment in SGRQ 
Total Score (Repeated Measures Model)
EOT, SAC
2.79.
MITT
Example 11
Subgroup Analysis of Change from End of Treatment in SGRQ 
Total Score (Repeated Measures Model) by Index Exacerbation 
Severity
EOT, SAC
E-RS: COPD
2.80.
MITT
Example 3
Summary of Change from Baseline in E-RS: COPD and 
Subscales
SAC
Rescue Medication Use
2.81.
MITT
RM1
Summary of Mean Number of Occasions of Rescue Medication 
Use Per Day
EOT, SAC
2.82.
MITT
RM1
Summary of Percentage of Rescue-Free Days
EOT, SAC
2.83.
MITT
RM1
Summary of Mean Number of Actuations of Rescue Medication 
Use Per Day Via the Clip-on Propeller Sensor for MDI
EOT, SAC
2.84.
MITT
RM1
Summary of Percentage of Rescue-Free Days Via the Clip-on 
Propeller Sensor for MDI
EOT, SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Compliance
2.85.
MITT
IP1
Summary of Overall IP Compliance
EOT, SAC
2.86.
MITT
IP1
Summary of Overall IP Compliance Via the Clip-on Propeller 
Sensor for ELLIPTA
EOT, SAC
Healthcare Resource Utilisation
2.87.
MITT
Example 19
Summary of Exacerbation Related Unscheduled Healthcare 
Resource Utilisation 
EOT, SA
2.88.
MITT
Example 19
Summary of Exacerbation Related Unscheduled Healthcare 
Resource Utilization by Index Exacerbation Severity
EOT, SA
2.89.
MITT
Example 21
Summary of Exacerbation Related Hospitalizations
EOT, SAC
2.90.
MITT
Example 19
Summary of COPD Related Unscheduled Healthcare Resource 
Utilisation 
EOT, SAC
2.91.
MITT
Example 19
Summary of COPD Related Unscheduled Healthcare Resource 
Utilisation by Index Exacerbation Severity
EOT, SAC
2.92.
MITT
Example 20
Summary of Non-COPD Related Unscheduled Healthcare 
Resource Utilisation 
EOT, SAC
2.93.
MITT
Example 20
Summary of Non-COPD Related Unscheduled Healthcare 
Resource Utilisation by Index Exacerbation Severity
EOT, SAC
2.94.
MITT 
Example 22
Summary of Re-hospitalization Within 30 days of Index 
Exacerbation
EOT, SAC
2.95.
MITT
Example 24
Summary of Time from Resolution of Index Exacerbation to Next 
Exacerbation
EOT, SAC
2.96.
MITT
Example 23
Summary of Subsequent Exacerbation Treatment
EOT, SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Other Spirometry Measures
2.97.
MITT
Example 3
Summary of Spirometry Measurements
EOT, SAC
2.98.
MITT
Example 3
Summary of Change from Baseline in Spirometry Measurements
EOT, SAC
Inflammatory/infective Markers in Blood and Sputum
2.99.
MITT
Example 3
Summary of Inflammatory Markers in Blood
SAC
2.100.
MITT
Example 3
Summary of Inflammatory Markers in Sputum
SAC
 
 
 
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13.11.6.
Efficacy Figures
13.11.6.1. Efficacy Figures for Interim Analysis 1
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in Clinic Visit trough FEV1
2.1.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 14 Measured Post-bronchodilator
IA1
2.2.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 28 Measured Post-bronchodilator 
IA1
2.3.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 56 measured post-bronchodilator 
IA1
2.4.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 14 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate
IA1
2.5.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 14 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe
IA1
2.6.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 28 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate
IA1
2.7.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 28 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe
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13.11.6.2. Efficacy Figures for Interim Analysis 2
Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in Clinic Visit trough FEV1
2.1.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 14 Measured Post-bronchodilator
IA2
2.2.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 28 Measured Post-bronchodilator 
IA2
2.3.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 56 Measured Post-bronchodilator
IA2
2.4.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 84 Measured Post-bronchodilator
IA2
2.5.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 14 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate
IA2
2.6.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 14 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe
IA2
2.7.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 28 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate
IA2
2.8.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 28 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe
IA2
2.9.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 56 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate
IA2
 
 
 
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.10.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 56 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe
IA2
2.11.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 84 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate
IA2
2.12.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 84 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe
IA2
2.13.
MITT
Example 31
Plot of Repeated Measures Model of Change from Baseline in 
FEV1 Measured Post-bronchodilator
IA2
2.14.
MITT
Example 31
Plot of Repeated Measures Model of Change from Baseline in 
FEV1 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate
IA2
2.15.
MITT
Example 31
Plot of Repeated Measures Model of Change from Baseline in 
FEV1 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe
IA2
Time to Next Exacerbation 
2.16.
MITT
Example 30
Kaplan-Meier Plot of Time to Next On-treatment 
(Moderate/Severe) Exacerbation
IA2
2.17.
MITT
Example 30
Kaplan-Meier Plot of Time to Next On-treatment 
(Mild/Moderate/Severe) Exacerbation
IA2
 
 
 
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13.11.6.3. Efficacy Figures for End of Treatment Interim Analysis and SAC
Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in Clinic Visit trough FEV1
2.1.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 14 Measured Post-bronchodilator
EOT, SAC
2.2.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 28 Measured Post-bronchodilator 
EOT, SAC
2.3.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 56 Measured Post-bronchodilator
EOT, SAC
2.4.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 84 Measured Post-bronchodilator
EOT, SAC
2.5.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 14 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate
EOT, SAC
2.6.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 14 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe
EOT, SAC
2.7.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 28 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate
EOT, SAC
2.8.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 28 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe
EOT, SAC
2.9.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 56 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate
EOT, SAC
 
 
 
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.10.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 56 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe
EOT, SAC
2.11.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 84 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate
EOT, SAC
2.12.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 84 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe
EOT, SAC
2.13.
MITT
Example 31
Plot of Repeated Measures Model of Change from Baseline in 
FEV1 Measured Post-bronchodilator
EOT, SAC
2.14.
MITT
Example 31
Plot of Repeated Measures Model of Change from Baseline in 
FEV1 Measured Post-bronchodilator by Index Exacerbation 
Severity: Moderate
EOT, SAC
2.15.
MITT
Example 31
Plot of Repeated Measures Model of Change from Baseline in 
FEV1 Measured Post-bronchodilator by Index Exacerbation 
Severity: Severe
EOT, SAC
Time to Next Exacerbation
2.16.
MITT
Example 30
Kaplan-Meier Plot of Time to Next On-treatment 
(Moderate/Severe) Exacerbation
EOT, SAC
2.17.
MITT
Example 30
Kaplan-Meier Plot of Time to Next On-treatment 
(Mild/Moderate/Severe) Exacerbation
EOT, SAC
2.18.
MITT
Example 30
Kaplan-Meier Plot of Time to Next On-or Off-treatment 
(Moderate/Severe) Exacerbation During the 12-Week Treatment 
Period
EOT, SAC
 
 
 
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.19.
MITT
Example 30
Kaplan-Meier Plot of Time to Next On-or Off-treatment 
(Mild/Moderate/Severe) Exacerbation During the 12-Week 
Treatment Period
EOT, SAC
2.20.
MITT
Example 30
Kaplan-Meier Plot of Time to Next (Moderate/Severe) 
Exacerbation Following Cessation of Study Treatment
SAC
13.11.7.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.1.
Safety
AE1
Summary of Treatment Emergent Adverse Events by System 
Organ Class and Preferred Term
EOT, SAC
3.2.
Safety
AE1
Summary of Post-Treatment Adverse Events by System Organ 
Class and Preferred Term
SAC
3.3.
Safety
AE3
Summary of Common (>=5%) Treatment Emergent Adverse 
Events by Overall Frequency
EOT, SAC
3.4.
Safety
AE1
Summary of Drug-Related Treatment Emergent Adverse Events 
by System Organ Class and Preferred Term
EOT, SAC
3.5.
Safety
AE15
Summary of Common (>=5%) Non-serious Treatment Emergent 
Adverse Events by System Organ Class and Preferred Term 
(Number of Participant and Occurrences)
SAC
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.6.
Safety
AE1
Summary of Treatment Emergent Adverse Events for 
Participants with Absolute Neutrophil Count Below Lower Value 
of PCI
SAC
Serious and Other Significant Adverse Events
3.7.
Safety
AE16
Summary of Serious Treatment Emergent Adverse Events by 
System Organ Class and Preferred Term (Number of 
Participants and Occurrences)
EOT, SAC
3.8.
Safety
AE16
Summary of Fatal Serious Treatment Emergent Adverse Events 
by System Organ Class and Preferred Term (Number of 
Participants and Occurrences)
Only with subcategory: Number of Fatal 
SAEs
EOT, SAC
3.9.
Safety
AE1
Summary of Serious Treatment Emergent Drug-related Adverse 
Events by System Organ Class and Preferred Term
SAC
3.10.
Safety
AE1 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term
EOT, SAC
3.11.
Safety
AE1
Summary of Post-treatment Serious Adverse Events by System 
Organ Class and Preferred Term
SAC
3.12.
Safety
AE1
Summary of Treatment Emergent Adverse Events of Special 
Interest by Lower Level Term
EOT, SAC
3.13.
Safety
Example 17
Summary of Post-Inhalation Cough by Visit
EOT, SAC
3.14.
Safety
Example 28
Summary of Post-Inhalation Cough by Visit and Cough Type
EOT, SAC
3.15.
Safety
Example 33
Summary of Post-Inhalation (PI) Cough at Any Visit
EOT, SAC
Laboratory: Chemistry 
3.16.
Safety
LB1
Summary of Chemistry Data 
SAC
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.17.
Safety
LB17
Summary of Worst Case Chemistry Results by PCI Criteria 
Post-Baseline Relative to Baseline
EOT, SAC
Laboratory: Hematology
3.18.
Safety
LB1
Summary of Hematology Data
SAC
3.19.
Safety
LB1
Summary of Change from Baseline in Hematology
Only for WBC, lymphocytes, neutrophils
SAC
3.20.
Safety
LB17
Summary of Worst Case Hematology Results by PCI Criteria 
Post-Baseline Relative to Baseline
EOT, SAC
Laboratory: Hepatobiliary (Liver)
3.21.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting
SAC
3.22.
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities
SAC
ECG
3.23.
Safety
EG1
Summary of ECG Findings 
EOT, SAC
3.24.
Safety
EG2
Summary of ECG Values by Visit
For the following parameters: QTcF, 
QTcB, PR, Heart rate 
EOT, SAC
3.25.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit
For the following parameters: QTcF, 
QTcB, PR, Heart rate
SAC
3.26.
Safety
Example 27
Summary of QTcF Categories
SAC
3.27.
Safety
Example 27
Summary of QTcB Categories
SAC
3.28.
Safety
EG10
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category
SAC
3.29.
Safety
EG11
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category
SAC
3.30.
Safety
Example 25
Summary of ECG Abnormalities for Participants with Any 
Abnormal ECG Interpretation
EOT, SAC
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Vital Signs
3.31.
Safety
VS1
Summary of Vital Signs
SAC
3.32.
Safety
VS7
Summary of Worst Case Vital Signs Results by PCI Criteria 
Post-Baseline Relative to Baseline
EOT, SAC
 
 
 
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13.11.8.
Safety Figures
Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory
3.1.
Safety
LB7
LFT Shift from Baseline to Maximum
EOT, SAC
3.2.
Safety
Example 13
Median (range) Absolute Neutrophil Count by Time and 
Treatment
SAC
ECG
3.3.
Safety
EG8
Distribution of QTcF Change by Time and Treatment
SAC
13.11.9.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetic Concentration-Time Data
4.1.
PK
PK01
Summary of Plasma GSK2269557 Pharmacokinetic 
Concentration-Time Data
SAC
4.2.
PK
PK05
Summary of Log-Transformed Plasma GSK2269557 
Pharmacokinetic Concentration-Time Data
SAC
 
 
 
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13.11.10. ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
APE
ES7
Listing of Reasons for Screen Failure
SAC
2.
MITT
ES2
Listing of Reasons for Study Withdrawal
SAC
3.
MITT
SD2
Listing of Reasons for Study Treatment Discontinuation
SAC
4.
MITT
BL1
Listing of Participants for Whom the Treatment Blind was Broken
SAC
5.
MITT
TA1
Listing of Planned and Actual Treatments
SAC
Protocol Deviations
6.
MITT
DV2
Listing of Important Protocol Deviations 
SAC
7.
MITT
IE3
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations
SAC
Populations Analysed
8.
MITT
SP3
Listing of Participants Excluded from Per Protocol Population
For participants excluded from MITT 
population (i.e. participants in the MITT 
but not in PP)
SAC
Demographic and Baseline Characteristics
9.
MITT
DM2
Listing of Demographic Characteristics
SAC
10.
MITT
DM9
Listing of Race
SAC
Prior and Concomitant Medications
11.
MITT
CP_CM3
Listing of Concomitant Medications
SAC
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Exposure and Treatment Compliance
12.
Safety
EX3
Listing of Exposure Data
SAC
Adverse Events
13.
Safety
AE8
Listing of All Adverse Events
SAC
14.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
SAC
15.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
SAC
Serious and Other Significant Adverse Events
16.
Safety
AE8
Listing of Fatal Serious Adverse Events
SAC
17.
Safety
AE8
Listing of Non-Fatal Serious Adverse Events
SAC 
18.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse Event
SAC
19.
Safety
AE8
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
SAC
Hepatobiliary (Liver)
20.
Safety
MH2
Listing of Medical Conditions for Participants with Liver Stopping 
Events
SAC
21.
Safety
SU2
Listing of Substance Use for Participants with Liver Stopping 
Events
SAC
All Laboratory
22.
Safety
LB5
Listing of All Chemistry Data for Participants with Any Value of 
Potential Clinical Importance
SAC
23.
Safety
LB14
Listing of Chemistry Data with Character Results
SAC
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
24.
Safety
LB5
Listing of All Hematology Data for Participants with Any Value of 
Potential Clinical Importance
SAC
25.
Safety
LB14
Listing of all Hematology Data with Character Results
SAC
ECG
26.
Safety
EG3
Listing of All ECG Values for Participants with Any Value of 
Potential Clinical Importance
SAC
27.
Safety
EG5
Listing of All ECG Findings for Participants with an Abnormal 
Finding
SAC
13.11.11. Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
28.
MITT
Example 29
Listing of Subjects who Received Incorrect Medication
SAC
29.
PK
PK07
Listing of Plasma Pharmacokinetic Concentration-Time Data
SAC
30.
Safety
EG5
Listing of All ECG Findings for Subjects with an Abnormal 
Finding
SAC
 
 
 
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13.12.
Appendix 12: Example Mock Shells for Data Displays
13.12.1.
Example shell 1
Example Shell X
Protocol: XYZ100001                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
                             Summary of COPD Exacerbation History at Screening
                                                                  Treatment A  Treatment B   Total
                                                                  (N=100)      (N=100)      (N=200)
   -----------------------------------------------------------------------------------------------------
   Moderate COPD exacerbations
     n                                                            X            X             X
     0                                                            xx (x%)      xx (x%)       xx (x%)    
     1                                                            xx (x%)      xx (x%)       xx (x%)  
     >=2                                                          xx (x%)      xx (x%)       xx (x%)    
   Severe COPD exacerbations
     n                                                            X            X             X
     0                                                            xx (x%)      xx (x%)       xx (x%)
     1                                                            xx (x%)      xx (x%)       xx (x%)
     >=2                                                          xx (x%)      xx (x%)       xx (x%)
   Total number of moderate/severe COPD exacerbations
     n                                                            911          899          1810
     0                                                            313 (34%)    317 (35%)     630 (35%)
     1                                                            252 (28%)    253 (28%)     505 (28%)
     >=2                                                          346 (38%)    329 (37%)     675 (37%)
Note: Number of COPD exacerbations reported in the 12 months prior to the Screening Visit.
 
 
 
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13.12.2.
Example Shell 2
Protocol: XYZ100001                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
Summary of Treatment Compliance
                                                                  Treatment A  Treatment B   Total
                                                                  (N=100)      (N=100)      (N=200)
   -----------------------------------------------------------------------------------------------------
   Overall compliance (%)
     n                                                            xx           xx            xx
     Mean                                                         xx           xx            xx 
     SD                                                           xx           xx            xx 
     Median                                                       xx           xx            xx
     Min.                                                         xx           xx            xx
     Max.                                                         xx           xx            xx
   Compliance interval
     < 80%                                                         xx (x%)      xx (x%)       xx (x%)
     80% - < 100%                                                  xx (x%)      xx (x%)       xx (x%)
     100% - < 120%                                                 xx (x%)      xx (x%)       xx (x%)
     >=120%                                                        xx (x%)      xx (x%)       xx (x%)
 
 
 
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13.12.3.
Example shell 3
Example Shell X
Protocol: ABC123456                                                                            Page 1 of n
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
                             Summary of Change from Baseline in FEV1 (L)
Measured post-bronchodilator
                                              
Visit             N      Treatment Arm       n    Mean    SD      Median  Min.   Max.
----------------------------------------------------------------------------------------------------------
Day 1
200    Placebo             200   0.111  0.1111   0.100  -0.11  1.11
                   200    GSK2269557 12.5 mcg 190   0.222  0.2222   0.200  -0.22  1.22
                   200    GSK2269557   50 mcg 195   0.333  0.3333   0.300  -0.33  1.33
                   200    GSK2269557  100 mcg 195   0.444  0.4444   0.400  -0.44  1.44
                   200    GSK2269557  250 mcg 190   0.555  0.5555   0.500  -0.55  1.55
                   200    GSK2269557  500 mcg 190   0.555  0.5555   0.500  -0.55  1.55
                  200    GSK2269557  750 mcg 190   0.555  0.5555   0.500  -0.55  1.55
Day 14
200    Placebo             200   0.111  0.1111   0.100  -0.11  1.11
                   200    GSK2269557 12.5 mcg 190   0.222  0.2222   0.200  -0.22  1.22
                   200    GSK2269557   50 mcg 195   0.333  0.3333   0.300  -0.33  1.33
                   200    GSK2269557  250 mcg 195   0.444  0.4444   0.400  -0.44  1.44
                   200    GSK2269557  500 mcg 190   0.555  0.5555   0.500  -0.55  1.55
200    GSK2269557  750 mcg 190   0.555  0.5555   0.500  -0.55  1.55
                                              
 
 
 
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13.12.4.
Example Shell 4
Protocol: ABC123456                                                                             Page 1 of 2
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
                        Statistical Analysis of Change from Baseline in FEV1 (ml)
Measured post-bronchodilator
Visit
N
Treatment Arm
n
Posterior 
Median 
95% Credible 
Interval
Day 14
x
Placebo
x
x.xx
(x.xx, x.xx)
x
GSK2269557 12.5 mcg
x
x.xx
(x.xx, x.xx)
x
GSK2269557   50 mcg
x
x.xx
(x.xx, x.xx)
x
GSK2269557  100 mcg
x
x.xx
(x.xx, x.xx)
x
GSK2269557  250 mcg
x
x.xx
(x.xx, x.xx)
x
GSK2269557  500 mcg
x
x.xx
(x.xx, x.xx)
x
GSK2269557  750 mcg
x
x.xx
(x.xx, x.xx)
Day 28
x
Placebo
x
x.xx
(x.xx, x.xx)
x
GSK2269557 12.5 mcg
x
x.xx
(x.xx, x.xx)
x
GSK2269557   50 mcg
x
x.xx
(x.xx, x.xx)
x
GSK2269557  100 mcg
x
x.xx
(x.xx, x.xx)
x
GSK2269557  250 mcg
x
x.xx
(x.xx, x.xx)
x
GSK2269557  500 mcg
x
x.xx
(x.xx, x.xx)
x
GSK2269557  750 mcg
x
x.xx
(x.xx, x.xx)
 
 
 
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Protocol: ABC123456                                                                             Page 2 of 2
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
                        Statistical Analysis of Change from Baseline in FEV1 (ml)
Measured post-bronchodilator
Visit
Treatment Comparison
Adjusted
Median
Difference
Std Dev
95% Credible 
Interval
Prob Treat. 
Diff >0 (%)
Day 14
GSK2269557 12.5 mg vs
x.xx
x.xx
(x.xx, x.xx)
x.xx
Placebo
GSK2269557   50 mg vs
x.xx
x.xx
(x.xx, x.xx)
x.xx
Placebo
GSK2269557 100 mg vs
x.xx
x.xx
(x.xx, x.xx)
x.xx
Placebo
GSK2269557 250 mg vs
x.xx
x.xx
(x.xx, x.xx)
x.xx
Placebo
GSK2269557 500 mg vs
x.xx
x.xx
(x.xx, x.xx)
x.xx
Placebo
GSK2269557 750 mg vs
x.xx
x.xx
(x.xx, x.xx)
x.xx
Placebo
Day 28
GSK2269557 12.5 mg vs
x.xx
x.xx
(x.xx, x.xx)
x.xx
Placebo
GSK2269557   50 mg vs
x.xx
x.xx
(x.xx, x.xx)
x.xx
Placebo
GSK2269557 100 mg vs
x.xx
x.xx
(x.xx, x.xx)
x.xx
Placebo
 
 
 
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13.12.5.
Example Shell 5
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
                                  Summary of On-treatment Exacerbations
                                                                      
                                                               Treatment A       Treatment B
                                                                  (N=100)         (N=100)
        -------------------------------------------------------------------------------------------
        Number of moderate/severe exacerbations per subject                      
         0                                                      50 (50%)       98 (98%)
         1                                                       6  (6%)       15 (15%)
         2                                                       6  (6%)        9  (9%)
         3                                                       1  (1%)        1  (1%)
         4                                                       0              2  (2%)
         5                                                       0              1  (1%)
   >5                                                      0              1  (1%)
        Subjects with >=1 moderate/severe exacerbation         13 (13%)       28 (28%)
        Total Number of moderate/severe exacerbations          21             49
        Number of moderate exacerbations per Subject                      
         0                                                      50 (50%)       98 (98%)
         1                                                       6  (6%)       15 (15%)
         2                                                       6  (6%)        9  (9%)
         3                                                       1  (1%)        1  (1%)
        
 
 
 
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13.12.6.
Example Shell 6
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
                           Statistical Analysis of On-treatment Exacerbations
                                                                      
                                                               Treatment A       Treatment B
                                                                  (N=100)         (N=100)
        -------------------------------------------------------------------------------------------
        Moderate/severe exacerbations
        Annual exacerbation rate (95% CrI)                  0.35 (x.xx, x.xx)   0.30 (x.xx, x.xx)                     
        Active vs. Placebo
          Ratio                                                                 0.85 (x.xx, x.xx)   
          Pr Diff <1                                                            x.xx   
        Percent reduction in rate (95% CrI)                                     15% (x.xx, x.xx)
  Predictive probability (%) [1]  
  xx%
        [only when required] 
        Moderate exacerbations
        Annual exacerbation rate (95% CrI)                  0.35 (x.xx, x.xx)   0.30 (x.xx, x.xx)                     
        Active vs. Placebo
          Ratio                                                                 0.85 (x.xx, x.xx)   
          Pr Diff <1                                                            x.xx   
        Percent reduction in rate (95% CrI)                                     15% (x.xx, x.xx)                          
[1] Predictive posterior probability of success at end of study, where success is Pr(Reduction>0%)>80%
 
 
 
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13.12.7.
Example Shell 7
Protocol: ABC123456                                                                           Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
                                   Summary of COPD Duration at Screening
                                                   
                                                   Treatment A   Treatment B    Total
                                                   (N=100)       (N=100)       (N=200)
                 --------------------------------------------------------------------------
                 Duration of COPD:
                   n                                 100            99          199
                   <1 year                            XX   (x%)     XX   (x%)     XX   (x%)
                   >=1 to <5 years                    XX   (x%)     XX   (x%)     XX   (x%)
                   >=5 to <10 years                   XX   (x%)     XX   (x%)     XX   (x%)
                   >=10 to <15 years                  XX   (x%)     XX   (x%)     XX   (x%)
                   >=15 to <20 years                  XX   (x%)     XX   (x%)     XX   (x%)
                   >=20 to <25 years                  XX   (x%)     XX   (x%)     XX   (x%)
                   >=25 years                         XX   (x%)     XX   (x%)     XX   (x%)
 
 
 
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13.12.8.
Example Shell 8
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
         Summary and Analysis of Time to Next On-treatment Moderate/Severe Exacerbation (days)
                                               up to Day 84
                                                                  Treatment A      Treatment B
                                                                  (N=100)          (N=100)
            ------------------------------------------------------------------------------------
            Number of Subjects with Event                           10  (10%)        14  (14%)
            Number of Subjects Censored                             90  (90%)        86  (86%)
            
            
            Treatment A vs. Placebo
              Hazard Ratio                                           X.XX
              95% Credible Interval                                 (x.xx, x.xx)
              
Note: Hazard ratio and 95% Credible Interval are from a Bayesian Cox proportional hazards model 
 
 
 
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13.12.9.
Example Shell 9
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
            Statistical Analysis of Proportion of Participants Achieving EXACT-definition of Response
                                                                      
                                                               Treatment A       Treatment B
                                                                  (N=100)         (N=100)
        -------------------------------------------------------------------------------------------
        Day 14
          n                                                   x.xx                x.xx                    
          Responder          
  x.xx (x%)           x.xx (x%)                     
          Non-responder                                       x.xx (x%)           x.xx (x%)                     
          Active vs. Placebo
           Odds Ratio (OR) (95% CrI)                              x.xx (x.xx, x.xx)   x.xx (x.xx, x.xx)
           Pr OR >1   
                     x.xx               x.xx
        Day 28
          n                                                   x.xx                x.xx                    
          Responder          
  x.xx (x%)           x.xx (x%)                     
          Non-responder                                       x.xx (x%)           x.xx (x%)                     
          Active vs. Placebo
           Odds Ratio (95% CrI)                                x.xx (x.xx, x.xx)   x.xx (x.xx, x.xx)
           Pr Diff >1   
                     x.xx               x.xx
        
        
        
 
 
 
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13.12.10. Example Shell 10
Protocol: XYZ100001                                                                    Page 1 of n
Population: Intent-to-Treat/Safety/Other study specific
Table X
Summary of severity of subsequent HCRU-defined exacerbation during 12-Week Treatment Period
Treatment
N
n
Mean
SD
Median
Min.
Max.
Placebo
30
30
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Trt A
30
30
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Trt B
30
30
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
 
 
 
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13.12.11. Example Shell 11
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
                        Mixed Model Repeated Measures Analysis of CAT Total Score
                                                                      
                                                               Treatment A       Treatment B
                                                                  (N=100)         (N=100)
        -------------------------------------------------------------------------------------------
        Day 28
          n                                                   x.xx               x.xx                    
          Adjusted mean score change (SE)                     x.xx (x)           x.xx (x)                     
          Active - Placebo
           Difference (SE)                                    x.xx (x.xx)        x.xx (x.xx)
           95% (CrI)                                          x.xx               x.xx
           Pr Diff >0  
                          x.xx               x.xx
        Day 56
          n                                                   x.xx                x.xx                    
          Adjusted mean score change (SE)                     x.xx (x)           x.xx (x)                     
          Active - Placebo
           Difference (SE)                                    x.xx (x.xx)        x.xx (x.xx)
           95% (CrI)                                          x.xx               x.xx
           Pr Diff >0  
                          x.xx               x.xx
        
           
 
 
 
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13.12.12. Example Shell 12
Protocol: ABC123456                                                                             Page 1 of 3
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
             Summary of COPD Related Unscheduled Healthcare Resource Utilization
                                                                        
                                                                        Treatment A    Treatment B
                                                                        (N=100)        (N=100)
        --------------------------------------------------------------------------------------------
          Unscheduled Healthcare Utilisation                Yes          97  (97%)      19  (19%)
                                                            No            3  ( 3%)      81  (81%)
          Number of Home Visits (day)                       n           100            100
                                                            0            90  (90%)      92  (92%)
                                                            1             4   (4%)       4   (4%)
                                                            2             0              0  
                                                            3             0              0
                                                            >3            0              2  (<1%)
                                                            Total [1]     4              4
          Number of Home Visits (night)                     n           100            100
                                                            0           100 (100%)     100 (100%)
                                                            1             0              0  
                                                            2             0              0
                                                            3             0              0
                                                            >3            0              0
                                                            Total [1]     0              0
[1] Total number of contacts across all subjects.
[2] Total number of days across all subjects.
 
 
 
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Protocol: ABC123456                                                                             Page 2 of 3
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
             Summary of COPD Related Unscheduled Healthcare Resource Utilization 
                                                                        
                                                                        Treatment A    Treatment B
                                                                        (N=100)        (N=100)
        --------------------------------------------------------------------------------------------
          Number of Office/Practice Visits                  n           911            899
                                                            0           846  (93%)     808  (90%)
                                                            1            42   (5%)      58   (6%)
                                                            2            13   (1%)      23   (3%)
                                                            3             7  (<1%)       8  (<1%)
                                                            >3            3  (<1%)       2  (<1%)
                                                            Total [1]   103            140
          Number of Urgent Care/Outpatient Visits           n           911            899
                                                            0           886  (97%)     882  (98%)
                                                            1            15   (2%)      10   (1%)
                                                            2             3  (<1%)       2  (<1%)
                                                            3             3  (<1%)       3  (<1%)
                                                            >3            4  (<1%)       2  (<1%)
                                                            Total [1]    54             37
          Number of Emergency Room Visits                   n           911            899
                                                            0           906 (>99%)     893 (>99%)
                                                            1             5  (<1%)       5  (<1%)
                                                            2             0              1  (<1%)
                                                            3             0              0
                                                            >3            0              0
                                                            Total [1]     5              7
[1] Total number of contacts across all subjects.
[2] Total number of days across all subjects.
 
 
 
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Protocol: ABC123456                                                                             Page 3 of 3
Population: Intent-to-Treat/Safety/Other study specific
                                                Table 2.159
             Summary of COPD Related Unscheduled Healthcare Resource Utilization
                                                                        
                                                                        Treatment A    Treatment B
                                                                        (N=100)        (N=100)
        --------------------------------------------------------------------------------------------
          Number of Days in Intensive Care                  n           911            899
                                                            0           910 (>99%)     894 (>99%)
                                                            1             0              0
                                                            2             0              1  (<1%)
                                                            3             0              0
                                                            >3            1  (<1%)       4  (<1%)
                                                            Total [2]    12             40
          Number of Days in General Ward                    n           911            899
                                                            0           896  (98%)     878  (98%)
                                                            1             0              2  (<1%)
                                                            2             1  (<1%)       1  (<1%)
                                                            3             0              0
                                                            >3           14   (2%)      18   (2%)
                                                            Total [2]   119            258
[1] Total number of contacts across all subjects.
[2] Total number of days across all subjects.
 
 
 
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13.12.13. Example shell 13
Protocol: XYZ100001                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific 
       
Figure X
Median (range) Absolute Neutrophil Count by Time and Treatment
 
 
 
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13.12.14. Example Shell 14
Protocol: XYZ100001                                                                             Page 1 of n
Population: Intent-to-Treat/Safety/Other study specific
Table X
Summary of Baseline COPD Maintenance Therapy
Therapy category
Treatment A
(N=81)
Treatment B
(N=79)
Any medication at baseline
70 (86%)
50 (63%)
Monotherapy
X (x%)
X (x%)
  LAMA only
x  (x%)
x  (x%)
Dual therapy                          
x (x%)
x (x%)
  ICS/LABA
x  (x%)
x  (x%)
  Dual bronchodilator
xx (xx%)
xx (xx%)
Triple therapy
X (x%)
    X (x%)
  LAMA/ICS/LABA
x  (x%)
    0
 
 
 
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13.12.15. Example Shell 15
Protocol: XYZ100001                                                                             Page 1 of n
Population: Intent-to-Treat/Safety/Other study specific
Table X
Summary of On-Treatment COPD Maintenance (Step-up) Therapy
Therapy category
Treatment A
(N=81)
Treatment B
(N=79)
Any Step-up Therapy
70 (86%)
50 (63%)
 
 
 
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13.12.16. Example shell 16
Protocol: XYZ100001                                                                             Page 1 of n
Population: Intent-to-Treat/Safety/Other study specific
Table X
Summary of OCS use 
Treatment A
(N=81)
Treatment B
(N=79)
OCS use for index exacerbation
81 (100%)
79 (100%)
  Total number of Days of OCS use
    Mean
Xx
xx
    SD
Xx
xx
    Median
Xx
xx
    Min.
Xx
xx
    Max.
Xx
xx
On-treatment OCS use
xx (xx%)
xx (xx%)
  Total number of Days of OCS use
    Mean
Xx
xx
    SD
Xx
xx
    Median
Xx
xx
    Min.
Xx
xx
    Max.
Xx
xx
 
 
 
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13.12.17. Example Shell 17
Protocol: ABC123456                                                                               Page 1 of x
Population: Safety
                                                 Table X
                                 Summary of Post-Inhalation Cough by Visit
Visit: VISIT 2 (RANDOMISATION)
                                                     GSK2269557 GSK2269557 GSK2269557 GSK2269557 GSK2269557
                                          Placebo    50 mcg     100 mcg    250 mcg    500 mcg    750 mcg
                                          (N=43)     (N=14)     (N=15)     (N=16)     (N=14)     (N=42)
----------------------------------------------------------------------------------------------------------
Did subject experience PI cough? [1]       
  n                                      20         10          12         15          12         35
  Yes                                     7  (35%)   4  (40%)    6  (50%)   3  (20%)    6  (50%)  12  (34%)
  No                                     13  (65%)   6  (60%)   6  (50%)  12  (80%)    6  (50%)  23  (66%)
Type of cough
   Single cough                           4  (57%)   2  (50%)   1  (17%)   1  (33%)   1  (17%)    2  (17%)
   Intermittent cough                     2  (29%)   2  (50%)   5  (83%)   1  (33%)   4  (67%)    5  (42%)
   Continuous cough                       1  (14%)   0          0          1  (33%)   1  (17%)    5  (42%)
Severity of cough
   Mild                                   5  (71%)   3  (75%)   3  (50%)   2  (67%)   1  (17%)    6  (50%)
   Moderate                               2  (29%)   1  (25%)   2  (33%)   1  (33%)   5  (83%)    4  (33%)
   Severe                                 0          0          1  (17%)   0          0           2  (17%)
Time to onset of PI cough (minutes)
   0-1                                    6  (86%)   3  (75%)   6 (100%)   3 (100%)   6 (100%)   12 (100%)
   >1-2                                   1  (14%)   1  (25%)   0          0          0           0
   >2-3                                   0          0          0          0          0           0
   >3-4                                   0          0          0          0          0           0
   >4-5                                   0          0          0          0          0           0
   >5                                     0          0          0          0          0           0
Duration of PI cough (minutes)
   <=1                                    6  (86%)   3  (75%)   5  (83%)   3 (100%)   5  (83%)   11  (92%)
   >1-2                                   1  (14%)   1  (25%)   1  (17%)   0          1  (17%)    1   (8%)
   >2-3                                   0          0          0          0          0           0
   >3-4                                   0          0          0          0          0           0
   >4-5                                   0          0          0          0          0           0
 
 
 
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   >5-10                                  x          x
   >10-30                                 x          x
   >30                                    x          x
Number of subjects reporting cough as
AE/SAE                                   2  (29%)   1  (25%)   4  (67%)   0          2  (33%)    3  (25%)
   Mild                                   x  (x%)    x
   Moderate                               x  (x%)    x
   Severe                                 x  (x%)    x
[1] Percentages are calculated using the number of subjects evaluated at visit as the denominator.
All other percentages are calculated using the number of subjects with a PI cough at visit as the denominator.
 
 
 
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13.12.18. Example shell 18
Protocol: ABC123456                                                                             Page 1 of x
Population: Intent-to-Treat/Safety/Other study specific
                                                 Figure X
Plot of Dose Response Model of Change from Baseline in FEV1 
[Footnote to describe the fitted model]
 
 
 
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13.12.19. Example Shell 19
Protocol: ABC123456                                                                             Page 1 of 3
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
             Summary of COPD Related Unscheduled Healthcare Resource Utilization
                                                                        
                                                                        Treatment A    Treatment B
                                                                        (N=100)        (N=100)
        --------------------------------------------------------------------------------------------
          Unscheduled Healthcare Utilisation                Yes          97  (97%)      19  (19%)
                                                            No            3  ( 3%)      81  (81%)
          Number of Home Visits (day)                       n           100            100
                                                            0            90  (90%)      92  (92%)
                                                            1             4   (4%)       4   (4%)
                                                            2             0              0  
                                                            3             0              0
                                                            >3            0              2  (<1%)
                                                            Total [1]     4              4
          Number of Home Visits (night)                     n           100            100
                                                            0           100 (100%)     100 (100%)
                                                            1             0              0  
                                                            2             0              0
                                                            3             0              0
                                                            >3            0              0
                                                            Total [1]     0              0
[1] Total number of contacts across all subjects.
[2] Total number of days across all subjects.
 
 
 
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Protocol: ABC123456                                                                             Page 2 of 3
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
             Summary of COPD Related Unscheduled Healthcare Resource Utilization 
                                                                        
                                                                        Treatment A    Treatment B
                                                                        (N=100)        (N=100)
        --------------------------------------------------------------------------------------------
          Number of Office/Practice Visits                  n           911            899
                                                            0           846  (93%)     808  (90%)
                                                            1            42   (5%)      58   (6%)
                                                            2            13   (1%)      23   (3%)
                                                            3             7  (<1%)       8  (<1%)
                                                            >3            3  (<1%)       2  (<1%)
                                                            Total [1]   103            140
          Number of Urgent Care/Outpatient Visits           n           911            899
                                                            0           886  (97%)     882  (98%)
                                                            1            15   (2%)      10   (1%)
                                                            2             3  (<1%)       2  (<1%)
                                                            3             3  (<1%)       3  (<1%)
                                                            >3            4  (<1%)       2  (<1%)
                                                            Total [1]    54             37
          Number of Emergency Room Visits                   n           911            899
                                                            0           906 (>99%)     893 (>99%)
                                                            1             5  (<1%)       5  (<1%)
                                                            2             0              1  (<1%)
                                                            3             0              0
                                                            >3            0              0
                                                            Total [1]     5              7
[1] Total number of contacts across all subjects.
[2] Total number of days across all subjects.
 
 
 
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Protocol: ABC123456                                                                             Page 3 of 3
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
             Summary of COPD Related Unscheduled Healthcare Resource Utilization
                                                                        
                                                                        Treatment A    Treatment B
                                                                       (N=100)        (N=100)
        --------------------------------------------------------------------------------------------
          Number of Days in Intensive Care                  n           911            899
                                                            0           910 (>99%)     894 (>99%)
                                                            1             0              0
                                                            2             0              1  (<1%)
                                                            3             0              0
                                                            >3            1  (<1%)       4  (<1%)
                                                            Total [2]    12             40
          Number of Days in General Ward                    n           911            899
                                                            0           896  (98%)     878  (98%)
                                                            1             0              2  (<1%)
                                                            2             1  (<1%)       1  (<1%)
                                                            3             0              0
                                                            >3           14   (2%)      18   (2%)
                                                            Total [2]   119            258
[1] Total number of contacts across all subjects.
[2] Total number of days across all subjects.
 
 
 
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13.12.20. Example Shell 20
Protocol: ABC123456                                                                             Page 1 of x
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
             Summary of Non-COPD Related Unscheduled Healthcare Resource Utilization
                                                                        
                                                                        Treatment A    Treatment B
                                                                        (N=100)        (N=100)
        --------------------------------------------------------------------------------------------
         Unscheduled Healthcare Utilisation                Yes          97  (97%)      19  (19%)
                                                            No            3  ( 3%)      81  (81%)
          Number of Days in Accident and emergency          n           100            100
                                                            0            90  (90%)      92  (92%)
                                                            1             4   (4%)       4   (4%)
                                                            2             0              0  
                                                            3             0              0
                                                            >3            0              2  (<1%)
                                                            Total         4              4
          Number of Days in General Ward                    n           100            100
                                                            0           100 (100%)     100 (100%)
                                                            1             0              0  
                                                            2             0              0
                                                            3             0              0
                                                            >3            0              0
                                                            Total         0              0
 
 
 
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13.12.21. Example Shell 21
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
Summary of Exacerbation Related Hospitalizations
                                                                      
                                                               Treatment A       Treatment B
                                                                  (N=100)         (N=100)
        -------------------------------------------------------------------------------------------
        Index exacerbation
          Participants with hospitalization                   x.xx               x.xx                    
          Number of hospitalizations          
  x.xx               x.xx                      
          Mean duration (days)                                x.xx               x.xx                      
          SD                                                  x.xx               x.xx
          Median duration (days)                              x.xx               x.xx
          Minimum duration (days)                             x.xx               x.xx
          Maximum duration (days)                             x.xx               x.xx                      
        Subsequent exacerbations
          Participants with hospitalization                   x.xx               x.xx                    
          Number of hospitalizations          
  x.xx               x.xx                      
          Mean duration (days)                                x.xx               x.xx                      
          SD                                                  x.xx               x.xx
          Median duration (days)                              x.xx               x.xx
          Minimum duration (days)                             x.xx               x.xx
          Maximum duration (days)                             x.xx               x.xx                              
        
      
 
 
 
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13.12.22. Example Shell 22
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
Summary of Re-hospitalization Within 30 days of Index Exacerbation
                                                                        
                                                                        Treatment A    Treatment B
                                                                        (N=100)        (N=100)
        --------------------------------------------------------------------------------------------
          Re-hospitalization Within 30 days                 Yes          97  (97%)      19  (19%)
                                                            No            3  ( 3%)      81  (81%)
          
 
 
 
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13.12.23. Example Shell 23
Protocol: XYZ100001                                                                             Page 1 of n
Population: Intent-to-Treat/Safety/Other study specific
Table X
Summary of Subsequent Exacerbation Treatment
Treatment A
(N=81)
Treatment B
(N=79)
Subsequent exacerbation
70 (86%)
50 (63%)
OCS
X (x%)
X (x%)
Antibiotics                           
x (x%)
x (x%)
OCS and antibiotics
X (x%)
    X (x%)
 
 
 
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13.12.24. Example Shell 24
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
Summary of Time from Resolution of Index Exacerbation to Next Exacerbation
                                                                      
                                                               Treatment A       Treatment B
                                                                  (N=100)         (N=100)
        -------------------------------------------------------------------------------------------
          Subsequent exacerbation                             x.xx               x.xx                    
          
          Mean duration (days)                                x.xx               x.xx                      
          SD                                                  x.xx               x.xx
          Median duration (days)                              x.xx               x.xx
          Minimum duration (days)                             x.xx               x.xx
          Maximum duration (days)                             x.xx               x.xx                      
        
        
        
 
 
 
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13.12.25. Example Shell 25
Protocol: ABC123456                                                                             Page 1 of x
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
Summary of ECG Abnormalities for Participants with Any Abnormal Clinically Significant ECG Interpretation
                                                                      
                                                               Treatment A       Treatment B
                                                                  (N=100)         (N=100)
        -------------------------------------------------------------------------------------------
        Visit 2 (Day 1)
         Abnormal – Clinically significant                        10 (10%)       15 (15%)
           Any finding                                             5 (50%)        5 (33%)
           ST depression                                           5 (50%)        5 (33%)
           Short PR Interval                                       0              5 (33%)
           T wave inversion                                        0              5 (33%)
           …….
Includes Scheduled, unscheduled and Early Withdrawal visits.
Participants may have more than one abnormality at each visit. 
 
 
 
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13.12.26. Example Shell 26
Protocol: ABC123456   
Page 1 of n
Population: Intent-to-Treat/Safety/Other study specific
Table X
Statistical Analysis of Change from Baseline in FEV1 (mL) (Dose Response Model)
Measured post-bronchodilator
Placebo
(N=xx)
DNX 5mg
(N=xx)
DNX 10mg
(N=xx)
DNX 25mg
(N=xx)
DNX 35mg
(N=xx)
DNX 50mg
(N=xx)
n [1]
xx
xx
xx
xx
xx
xx
Posterior Adj. Median Change
x.xx
x.xx
x.xx
x.xx
x.xx
x.xx 
95% HPD Credible Interval 
(x.xx,x.xx)
(x.xx,x.xx)
(x.xx,x.xx)
(x.xx,x.xx)
(x.xx,x.xx)
(x.xx,x.xx)
Active - Placebo  
  Posterior Adj. Median 
Difference
x.xx
x.xx
x.xx
x.xx
x.xx
  95% HPD Credible Interval
(x.xx, 
x.xx)
(x.xx, 
x.xx)
(x.xx, 
x.xx)
(x.xx, 
x.xx)
(x.xx, 
x.xx)
  Prob(Difference>0) 
xx%
xx%
xx%
xx%
xx%
  Predictive probability (%) [2] 
[only if required]
xx%
xx%
xx%
xx%
xx%
[1] Number of subjects with data contributing to the analysis.
[2] Predictive posterior probability of success at end of study, where success is Pr(Difference>0)>90%.
Note: Model fitted was a…..[insert as appropriate]. 
 
 
 
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13.12.27. Example Shell 27
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
Summary of QTc(F) (msec) Categories
                                                                  Treatment A      Treatment B
                                                                  (N=100)          (N=100)
            ------------------------------------------------------------------------------------
            Screening                                           
              n                                                    xx               xx   
              <=450                                                xx  (xx%)        xx  (xx%) 
              >450 to <=480                                        xx  (xx%)        xx  (xx%)
              >480 to <=500                                        xx  (xx%)        xx  (xx%)
              >500                                                 xx  (xx%)        xx  (xx%)
            
            Day 1 (Baseline)                                          
              n                                                    xx               xx   
              <=450                                                xx  (xx%)        xx  (xx%) 
              >450 to <=480                                        xx  (xx%)        xx  (xx%)
              >480 to <=500                                        xx  (xx%)        xx  (xx%)
              >500                                                 xx  (xx%)        xx  (xx%)
             Day 14                                          
              n                                                    xx               xx   
              <=450                                                xx  (xx%)        xx  (xx%) 
              >450 to <=480                                        xx  (xx%)        xx  (xx%)
              >480 to <=500                                        xx  (xx%)        xx  (xx%)
              >500                                                 xx  (xx%)        xx  (xx%)
 
 
 
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13.12.28. Example Shell 28
Protocol: ABC123456                                                                             Page 1 of x
Population: Safety
                                                 Table X
                         Summary of Post-Inhalation Cough by Visit and Cough Type
                                                                      
          Visit 2 (Day 1)                             
          Type of cough: Single cough                        Treatment A       
                                                                (N=100)         
        -------------------------------------------------------------------------------------------
         
           Did subject experience event [1]?                           12 (24%)        
           Cough severity              
             Mild                                                    6 (50%)       
             Moderate                                                5 (42%)        
             Severe                                                  1 (8%)             
           Time to onset of PI cough (minutes)                      
             0-1                                                     2(17%)          
             >1-2                                                    3(25%)          
             >2-3                                                    4(33%)          
             >3-4                                                    3(25%)          
             >4-5                                                    0          
             >5                                                      0  
       
           Duration of PI cough (minutes)                      
             <=1                                                     7(58%)          
             >1  - 2                                                 2(17%)          
             >2  - 3                                                 3(25%)          
             >3  - 4                                                 0          
             >4  - 5                                                 0          
             >5  - 10                                                0          
             >10 - 30                                                0          
             >30                                                     0         
[1] Percentages are calculated using the number of subjects evaluated at visit as the denominator.
All other percentages are calculated using the number of subjects with particular cough type at visit as the 
denominator.
 
 
 
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Protocol: ABC123456                                                                             Page 2 of x
Population: Safety
                                                 Table X
                         Summary of Post-Inhalation Cough by Visit and Cough Type
                                                                      
          Visit 2 (Day 1)                                           
          Type of cough: Single cough                        Treatment A            
                                                              (N=100)         
        -------------------------------------------------------------------------------------------
   Number of subjects reporting cough as AE/SAE              4 (33%)  
      Mild                                                   2 (17%)
      Moderate                                               2 (17%)
      Severe                                                 0
 
 
 
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Protocol: ABC123456                                                                             Page 3 of x
Population: Safety
                                                 Table X
                           Summary of Post-Inhalation Cough by Visit and Cough Type
                                                                      
          Visit 2 (Day 1)                                           
          Type of cough: Intermittent cough                        Treatment A     
                                                                    (N=100)         
        -------------------------------------------------------------------------------------------
                      
           Did subject experience event [1]?                           11 (22%)        
           Cough severity              
             Mild                                                    2 (18%)       
             Moderate                                                6 (55%)        
             Severe                                                  3 (27%)             
           Time to onset of PI cough (minutes)                      
             0-1                                                     1(9%)          
             >1-2                                                    4(36%)          
             >2-3                                                    6(55%)          
             >3-4                                                    0          
             >4-5                                                    0          
             >5                                                      0    
     
           Duration of PI cough (minutes)                      
             <=1                                                     0          
             >1  - 2                                                 3(27%)          
             >2  - 3                                                 6(55%)          
             >3  - 4                                                 1(9%)          
             >4  - 5                                                 0          
             >5  - 10                                                0          
             >10 - 30                                                1(9%)      
             >30                                                     0        
   
 
 
 
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Protocol: ABC123456                                                                             Page 4 of x
Population: Safety
                                                 Table X
                      Summary of Post-Inhalation Cough by Visit and Cough Type
                                                                      
          Visit 2 (Day 1)                                              
          Type of cough: Intermittent cough                      Treatment A              
                                                                  (N=100)         
        -------------------------------------------------------------------------------------------
   Number of subjects reporting cough as AE/SAE              5 (45%)  
      Mild                                                   1 (9%)
      Moderate                                               2 (18%)
      Severe                                                 2 (18%)
 
 
 
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Protocol: ABC123456                                                                             Page 5 of x
Population: Safety
                                                 Table X
                      Summary of Post-Inhalation Cough by Visit and Cough Type
                                                                      
          Visit 2 (Day 1)                                       
          Type of cough: Continuous cough                      Treatment A                   
                                                                  (N=100)         
        -------------------------------------------------------------------------------------------
                    
           Did subject experience event [1]?                            4 (8%)        
           Cough severity              
             Mild                                                    1 (25%)       
             Moderate                                                2 (50%)        
             Severe                                                  1 (25%)             
           Time to onset of PI cough (minutes)                      
             0-1                                                     3(75%)          
             >1-2                                                    1(25%)          
             >2-3                                                    0          
             >3-4                                                    0          
             >4-5                                                    0          
             >5                                                      0   
      
           Duration of PI cough (minutes)                      
             <=1                                                     0         
             >1  - 2                                                 0          
             >2  - 3                                                 0 
             >3  - 4                                                 1 (25%)                    
             >4  - 5                                                 1 (25%)                   
             >5  - 10                                                0          
             >10 - 30                                                1 (25%)                   
             >30                                                     1 (25%)                   
   
 
 
 
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Protocol: ABC123456                                                                             Page 6 of x
Population: Safety
                                                 Table X
                        Summary of Post-Inhalation Cough by Visit and Cough Type
                                                                      
          Visit 2 (Day 1)                                      
          Type of cough: Continuous cough                      Treatment A                         
                                                                  (N=100)         
        -------------------------------------------------------------------------------------------
  Number of subjects reporting cough as AE/SAE              2 (50%)  
      Mild                                                   1 (25%)
      Moderate                                               1 (25%)
      Severe                                                 0
REPEAT FOR EACH VISIT
 
 
 
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13.12.29. Example Shell 29
Protocol: MID200879                                                                              Page 1 of 1
Population: Intent-to-Treat
                                                Listing X
                           Listing of Subjects who Received Incorrect Medication
                             Start      End                                              Actual
Randomized         Centre/   Date of    Date of    Duration                   Dispense   Treatment
Treatment          Subj      Dosing     Dosing     (Days)   Dispense Visit    Date       Dispensed
------------------------------------------------------------------------------------------------------------
GSK2269557 500 mcg 
  XXXXXXXXX  XXXXXXXXX    XX     Visit 3 (Week 0)  XXFEB2013  GSK2269557 500 mcg
                   
                                                              
                             XXXXXXXXX  XXXXXXXXX    XX     Visit 5 (Week 4)  XXMAR2013  GSK2269557 100 mcg
                             XXXXXXXXX  XXXXXXXXX    XX     Visit 6 (Week 8)  XXAPR2013  GSK2269557 500 mcg
 
 
 
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13.12.30. Example Shell 30
Protocol: ABC123456                                                                             Page 1 of x
Population: Intent-to-Treat/Safety/Other study specific
                                                 
Figure X
Kaplan-Meier Plot of Time to Next On-treatment Exacerbation During the 12-Week Treatment Period
 
 
 
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13.12.31. Example Shell 31
Protocol: ABC123456                                                                             Page 1 of x
Population: Intent-to-Treat/Safety/Other study specific
                                                 
Figure X
Plot of Repeated Measures Model of Change from Baseline in FEV1 Measured Post-bronchodilator
 
 
 
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13.12.32. Example Shell 32
Protocol: XYZ100001                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
                             Summary of Efficiency Ratio for Possible Adaptions to Randomization Ratio 
                                                                  
                                                                  Median      10th Percentile
   -----------------------------------------------------------------------------------------------------
   
     Design 1: Add 25mcg dose                                     xx           xx
     Design 2: Add 25mcg dose, drop 500mcg dose                   xx           xx    
     Design 3: Add 25mcg dose, drop 250 mcg and 500 mcg doses     xx           xx
    Design 4: Drop 12.5mcg dose                                  xx           xx
     Design 5: Drop 12.5mcg and 50mcg doses                       xx           xx
   
 
 
 
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13.12.33. Example Shell 33
Protocol: ABC123456                                                                               Page 1 of x
Population: Safety
                                                 Table X
                                   Summary of Post-Inhalation (PI) Cough at Any Visit
                                                     GSK2269557 GSK2269557 GSK2269557 GSK2269557 GSK2269557
                                          Placebo    50 mcg     100 mcg    250 mcg    500 mcg    750 mcg
                                          (N=43)     (N=14)     (N=15)     (N=16)     (N=14)     (N=42)
----------------------------------------------------------------------------------------------------------
Did subject experience PI cough at any visit?        
  Yes                                     X  (xx%)   X  (xx%)   X  (xx%)   X  (xx%)    X  (xx%)  X  (xx%)
  No                                      X  (xx%)   X  (xx%)   X  (xx%)  X  (xx%)    X  (xx%)  X  (xx%)
Maximum Severity of cough
   Mild                                   X  (xx%)   X  (xx%)   X  (xx%)   X  (xx%)   X  (xx%)    X  (xx%)
   Moderate                               X  (xx%)   X  (xx%)   X  (xx%)   X  (xx)   X  (xx%)    X  (xx%)
   Severe                                 0          0          X  (xx%)   0          0           X  (xx%)
Maximum Duration of PI cough (minutes)[1]
   Mean                                    x         x          x          x          x           x
   SD                                      x         x          x          x          x           x   
   Median                                  x         x          x          x          x           x
   Minimum                                 x         x          x          x         x           x
   Maximum                                 x         x          x          x          x           x
   
Number of occurrences of PI cough
   0                                       x         x          x          x          x           x
   1                                       x         x          x          x          x           x   
   2                                       x         x          x          x          x           x
   3                                       x         x          x          x          x           x
   4                                       x         x          x          x          x           x
   
[1] Duration from the maximum severity cough
 
 
 
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CONFIDENTIAL
The GlaxoSmithKline group of companies
200879
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for 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)
Compound Number 
:
GSK2269557
Effective Date 
:
08-MAR-2018
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 200879 and at the planned interim 
analyses.

This RAP is intended to describe the efficacy, safety and pharmacokinetic analyses 
required for the study. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
 
Statistics Leader, (Respiratory Clinical Statistics)
Approver
Date
Approval Method
07-MAR-2018
Email
TA Director (Respiratory Clinical Statistics)
08-MAR-2018
Email
Programming Manager (Respiratory Clinical 
Programming)
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
 
 
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RAP Team Approvals:
Approver
Date
Approval Method
07-MAR-2018
Email
Principal Programmer (Respiratory Clinical 
Programming)
07-MAR-2018
Email
Clinical Development Director (Respiratory)
06-MAR-2018
Email
Clinical Development Manager (Respiratory)
06-MAR-2018
Email
Medical Director (Global Clinical Safety and 
Pharmacovigilance)
06-MAR-2018
Email
Manager, Clinical Pharmacology (Clinical 
Pharmacology Modelling and Simulation)
02-MAR-2018
Email
Director, Patient Centred Outcomes (Value 
Evidence & Outcomes)
 
 
 
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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................8
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................8
2.1.
Study Objective(s) and Endpoint(s)...............................................................8
2.2.
Study Design ..............................................................................................11
3.
PLANNED ANALYSES ..........................................................................................11
3.1.
Interim Analyses .........................................................................................11
3.1.1.
Futility analyses ...........................................................................13
3.1.1.1.
Futility rules ................................................................14
3.2.
Final Analyses ............................................................................................14
4.
ANALYSIS POPULATIONS ...................................................................................15
4.1.
Protocol Deviations.....................................................................................15
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................16
5.1.
Study Treatment & Sub-group Display Descriptors.....................................16
5.2.
Baseline Definitions ....................................................................................16
5.3.
Multicentre Studies .....................................................................................17
5.4.
Examination of Covariates and Subgroups .................................................17
5.4.1.
Covariates ...................................................................................17
5.4.2.
Examination of Subgroups...........................................................18
5.5.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................19
6.
STUDY POPULATION ANALYSES .......................................................................19
6.1.
Overview of Planned Study Population Analyses........................................19
6.1.1.
Concomitant medications.............................................................19
7.
EFFICACY ANALYSES..........................................................................................20
7.1.
Primary Efficacy Analyses ..........................................................................20
7.1.1.
Primary Endpoint .........................................................................20
7.1.2.
Primary Statistical Analyses.........................................................20
7.1.2.1.
Model Checking & Diagnostics ...................................22
7.1.3.
Sensitivity and Supportive Analyses ............................................22
7.1.4.
Subgroup Analyses......................................................................22
7.2.
Secondary Efficacy Analyses......................................................................23
7.2.1.
Rate of exacerbations..................................................................23
7.2.1.1.
Statistical analyses.....................................................24
7.2.1.2.
Subgroup analyses.....................................................24
7.2.1.3.
Exploratory analyses ..................................................24
7.2.2.
Time to next exacerbation............................................................25
7.2.2.1.
Statistical analyses.....................................................25
7.2.2.2.
Subgroup analyses.....................................................26
7.2.3.
Change from baseline in Clinic Visit trough FEV1.........................26
7.2.3.1.
Statistical Analyses.....................................................26
7.2.3.2.
Subgroup analyses.....................................................26
7.2.4.
Change from hospital discharge in clinic visit trough FEV1...........26
 
 
 
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7.2.4.1.
Statistical analyses.....................................................27
7.2.5.
EXAcerbations of Chronic Pulmonary Disease Tool -
Patient Reported Outcome (EXACT) ...........................................27
7.2.5.1.
Proportion of participants achieving EXACT-
defined recovery from index exacerbation ..................28
7.2.5.2.
Time to EXACT-defined recovery from index 
exacerbation...............................................................28
7.2.5.3.
Severity of subsequent HCRU-defined 
exacerbation(s) defined by EXACT.............................28
7.2.5.4.
Statistical analyses.....................................................29
7.2.5.5.
Subgroup analyses.....................................................29
7.2.5.6.
Sensitivity and supportive analyses............................29
7.2.6.
COPD Assessment Test (CAT)....................................................30
7.2.6.1.
Proportion of responders using the CAT.....................30
7.2.6.2.
Change from baseline in CAT Total Score..................30
7.2.6.3.
Statistical analyses.....................................................31
7.2.6.4.
Subgroup analyses.....................................................31
7.2.7.
St. George’s Respiratory Questionnaire for COPD 
Patients (SGRQ-C)......................................................................31
7.2.7.1.
Proportion of responders on the SGRQ Total 
Score..........................................................................32
7.2.7.2.
Change from baseline in SGRQ Total Score ..............32
7.2.7.3.
Statistical analyses.....................................................33
7.2.7.4.
Subgroup analyses.....................................................33
7.2.8.
Rescue medication use................................................................33
7.2.8.1.
Rescue medication use via the clip-on 
Propeller Sensor for MDI ............................................34
7.2.8.2.
Statistical analyses.....................................................34
7.3.
Exploratory Efficacy Analyses.....................................................................35
7.3.1.
Change from Day 84 in Clinic Visit trough FEV1...........................35
7.3.1.1.
Statistical analysis ......................................................35
7.3.2.
E-RS:COPD (Evaluating Respiratory Symptoms in COPD) .........35
7.3.3.
Measures of HCRU related to exacerbations...............................35
7.3.3.1.
Re-hospitalisation within 30 days of index 
exacerbation...............................................................36
7.3.3.2.
Time from resolution of index exacerbation to 
next exacerbation .......................................................36
7.3.3.3.
Subsequent exacerbation treatment type ...................36
7.3.4.
Compliance..................................................................................36
7.3.4.1.
Number of actuations of double-blind study 
treatment measured by the clip-on Propeller 
Sensor........................................................................37
7.3.5.
Inflammatory/infective markers in blood and sputum in 
relation to acute exacerbation of COPD.......................................37
7.3.6.
Other spirometry measurements..................................................37
7.3.7.
Other PRO symptoms suggestive of exacerbation.......................37
8.
SAFETY ANALYSES .............................................................................................37
8.1.
Adverse Events Analyses ...........................................................................37
8.1.1.
Adverse Events of Special Interest ..............................................37
8.1.1.1.
Post-inhalation Cough Immediately Following 
Dosing........................................................................37
 
 
 
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8.2.
Clinical Laboratory Analyses.......................................................................38
8.3.
Other Safety Analyses ................................................................................38
8.4.
Mortality......................................................................................................38
9.
PHARMACOKINETIC ANALYSES.........................................................................38
9.1.
Population of Interest..................................................................................38
9.2.
Drug Concentration Measures ....................................................................38
10. POPULATION PK ANALYSIS ................................................................................39
10.1.
Derived Pharmacokinetic Parameters.........................................................39
11. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES .................................39
12. REFERENCES.......................................................................................................40
13. APPENDICES........................................................................................................41
13.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................41
13.1.1.
Exclusions from Per Protocol Population .....................................41
13.2.
Appendix 2: Assessment Windows .............................................................42
13.2.1.
Definitions of Assessment Windows for Analyses........................42
13.2.1.1.
Hospital discharge......................................................42
13.2.1.2.
EXACT-Defined Recovery for CAT Trigger.................43
13.3.
Appendix 3: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................44
13.3.1.
Study Periods ..............................................................................44
13.3.1.1.
12-Week Treatment Period.........................................44
13.3.1.2.
12-Week Follow-Up Period.........................................44
13.3.2.
Study Phases ..............................................................................44
13.3.2.1.
Study Phases for Concomitant Medication .................44
13.3.3.
Treatment Emergent Flag for Adverse Events .............................44
13.4.
Appendix 4: Data Display Standards & Handling Conventions....................45
13.4.1.
Reporting Process .......................................................................45
13.4.2.
Reporting Standards....................................................................45
13.4.3.
Reporting Standards for Pharmacokinetic....................................46
13.5.
Appendix 5: Derived and Transformed Data ...............................................47
13.5.1.
General........................................................................................47
13.5.2.
Study Population..........................................................................47
13.5.3.
Safety ..........................................................................................47
13.6.
Appendix 6: Reporting Standards for Missing Data.....................................48
13.6.1.
Premature Withdrawals................................................................48
13.6.2.
Handling of Missing Data.............................................................48
13.6.2.1.
Handling of Missing and Partial Dates ........................48
13.7.
Appendix 7: Values of Potential Clinical Importance ...................................50
13.7.1.
Laboratory Values........................................................................50
13.7.2.
ECG.............................................................................................51
13.7.3.
Vital Signs....................................................................................51
13.8.
Appendix 8: Population Pharmacokinetic (PopPK) Analyses ......................52
13.8.1.
Population Pharmacokinetic (PopPK) Methodology.....................52
13.8.2.
Population Pharmacokinetic (PopPK) Dataset 
Specification ................................................................................52
13.9.
Appendix 9: Pharmacokinetic / Pharmacodynamic Analyses ......................54
 
 
 
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13.9.1.
Pharmacokinetic/Pharmacodynamic Methodology.......................54
13.10. Appendix 10: Abbreviations & Trade Marks ................................................55
13.10.1. Abbreviations...............................................................................55
13.10.2. Trademarks .................................................................................56
13.11. Appendix 11: List of Data Displays..............................................................57
13.11.1. Data Display Numbering..............................................................57
13.11.2. Mock Example Shell Referencing ................................................57
13.11.3. Deliverables.................................................................................57
13.11.4. Study Population Tables..............................................................58
13.11.5. Efficacy Tables ............................................................................60
13.11.5.1. Efficacy tables for Interim Analysis 1 ..........................60
13.11.5.2. Efficacy tables for Interim Analysis 2 ..........................63
13.11.5.3. Efficacy tables for End of Treatment Interim 
Analysis and SAC.......................................................67
13.11.6. Efficacy Figures ...........................................................................79
13.11.6.1. Efficacy Figures for Interim Analysis 1........................79
13.11.6.2. Efficacy Figures for Interim Analysis 2........................80
13.11.6.3. Efficacy Figures for End of Treatment Interim 
Analysis and SAC.......................................................82
13.11.7. Safety Tables...............................................................................84
13.11.8. Safety Figures .............................................................................87
13.11.9. Pharmacokinetic Tables...............................................................87
13.11.10.ICH Listings .................................................................................88
13.11.11.Non-ICH Listings..........................................................................90
13.12. Appendix 12: Example Mock Shells for Data Displays ................................91
13.12.1. Example shell 1 ...........................................................................91
13.12.2. Example Shell 2...........................................................................92
13.12.3. Example shell 3 ...........................................................................93
13.12.4. Example Shell 4...........................................................................94
13.12.5. Example Shell 5...........................................................................96
13.12.6. Example Shell 6...........................................................................97
13.12.7. Example Shell 7...........................................................................98
13.12.8. Example Shell 8...........................................................................99
13.12.9. Example Shell 9.........................................................................100
13.12.10.Example Shell 10.......................................................................101
13.12.11.Example Shell 11.......................................................................102
13.12.12.Example Shell 12.......................................................................103
13.12.13.Example shell 13 .......................................................................106
13.12.14.Example Shell 14.......................................................................107
13.12.15.Example Shell 15.......................................................................108
13.12.16.Example shell 16 .......................................................................109
13.12.17.Example Shell 17.......................................................................110
13.12.18.Example shell 18 .......................................................................112
13.12.19.Example Shell 19.......................................................................113
13.12.20.Example Shell 20.......................................................................116
13.12.21.Example Shell 21.......................................................................117
13.12.22.Example Shell 22.......................................................................118
13.12.23.Example Shell 23.......................................................................119
13.12.24.Example Shell 24.......................................................................120
13.12.25.Example Shell 25.......................................................................121
13.12.26.Example Shell 26.......................................................................122
13.12.27.Example Shell 27.......................................................................123
 
 
 
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13.12.28.Example Shell 28.......................................................................124
13.12.29.Example Shell 29.......................................................................130
 
 
 
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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol 200879.
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To characterise 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
Secondary Objectives
Secondary Endpoints

To characterise 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 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)

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
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 
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Objectives
Endpoints
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

To evaluate the usage of rescue 
medication in patients diagnosed with 
an acute moderate or severe 
exacerbation of COPD

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

To evaluate the population 
pharmacokinetics of nemiralisib in 
participants diagnosed with an acute 
moderate or severe exacerbation of 
COPD

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

To assess the safety and tolerability of 
nemiralisib and placebo in participants 
diagnosed with an acute moderate or 
severe exacerbation of COPD

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 Objectives
Exploratory Endpoints

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 and severe 
combined)
 
 
 
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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

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)

To explore the PK/PD relationship for 
nemiralisib

Relationship between drug exposure and 
Pharmacodynamic responses (e.g. efficacy, heart rate, 
clinical laboratory analytes and blood biomarkers) in the 
PK subset of participants (approximately 300) at selected 
sites

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

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.)

To evaluate compliance with study 
treatment

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)

To evaluate inflammatory markers in 
blood in relation to acute exacerbation 
of COPD

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)

To evaluate inflammatory and 
infective markers in sputum in relation 
to acute exacerbation of COPD

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

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 postbronchodilator 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 
 
 
 
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Objectives
Endpoints
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
2.2.
Study Design
This is a Phase IIb, multicenter, randomized, stratified (by index COPD exacerbation
severity [moderate or severe] and by whether or not the participant is in the PK
Subgroup), double-blind (Sponsor Open), placebo-controlled, parallel-group study in
participants who present with an acute moderate or severe exacerbation of COPD
requiring Standard of Care (SoC).
This study consists of a Screening Period, a 12-Week Treatment Period and a 12-Week
Post-Treatment Follow-Up Period. 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 
measures, including the EXACT-PRO questionnaire for the day of randomization, and 
FEV1 measurement and no later than 48 hours after the start of SoC.
PK Subgroup: Sparse PK sampling will be conducted in a subgroup of participants 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.
3.
PLANNED ANALYSES
3.1.
Interim Analyses
Ongoing data reviews of unblinded safety data, conducted by an Internal Safety Review 
Committee (iSRC), will be performed throughout the trial. Details will be documented in 
the iSRC charter.  
Interim analyses of the primary endpoint and key secondary endpoints to inform internal 
decision making will be conducted periodically throughout the trial. The first analysis 
(Interim Analysis 1) is planned to occur when approximately 170 participants complete 
28 days of treatment, where approximately 50 of the 170 participants have an index 
exacerbation defined as severe. A change that could arise from this interim analysis is a 
specification of the stratification proportions by index exacerbation severity status 
(moderate or severe). This decision will be based on inspection of all available endpoints 
at the interim analysis. 
Further interim analyses will be performed, depending on the observed recruitment rate. 
At least one interim analysis of the primary endpoint of change from baseline in clinic 
visit trough FEV1 at Day 84 measured post-bronchodilator will be performed to 
 
 
 
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determine whether or not any adjustments to the randomization ratio across doses would 
help optimize the characterization of the dose response profile for nemiralisib. This 
analysis (Interim Analysis 2) is planned to occur when approximately 300 participants 
complete 84 days of treatment or when approximately 400 participants remain to be 
randomised, whichever occurs first. Adjustments could include ceasing randomization to 
an existing dose(s) of nemiralisib and/or modification of the allocation ratios for the 
existing nemiralisib doses and/or addition of a 25mcg dose. Other changes may include 
specification of the stratification proportions by index exacerbation severity status. 
An interim analysis of efficacy data collected during the Double-Blind Treatment Period 
will be conducted when the last participant in the study has completed the 12-week 
Double-Blind Treatment Period (End of Treatment Interim Analysis). The aim of this 
analysis is to provide GSK with timely data to inform internal decision making, prior to 
the end of study. 
The following table describes the endpoints that will be analysed/summarised at each 
interim:
Interim
Purpose of interim
Endpoints
Interim Analysis 1
To inform internal decision making 

Change from baseline in FEV1 at Days 
14, 28, 56 and 84 measured pre- and 
post-bronchodilator

Change from hospital discharge in 
FEV1 at Day 14, 28, 56 and 84
measured pre- and post-bronchodilator 
in participants hospitalized for the 
index exacerbation

Other spirometry measures (percent 
predicted FEV1, Forced Vital Capacity 
(FVC), percent predicted FVC and 
FEV/FVC ratio

Summary of on-treatment 
exacerbations

Summary of proportion of participants 
achieving EXACT-defined recovery by 
Days 14, 28, 56 and 84
 
 
 
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Interim
Purpose of interim
Endpoints
Interim Analysis 2
To determine if any adjustments to the 
randomization ratio would help 
characterize the dose response profile 
for nemiralisib
Endpoints listed for Interim Analysis 1 and 
also:

Rate of (on-treatment) exacerbations 
over the 12-Week Treatment Period

Time to next (on-treatment) 
exacerbation during the 12-Week 
Treatment Period

Analysis of proportion of participants 
achieving the EXACT-defined recovery 
by Days 14, 28, 56, and 84

Rescue medication use, as measured 
in eDiary 
End of Treatment 
Interim Analysis
To inform internal decision making
All endpoints to be reported as per 
Statistical Analysis Complete (SAC)
deliverable
The statistical methods of analyses are described in Section 7.
The Respiratory Data Sciences Group will apply machine learning techniques to the 
interim data to determine if identifiable phenotypic sub-population(s) of COPD 
participants are present at baseline, and if they result in different responses to 
Nemiralisib, to predict which participants will respond to Nemiralisib therapy, and to 
identify/quantify relationship(s) between different endpoints and response measures.
Details of these analyses will be described in a separate RAP and results will be reported 
separately to the Clinical Study Report (CSR). 
The following functions will be unblinded to interim analysis data: Clinical Statistics, 
Clinical Programming and Respiratory Data Sciences Group. Other member of GSK will 
be unblinded to group level summary data following the interim analyses (as documented 
internally). 
3.1.1.
Futility analyses
At least one interim analysis for futility will be performed. The first analysis will occur at 
Interim Analysis 2, i.e. when 300 participants complete 84 days of treatment, or when 
approximately 400 participants remain to be randomised, whichever occurs first. 
Futility will be assessed in a sequential manner. 
1) Futility will first be assessed for the primary endpoint of change from baseline in 
FEV1 at Day 84 by fitting a suitable dose response model, as described in Section 
7.1.2. 
2) If the posterior predictive probability of declaring success for this endpoint is low
across all doses, then futility will be assessed for the rate of (on-treatment) 
exacerbations endpoint.
3) If the posterior predictive probability of declaring success for this endpoint is low, 
then the study may be stopped.
 
 
 
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Any decision to stop will be made after a review of all the data summarised/analysed at 
the time of the interim, including the proportion of participants achieving the EXACT-
defined recovery.
3.1.1.1.
Futility rules
The decision rules for futility are defined as follows.
Change from baseline in FEV1 at Day 84
Stop study for futility if the predictive probability of success at the end of the trial, given 
the data at the interim is <20%, across all doses, where success at the end of the trial for 
change from baseline in FEV1 is defined as demonstrating >90% posterior probability 
that the true difference from placebo for any dose of nemiralisib is greater than 0.
Rate of on-treatment exacerbations
Stop study for futility if the predictive probability of success at the end of the trial, given 
the data at the interim is <20%, where success at the end of the trial for rate of 
exacerbations is defined as demonstrating >80% posterior probability that the true rate 
reduction on 750 mcg dose versus placebo > 0%.
If a different dose arm appears to be more efficacious than the 750 mcg arm, then futility 
may be assessed using the rate reduction for this arm versus placebo. 
The pre-determined rules will act as guidelines for stopping the study for futility. All of 
the data summarised/analysed at the time of the interim will be reviewed prior to any 
decision to stop the study. 
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All participants have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management.
3.
All criteria for unblinding the randomization codes have been met. 
4.
Randomization codes have been distributed according to RandAll NG procedures.
 
 
 
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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Participants 
Enrolled (APE) 
Population

All participants who are screened for eligibility.

Study Population
Modified Intent 
To treat (MITT) 
Population

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.

Study Population

Efficacy
Per Protocol (PP) 
Population

All randomized participants who receive at least one 
dose of study treatment, excluding any participants with 
an important protocol deviation.

Participants will be analyzed according to the treatment 
that they were randomised to.

Sensitivity
analyses of 
efficacy
Safety Population

All randomized participants who received at least one 
dose of study treatment.

Participants will be summarised according to the 
treatment that they actually received.
o If participants receive >1 treatment, then they will 
be summarised according to the most frequently 
dosed treatment. In cases where the frequency is 
equal, the participant will be assigned the lowest 
dose strength of nemiralisib

Safety
Pharmacokinetic
(PK) Population

All participants in the Safety population who had at least 
1 non-missing PK assessment (Non-quantifiable [NQ] 
values will be considered as non-missing values).

Participants will be summarised according to the 
treatment that they actually received

PK
Refer to Appendix 11: List of Data Displays which details the population used for each display.
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
Important deviations which result in exclusion from the analysis population will also be 
summarised and listed. (Please refer to Appendix 1: Protocol Deviation Management and 
Definitions for Per Protocol Population).
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan.
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations and deviations which may lead to exclusion from the 
analysis are captured and categorised on the protocol deviations dataset. 
o This dataset will be the basis for the summaries and listings of protocol 
deviations.
 
 
 
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A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF.
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG Randomization System
Data Displays for Reporting 
Code
Description
Description
Order in TLF 
A
Placebo
Placebo
1
B
GSK2269557 12.5 mcg
NEMI 12.5 mcg
2
C
GSK2269557 25 mcg*
NEMI 25 mcg
3
D
GSK2269557 50 mcg
NEMI 50 mcg
4
E
GSK2269557 100 mcg
NEMI 100 mcg
5
F
GSK2269557 250 mcg
NEMI 250 mcg
6
G
GSK2269557 500 mcg
NEMI 500 mcg
7
H
GSK2269557 750 mcg
NEMI 750 mcg
8
* The nemiralisib dose of 25 mcg may be added following the results of an un-blinded interim analysis if 
further characterization of the lower end of the dose response curve is required.
Treatment comparisons will be displayed as follows using the descriptors as specified:
1.
NEMI 12.5 mcg vs Placebo
2.
NEMI 25 mcg vs Placebo
3.
NEMI 50 mcg vs Placebo
4.
NEMI 100 mcg vs Placebo
5.
NEMI 250 mcg vs Placebo
6.
NEMI 500 mcg vs Placebo
7.
NEMI 750 mcg vs Placebo
5.2.
Baseline Definitions
For all endpoints, the baseline value will be the latest pre-dose assessment with a non-
missing value, including those from unscheduled visits. If time is not collected, Day 1 
assessments are assumed to be taken prior to first dose and used as baseline.
Baseline FEV1 is defined as FEV1 measured prior to the first dose of study treatment and 
post-bronchodilator on Day 1.
 
 
 
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Baseline CAT Total Score is defined as CAT Total Score measured prior to the first dose 
of study treatment on Day 1.
Baseline SGRQ Total Score is defined as SGRQ Total Score measured prior to the first 
dose of study treatment on Day 1.
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing.  
Prior to use in any statistical model, Baseline will be ‘centred’. A centred baseline will be 
derived for each participant by subtracting the mean baseline across all participants from 
each participant’s baseline value. 
5.3.
Multicentre Studies
In this multicentre global study, enrolment will be presented by investigative site and
country.
5.4.
Examination of Covariates and Subgroups
5.4.1.
Covariates
The list of covariates may be used in descriptive summaries and statistical analyses, some 
of which may also be used for subgroup analyses. Additional covariates of clinical 
interest may also be considered. The decision to include covariates in the model will be 
based on their impact on the model fit and will be detailed in the CSR.
Any continuous covariates will be ‘centred’ prior to use in statistical models. A centred 
covariate will be derived for each participant by subtracting the mean covariate across all 
participants from each participant’s covariate value.
 
 
 
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Covariate
Details
Index exacerbation severity
Categorical variable (Moderate or Severe), collected in eCRF. The 
stratification variable from the randomisation system may be used 
at the interim analyses if data in eCRF is sparse.
Age (at screening)
Continuous variable derived as described in Section 13.6.2.1
BMI
Continuous variable derived using Height and Weight variables 
collected in eCRF:
BMI = Weight (kg) / (Height (m))2
Gender
Categorical variable (Male or Female), collected in eCRF
Country
Categorical variable
Smoking status
Categorical variable (Current or Former), collected in eCRF
Baseline COPD maintenance 
therapy type
Categorical variable derived depending on data observed
Index exacerbation type
Categorical variable: New or Relapse, derived using the question: 
“Other than the current prescription, for the index exacerbation, has 
the subject received oral/systemic corticosteroids and/or antibiotics 
for a COPD exacerbation within the last 7 days?” in the eCRF:
New = No
Relapse = Yes
Number of exacerbations in the 
previous 12 months
Categorical variable derived from “Total number of COPD 
exacerbations in the last 12 months” in the eCRF
5.4.2.
Examination of Subgroups
The list of subgroups may be used in descriptive summaries and statistical analyses.
Additional subgroups of clinical interest may also be considered.

If the percentage of subjects is small within a particular subgroup, then the subgroup 
categories may be refined.

If the category cannot be refined further, then descriptive rather than statistical 
comparisons may be performed for the particular subgroup.
Subgroup
Categories 
Index exacerbation severity
Moderate vs. Severe  
Baseline COPD maintenance therapy type
Possible categories of interest are: Monotherapy vs. Dual 
therapy vs. Triple therapy
Index exacerbation type
New vs. Relapse
Number of exacerbations in the previous 12 
months
Possible categories of interest are: 0 vs. 1 vs. ≥2
Gender
Male vs. Female
Smoking status
Current vs. Former
 
 
 
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5.5.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
Section 13.2
Appendix 2: Assessment Windows
Section 13.3
Appendix 3: Study Phases and Treatment Emergent Adverse Events
Section 13.4
Appendix 4: Data Display Standards & Handling Conventions
Section 13.5
Appendix 5: Derived and Transformed Data
Section 13.6
Appendix 6: Reporting Standards for Missing Data
Section 13.7
Appendix 7: Values of Potential Clinical Importance
6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the “APE” and/or “MITT” populations, 
unless otherwise specified.
Study population analyses including analyses of participant’s disposition, protocol 
deviations, demographic and baseline characteristics, and exposure and treatment 
compliance will be based on GSK Core Data Standards.  Details of the planned displays
are presented in Appendix 11: List of Data Displays.
6.1.1.
Concomitant medications
Concomitant medications will be summarised by treatment group. Separate summaries of
Baseline and On-treatment (Step-up) COPD Maintenance Therapy, and duration of OCS 
use will also be presented. 
Additional summaries or sensitivity analyses of on-treatment COPD maintenance therapy
(step-up therapy) may be performed if the data indicate that further investigation is 
warranted.
 
 
 
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7.
EFFICACY ANALYSES
Details of the outputs are provided in Appendix 11: List of Data Displays and will be 
based on GSK data standards and statistical principles.
Details of Study Day calculations, including protocol-defined time windows, for use in 
the endpoint derivations below can be found in Section 13.2. 
7.1.
Primary Efficacy Analyses
7.1.1.
Primary Endpoint
The primary endpoint of change from baseline in clinic visit trough FEV1 at Day 84 
measured post-bronchodilator is defined as:
FEV1 measured prior to dosing and post-bronchodilator on Day 84 – Baseline FEV1
7.1.2.
Primary Statistical Analyses
The primary endpoint will be analysed, by first intent, using a Bayesian 4-parameter Emax
dose response model.  Should the data not allow for a suitable model fit, then the 
following Bayesian models will be attempted in this sequential order: a 3-parameter Emax
model and a Log-linear model.
The 4-parameter Emax dose response model will take the form:
Change from baseline FEV1 =



Dose
ED
Dose
baseline
b
E
baseline
a
E




50
*
)
*
(
)
*
0
(
1
max
1
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
a1, b1, are covariates for explanatory parameters
Initially, normal non-informative priors will be used for the E0, a1, a2, and Emax
parameters with mean 0 and standard deviation 1E6 L. A functional uniform prior will be 
used for the ED50 and slope parameters (Bornkamp, 2014), where the prior density for 
the functional uniform prior is based on all the parameters in the model. An inverse -
gamma prior with shape of 0.001 and scale of 0.001 will be used for the residual 
variance. However, if a prior distribution appears not to be truly non-informative then 
alternative prior distributions may be used.
Parameters will be blocked such that the MCMC procedure samples from E0, a1, b1, and 
Emax, first, then the ED50 and slope parameters and then finally the residual variance 
 
 
 
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parameter. For the functional uniform priors, the density will be calculated for values of 
dose from 0.0001 to 750 in steps of 50 (i.e. 0.0001, 50.0001, 100.0001,…, 750.0001). For 
the continuous covariates, the density will be calculated from the minimum to the 
maximum in 10 equal steps.  For binary covariates the density will be calculated for 
values 0 and 1.  If the model does not converge including covariates, the model may be 
fitted with covariates removed. 
If the log-linear model is fitted an offset of 1 will be used. 
The posterior median change from baseline with 95% Highest Posterior Density (HPD) 
Credible Intervals, will be presented for each dose along with the adjusted median 
difference from placebo with 95% HPD. Posterior probabilities that the true improvement 
is greater than 0 mL, 50 mL and 100 mL will also be presented. 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. 
For the futility analysis: 
The predictive probability of success at the end of the study will be calculated for each 
dose using the formula suggested by Spiegelhalter et al., 2004 as follows:
Where m is the average number of subjects with Day 84 data in the placebo and dose arm 
of interest, n is the average number of subjects yet to be observed, ym is the posterior 
mean difference from placebo from the fitted model, σ is the standard deviation of the 
posterior mean difference from placebo. 
For the possible adaptations at Interim Analysis 2:
If the study is not deemed futile, and either the 4 parameter or 3 parameter Emax dose 
response curves has successfully been fitted to the data then adaptation of the 
randomisation schedule will be considered, to drop, add or amend doses from the 
randomisation scheme. 
The adaptation will be done by comparing the relative information from alternative 
randomisation schemes with the original randomisation schemes, such to find the design 
that provides the most information about the dose response relationship.  The efficiency 
ratio (ER) for an alternative scheme comparted to the original, will be calculated as:
, i=1,…,1000
Where 
is the information matrix for the design and model parameters 
, 
is the alternative design one and 
is the fixed original 
design.  In order to ensure any adaptation is robust to the variability in the parameter 
estimates at the interim analysis, 1000 samples will be generated from the posterior 
distribution of the parameters 
and the ER calculated for each set of 
 
 
 
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parameter.  Adaptation will then only take place if the median ER is >1.05 and the 10th
percentile of the ER is >1.
7.1.2.1.
Model Checking & Diagnostics
The following list of convergence diagnostics will be applied for each parameter: 

The Monte Carlo Standard Errors (MCSE) should be compared with the standard 
deviation of the posterior distribution (SD) to ensure that only a fraction of the 
posterior variability is due to the simulation. The number of samples generated 
and/or the thinning may be increased to reduce the ratio of the MCSE/SD as 
deemed necessary.

The Geweke diagnostic test will be used to assess whether the mean estimates 
have converged by comparing means from the early and latter part of the Markov 
chain using a z-score t-test. Large absolute values of the z-score statistic indicate 
rejection of the null hypothesis of no difference between the mean estimates 
obtained from the early and latter parts of the chain.

Trace plots of samples versus the simulation index will be visually inspected to 
assess some aspects of convergence. The centre of the chain should appear stable 
with very small fluctuations, i.e., the distribution of points should not change as 
the chain progresses and the posterior mean and variance are relatively constant.

Autocorrelation plots will be visually inspected to assess degree of autocorrelation 
(should decline rapidly and show no oscillation patterns).
7.1.3.
Sensitivity and Supportive Analyses
If there are greater than 20% of participants with an important protocol deviation that 
results in exclusion from the Per Protocol Population, the primary analysis may be 
repeated using the Per Protocol Population. 
Change from baseline in clinic visit trough FEV1 at Day 84 will also be compared 
between treatment groups using a Bayesian Repeated Measures analysis with covariates 
for baseline-by-Day interaction and treatment-by-Day interaction. Day will be fitted as a 
repeated effect within each participant. All post-baseline scheduled visits will be included 
in the analysis using Day. Non-informative priors will be used for all modelling 
parameters. Wherever possible conjugate priors will be utilised. An unstructured 
covariance matrix will be used to model the within-subject error.
A further sensitivity analysis may be performed where Baseline FEV1 is replaced with 
the FEV1 measured post-bronchodilator and prior to dosing on day of hospital discharge 
for participants who were hospitalised for their index exacerbation, i.e. who were 
randomised with a Severe index exacerbation but kept as Baseline FEV1 for participants 
who were randomised with a Moderate index exacerbation.
7.1.4.
Subgroup Analyses
A subgroup analysis of change from baseline in clinic visit trough FEV1 by index 
exacerbation severity will be performed by including the severity covariate term in the 
 
 
 
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model, if possible. For the Bayesian 4-parameter Emax dose response model this would 
take the form:
Change from baseline FEV1 =



Dose
ED
Dose
severity
b
baseline
b
E
severity
a
baseline
a
E






50
*
)
*
*
(
)
*
0
(
2
1
max
2
1
Where a1, a2, b1, b2 are covariates for explanatory parameters.
If there are convergence issues, then the model for the primary endpoint may be fitted 
separately to each level of the subgroup. 
A subgroup analysis of change from baseline in clinic visit trough FEV1 by index 
exacerbation severity will also be performed by including a treatment-by-severity-by-Day
interaction term in the Bayesian Repeated Measures model. 
7.2.
Secondary Efficacy Analyses
7.2.1.
Rate of exacerbations
Rate of exacerbation is defined as the frequency of exacerbations (subsequent to the 
index exacerbation) within the specified time period, for example, the 12-Week 
Treatment Period or the 24-Week Study Period.
The length of time on treatment or in study, depending on the specified time-period, for 
each participant will be calculated for each endpoint as follows:
Endpoint
Time period
Length of time derivation
Rate of (on-treatment) 
exacerbations, summarised by:

Moderate and severe 
exacerbations

Moderate exacerbations

Severe exacerbations

All (mild, moderate and 
severe) exacerbations
12-Week Treatment Period
Time from date of randomisation 
to date of last dose of study 
treatment 
Rate of (on-or off-treatment) 
exacerbations, summarised by:

Moderate and severe 
exacerbations

All exacerbations
12-Week Treatment Period
Time from date of randomisation 
to Day 84. 
For participants who withdraw 
early from the study: Time from
date of randomisation to date of 
study withdrawal
Rate of (off-treatment) 
exacerbations, summarised by:

Moderate and severe 
exacerbations

Moderate exacerbations
12-Week Follow Up Period
Time from date of last dose of 
study treatment to date of last 
follow up assessment
 
 
 
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Endpoint
Time period
Length of time derivation

Severe exacerbations
Rate of (on- and off- treatment)
exacerbations, summarised by:

Moderate and severe 
exacerbations

Moderate exacerbations

Severe exacerbations
Full 24-Week Study Period
Time from date of randomisation 
to date of last follow up 
assessment
Refer to Section 13.5 for further details regarding the length of time derivation
7.2.1.1.
Statistical analyses
The rate of exacerbations will be analysed using a Bayesian generalized linear model 
assuming a negative binomial distribution for the underlying exacerbation rate with a log 
link function. An offset to account for the length of time on treatment or in study, 
depending on the specified time-period, for each participant (as described above) will be 
included in the model as loge (length of time). 
Non-informative priors will be used for all modelling parameters. Wherever possible 
conjugate priors will be utilised.
The median exacerbation rates for each dose arm per 12 weeks, along with the median 
ratio in exacerbation rates (nemiralisib/placebo) per 12 weeks for each dose, will be 
estimated and corresponding 95% HPD credible intervals presented. The probability that 
the true exacerbation rate ratio is less than 1, in addition to other values appropriately 
selected based on the data, will be presented.
Based on pharmacological predictions, the 500 mcg and 750 mcg doses are expected to 
result in similar levels of target inhibition and thus potentially translate to similar clinical 
benefit, therefore estimates of the exacerbation rates for pooled data from 500 mcg plus 
750 mcg will also be presented.
7.2.1.2.
Subgroup analyses
A subgroup analysis of exacerbation rate by Index exacerbation severity will be 
performed by including a treatment-by-severity term in the model.
7.2.1.3.
Exploratory analyses
A summary of exacerbation rate by the following groups will be presented and, if 
feasible, a subgroup analyses may be performed:

Index exacerbation type (New or Relapse)

Number of exacerbations in previous 12 months (0, 1 or ≥2). 
 
 
 
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7.2.2.
Time to next exacerbation
Time to next (on-treatment) exacerbation following index exacerbation during the 12-
Week Treatment Period is defined as time from the date of randomisation until the date 
of onset of the first exacerbation whilst on study treatment. Participants who did not have 
an exacerbation whilst on study treatment will be censored at the date of their last dose of 
study treatment. 
Time to next (on-or off-treatment) exacerbation during the 12-Week Treatment Period is 
defined as time from the date of randomisation until the date of onset of the first 
exacerbation occurring up to Day 84. Participants who have not had an exacerbation 
during the 12-Week Treatment Period will be censored at Day 84 or the date of study 
withdrawal, for participants who withdrew from the study prior to Day 84.
Time to next exacerbation following cessation of study treatment is defined as time from 
the date of last dose of study treatment until the date of onset of the next exacerbation 
whilst off study treatment during the 12-Week Follow Up Period. Participants who have 
not had an exacerbation off-treatment will be censored at the date of their last follow up 
assessment.
Time to next exacerbation will be analysed by severity, as follows: 
Endpoint
Time period
Time to next (on-treatment) exacerbation, 
summarised by:

Moderate and severe exacerbations

Moderate exacerbations

Severe exacerbations

All (mild, moderate and severe) exacerbations
12-Week Treatment Period
Time to next (on-or off-treatment) exacerbation, 
summarised by:

Moderate and severe exacerbations

All exacerbations
12-Week Treatment Period
Time to next exacerbation following cessation of 
treatment, summarised by:

Moderate and severe exacerbations

Moderate exacerbations

Severe exacerbations
12-Week Follow Up Period
Refer to Section 13.5 for further details regarding the length of time derivation
7.2.2.1.
Statistical analyses
Time to next exacerbation will be analysed using a Bayesian Cox proportional hazards 
model with the “Efron” method for handling ties. Kaplan-Meier (KM) estimates of the 
probability of exacerbation will also be presented.
 
 
 
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Non-informative priors will be used for all modelling parameters. Wherever possible 
conjugate priors will be utilised.
The hazard ratio and corresponding 95% HPD credible intervals for each nemiralisib 
dose versus placebo will be presented. The probability that the true hazard ratio is less 
than 1, in addition to other values appropriately selected based on the data, will be 
presented.
Based on pharmacological predictions, the 500 mcg and 750 mcg doses are expected to 
result in similar levels of target inhibition and thus potentially translate to similar clinical 
benefit, therefore an estimate of hazard ratio for pooled data from 500 mcg plus 750 mcg 
nemiralisib doses versus placebo will also be presented.
7.2.2.2.
Subgroup analyses
A subgroup analysis of time to exacerbation by Index exacerbation severity will be 
performed by including a treatment-by-severity term in the model.
7.2.3.
Change from baseline in Clinic Visit trough FEV1
Change from baseline in clinic visit trough FEV1 at Day 14, 28, 56 measured post-
bronchodilator is defined as:
FEV1 measured prior to dosing and post-bronchodilator on Day X – Baseline FEV1
Where Day X is Day 14, 28, and 56.
Change from baseline in clinic visit trough FEV1 at Day 14, 28, 56, 84 measured pre-
bronchodilator is defined as:
FEV1 measured prior to dosing and pre-bronchodilator on Day X – Baseline FEV1
Where Day X is Day 14, 28, 56, and 84.
7.2.3.1.
Statistical Analyses
Change from baseline in Clinic Visit trough FEV1 will be analysed using a dose response 
model and repeated measures analysis as described for the primary endpoint in Section 
7.1.2.
7.2.3.2.
Subgroup analyses
A subgroup analysis of change from baseline in clinic visit trough FEV1 by index 
exacerbation severity will be performed. 
7.2.4.
Change from hospital discharge in clinic visit trough FEV1
Change from hospital discharge in clinic visit trough FEV1 will be derived only for 
participants who were hospitalised for their index exacerbation and who have been 
subsequently discharged. 
 
 
 
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Change from hospital discharge in clinic visit trough FEV1 measured post-bronchodilator 
is defined as:
FEV1 measured prior to dosing and post-bronchodilator on Day X – FEV1 measured post-
bronchodilator and prior to dosing on day of hospital discharge.
Where Day X is 14, 28, 56 and 84.
Change from hospital discharge in clinic visit trough FEV1 measured pre-bronchodilator 
is defined as:
FEV1 measured prior to dosing and pre-bronchodilator on Day X – FEV1 measured prior 
to dosing and post-bronchodilator on day of hospital discharge.
Where Day X is 14, 28, 56 and 84.
Note, as per Section 5.1 of the Protocol, if discharge takes place between Day 11 and Day 
17 (inclusive), the assessments planned for Day 14 may be completed on the day of 
discharge. In these cases, for this endpoint only, the FEV1 assessment will be assigned 
the hospital discharge assessment and the Day 14 assessment will be missing. Refer to 
Section 13.2.1.1 for further details. 
In addition, if discharge takes place after Day 14, the Day 14 assessment will be missing 
for this analysis. 
7.2.4.1.
Statistical analyses
Change from hospital discharge in clinic visit trough FEV1 will be analysed using a dose 
response model and repeated measures analysis as described for the primary endpoint in 
Section 7.1.2 if there are a sufficient number of participants to provide a meaningful 
analysis, otherwise the data will be summarised.
7.2.5.
EXAcerbations of Chronic Pulmonary Disease Tool - Patient 
Reported Outcome (EXACT)
The EXACT is a 14-item daily diary designed to provide a measure of patient-reported 
symptoms of COPD exacerbation. An EXACT Total Score, ranging from 0 to 100, where 
higher scores indicate a more severe condition, will be derived for each day of diary 
collection according to the instructions in the EXACT User Manual (Version 8.0, 
Evidera, 2016).
The electronic EXACT diary does not allow a study patient to skip individual items, 
therefore no missing data are expected for individual items. However, if missing values 
occur for individual items, the Total Score that contains the item will be set to missing for 
that day. Moderate-to-severe COPD patients are expected to experience symptom(s) each 
day, and a score of zero on all 14 EXACT items is likely to represent a situation where in 
order to complete the diary quickly, the respondent did not accurately report their daily 
symptom(s), therefore if the EXACT Total Score is 0, it will be set to missing.
A 3-day Rolling Average EXACT Total Score will be calculated for each day, X, as:
 
 
 
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(EXACT Total Score on Day X-1 + EXACT Total Score on Day X + EXACT 
Total Score on Day X+1) / (Number of days with non-missing values)
Note, for Day 1, the Rolling Average EXACT Total Score will be calculated as the 
average of EXACT Total Score on Days 1 (Randomisation) and 2 only, since no EXACT 
data is collected prior to randomisation. Similarly, the Rolling Average EXACT Total 
Score for the last study day will be calculated as the average of EXACT Total Score on 
the last day and on the day before the last day.
The Rolling Average EXACT Total Score will be calculated for each day as long as at 
least 1 EXACT total score in the sequence is present. Therefore, only in the case where 
EXACT total scores are missing for 3 consecutive days in a row (or 2 consecutive days in 
the case of the first and last day rolling average calculation), will the rolling average 
score be missing.
The Maximum Observed Value (MOV) is defined as the highest Rolling Average 
EXACT Total Score observed within the first 14 days of randomisation. Note: this 
definition differs from the definition in the EXACT User Manual of "the highest rolling 
average EXACT score observed in the context of an EXACT exacerbation within the first 
14 days of the exacerbation", since the date of the index exacerbation is likely to be prior 
to randomisation.
7.2.5.1.
Proportion of participants achieving EXACT-defined recovery from 
index exacerbation
EXACT-defined recovery from the index exacerbation is defined as a decrease in the 
Rolling Average EXACT Total Score ≥9 points from the Maximum Observed Value, 
sustained for ≥7 days, with the first of the 7 days defined as the recovery day.
The proportion of participants achieving EXACT-defined recovery from the index 
exacerbation by Days 14, 28, 56, and 84 will be calculated as:
(Number of participants who experience an EXACT-defined recovery on or 
before Day X) / (Total number of participants in the MITT population) 
Where Day X is 14, 28, 56, and 84.
7.2.5.2.
Time to EXACT-defined recovery from index exacerbation
Time to EXACT-defined recovery from index exacerbation is defined as time from the 
date of randomisation until date of the first EXACT-defined recovery day during the 12-
Week Treatment Period, where EXACT-defined recovery is described in Section 7.2.5.1. 
Participants who did not experience EXACT-defined recovery during the 12-Week 
Treatment Period will be censored at the date of their last dose of study treatment.
7.2.5.3.
Severity of subsequent HCRU-defined exacerbation(s) defined by 
EXACT 
Severity of subsequent HCRU-defined exacerbation(s) defined by EXACT is defined as 
the highest EXACT Total Score (not using the 3-day Rolling Average) during the period 
 
 
 
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from date of onset of the subsequent HCRU-exacerbation until date of EXACT-defined 
recovery of subsequent exacerbation. 
Note, in this case, the Maximum Observed Value and EXACT-defined recovery are 
derived using the date of onset of the subsequent HCRU-exacerbation.
Severity of subsequent HCRU-defined exacerbation(s) defined by EXACT will only be 
derived for participants who have had a subsequent exacerbation. If a participant has 
more than one subsequent exacerbation, severity will be calculated for each subsequent 
exacerbation.
7.2.5.4.
Statistical analyses
The proportion of participants achieving EXACT-defined recovery from the index 
exacerbation will be analysed using a Bayesian logistic regression model. Separate 
models will be fitted for each time-point. 
Non-informative priors will be used for all modelling parameters. Wherever possible 
conjugate priors will be utilised.
The results of the analysis will be presented in terms of odds ratios together with its 
associated 95% HPD credible interval. The probability that the true odds ratio is greater 
than 1, in addition to other values appropriately selected based on the data, will be 
presented.
Time to EXACT-defined recovery from index exacerbation will be analysed using the 
same techniques as described in Section 7.2.2.1.
Severity of subsequent HCRU-defined exacerbation(s) defined by EXACT will be 
summarised for each treatment group and reported by study period. The severity of 
subsequent HCRU-defined exacerbation(s) occurring whilst a participant is on treatment 
will be reported as during the 12-Week Treatment Period and the severity of subsequent 
HCRU-defined exacerbation(s) occurring after the last dose of study treatment will be 
reported as during the 12-Week Follow-up Period.
7.2.5.5.
Subgroup analyses
A subgroup analysis of the proportion of participants achieving EXACT-defined recovery 
from the index exacerbation by Index Exacerbation Severity will be performed by 
including a treatment-by-severity term in the model.
7.2.5.6.
Sensitivity and supportive analyses
Sensitivity analyses exploring the impact of any missing data, and changes to the 
definition of EXACT-defined recovery may be conducted and may be performed post-
SAC. 
 
 
 
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7.2.6.
COPD Assessment Test (CAT)
The COPD Assessment Test (CAT) is a patient completed questionnaire developed to 
measure the health status of patients with COPD. The CAT consists of eight items, each 
on a six-point scale: 0 (no impact) to 5 (high impact). The CAT Score will be calculated 
for each study day of collection by summing the scores for all questions. The CAT Score 
ranges from 0 to 40, where higher scores indicate a more severe condition.
7.2.6.1.
Proportion of responders using the CAT
The proportion of responders using the CAT will only be derived for participants with a 
baseline CAT Total Score ≥2.
The Proportion of responders using the CAT is defined as:
(Number of participants with a decrease from baseline in CAT Total Score ≥2 on 
or before Day X)/(Total number of participants in the MITT population)
Where Day X is 28, 56, and 84, and the study day following EXACT-defined recovery 
from the index exacerbation.
Note: due to software limitations of the electronic PRO device, the study day following 
EXACT-defined recovery is not derived according to the EXACT User Manual, see 
Section 13.2.1.2 for further details. 
Exploratory – Follow-Up Period
The Proportion of responders using the CAT at Day 112 and 168 is defined as:
(Number of participants with a decrease from baseline in CAT Total Score ≥2 on 
or before Day X)/(Total number of participants in the MITT population)
Where Day X is FU Day 28 and FU Day 56, as defined in Section 13.2.1, and the study 
day following EXACT defined recovery, if it occurs during the Follow-up period. 
7.2.6.2.
Change from baseline in CAT Total Score
Change from baseline in CAT Total Score is defined as:
CAT Total Score on Day X – Baseline CAT Total Score
Where Day X is 28, 56, 84, and the study day following EXACT defined recovery from 
the index exacerbation.
Note: due to software limitations of the electronic PRO device, the study day following 
EXACT-defined recovery is not derived according to the EXACT User Manual, see 
Section 13.2.1.2 for further details.  
 
 
 
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Exploratory – Follow-Up Period
The Change from baseline in CAT Total Score at Day 112 and 168 is defined as:
CAT Total Score on Day X – Baseline CAT Total Score
Where Day X is FU Day 28 and FU Day 84, as defined in Section 13.2.1. 
The Change from end of treatment in CAT Total Score at Day 112 and 168 is defined as:
CAT Total Score on Day X – CAT Total Score on Day 84
Where Day X is FU Day 28 and FU Day 84, as defined in Section 13.2.1. 
7.2.6.3.
Statistical analyses
The proportion of responders using CAT will be analysed using the same techniques as 
described in Section 7.2.5.4.
Change from baseline in CAT Total Score will be compared between treatment groups 
using a Bayesian Repeated Measures analysis with covariates for baseline-by-Day
interaction and treatment-by-Day interaction. Day will be fitted as a repeated effect 
within each participant. 
All post-baseline scheduled visits will be included in the analysis using Day.
Non-informative priors will be used for all modelling parameters. Wherever possible 
conjugate priors will be utilised. An unstructured covariance matrix will be used to model 
the within-subject error.
Adjusted posterior median change from baseline and corresponding 95% HPD credible 
intervals will be summarised for each treatment by time-point, together with estimated 
treatment differences (GSK – Placebo) and corresponding 95% HPD credible intervals. 
The posterior probability that the true treatment difference is less than 0, in addition to 
other values appropriately selected based on the data, will also be presented.
7.2.6.4.
Subgroup analyses
A subgroup analysis of the proportion of responders using CAT and the change from 
baseline in CAT Total Score by Index exacerbation severity will be performed by 
including a treatment-by-severity term and a treatment-by-severity-by-Day term in the 
Bayesian logistic regression and Bayesian Repeated Measures models, respectively.
7.2.7.
St. George’s Respiratory Questionnaire for COPD Patients 
(SGRQ-C)
St. George’s Respiratory Questionnaire for COPD Patients (SGRQ-C) is a 40-item 
questionnaire designed specifically to focus on COPD patients. SGRQ-C will be scored 
to be equivalent to the SGRQ Total Score, ranging from 0 to 100, where higher scores 
reflect worse health-related quality of life. SGRQ Total Scores will be calculated for each 
 
 
 
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day of collection according to the instructions in SGRQ-C Manual (Version 1.3, March 
2016). 
7.2.7.1.
Proportion of responders on the SGRQ Total Score
The proportion of responders on the SGRQ Total Score will only be derived for 
participants with a baseline SGRQ Total Score ≥4.
Proportion of responders on the SGRQ Total Score is defined as:
(Number of participants with a decrease from baseline in SGRQ Total Score ≥4 
on or before Day X)/(Total number of participants in the MITT population)
Where Day X is 28, 56, and 84.
Exploratory – Follow-Up Period
The Proportion of responders on the SGRQ Total Score at Day 112 and 168 is defined as:
(Number of participants with a decrease from baseline in SGRQ Total Score ≥4 
on or before Day X)/(Total number of participants in the MITT population)
Where Day X is FU Day 28 and FU Day 84, as defined in Section 13.2.1 and the study 
day following EXACT defined recovery, if it occurs during the Follow-up period. 
7.2.7.2.
Change from baseline in SGRQ Total Score
Change from baseline in SGRQ Total Score is defined as:
SGRQ Total Score on Day X – Baseline SGRQ Total Score
Where Day X is Day 28, 56, and 84.
Exploratory – Follow-Up Period
The Change from baseline in SGRQ Total Score at Day 112 and 168 is defined as:
SGRQ Total Score on Day X – Baseline SGRQ Total Score
Where Day X is FU Day 28 and FU Day 84, as defined in Section 13.2.1. 
The Change from end of treatment in SGRQ Total Score at Day 112 and 168 is defined 
as:
SGRQ Total Score on Day X – SGRQ Total Score on Day 84
Where Day X is FU Day 28 and FU Day 84, as defined in Section 13.2.1. 
 
 
 
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7.2.7.3.
Statistical analyses
Change from baseline in SGRQ Total Score and the proportion of responders on the 
SGRQ Total Score will be analysed using the same techniques as described in Section 
7.2.6.3.
7.2.7.4.
Subgroup analyses
Subgroup analyses of change from baseline in SGRQ Total Score and the proportion of 
responders on the SGRQ Total Score by Index exacerbation severity will be conducted as 
described in Section 7.2.6.4.
7.2.8.
Rescue medication use
All participants will record rescue medication use in the eDiary. Rescue medication use 
will be recorded as the number of occasions of rescue medication use each day. 
The Mean Number of (on-treatment) Occasions of Rescue Medication Use Per Day is 
defined as:
(Sum of the number of occasions of rescue medication use each day within the 
time-period) / (Total number of days with non-missing values within the time-
period)
The Percentage of (on-treatment) Rescue-Free Days is defined as:
(Sum of the number of days where the number of occasions of rescue medication 
use is zero within the time-period) / (Total number of days with non-missing 
values within the time-period)*100
Where the time-period is defined as follows:
Week 1 of the 12-Week Treatment Period: Day 1 to Day 7
Week 2 of the 12-Week Treatment Period: Day 8 to Day 14
Week 3 of the 12-Week Treatment Period: Day 15 to Day 21
Week 4 of the 12-Week Treatment Period: Day 22 to Day 28
Week 5 of the 12-Week Treatment Period: Day 29 to Day 35
Week 6 of the 12-Week Treatment Period: Day 36 to Day 42
Week 7 of the 12-Week Treatment Period: Day 43 to Day 49
Week 8 of the 12-Week Treatment Period: Day 50 to Day 56
Week 9 of the 12-Week Treatment Period: Day 57 to Day 63
Week 10 of the 12-Week Treatment Period: Day 64 to Day 70
 
 
 
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Week 11 of the 12-Week Treatment Period: Day 71 to Day 77
Week 12 of the 12-Week Treatment Period: Day 78 to Day of last dose
Over the 12-Week Treatment Period: Day 1 to Day of last dose. 
Exploratory – Follow-Up Period
Rescue medication use up to Day 112 will also be summarised by including the time-
periods:
Week 13 (Follow-up Period): (Day of last dose + 1)  to (Day of last dose + 1) + 6 days
Week 14 (Follow-up Period): (Day of last dose + 7)  to (Day of last dose + 1) + 13 days
Week 15 (Follow-up Period): (Day of last dose + 14)  to (Day of last dose + 1) + 20 days
Week 16 (Follow-up Period): (Day of last dose + 21)  to (Day of last dose + 1) + 27 days
For a subject to be counted in the time periods for rescue medication use, they must have 
at least one eDiary entry recorded during that time period.
7.2.8.1.
Rescue medication use via the clip-on Propeller Sensor for MDI
A subset of participants from countries where the Propeller Sensor for MDI is available 
will also record rescue medication use via the clip-on Propeller Sensor for MDI. A 
supportive summary of rescue medication use via the clip-on Propeller Sensor for MDI 
for these participants will be presented. 
Rescue medication use via the clip-on Propeller Sensor for MDI is defined in the same 
way as rescue medication use via the eDiary, except that the number of actuations will be 
used instead of the number of occasions in accordance with the way the data is captured. 
7.2.8.2.
Statistical analyses
The Mean Number of (on-treatment) Occasions of Rescue Medication Use Per Day will 
be summarised between each treatment group using means, standard deviations, medians, 
minimum and maximum.
The Percentage of (on-treatment) Rescue-Free Days will be summarised between each 
treatment group using means, standard deviations, medians, minimum and maximum.
The Percentage of Participants Taking (on-treatment) Rescue Medication By Day for 
each treatment group will also be presented.
Rescue medication use via the clip-on Propeller Sensor for MDI will be summarised in 
the same way as rescue medication use via the eDiary.
 
 
 
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7.3.
Exploratory Efficacy Analyses
7.3.1.
Change from Day 84 in Clinic Visit trough FEV1
Change from Day 84 in clinic visit trough FEV1 measured post-bronchodilator is defined 
as:
FEV1 measured prior to dosing and post-bronchodilator on Day X – Day 84 post-
bronchodilator FEV1
Where Day X is FU Day 28, FU Day 56 and FU Day 84, as defined in Section 13.2.1.
Change from Day 84 in clinic visit trough FEV1 measured pre-bronchodilator is defined 
as:
FEV1 measured prior to dosing and pre-bronchodilator on Day X – Day 84 post-
bronchodilator FEV1
Where Day X is FU Day 28, FU Day 56 and FU Day 84, as defined in Section 13.2.1.
Participants who discontinue study treatment prior to Day 84 will be excluded from this 
analysis. 
7.3.1.1.
Statistical analysis
Change from Day 84 in Clinic Visit trough FEV1 will be analysed using the same 
techniques as described for Change from baseline in CAT Total Score in Section 7.2.6.3.
A subgroup analysis of change from Day 84 in FEV1 will be performed by including a 
treatment-by-severity-by-Day term in the Bayesian Repeated Measures model.
7.3.2.
E-RS:COPD (Evaluating Respiratory Symptoms in COPD)
Change from baseline in E-RS: COPD and subscales will be summarised by treatment 
group. Exploratory analyses related to E-RS: COPD and subscales may be performed 
post SAC.
7.3.3.
Measures of HCRU related to exacerbations
Unscheduled Healthcare Utilisation will be summarised separately for exacerbation-
related, COPD-related or non-COPD related; each summary will be presented by all 
patients (i.e. moderate and severe index exacerbation combined), and separately by index 
exacerbation severity. 
The number of days of hospital admission for the index and subsequent exacerbations 
will also be summarised by treatment group.
 
 
 
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7.3.3.1.
Re-hospitalisation within 30 days of index exacerbation
Re-hospitalisation within 30 days of index exacerbation is defined as 30 days from the 
date of hospital discharge until the date of next hospital admission (+ 1 day, to account 
for study day derivation), for participants who were hospitalised for their index 
exacerbation. 
Exacerbation-related, COPD-related and Non-COPD-related hospital admissions are 
collected in separate eCRFs. The date of hospital admission is not collected in the COPD-
related eCRF, therefore the date of next hospital admission will be estimated using the 
earliest of:

Date of hospital admission for exacerbation-related hospitalisations

Date of contact for COPD-related hospitalisations, where the number of inpatient 
hospitalisation days >0

Date of hospital admission for non-COPD-related hospitalisations.
The proportion of participants who were re-hospitalised within 30 days of the index 
exacerbation will be summarised by each treatment arm.
7.3.3.2.
Time from resolution of index exacerbation to next exacerbation
Time from resolution of index exacerbation to next exacerbation is defined as time from 
the date of (Investigator-defined) resolution of index exacerbation until the date of onset 
of the subsequent exacerbation. 
A summary of time from resolution of index exacerbation to next exacerbation will be 
presented. Participants who did not have a subsequent exacerbation or for whom the 
index exacerbation was not resolved will be excluded from the summary. 
Time from resolution of index exacerbation to next exacerbation will only be derived for 
the first subsequent exacerbation following the index exacerbation. 
7.3.3.3.
Subsequent exacerbation treatment type 
A summary of the type of treatment for subsequent exacerbations (OCS, antibiotics, or 
both) may also be presented.
7.3.4.
Compliance
Reported compliance for all participants is captured daily in the eDiary from the question
"Did you take this morning’s dose of study medication”? 
Percentage compliance for each participant is calculated as:
(Sum of the number of days where the question was answered with ‘Y’) / (Number of 
days from first dose of study treatment to last dose of study treatment) x 100
Overall percentage compliance will be summarised by each treatment group.
 
 
 
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7.3.4.1.
Number of actuations of double-blind study treatment measured by the 
clip-on Propeller Sensor
Percentage compliance via the clip-on Propeller Sensor for ELLIPTA in the subset of 
participants from countries where the Propeller Sensor for ELLIPTA is available is 
calculated as:
(Sum of the total number of actuations) / (Number of days from first dose of study 
treatment to last dose of study treatment) x 100
Overall percentage compliance will be summarised by each treatment group.
7.3.5.
Inflammatory/infective markers in blood and sputum in relation to 
acute exacerbation of COPD
Results of the analysis of blood/spontaneous sputum samples of eosinophil counts and 
inflammatory/infective mediators/markers will be summarised by treatment group.
Further analyses of inflammatory/infective markers may be performed, for example split 
by CRP high, CRP low, Procalcitonin high, etc. categories.
7.3.6.
Other spirometry measurements
Percent predicted FEV1, Forced Vital Capacity (FVC), percent predicted FVC and 
FEV/FVC ratio will be summarised by treatment group. 
7.3.7.
Other PRO symptoms suggestive of exacerbation
Responses to questions related to PRO symptoms of sputum purulence (colour), fever, 
sore throat, wheezing and colds collected in the eDiary will be listed by treatment group.
8.
SAFETY ANALYSES
The safety analyses will be based on the Safety population, unless otherwise specified.
The details of the planned displays will be provided in Appendix 11: List of Data 
Displays.
8.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs) and Serious
(SAEs) will be based on GSK Core Data Standards. 
8.1.1.
Adverse Events of Special Interest
8.1.1.1.
Post-inhalation Cough Immediately Following Dosing
Post-inhalation cough immediately following dosing is an Adverse Event of Special 
Interest (AESI).
 
 
 
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Post-inhalation cough immediately following dosing will be evaluated 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.
The percentage of patients experiencing post-inhalation cough following dosing, 
regardless of whether it was also reported as an AE, overall and by each visit will be 
summarised for each treatment group. The type of cough, time to onset and duration of 
cough, and severity will also be summarised.
In addition, any post-inhalation cough immediately following dosing reported as an
adverse event during the clinic visit observation or during the course of the study will be 
summarised by treatment group.  
8.2.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, 
Haematology laboratory tests and liver function tests will be based on GSK Core Data 
Standards.
8.3.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. 
8.4.
Mortality
A summary of all-cause mortality by treatment will be presented. 
9.
PHARMACOKINETIC ANALYSES
9.1.
Population of Interest 
The primary pharmacokinetic analyses will be based on the “Pharmacokinetic” 
population, unless otherwise specified.
9.2.
Drug Concentration Measures
Plasma nemiralisib concentrations of GSK2269557 will be listed and summarised by 
dose, day and time. Drug levels will be summarised by day (14, 28), dose and time 
intervals (trough, 0-<1h, 1-6h).
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 13.4.3
Reporting Standards for Pharmacokinetic).
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
 
 
 
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10.
POPULATION PK ANALYSIS
A dataset for population PK analysis will be provided by Statistics and Programming
based on the NONMEM data specifications in Section 13.8.2.
Conduct of the population PK analyses will be based on the current guidance which 
contains specific recommendations for working practices, processes and standards for 
population PK and PK/PD analysis conducted by Clinical Pharmacology Modelling and 
Simulation (CPMS) [Analysis & Reporting, 2017].
The sparse PK samples will be subjected to a validated population PK model for 
nemiralisib currently under development.
Details of these analyses will be described in a separate CPMS RAP and results will be 
reported separately to the CSR. Analyses and reporting of the population PK model will 
be in accordance with the FDA and EMEA guidance on population PK, PK-PD analyses.
10.1.
Derived Pharmacokinetic Parameters
The exposure parameters (e.g. AUC, Cmax) will be derived from the individual post-hoc 
estimates from the POP PK model. These will be summarized across dose treatments, 
subgroups (e.g., gender, race) or as a function of a continuous variable (e.g., age).
11.
PHARMACOKINETIC / PHARMACODYNAMIC 
ANALYSES
If statistical analyses suggest an effect of nemiralisib on primary and other key clinical 
endpoints, an integrated longitudinal population dose/exposure versus clinical response 
on analysis key parameters including FEV1 and exacerbation rate will be undertaken. 
Participant characteristics influencing the relationship will be evaluated. 
Details of these analyses will be described in a separate CPMS RAP and results will be 
reported separately to the CSR.
 
 
 
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12.
REFERENCES
Bornkamp, B. (2014). Practical considerations for using functional uniform prior 
distributions for dose-response estimation in clinical trials. Biometrical Journal, 56(6), 
947-962. doi: 10.1002/bimj.201300138
Evidera. (2016). The Exacerbations of Chronic Pulmonary Disease Tool (EXACT®) 
Patient-Reported Outcome (PRO) USER MANUAL (Version 8.0). 
Spiegelhalter, D.J., Abrams, K.R. & Myles, J.P., (2004). Bayesian Approaches to Clinical 
Trials and Health-Care Evaluation. John Wiley & Sons, Ltd.
 
 
 
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13.
APPENDICES
13.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
13.1.1.
Exclusions from Per Protocol Population
Protocol deviations will be reviewed regularly throughout the course of the study, as 
described in Protocol Deviation Management Plan (PDMP). Deviations which will result 
in exclusion from the Per Protocol population will be assigned on a case-by-case basis
prior to database freeze (DBF).  
Decisions on whether or not the subject should be excluded from the PP population 
because the incorrect treatment was taken, due to the incorrect container being dispensed, 
will be identified after unblinding (i.e. post DBF). A PD of “incorrect treatment” will be 
added to the reporting dataset. 
 
 
 
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13.2.
Appendix 2: Assessment Windows
13.2.1.
Definitions of Assessment Windows for Analyses
The target Study Day and Analysis Timepoint for summaries and analyses for 
participants who do not discontinue treatment prior to the Day 84 (+window) is shown in 
the table below:
Target 
Analysis Window
Analysis Timepoint
Beginning Timepoint
Ending Timepoint
Study Day 1
Day 1
Day 1
DAY 1
Study Day 14
Day 11
Day 17
DAY 14
Study Day 28
Day 25
Day 31
DAY 28
Study Day 56
Day 52
Day 59
DAY 56
Study Day 84
Day 80
Day 87
DAY 84
Study Day 112
Day 108
Day 115
FU DAY 28
Study Day 140
Day 136
Day 143
FU DAY 56
Study Day 168
Day 164
Day 171
FU DAY 84
FU = Follow Up
For participants who discontinue treatment prior to Day 84 (+window), a follow-up (FU) 
Study Day will be derived as:
FU Study Day = (Date of follow-up assessment – Date of last dose of study treatment) +1
The FU Study Day will then be used to assign Study Days and Analysis Timepoints for 
summaries and analyses as shown in the table below:
Derived follow-up (FU) 
Study day
Analysis Window
Analysis Timepoint
Beginning Timepoint
Ending Timepoint
FU Study Day 28
FU Study Day 24
FU Study Day 31
FU DAY 28
FU Study Day 56
FU Study Day 52
FU Study Day 59
FU DAY 56
FU Study Day 84
FU Study Day 80
FU Study Day 87
FU DAY 84
13.2.1.1.
Hospital discharge
For the change from hospital discharge in clinic visit trough FEV1 endpoint, the 
assessment on the day of hospital discharge can be derived using the date of hospital 
discharge for the index exacerbation from the eCRF. As per Section 5.1 of the Protocol, if 
discharge takes place between Day 11 and Day 17 (inclusive), the assessments planned 
for Day 14 may be completed on the day of discharge. In these cases, for this endpoint 
only, the FEV1 assessment will be assigned the hospital discharge FEV1 assessment and 
the Day 14 assessment will be missing. 
 
 
 
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For all other analyses and summaries that include participants who were hospitalised for 
their index exacerbation, an additional Analysis Timepoint of “HOSPTIAL 
DISCHARGE” will be derived. However, in the cases where discharge takes place 
between Day 11 and Day 17 (inclusive), participants will be summarised under DAY 14 
and a footnote to say that participants who were discharged at Day 14 are summarised 
under DAY 14 will be included.  
13.2.1.2.
EXACT-Defined Recovery for CAT Trigger
Due to software limitations of the electronic PRO device, the study day following 
EXACT-defined recovery from the index exacerbation is not derived according to the 
EXACT User Manual. Instead, it has been derived using a 3-day Rolling Average that is 
calculated as the mean EXACT score [Day X-2, Day X-1, Day X] . 
 
 
 
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13.3.
Appendix 3: Study Phases and Treatment Emergent 
Adverse Events
13.3.1.
Study Periods
13.3.1.1.
12-Week Treatment Period 
The 12-Week Treatment Period is assigned from Study Day 1 to Study Day 84.
13.3.1.2.
12-Week Follow-Up Period
The 12-Week Follow-up Period is assigned from Study Day 85 to Study Day 168.
Refer to Section 13.2.1 for details on how Study Days and Analysis Timepoints will be 
derived for participants who discontinue treatment prior to Day 84.
13.3.2.
Study Phases
Exacerbation events during the 12-Week Treatment Period will be classified according to 
their occurrence from randomisation until treatment discontinuation/study withdrawal 
days, as detailed below.
Study Phase
Occurring from randomisation until
On-Treatment during the 12-Week Treatment Period
Treatment Stop Day
On- or Off-Treatment during the 12-Week Treatment 
Period
Day 84 or Study Withdrawal Day if Treatment Stop 
Day is < Day 84
13.3.2.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before Randomisation Date
Concomitant
Any medication that is not a prior
NOTES: 

Please refer to Appendix 6: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.
13.3.3.
Treatment Emergent Flag for Adverse Events
Flag
Definition
Treatment 
Emergent

If AE onset date is on or after treatment start date & on or before treatment stop 
date plus 10 days.
NOTES: 

If the study treatment stop date is missing, then the AE will be considered to be On-Treatment.

Time of study treatment dosing and start/stop time of AEs should be considered, if collected.
 
 
 
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13.4.
Appendix 4: Data Display Standards & Handling 
Conventions
13.4.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: uk1salx00175
HARP Compound
: \arprod\gsk2269557\mid200879
Analysis Datasets 

For all interim analyses, except for the End of Treatment Interim Analysis, datasets will be created 
according to Legacy GSK A&R dataset standards.

For the End of Treatment Interim Analysis and the final reporting effort, datasets will be created 
according to current CDISC standards
Generation of RTF Files

RTF files will be generated for the final reporting effort.
13.4.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 

Figures will be produced using PROC SGPLOT in SAS 
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may be
adjusted to a clinically interpretable number of DP’s. 
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 
 
 
 
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Unscheduled Visits

Unscheduled visits will be included in summary tables of the worst-case results by potential clinical 
importance criteria only.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principles 7.01 to 7.13.
13.4.3.
Reporting Standards for Pharmacokinetic
Pharmacokinetic Concentration Data
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
NONMEM/Pop PK 
File
Pop-PK file (CSV format) for the POP-PK analysis by Clinical Pharmacology 
Modelling and Simulation function will be created according to the data specification 
detailed in Section 13.8.2 Population Pharmacokinetic (PopPK) Dataset 
Specification.
NONMEM/PK/PD 
File
PK/PD file (CSV format) for the PK/PD analysis by Clinical Pharmacology Modelling 
and Simulation function will be created according to the data specification detailed 
in the CPMS RAP.
 
 
 
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13.5.
Appendix 5: Derived and Transformed Data
13.5.1.
General
Multiple Measurements at One Analysis Time Point

If there are two values within a time window (as per Section 13.2.1) the value closest to the target day 
for that window will be used. If values are the same distance from the target, then the mean will be 
taken.

Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables.
Study Day

Calculated as the number of days from Randomisation Date:

Ref Date = Missing              → Study Day = Missing 

Ref Date < Randomisation Date → Study Day = Ref Date – Randomisation Date

Ref Data ≥ Randomisation Date → Study Day = Ref Date – (Randomisation Date) + 1    
Time from date of randomisation and time from date of last dose of study treatment

For endpoints that use the time from the date of randomisation to a reference date, time will be 
calculated as

(Ref Date – Randomisation Date) + 1

For endpoints that use the time from the date of last dose of study treatment to a reference date, time 
will be calculated as

(Ref Date – (Last Dose Date + 1)) +1
13.5.2.
Study Population
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1

The cumulative dose will be based on the formula:
Cumulative Dose = Sum of (Number of Days x Total Daily Dose)

If there are any treatment breaks during the study, exposure data will be adjusted accordingly.
13.5.3.
Safety
Adverse Events
AE’S of Special Interest

Post-inhalation cough is an AE of special interest. The lower level term (LLT) to be included is 
“coughing after drug inhalation”
 
 
 
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13.6.
Appendix 6: Reporting Standards for Missing Data
13.6.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) is defined as completing all 
phases of the study including the last scheduled study visit

A participant is considered to have completed the Treatment Period, if he/she has 
completed the last on-treatment study visit (Visit 6) 

Withdrawn subjects were not replaced in the study.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.

Withdrawal visits will be slotted as per Appendix 2: Assessment Windows otherwise 
they will not be summarised (and will be listed only).
13.6.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:

These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 

Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
13.6.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to be 
recorded for AE start and end dates; that is, the day of the month may be missing. In 
such a case, the following conventions will be applied for calculating the time to onset 
and the duration of the event:

Missing Start Day: First of the month will be used unless this is before the start 
date of study treatment; in this case the study treatment start date will be used and 
hence the event is considered On-treatment as per Appendix 3: Study Phases and 
Treatment Emergent Adverse Events.

Missing Stop Day: Last day of the month will be used, unless this is after the stop 
date of study treatment; in this case the study treatment stop date will be used.

Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing.
 
 
 
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Element
Reporting Detail
Concomitant 
Medications/
Medical 
History

Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention:

If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month

If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.
Age

The eCRF collects year of birth only. Day and Month will be imputed by Data 
Management using a 
 for the day and 
 for the month

Age will then be derived referenced to the Screening Date

A footnote to say that age has been imputed will be included in any outputs containing 
age.
 
 
 
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13.7.
Appendix 7: Values of Potential Clinical Importance
13.7.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Haemoglobin 
G/DL
Male 18-64 years
7.1
19.9
Male 65+ years
7.1
19.9
Female 18-64 years
7.1
19.9
Female 65+ years
7.1
19.9
Lymphocytes 
GI/L
0.85
4.1
Total Absolute Neutrophil Count 
GI/L
1.5
8
Platelet Count 
GI/L
31
1499
White Blood Cell count
GI/L
18-64 years
1.1
10.8
65+ years
1.1
10.8
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Albumin
g/L
32
50
Calcium
mmol/L
1.5
3.24
Creatinine
Male 40-49 years
69
160
Male 50-59 years
67.2
160
Male 60-69 years
67.2
160
Male 70+ years
59.2
160
Female 40-49 years
52.2
160
Female 50-59 years
53
160
Female 60-69 years
53
160
Female 70+ years
55.7
160
Glucose
mmol/L
13-49 years
2.2
27.8
50+ years
2.2
27.8
Potassium
mmol/L
2.8
6.5
Sodium
mmol/L
120
160
Urea/BUN
mmol/L
13-64 years
2.5
15
65+ years
2.5
15
 
 
 
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Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
≥ 2x ULN
AST/SGOT 
U/L
High
≥ 2x ULN
AlkPhos 
U/L
High
≥ 2x ULN
T Bilirubin 
µmol/L
High
≥ 2x ULN
T. Bilirubin + ALT
µmol/L
High
2xULN T.Bilirubin + ≥ 3x ULN ALT
U/L
Direct Bilirubin
µmol/L
0 – 6
13.7.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 530
Absolute PR Interval
msec
< 110
> 240
Absolute QRS Interval
msec
< 75
> 110
Change from Baseline
Increase from Baseline QTc
msec
> 60
13.7.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 90
> 140 
Diastolic Blood Pressure
mmHg
< 60
> 90
Heart Rate
bpm
< 40 
> 110 
 
 
 
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13.8.
Appendix 8: Population Pharmacokinetic (PopPK) Analyses
13.8.1.
Population Pharmacokinetic (PopPK) Methodology
All analysis will be performed in the validated Modelling and Analysis Platform (MAP). 
MAP consists of a Linux desktop containing various modelling applications, including 
NONMEM, PsN, Pirana, R and RStudio. All software versions used will be documented.
The population PK analysis will be performed in the following sequence of steps:
1. Exploratory data analysis/data check out.
2. Base structural model development.
3. Covariate analysis.
4. Model refinement.
5. Model evaluation.
6. Model application using simulation
The above analysis and reporting steps follow EMEA 
(http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/
WC500003067.pdf) and FDA population PK guidances 
(https://www.fda.gov/downloads/drugs/guidances/UCM072137.pdf ) 
Key components of these regulatory guidelines on population PK are also included in the 
Global CPMS guidance for pop pk RAP
(https://connect.gsk.com/sites/cpms/TandD/Guidances).
13.8.2.
Population Pharmacokinetic (PopPK) Dataset Specification
Statistics & Programming, in discussion with CPMS, will provide a NONMEM dataset.  
Column headings in NONMEM-ready datasets and specifications should be consistent to 
minimise the programming process, and facilitate a smooth transfer of projects between 
users as needed. IDSL standards will be followed where possible.
A list of most common standardised variable names for NONMEM datasets can be found 
in Table below.
 
 
 
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List of Variable Names for NONMEM-Ready Datasets for PopPK Analysis
Variable
Label (Variable description)
C
NONMEM line exclusion identifier
ID
NONMEM subject identifier
STUD
Study ID
SUBJID
Subject identifier for study
SITEID
Unique identifier for a study site
AMT
NONMEM Amount of drug administered then EVID =1- dose event record
UAMT
Unit of AMT (mg)
ADDL
NONMEM Additional dose
CONC
Drug Concentration 
UCONC
Unit of CONC (ng/mL)
LNCONC
Natural log of CONC column 
ANALYTE
Drug label e.g 557
LLQ
Lower Limit of quantification
LNLLQ
Natural log of LLQ column
DAY
Study day number of record or of dosing
TIME
Plasma sample time after last dose
UTIME
Unit of TIME (h)
DOSE
Dose amount
EVID
NONMEM Event ID If row has dose then EVID=1 else EVID =0  
If EVID=1 then this is a dose event record
If EVID = 0 then this is an observation record 
II
NONMEM Inter-dose interval II=24 – dose every day
SS
Steady state item SS= 1 refers to steady state
MDV
NONMEM Missing data value then MDV=1 else MDV=0
AGE
Subject Age (yrs)
SEX
Subject gender 0 = Male 1 =Female
SEXTEXT
Subject gender text Male or Female
BMI
Baseline Body Mass Index
WT
Baseline Subject weight
CONMED1
Identifier for inhibitor CYP3A4 1 =Yes, 0 = No
CONMED1TXT
Inhibitor Name
CONMED2
Identifier for inducer CYP3A4 1 =Yes, 0 = No
CONMED2TXT
Inducer Name
If observation record e.g CONC  has “NA” or “NS” then assign CONC cell as  “.”
If observation record e.g CONC  has “NQ” or “BQL” then assign CONC cell as  “.” and MDV = 1 -this means 
value can be estimated by model
Missing covariate data should be imputed as “-99. 
 
 
 
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13.9.
Appendix 9: Pharmacokinetic / Pharmacodynamic Analyses
13.9.1.
Pharmacokinetic/Pharmacodynamic Methodology
PK-PD analysis of Nemiralisib will be guided by the results of the formal statistical 
analyses on the key clinical endpoints. The aims of the PK-PD analyses will contribute 
towards the dose selection in future studies using an integrated longitudinal analysis 
framework.
The objective is to explore an integrated modelling framework to characterise the 
longitudinal FEV1 response versus dose (average systemic exposure) during on- & off-  
treatment phases
FEV1i (ti j ) = FEV1i,base · (1 + f (ti j , dosei , xi ) + εi j with εi j ∼N(0, σ2)
A longitudinal nonlinear mixed-effects model will be used to describe the FEV1 response 
over time measured for each patient (i) at each visit (tij) with ɛ denoting the normal 
distributed residual variability with mean 0 and variance σ2. The function f() describes 
the relative change from observed FEV1 at baseline (FEV1,base) and any influence of 
patient characteristics on FEV1 response will be assessed.
Joint relationship between time to first exacerbation and FEV1 change as function of 
dose/exposure and patient covariates will be assessed.
Details of these analyses will be described in a separate CPMS RAP and results will be 
reported separately to the CSR.
 
 
 
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13.10.
Appendix 10: Abbreviations & Trade Marks
13.10.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GSK
GlaxoSmithKline
IA
Interim Analysis
ICH
International Conference on Harmonization
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
QC
Quality Control
QTcF
Fridericia’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
TFL
Tables, Figures & Listings 
 
 
 
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13.10.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
COPD Assessment Test (CAT)
E-RS: COPD
ELLIPTA
EXACT-PRO
HARP
NONMEM
Propeller Sensor
SAS
SGRQ
 
 
 
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13.11.
Appendix 11: List of Data Displays
13.11.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays for SAC:
Section
Tables
Figures
Study Population
1.1 to 1.28
Not applicable 
Efficacy
2.1 to 2.121
2.1 to 2.12
Safety
3.1 to 3.31
3.1 to 3.3
Pharmacokinetic
4.1 to 4.2
Not applicable
Section
Listings
ICH Listings
1 to 27
Other Listings
28 to 30
13.11.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 12: Example Mock Shells for Data Displays.
13.11.3.
Deliverables
Delivery
Description
IA
Interim Analyses (except the End of treatment Phase Interim Analysis)
EOT
End of Treatment Phase Interim Analysis
SAC
Statistical Analysis Complete
 
 
 
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13.11.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
MITT
ES8
Summary of Subject Status and Reason for Study Withdrawal
EOT, SAC
1.2.
MITT
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
EOT, SAC
1.3.
APE
ES6
Summary of Screening Status and Reasons for Screen Failure
SAC
1.4.
APE
NS1
Summary of Number of Participants by Country and Site ID
SAC
Protocol Deviation
1.5.
MITT
DV1
Summary of Important Protocol Deviations
EOT, SAC
1.6.
MITT
IE1
Summary of Inclusion/Exclusion Criteria Deviations
EOT, SAC
Population Analysed
1.7.
MITT
SP1
Summary of Study Populations 
SAC
1.8.
MITT
SP2
Summary of Exclusions from the Per Protocol/Safety Population
SAC
Demographic and Baseline Characteristics
1.9.
MITT
DM1
Summary of Demographic Characteristics
EOT, SAC
1.10.
APE
DM11
Summary of Age Ranges
SAC
1.11.
MITT
DM5
Summary of Race and Racial Combinations
SAC
1.12.
MITT
MH4
Summary of Past Medical Conditions
EOT, SAC
1.13.
MITT
MH4
Summary of Current Medical Conditions
EOT, SAC
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.14.
MITT
FH1
Summary of Family History of Cardiovascular Risk Factors
EOT, SAC
1.15.
MITT
SU1
Summary of Smoking History at Screening
EOT, SAC
1.16.
MITT
SU1
Summary of Smoking Status over the 12-Week Treatment 
Period
EOT, SAC
1.17.
MITT
SU1
Summary of Smoking Status over the 12-Week Follow-Up 
Period
EOT, SAC
1.18.
MITT
Example 7
Summary of COPD Duration at Screening
EOT, SAC
1.19.
MITT
Example 1
Summary of COPD Exacerbation History at Screening
Use categories 0;1;2;3;≥3. Summarise 
moderate/severe, moderate; severe
Include 7-Day History of COPD 
Exacerbations
EOT, SAC
1.20.
MITT
Example 1
Summary of COPD Exacerbation History at Screening by 
Country
EOT, SAC
Concomitant Medications
1.21.
MITT
Example 14
Summary of Baseline COPD Maintenance Therapy
EOT, SAC
1.22.
MITT
Example 15
Summary of On-Treatment COPD Maintenance (Step-up) 
Therapy 
EOT, SAC
1.23.
MITT
CM1
Summary of Concomitant Medications during 12-Week 
Treatment Period
EOT, SAC
1.24.
MITT
Example 16
Summary of OCS Use
EOT, SAC
1.25.
MITT
CM1
Summary of Concomitant Medications during 12-Week Follow-
Up Period
EOT, SAC
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Exposure and Treatment Compliance
1.26.
MITT
EX1
Summary of Exposure to Study Treatment
EOT, SAC
1.27.
MITT
Example 2
Summary of Treatment Compliance
EOT, SAC
1.28.
MITT
Example 2
Summary of actuations of study treatment measured by the clip-
on Propeller Sensor
EOT, SAC
13.11.5.
Efficacy Tables
13.11.5.1. Efficacy tables for Interim Analysis 1
Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in Clinic Visit trough FEV1
2.1.
MITT
Example 3
Summary of FEV1 (L) 
Include pre- and post-bronchodilator
IA1
2.2.
MITT
Example 3
Summary of FEV1 (L) by Index Exacerbation Severity
Include pre- and post-bronchodilator 
Include additional row for hospital 
discharge visit for Severe group
IA1
2.3.
MITT
Example 3
Summary of Change from Baseline in FEV1 (L)
Include pre- and post-bronchodilator
IA1
2.4.
MITT
Example 3
Summary of Change from Baseline in FEV1 (L) by Index 
Exacerbation Severity
Include pre- and post-bronchodilator. 
Include additional row for hospital 
discharge visit for Severe group
IA1
2.5.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 at Day 14 
measured post-bronchodilator (Dose Response Model)
IA1
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.6.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 at Day 28 
measured post-bronchodilator (Dose Response Model) 
IA1
2.7.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
14 measured post-bronchodilator by Index Exacerbation 
Severity (Dose Response Model)
IA1
2.8.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
28 measured post-bronchodilator by Index Exacerbation 
Severity (Dose Response Model)
IA1
2.9.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
measured post- bronchodilator (Repeated Measures Model)
IA1
2.10.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
measured pre- bronchodilator (Repeated Measures Model)
IA1
2.11.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
measured post- bronchodilator by Index Exacerbation Severity
(Repeated Measures Model)
IA1
2.12.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
measured pre- bronchodilator by Index Exacerbation Severity
(Repeated Measures Model)
IA1
Change from Hospital Discharge in Clinic Visit trough FEV1
2.13.
MITT
Example 3
Summary of Change from Hospital Discharge in FEV1 (L)
Include pre- and post-bronchodilator
IA1
2.14.
MITT
Example 11
Sensitivity Analysis of Change from Hospital Discharge in FEV1
(L) measured post- bronchodilator (Repeated Measures Model)
IA1
2.15.
MITT
Example 11
Sensitivity Analysis of Change from Hospital Discharge in FEV1
(L) measured pre- bronchodilator (Repeated Measures Model)
IA1
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.16.
MITT
Example 11
Sensitivity Analysis of Change from Hospital Discharge in FEV1
(L) measured post- bronchodilator by Index Exacerbation Severity 
(Repeated Measures Model)
IA1
2.17.
MITT
Example 11
Sensitivity Analysis of Change from Hospital Discharge in FEV1
(L) measured pre- bronchodilator by Index Exacerbation Severity 
(Repeated Measures Model)
IA1
Rate of Exacerbations
2.18.
MITT
Example 5
Summary of On-treatment Exacerbations
IA1
2.19.
MITT
Example 5
Summary of On-treatment Exacerbations by Index Exacerbation 
Severity
IA1
EXAcerbations of Chronic Pulmonary Disease Tool - Patient Reported Outcome (EXACT)
2.20.
MITT
Example 9
Statistical Analysis of Proportion of Participants Achieving the 
EXACT-definition of Recovery by Visit
Exclude statistical analysis 
information (summary only)
IA1
2.21.
MITT
Example 9
Subgroup Analysis of Proportion of Participants Achieving the 
EXACT-definition of Recovery by Index Exacerbation Severity
Exclude statistical analysis 
information (summary only)
IA1
Other Spirometry Measures
2.22.
MITT
Example 3
Summary of Spirometry Measurements
IA1
2.23.
MITT
Example 3
Summary of Change from Baseline in Spirometry Measurements
IA1
 
 
 
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13.11.5.2. Efficacy tables for Interim Analysis 2
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in Clinic Visit trough FEV1
2.1.
MITT
Example 3
Summary of FEV1 (L) 
Include pre- and post-bronchodilator
IA2
2.2.
MITT
Example 3
Summary of FEV1 (L) by Index Exacerbation Severity
Include pre- and post-bronchodilator 
Include additional row for hospital 
discharge visit for Severe group
IA2
2.3.
MITT
Example 3
Summary of Change from Baseline in FEV1 (L)
Include pre- and post-bronchodilator
IA2
2.4.
MITT
Example 3
Summary of Change from Baseline in FEV1 (L) by Index 
Exacerbation Severity
Include pre- and post-bronchodilator. 
Include additional row for hospital 
discharge visit for Severe group
IA2
2.5.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
14 measured post-bronchodilator (Dose Response Model)
IA2
2.6.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
28 measured post-bronchodilator (Dose Response Model)
IA2
2.7.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
56 measured post-bronchodilator (Dose Response Model)
IA2
2.8.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
84 measured post-bronchodilator (Dose Response Model)
IA2
2.9.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
14 measured post-bronchodilator by Index Exacerbation 
Severity (Dose Response Model)
IA2
2.10.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
28 measured post-bronchodilator by Index Exacerbation 
Severity (Dose Response Model)
IA2
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.11.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
56 measured post-bronchodilator by Index Exacerbation 
Severity (Dose Response Model)
IA2
2.12.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
84 measured post-bronchodilator by Index Exacerbation 
Severity (Dose Response Model)
IA2
2.13.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
measured post-bronchodilator (Repeated Measures Model)
IA2
2.14.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
measured pre-bronchodilator (Repeated Measures Model)
IA2
2.15.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
measured post-bronchodilator by Index Exacerbation Severity 
(Repeated Measures Model)
IA2
2.16.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
measured pre-bronchodilator by Index Exacerbation Severity 
(Repeated Measures Model)
IA2
Change from Hospital Discharge in Clinic Visit trough FEV1
2.17.
MITT
Example 3
Summary of Change from Hospital Discharge in FEV1 (L)
Include pre- and post-bronchodilator
IA2
2.18.
MITT
Example 26
Statistical Analysis of Change from Hospital Discharge in FEV1
(L) at Day 28 measured post-bronchodilator (Dose Response 
Model)
IA2
2.19.
MITT
Example 26
Statistical Analysis of Change from Hospital Discharge in FEV1
(L) at Day 56 measured post-bronchodilator (Dose Response 
Model)
IA2
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.20.
MITT
Example 26
Statistical Analysis of Change from Hospital Discharge in FEV1
(L) at Day 84 measured post-bronchodilator (Dose Response 
Model)
IA2
2.21.
MITT
Example 26
Subgroup Analysis of Change from Hospital Discharge in FEV1
(L) at Day 28 measured post-bronchodilator by Index 
Exacerbation Severity (Dose Response Model)
IA2
2.22.
MITT
Example 26
Subgroup Analysis of Change from Hospital Discharge in FEV1
(L) at Day 56 measured post-bronchodilator by Index 
Exacerbation Severity (Dose Response Model)
IA2
2.23.
MITT
Example 26
Subgroup Analysis of Change from Hospital Discharge in FEV1
(L) at Day 84 measured post-bronchodilator by Index 
Exacerbation Severity (Dose Response Model)
IA2
2.24.
MITT
Example 11
Sensitivity Analysis of Change from Hospital Discharge in FEV1
(L) measured post-bronchodilator (Repeated Measures Model)
IA2
2.25.
MITT
Example 11
Sensitivity Analysis of Change from Hospital Discharge in FEV1
(L) measured pre-bronchodilator (Repeated Measures Model)
IA2
2.26.
MITT
Example 11
Sensitivity Analysis of Change from Hospital Discharge in FEV1
(L) measured post-bronchodilator by Index Exacerbation 
Severity (Repeated Measures Model)
IA2
2.27.
MITT
Example 11
Sensitivity Analysis of Change from Hospital Discharge in FEV1
(L) measured pre-bronchodilator by Index Exacerbation Severity 
(Repeated Measures Model)
IA2
Rate of Exacerbations
2.28.
MITT
Example 5
Summary of On-treatment Exacerbations
IA2
2.29.
MITT
Example 5
Summary of On-treatment Exacerbations by Index Exacerbation 
Severity
IA2
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.30.
MITT
Example 6
Statistical Analysis of On-treatment Exacerbations
IA2
2.31.
MITT
Example 6
Subgroup Analysis of On-treatment Exacerbations by Index 
Exacerbation Severity
IA2
Time to Next Exacerbation
2.32.
MITT
Example 8
Summary and Statistical Analysis of Time to next On-treatment 
Exacerbation During the 12-Week Treatment Period
IA2
2.33.
MITT
Example 8
Subgroup Analysis of Time to next On-treatment Exacerbation  
During the 12-Week Treatment Period by Index Exacerbation 
Severity
IA2
EXAcerbations of Chronic Pulmonary Disease Tool - Patient Reported Outcome (EXACT)
2.34.
MITT
Example 9
Statistical Analysis of Proportion of Participants Achieving the 
EXACT-definition of Recovery by Visit
IA2
2.35.
MITT
Example 9
Subgroup Analysis of Proportion of Participants Achieving the 
EXACT-definition of Recovery by Index Exacerbation Severity
IA2
Rescue Medication Use
2.36.
MITT
RM1
Summary of Mean Number of Occasions of Rescue Medication 
Use Per Day
IA2
2.37.
MITT
RM1
Summary of Percentage of Rescue-Free Days
IA2
Other Spirometry Measures
2.38.
MITT
Example 3
Summary of Spirometry Measurements
IA2
2.39.
MITT
Example 3
Summary of Change from Baseline in Spirometry Measurements
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13.11.5.3. Efficacy tables for End of Treatment Interim Analysis and SAC
Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in Clinic Visit trough FEV1
2.1.
MITT
Example 3
Summary of FEV1 (L) 
Include pre- and post-bronchodilator
EOT, SAC
2.2.
MITT
Example 3
Summary of FEV1 (L) by Index Exacerbation Severity
Include pre- and post-bronchodilator 
Include additional row for hospital 
discharge visit for Severe group
EOT, SAC
2.3.
MITT
Example 3
Summary of Change from Baseline in FEV1 (L)
Include pre- and post-bronchodilator
EOT, SAC
2.4.
MITT
Example 3
Summary of Change from Baseline in FEV1 (L) by Index 
Exacerbation Severity
Include pre- and post-bronchodilator. 
Include additional row for hospital 
discharge visit for Severe group
EOT, SAC
2.5.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
14 measured post-bronchodilator (Dose Response Model)
EOT, SAC
2.6.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
14 measured pre-bronchodilator (Dose Response Model)
EOT, SAC
2.7.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
28 measured post-bronchodilator (Dose Response Model)
EOT, SAC
2.8.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
28 measured pre-bronchodilator (Dose Response Model)
EOT, SAC
2.9.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
56 measured post-bronchodilator (Dose Response Model)
EOT, SAC
2.10.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
56 measured pre-bronchodilator (Dose Response Model)
EOT, SAC
2.11.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
84 measured post-bronchodilator (Dose Response Model)
EOT, SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.12.
MITT
Example 26
Statistical Analysis of Change from Baseline in FEV1 (L) at Day 
84 measured pre-bronchodilator (Dose Response Model)
EOT, SAC
2.13.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
14 measured post-bronchodilator by Index Exacerbation Severity 
(Dose Response Model)
EOT, SAC
2.14.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
14 measured pre-bronchodilator by Index Exacerbation Severity 
(Dose Response Model)
EOT, SAC
2.15.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
28 measured post-bronchodilator by Index Exacerbation Severity 
(Dose Response Model)
EOT, SAC
2.16.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
28 measured pre-bronchodilator by Index Exacerbation Severity 
(Dose Response Model)
EOT, SAC
2.17.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
56 measured post-bronchodilator by Index Exacerbation Severity 
(Dose Response Model)
EOT, SAC
2.18.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
56 measured pre-bronchodilator by Index Exacerbation Severity 
(Dose Response Model)
EOT, SAC
2.19.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
84 measured post-bronchodilator by Index Exacerbation Severity 
(Dose Response Model)
EOT, SAC
2.20.
MITT
Example 26
Subgroup Analysis of Change from Baseline in FEV1 (L) at Day 
84 measured pre-bronchodilator by Index Exacerbation Severity 
(Dose Response Model)
EOT, SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.21.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
measured post-bronchodilator (Repeated Measures Model)
EOT, SAC
2.22.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
measured pre-bronchodilator (Repeated Measures Model)
EOT, SAC
2.23.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
measured post-bronchodilator by Index Exacerbation Severity 
(Repeated Measures Model)
EOT, SAC
2.24.
MITT
Example 11
Sensitivity Analysis of Change from Baseline in FEV1 (L) 
measured pre-bronchodilator by Index Exacerbation Severity 
(Repeated Measures Model)
EOT, SAC
Change from Hospital Discharge in Clinic Visit trough FEV1
2.25.
MITT
Example 3
Summary of Change from Hospital Discharge in FEV1 (L)
Include pre- and post-bronchodilator
EOT, SAC
2.26.
MITT
Example 26
Statistical Analysis of Change from Hospital Discharge in FEV1
(L) at Day 14 measured post-bronchodilator (Dose Response 
Model)
EOT, SAC
2.27.
MITT
Example 26
Statistical Analysis of Change from Hospital Discharge in FEV1
(L) at Day 14 measured pre-bronchodilator (Dose Response 
Model)
EOT, SAC
2.28.
MITT
Example 26
Statistical Analysis of Change from Hospital Discharge in FEV1
(L) at Day 28 measured post-bronchodilator (Dose Response 
Model)
EOT, SAC
2.29.
MITT
Example 26
Statistical Analysis of Change from Hospital Discharge in FEV1
(L) at Day 28 measured pre-bronchodilator (Dose Response 
Model)
EOT, SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.30.
MITT
Example 26
Statistical Analysis of Change from Hospital Discharge in FEV1
(L) at Day 56 measured post-bronchodilator (Dose Response 
Model)
EOT, SAC
2.31.
MITT
Example 26
Statistical Analysis of Change from Hospital Discharge in FEV1
(L) at Day 56 measured pre-bronchodilator (Dose Response 
Model)
EOT, SAC
2.32.
MITT
Example 26
Statistical Analysis of Change from Hospital Discharge in FEV1
(L) at Day 84 measured post-bronchodilator (Dose Response 
Model)
EOT, SAC
2.33.
MITT
Example 26
Statistical Analysis of Change from Hospital Discharge in FEV1
(L) at Day 84 measured pre-bronchodilator (Dose Response 
Model)
EOT, SAC
2.34.
MITT
Example 26
Subgroup Analysis of Change from Hospital Discharge in FEV1
(L) at Day 14 measured post-bronchodilator by Index 
Exacerbation Severity (Dose Response Model)
EOT, SAC
2.35.
MITT
Example 26
Subgroup Analysis of Change from Hospital Discharge in FEV1
(L) at Day 14 measured pre-bronchodilator by Index 
Exacerbation Severity (Dose Response Model)
EOT, SAC
2.36.
MITT
Example 26
Subgroup Analysis of Change from Hospital Discharge in FEV1
(L) at Day 28 measured post-bronchodilator by Index 
Exacerbation Severity (Dose Response Model)
EOT, SAC
2.37.
MITT
Example 26
Subgroup Analysis of Change from Hospital Discharge in FEV1
(L) at Day 28 measured pre-bronchodilator by Index 
Exacerbation Severity (Dose Response Model)
EOT, SAC
2.38.
MITT
Example 26
Subgroup Analysis of Change from Hospital Discharge in FEV1
(L) at Day 56 measured post-bronchodilator by Index 
Exacerbation Severity (Dose Response Model)
EOT, SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.39.
MITT
Example 26
Subgroup Analysis of Change from Hospital Discharge in FEV1
(L) at Day 56 measured pre-bronchodilator by Index 
Exacerbation Severity (Dose Response Model)
EOT, SAC
2.40.
MITT
Example 26
Subgroup Analysis of Change from Hospital Discharge in FEV1
(L) at Day 84 measured post-bronchodilator by Index 
Exacerbation Severity (Dose Response Model)
EOT, SAC
2.41.
MITT
Example 26
Subgroup Analysis of Change from Hospital Discharge in FEV1
(L) at Day 84 measured pre-bronchodilator by Index 
Exacerbation Severity (Dose Response Model)
EOT, SAC
2.42.
MITT
Example 11
Sensitivity Analysis of Change from Hospital Discharge in FEV1
(L) measured post-bronchodilator (Repeated Measures Model)
EOT, SAC
2.43.
MITT
Example 11
Sensitivity Analysis of Change from Hospital Discharge in FEV1
(L) measured pre-bronchodilator (Repeated Measures Model)
EOT, SAC
2.44.
MITT
Example 11
Sensitivity Analysis of Change from Hospital Discharge in FEV1
(L) measured post-bronchodilator by Index Exacerbation 
Severity (Repeated Measures Model)
EOT, SAC
2.45.
MITT
Example 11
Sensitivity Analysis of Change from Hospital Discharge in FEV1
(L) measured pre-bronchodilator by Index Exacerbation Severity 
(Repeated Measures Model)
EOT, SAC
Change from Day 84 in Clinic Visit trough FEV1
2.46.
MITT
Example 3
Summary of Change from Day 84 in FEV1 (L) 
Include pre- and post-bronchodilator
EOT, SAC
2.47.
MITT
Example 11
Statistical Analysis of Change from Day 84 in FEV1 (L) 
measured post-bronchodilator (Repeated Measures Model)
EOT, SAC
2.48.
MITT
Example 11
Statistical Analysis of Change from Day 84 in FEV1 (L) 
measured pre-bronchodilator (Repeated Measures Model)
EOT, SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.49.
MITT
Example 11
Subgroup Analysis of Change from Day 84 in FEV1 (L) 
measured post-bronchodilator by Index Exacerbation Severity 
(Repeated Measures Model)
EOT, SAC
2.50.
MITT
Example 11
Subgroup Analysis of Change from Day 84 in FEV1 (L) 
measured pre-bronchodilator by Index Exacerbation Severity 
(Repeated Measures Model)
EOT, SAC
Rate of Exacerbations
2.51.
MITT
Example 5
Summary of On-treatment Exacerbations
EOT, SAC
2.52.
MITT
Example 5
Summary of On-treatment Exacerbations by Index Exacerbation 
Severity
EOT, SAC
2.53.
MITT
Example 6
Statistical Analysis of On-treatment Exacerbations
EOT, SAC
2.54.
MITT
Example 6
Subgroup Analysis of On-treatment Exacerbations by Index 
Exacerbation Severity
EOT, SAC
2.55.
MITT
Example 5
Summary of On-treatment Exacerbations by Index Exacerbation 
Type
EOT, SAC
2.56.
MITT
Example 5
Summary of On-treatment Exacerbations by Number of 
Exacerbations in Previous 12 Months
EOT, SAC
2.57.
MITT
Example 5
Summary of On-or Off-treatment Exacerbations During the 12-
Week Treatment Period
EOT, SAC
2.58.
MITT
Example 5
Summary of On-or Off-treatment Exacerbations During the 12-
Week Treatment Period by Index Exacerbation Severity
EOT, SAC
2.59.
MITT
Example 6
Statistical Analysis of On- or Off-treatment Exacerbations During 
the 12-Week Treatment Period
EOT, SAC
2.60.
MITT
Example 6
Subgroup Analysis of On- or Off-treatment Exacerbations During 
the 12-Week Treatment Period by Index Exacerbation Severity
EOT, SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.61.
MITT
Example 5
Summary of Off-treatment Exacerbations 
EOT, SAC
2.62.
MITT
Example 5
Summary of Off-treatment Exacerbations by Index Exacerbation 
Severity
EOT, SAC
2.63.
MITT
Example 6
Statistical Analysis of Off-treatment Exacerbations
EOT, SAC
2.64.
MITT
Example 6
Subgroup Analysis of Off-treatment Exacerbations by Index 
Exacerbation Severity
EOT, SAC
2.65.
MITT
Example 5
Summary of On- and Off-treatment Exacerbations During the 
24-Week Study Period
EOT, SAC
2.66.
MITT
Example 5
Summary of On- and Off-treatment Exacerbations During the 
24-Week Study Period by Index Exacerbation Severity
EOT, SAC
2.67.
MITT
Example 6
Statistical Analysis of On- and Off-treatment Exacerbations 
During the 24-Week Study Period
EOT, SAC
2.68.
MITT
Example 6
Subgroup Analysis of On- and Off-treatment Exacerbations 
During the 24-Week Study Period by Index Exacerbation 
Severity
EOT, SAC
Time to Next Exacerbation
2.69.
MITT
Example 8
Summary and Statistical Analysis of Time to next On-treatment 
Exacerbation During the 12-Week Treatment Period
EOT, SAC
2.70.
MITT
Example 8
Subgroup Analysis of Time to next On-treatment Exacerbation  
During the 12-Week Treatment Period by Index Exacerbation 
Severity
EOT, SAC
2.71.
MITT
Example 8
Summary and Statistical Analysis of Time to next On- or Off-
treatment Exacerbation During the 12-Week Treatment Period
EOT, SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.72.
MITT
Example 8
Statistical Analysis of Time to next On- or Off-treatment 
Exacerbation During the 12-Week Treatment Period by Index 
Exacerbation Severity
EOT, SAC
2.73.
MITT
Example 8
Summary and Statistical Analysis of Time to Next Exacerbation 
Following Cessation of Study Treatment
EOT, SAC
2.74.
MITT
Example 8
Statistical Analysis of Time to Next Exacerbation Following 
Cessation of Study Treatment by Index Exacerbation Severity
EOT, SAC
EXAcerbations of Chronic Pulmonary Disease Tool - Patient Reported Outcome (EXACT)
2.75.
MITT
Example 9
Statistical Analysis of Proportion of Participants Achieving the 
EXACT-definition of Recovery by Visit
EOT, SAC
2.76.
MITT
Example 9
Subgroup Analysis of Proportion of Participants Achieving the 
EXACT-definition of Recovery by Index Exacerbation Severity
EOT, SAC
2.77.
MITT
Example 8
Summary and Statistical Analysis of Time to EXACT-defined 
Recovery
EOT, SAC
2.78.
MITT
Example 8
Subgroup Analysis of Time to EXACT-defined Recovery by 
Index Exacerbation Severity
EOT, SAC
2.79.
MITT
Example 10
Summary of severity of subsequent HCRU-defined exacerbation 
during 12-Week Treatment Period
Also split by moderate and severe
EOT, SAC
2.80.
MITT
Example 10
Summary of severity of subsequent HCRU-defined exacerbation 
during 12-Week Follow-up Period
Also split by moderate and severe
EOT, SAC
COPD Assessment Test (CAT)
2.81.
MITT
Example 3
Summary of Change from Baseline in CAT Total Score
EOT, SAC
2.82.
MITT
Example 3
Summary of Change from Baseline in CAT Total Score by Index 
Exacerbation Severity
EOT, SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.83.
MITT
Example 9
Statistical Analysis of Proportion of Responders Using the CAT 
Total Score by Visit
EOT, SAC
2.84.
MITT
Example 9
Subgroup Analysis of Proportion of Responders Using the CAT 
Total Score by Visit by Index Exacerbation Severity
EOT, SAC
2.85.
MITT
Example 11
Statistical Analysis of Change from Baseline in CAT Total Score 
(Repeated Measures Model)
EOT, SAC
2.86.
MITT
Example 11
Subgroup Analysis of Change from Baseline in CAT Total Score 
(Repeated Measures Model) by Index Exacerbation Severity
EOT, SAC
2.87.
MITT
Example 3
Summary of Change from End of Treatment in CAT Total Score
EOT, SAC
2.88.
MITT
Example 3
Summary of Change from End of Treatment in CAT Total Score 
by Index Exacerbation Severity
EOT, SAC
2.89.
MITT
Example 11
Statistical Analysis of Change from End of Treatment in CAT 
Total Score (Repeated Measures Model)
EOT, SAC
2.90.
MITT
Example 11
Subgroup Analysis of Change from End of Treatment in CAT 
Total Score (Repeated Measures Model) by Index Exacerbation 
Severity
EOT, SAC
St. George’s Respiratory Questionnaire (SGRQ)
2.91.
MITT
Example 3
Summary of Change from Baseline in SGRQ Total Score
EOT, SAC
2.92.
MITT
Example 3
Summary of Change from Baseline in SGRQ Total Score by 
Index Exacerbation Severity
EOT, SAC
2.93.
MITT
Example 9
Statistical Analysis of Proportion of Responders on the SGRQ 
Total Score by Visit
EOT, SAC
2.94.
MITT
Example 9
Subgroup Analysis of Proportion of Responders on the SGRQ 
Total Score by Index Exacerbation Severity
EOT, SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.95.
MITT
Example 11
Statistical Analysis of Change from Baseline SGRQ Total Score 
(Repeated Measures Model)
EOT, SAC
2.96.
MITT
Example 11
Subgroup Analysis of Change from Baseline SGRQ Total Score 
(Repeated Measures Model) by Index Exacerbation Severity
EOT, SAC
2.97.
MITT
Example 3
Summary of Change from End of Treatment in SGRQ Total 
Score
EOT, SAC
2.98.
MITT
Example 3
Summary of Change from End of Treatment in SGRQ Total 
Score by Index Exacerbation Severity
EOT, SAC
2.99.
MITT
Example 11
Statistical Analysis of Change from End of Treatment in SGRQ 
Total Score (Repeated Measures Model)
EOT, SAC
2.100.
MITT
Example 11
Subgroup Analysis of Change from End of Treatment in SGRQ 
Total Score (Repeated Measures Model) by Index Exacerbation 
Severity
EOT, SAC
E-RS: COPD
2.101.
MITT
Example 3
Summary of Change from Baseline in E-RS: COPD and 
subscales
SAC
Rescue Medication Use
2.102.
MITT
RM1
Summary of Mean Number of Occasions of Rescue Medication 
Use Per Day
EOT, SAC
2.103.
MITT
RM1
Summary of Percentage of Rescue-Free Days
EOT, SAC
2.104.
MITT
RM1
Summary of Mean Number of Actuations of Rescue Medication 
Use Per Day via the clip-on Propeller Sensor for MDI
EOT, SAC
2.105.
MITT
RM1
Summary of Percentage of Rescue-Free Days via the clip-on 
Propeller Sensor for MDI
EOT, SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Compliance
2.106.
MITT
IP1
Summary of Overall IP Compliance
EOT, SAC
2.107.
MITT
IP1
Summary of Overall IP Compliance via the clip-on Propeller 
Sensor for ELLIPTA
EOT, SAC
Healthcare Resource Utilisation
2.108.
MITT
Example 19
Summary of Exacerbation Related Unscheduled Healthcare 
Resource Utilisation 
EOT, SA
2.109.
MITT
Example 19
Summary of Exacerbation Related Unscheduled Healthcare 
Resource Utilization by Index Exacerbation Severity
EOT, SA
2.110.
MITT
Example 21
Summary of Exacerbation Related Hospitalizations
EOT, SAC
2.111.
MITT
Example 19
Summary of COPD Related Unscheduled Healthcare Resource 
Utilisation 
EOT, SAC
2.112.
MITT
Example 19
Summary of COPD Related Unscheduled Healthcare Resource 
Utilisation by Index Exacerbation Severity
EOT, SAC
2.113.
MITT
Example 20
Summary of Non-COPD Related Unscheduled Healthcare 
Resource Utilisation 
EOT, SAC
2.114.
MITT
Example 20
Summary of Non-COPD Related Unscheduled Healthcare 
Resource Utilisation by Index Exacerbation Severity
EOT, SAC
2.115.
MITT 
Example 22
Summary of Re-hospitalization Within 30 days of Index 
Exacerbation
EOT, SAC
2.116.
MITT
Example 24
Summary of Time from Resolution of Index Exacerbation to Next 
Exacerbation
EOT, SAC
2.117.
MITT
Example 23
Summary of Subsequent Exacerbation Treatment
EOT, SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Other Spirometry Measures
2.118.
MITT
Example 3
Summary of Spirometry Measurements
EOT, SAC
2.119.
MITT
Example 3
Summary of Change from Baseline in Spirometry Measurements
EOT, SAC
Inflammatory/infective Markers in Blood and Sputum
2.120.
MITT
Example 3
Summary of Inflammatory Markers in Blood
SAC
2.121.
MITT
Example 3
Summary of Inflammatory Markers in Sputum
SAC
 
 
 
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13.11.6.
Efficacy Figures
13.11.6.1. Efficacy Figures for Interim Analysis 1
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in Clinic Visit trough FEV1
2.1.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 14 measured post-bronchodilator
IA1
2.2.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 28 measured post-bronchodilator 
IA1
2.3.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 14 measured post-bronchodilator by Index Exacerbation 
Severity: Moderate
IA1
2.4.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 14 measured post-bronchodilator by Index Exacerbation 
Severity: Severe
IA1
2.5.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 28 measured post-bronchodilator by Index Exacerbation 
Severity: Moderate
IA1
2.6.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 28 measured post-bronchodilator by Index Exacerbation 
Severity: Severe
IA1
 
 
 
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13.11.6.2. Efficacy Figures for Interim Analysis 2
Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in Clinic Visit trough FEV1
2.1.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 14 measured post-bronchodilator
IA2
2.2.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 28 measured post-bronchodilator 
IA2
2.3.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 56 measured post-bronchodilator
IA2
2.4.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 84 measured post-bronchodilator
IA2
2.5.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 14 measured post-bronchodilator by Index Exacerbation 
Severity: Moderate
IA2
2.6.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 14 measured post-bronchodilator by Index Exacerbation 
Severity: Severe
IA2
2.7.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 28 measured post-bronchodilator by Index Exacerbation 
Severity: Moderate
IA2
2.8.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 28 measured post-bronchodilator by Index Exacerbation 
Severity: Severe
IA2
2.9.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 56 measured post-bronchodilator by Index Exacerbation 
Severity: Moderate
IA2
 
 
 
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.10.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 56 measured post-bronchodilator by Index Exacerbation 
Severity: Severe
IA2
2.11.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 84 measured post-bronchodilator by Index Exacerbation 
Severity: Moderate
IA2
2.12.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
at Day 84 measured post-bronchodilator by Index Exacerbation 
Severity: Severe
IA2
Change from Hospital Discharge in Clinic Visit trough FEV1
2.13.
MITT
Example 18
Plot of Dose Response Model of Change from Hospital 
Discharge in FEV1 at Day 28 measured post-bronchodilator 
IA2
2.14.
MITT
Example 18
Plot of Dose Response Model of Change from Hospital 
Discharge in FEV1 at Day 56 measured post-bronchodilator 
IA2
2.15.
MITT
Example 18
Plot of Dose Response Model of Change from Hospital 
Discharge in FEV1 at Day 84 measured post-bronchodilator 
IA2
2.16.
MITT
Example 18
Plot of Dose Response Model of Change from Hospital 
Discharge in FEV1 at Day 28 measured post-bronchodilator by 
Index Exacerbation Severity: Moderate
IA2
2.17.
MITT
Example 18
Plot of Dose Response Model of Change from Hospital 
Discharge in FEV1 at Day 28 measured post-bronchodilator by 
Index Exacerbation Severity: Severe
IA2
2.18.
MITT
Example 18
Plot of Dose Response Model of Change from Hospital 
Discharge in FEV1 at Day 56 measured post-bronchodilator by 
Index Exacerbation Severity: Moderate
IA2
 
 
 
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.19.
MITT
Example 18
Plot of Dose Response Model of Change from Hospital 
Discharge in FEV1 at Day 56 measured post-bronchodilator by 
Index Exacerbation Severity: Severe
IA2
2.20.
MITT
Example 18
Plot of Dose Response Model of Change from Hospital 
Discharge in FEV1 at Day 84 measured post-bronchodilator by 
Index Exacerbation Severity: Moderate
IA2
2.21.
MITT
Example 18
Plot of Dose Response Model of Change from Hospital 
Discharge in FEV1 at Day 84 measured post-bronchodilator by 
Index Exacerbation Severity: Severe
IA2
13.11.6.3. Efficacy Figures for End of Treatment Interim Analysis and SAC
Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in Clinic Visit trough FEV1
2.1.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
measured post-bronchodilator
EOT, SAC
2.2.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
measured pre-bronchodilator 
EOT, SAC
2.3.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
measured post-bronchodilator by Index Exacerbation Severity: 
Moderate
EOT, SAC
2.4.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
measured post-bronchodilator by Index Exacerbation Severity: 
Severe
EOT, SAC
 
 
 
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.5.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
measured pre-bronchodilator by Index Exacerbation Severity: 
Moderate
EOT, SAC
2.6.
MITT
Example 18
Plot of Dose Response Model of Change from Baseline in FEV1
measured pre-bronchodilator by Index Exacerbation Severity: 
Severe
EOT, SAC
Change from Hospital Discharge in Clinic Visit trough FEV1
2.7.
MITT
Example 18
Plot of Dose Response Model of Change from Hospital 
Discharge in FEV1 measured post-bronchodilator 
EOT, SAC
2.8.
MITT
Example 18
Plot of Dose Response Model of Change from Hospital 
Discharge in FEV1 measured pre-bronchodilator 
EOT, SAC
2.9.
MITT
Example 18
Plot of Dose Response Model of Change from Hospital 
Discharge in FEV1 measured post-bronchodilator by Index 
Exacerbation Severity: Moderate
EOT, SAC
2.10.
MITT
Example 18
Plot of Dose Response Model of Change from Hospital 
Discharge in FEV1 measured post-bronchodilator by Index 
Exacerbation Severity: Severe
EOT, SAC
2.11.
MITT
Example 18
Plot of Dose Response Model of Change from Hospital 
Discharge in FEV1 measured pre-bronchodilator by Index 
Exacerbation Severity: Moderate
EOT, SAC
2.12.
MITT
Example 18
Plot of Dose Response Model of Change from Hospital 
Discharge in FEV1 measured pre-bronchodilator by Index 
Exacerbation Severity: Severe
EOT, SAC
 
 
 
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13.11.7.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.1.
Safety
AE1
Summary of Treatment Emergent Adverse Events by System 
Organ Class and Preferred Term
SAC
3.2.
Safety
AE1
Summary of Post-Treatment Adverse Events by System Organ 
Class and Preferred Term
SAC
3.3.
Safety
AE3
Summary of Common (>=5%) Treatment Emergent Adverse 
Events by Overall Frequency
SAC
3.4.
Safety
AE1
Summary of Treatment Emergent Drug-Related Adverse Events 
by System Organ Class and Preferred Term
SAC
3.5.
Safety
AE15
Summary of Common (>=5%) Non-serious Treatment Emergent 
Adverse Events by System Organ Class and Preferred Term 
(Number of Participant and Occurrences)
SAC
3.6.
Safety
AE1
Summary of Treatment Emergent Adverse Events for 
Participants with Absolute Neutrophil Count Below Lower Value 
of PCI
SAC
Serious and Other Significant Adverse Events
3.7.
Safety
AE16
Summary of Serious Treatment Emergent Adverse Events by 
System Organ Class and Preferred Term (Number of 
Participants and Occurrences)
SAC
3.8.
Safety
AE16
Summary of Fatal Serious Treatment Emergent Adverse Events 
by System Organ Class and Preferred Term (Number of 
Participants and Occurrences)
Only with subcategory: Number of Fatal 
SAEs
SAC
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.9.
Safety
AE1
Summary of Serious Treatment Emergent Drug-related Adverse 
Events by System Organ Class and Preferred Term
SAC
3.10.
Safety
AE1 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term
SAC
3.11.
Safety
AE1
Summary of Post-treatment Serious Adverse Events by System 
Organ Class and Preferred Term
SAC
3.12.
Safety
AE1
Summary of Treatment Emergent Adverse Events of Special 
Interest by Lower Level Term
SAC
3.13.
Safety
Example 17
Summary of Post-Inhalation Cough by Visit
SAC
3.14.
Safety
Example 28
Summary of Post-Inhalation Cough by Visit and Cough Type
SAC
Laboratory: Chemistry 
3.15.
Safety
LB1
Summary of Chemistry Data 
SAC
3.16.
Safety
LB17
Summary of Worst Case Chemistry Results by PCI Criteria 
Post-Baseline Relative to Baseline
SAC
Laboratory: Hematology
3.17.
Safety
LB1
Summary of Hematology Data
SAC
3.18.
Safety
LB1
Summary of Change from Baseline in Hematology
Only for WBC, lymphocytes, neutrophils
SAC
3.19.
Safety
LB17
Summary of Worst Case Hematology Results by PCI Criteria 
Post-Baseline Relative to Baseline
SAC
Laboratory: Hepatobiliary (Liver)
3.20.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting
SAC
3.21.
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities
SAC
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
ECG
3.22.
Safety
EG1
Summary of ECG Findings 
SAC
3.23.
Safety
EG2
Summary of ECG Values by Visit
For the following parameters: QTcF, 
QTcB, PR, Heart rate 
SAC
3.24.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit
For the following parameters: QTcF, 
QTcB, PR, Heart rate
SAC
3.25.
Safety
Example 27
Summary of QTcF Categories
SAC
3.26.
Safety
Example 27
Summary of QTcB Categories
SAC
3.27.
Safety
EG10
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category
SAC
3.28.
Safety
EG11
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category
SAC
3.29.
Safety
Example 25
Summary of ECG Abnormalities for Participants with Any 
Abnormal Clinically Significant ECG Interpretation
SAC
Vital Signs
3.30.
Safety
VS1
Summary of Vital Signs
SAC
3.31.
Safety
VS7
Summary of Worst Case Vital Signs Results by PCI Criteria 
Post-Baseline Relative to Baseline
SAC
 
 
 
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13.11.8.
Safety Figures
Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory
3.1.
Safety
LB7
LFT Shift from Baseline to Maximum
SAC
3.2.
Safety
Example 13
Median (range) Absolute Neutrophil Count by Time and 
Treatment
SAC
ECG
3.3.
Safety
EG8
Distribution of QTcF Change by Time and Treatment
SAC
13.11.9.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetic Concentration-Time Data
4.1.
PK
PK01
Summary of Plasma GSK2269557 Pharmacokinetic 
Concentration-Time Data
SAC
4.2.
PK
PK05
Summary of Log-Transformed Plasma GSK2269557 
Pharmacokinetic Concentration-Time Data
SAC
 
 
 
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13.11.10. ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
APE
ES7
Listing of Reasons for Screen Failure
SAC
2.
MITT
ES2
Listing of Reasons for Study Withdrawal
SAC
3.
MITT
SD2
Listing of Reasons for Study Treatment Discontinuation
SAC
4.
MITT
BL1
Listing of Participants for Whom the Treatment Blind was Broken
SAC
5.
MITT
TA1
Listing of Planned and Actual Treatments
SAC
Protocol Deviations
6.
MITT
DV2
Listing of Important Protocol Deviations 
SAC
7.
MITT
IE3
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations
SAC
Populations Analysed
8.
MITT
SP3
Listing of Participants Excluded from Any Population
For participants excluded from MITT 
population (i.e. participants in the MITT 
but not in PP)
SAC
Demographic and Baseline Characteristics
9.
MITT
DM2
Listing of Demographic Characteristics
SAC
10.
MITT
DM9
Listing of Race
SAC
Prior and Concomitant Medications
11.
MITT
CP_CM3
Listing of Concomitant Medications
SAC
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Exposure and Treatment Compliance
12.
Safety
EX3
Listing of Exposure Data
SAC
Adverse Events
13.
Safety
AE8
Listing of All Adverse Events
SAC
14.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
SAC
15.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
SAC
Serious and Other Significant Adverse Events
16.
Safety
AE8
Listing of Fatal Serious Adverse Events
SAC
17.
Safety
AE8
Listing of Non-Fatal Serious Adverse Events
SAC 
18.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse Event
SAC
19.
Safety
AE8
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
SAC
Hepatobiliary (Liver)
20.
Safety
MH2
Listing of Medical Conditions for Participants with Liver Stopping 
Events
SAC
21.
Safety
SU2
Listing of Substance Use for Participants with Liver Stopping 
Events
SAC
All Laboratory
22.
Safety
LB5
Listing of All Chemistry Data for Participants with Any Value of 
Potential Clinical Importance
SAC
23.
Safety
LB14
Listing of Chemistry Data with Character Results
SAC
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
24.
Safety
LB5
Listing of All Hematology Data for Participants with Any Value of 
Potential Clinical Importance
SAC
25.
Safety
LB14
Listing of all Hematology Data with Character Results
SAC
ECG
26.
Safety
EG3
Listing of All ECG Values for Participants with Any Value of 
Potential Clinical Importance
SAC
27.
Safety
EG5
Listing of All ECG Findings for Participants with an Abnormal 
Finding
SAC
13.11.11. Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
28.
MITT
Example 29
Listing of Subjects who Received Incorrect Medication
SAC
29.
PK
PK07
Listing of Plasma Pharmacokinetic Concentration-Time Data
SAC
30.
Safety
EG5
Listing of All ECG Findings for Subjects with an Abnormal 
Finding
SAC
 
 
 
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13.12.
Appendix 12: Example Mock Shells for Data Displays
13.12.1.
Example shell 1
Example Shell X
Protocol: XYZ100001                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
                             Summary of COPD Exacerbation History at Screening
                                                                  Treatment A  Treatment B   Total
                                                                  (N=100)      (N=100)      (N=200)
   -----------------------------------------------------------------------------------------------------
   Moderate COPD exacerbations
     n                                                            X            X             X
     0                                                            xx (x%)      xx (x%)       xx (x%)    
     1                                                            xx (x%)      xx (x%)       xx (x%)  
     >=2                                                          xx (x%)      xx (x%)       xx (x%)    
   Severe COPD exacerbations
     n                                                            X            X             X
     0                                                            xx (x%)      xx (x%)       xx (x%)
     1                                                            xx (x%)      xx (x%)       xx (x%)
     >=2                                                          xx (x%)      xx (x%)       xx (x%)
   Total number of moderate/severe COPD exacerbations
     n                                                            911          899          1810
     0                                                            313 (34%)    317 (35%)     630 (35%)
     1                                                            252 (28%)    253 (28%)     505 (28%)
     >=2                                                          346 (38%)    329 (37%)     675 (37%)
Note: Number of COPD exacerbations reported in the 12 months prior to the Screening Visit.
 
 
 
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13.12.2.
Example Shell 2
Protocol: XYZ100001                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
Summary of Treatment Compliance
                                                                  Treatment A  Treatment B   Total
                                                                  (N=100)      (N=100)      (N=200)
   -----------------------------------------------------------------------------------------------------
   Overall compliance (%)
     n                                                            xx           xx            xx
     Mean                                                         xx           xx            xx 
     SD                                                           xx           xx            xx 
     Median                                                       xx           xx            xx
     Min.                                                         xx           xx            xx
     Max.                                                         xx           xx            xx
   Compliance interval
     < 80%                                                         xx (x%)      xx (x%)       xx (x%)
     80% - < 100%                                                  xx (x%)      xx (x%)       xx (x%)
     100% - < 120%                                                 xx (x%)      xx (x%)       xx (x%)
     >=120%                                                        xx (x%)      xx (x%)       xx (x%)
 
 
 
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13.12.3.
Example shell 3
Example Shell X
Protocol: ABC123456                                                                            Page 1 of n
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
                             Summary of Change from Baseline in FEV1 (L)
Measured post-bronchodilator
                                              
Visit             N      Treatment Arm       n    Mean    SD      Median  Min.   Max.
----------------------------------------------------------------------------------------------------------
Day 1
200    Placebo             200   0.111  0.1111   0.100  -0.11  1.11
                   200    GSK2269557 12.5 mcg 190   0.222  0.2222   0.200  -0.22  1.22
                   200    GSK2269557   50 mcg 195   0.333  0.3333   0.300  -0.33  1.33
                   200    GSK2269557  100 mcg 195   0.444  0.4444   0.400  -0.44  1.44
                   200   GSK2269557  250 mcg 190   0.555  0.5555   0.500  -0.55  1.55
                   200    GSK2269557  500 mcg 190   0.555  0.5555   0.500  -0.55  1.55
                   200    GSK2269557  750 mcg 190   0.555  0.5555   0.500  -0.55  1.55
Day 14
200    Placebo             200   0.111  0.1111   0.100  -0.11  1.11
                   200    GSK2269557 12.5 mcg 190   0.222  0.2222   0.200  -0.22  1.22
                   200    GSK2269557   50 mcg 195   0.333  0.3333   0.300  -0.33  1.33
                   200    GSK2269557  250 mcg 195   0.444  0.4444   0.400  -0.44  1.44
                   200    GSK2269557  500 mcg 190   0.555  0.5555   0.500  -0.55  1.55
200    GSK2269557  750 mcg 190   0.555  0.5555   0.500  -0.55  1.55
                                              
 
 
 
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13.12.4.
Example Shell 4
Protocol: ABC123456                                                                             Page 1 of 2
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
                        Statistical Analysis of Change from Baseline in FEV1 (ml)
Measured post-bronchodilator
Visit
N
Treatment Arm
n
Posterior 
Median 
95% Credible 
Interval
Day 14
x
Placebo
x
x.xx
(x.xx, x.xx)
x
GSK2269557 12.5 mcg
x
x.xx
(x.xx, x.xx)
x
GSK2269557   50 mcg
x
x.xx
(x.xx, x.xx)
x
GSK2269557  100 mcg
x
x.xx
(x.xx, x.xx)
x
GSK2269557  250 mcg
x
x.xx
(x.xx, x.xx)
x
GSK2269557  500 mcg
x
x.xx
(x.xx, x.xx)
x
GSK2269557  750 mcg
x
x.xx
(x.xx, x.xx)
Day 28
x
Placebo
x
x.xx
(x.xx, x.xx)
x
GSK2269557 12.5 mcg
x
x.xx
(x.xx, x.xx)
x
GSK2269557   50 mcg
x
x.xx
(x.xx, x.xx)
x
GSK2269557  100 mcg
x
x.xx
(x.xx, x.xx)
x
GSK2269557  250 mcg
x
x.xx
(x.xx, x.xx)
x
GSK2269557  500 mcg
x
x.xx
(x.xx, x.xx)
x
GSK2269557  750 mcg
x
x.xx
(x.xx, x.xx)
 
 
 
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Protocol: ABC123456                                                                             Page 2 of 2
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
                        Statistical Analysis of Change from Baseline in FEV1 (ml)
Measured post-bronchodilator
Visit
Treatment Comparison
Adjusted
Median
Difference
Std Dev
95% Credible 
Interval
Prob Treat. 
Diff >0 (%)
Day 14
GSK2269557 12.5 mg vs
x.xx
x.xx
(x.xx, x.xx)
x.xx
Placebo
GSK2269557   50 mg vs
x.xx
x.xx
(x.xx, x.xx)
x.xx
Placebo
GSK2269557 100 mg vs
x.xx
x.xx
(x.xx, x.xx)
x.xx
Placebo
GSK2269557 250 mg vs
x.xx
x.xx
(x.xx, x.xx)
x.xx
Placebo
GSK2269557 500 mg vs
x.xx
x.xx
(x.xx, x.xx)
x.xx
Placebo
GSK2269557 750 mg vs
x.xx
x.xx
(x.xx, x.xx)
x.xx
Placebo
Day 28
GSK2269557 12.5 mg vs
x.xx
x.xx
(x.xx, x.xx)
x.xx
Placebo
GSK2269557   50 mg vs
x.xx
x.xx
(x.xx, x.xx)
x.xx
Placebo
GSK2269557 100 mg vs
x.xx
x.xx
(x.xx, x.xx)
x.xx
Placebo
 
 
 
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13.12.5.
Example Shell 5
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
                                  Summary of On-treatment Exacerbations
                                                                      
                                                               Treatment A       Treatment B
                                                                  (N=100)         (N=100)
        -------------------------------------------------------------------------------------------
        Number of moderate & severe exacerbations per subject                      
         0                                                      50 (50%)       98 (98%)
         1                                                       6  (6%)       15 (15%)
         2                                                       6  (6%)        9  (9%)
         3                                                       1  (1%)        1  (1%)
         4                                                       0              2  (2%)
         5                                                       0              1  (1%)
   >5                                                      0              1  (1%)
        Subjects with >=1 moderate & severe exacerbation         13 (13%)       28 (28%)
        Total Number of moderate & severe exacerbations          21             49
        Number of moderate exacerbations per Subject                      
         0                                                      50 (50%)       98 (98%)
         1                                                       6  (6%)       15 (15%)
         2                                                       6  (6%)        9  (9%)
         3                                                       1  (1%)        1  (1%)
        
 
 
 
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13.12.6.
Example Shell 6
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
                           Statistical Analysis of On-treatment Exacerbations
                                                                      
                                                               Treatment A       Treatment B
                                                                  (N=100)         (N=100)
        -------------------------------------------------------------------------------------------
        Moderate and severe exacerbations
        Annual exacerbation rate (95% CrI)                  0.35 (x.xx, x.xx)   0.30 (x.xx, x.xx)                     
        Active vs. Placebo
          Ratio                                                                 0.85 (x.xx, x.xx)   
          Pr Diff <1                                                            x.xx   
        Percent reduction in rate (95% CrI)                                     15% (x.xx, x.xx)  
        Moderate exacerbations
        Annual exacerbation rate (95% CrI)                  0.35 (x.xx, x.xx)   0.30 (x.xx, x.xx)                     
        Active vs. Placebo
          Ratio                                                                 0.85 (x.xx, x.xx)   
          Pr Diff <1                                                            x.xx   
        Percent reduction in rate (95% CrI)                                     15% (x.xx, x.xx)                          
 
 
 
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13.12.7.
Example Shell 7
Protocol: ABC123456                                                                           Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
                                   Summary of COPD Duration at Screening
                                                   
                                                   Treatment A   Treatment B    Total
                                                   (N=100)       (N=100)       (N=200)
                 --------------------------------------------------------------------------
                 Duration of COPD:
                   n                                 100            99          199
                   <1 year                            XX   (x%)     XX   (x%)     XX   (x%)
                   >=1 to <5 years                    XX   (x%)     XX   (x%)     XX   (x%)
                   >=5 to <10 years                   XX   (x%)     XX   (x%)     XX   (x%)
                   >=10 to <15 years                  XX   (x%)     XX   (x%)     XX   (x%)
                   >=15 to <20 years                 XX   (x%)     XX   (x%)     XX   (x%)
                   >=20 to <25 years                  XX   (x%)     XX   (x%)     XX   (x%)
                   >=25 years                         XX   (x%)     XX   (x%)     XX   (x%)
 
 
 
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13.12.8.
Example Shell 8
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
         Summary and Analysis of Time to Next On-treatment Moderate or Severe Exacerbation (days)
                                               up to Day 84
                                                                  Treatment A      Treatment B
                                                                  (N=100)          (N=100)
            ------------------------------------------------------------------------------------
            Number of Subjects with Event                           10  (10%)        14  (14%)
            Number of Subjects Censored                             90  (90%)        86  (86%)
            Probability of Having Event (%)                         X.X             XX
              95% C.I.                                            (x.x, x.x)      (x.x, x.x)
            
            Treatment A vs. Placebo
              Hazard Ratio                                           X.XX
              95% Credible Interval                                 (x.xx, x.xx)
              
Note: Probability of having event, 95% C.I. are taken from the Kaplan-Meier analysis.
Note: Hazard ratio and 95% Credible Interval are from a Bayesian Cox proportional hazards model 
 
 
 
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13.12.9.
Example Shell 9
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
             Statistical Analysis of Proportion of Participants Achieving EXACT-definition of Response
                                                                      
                                                               Treatment A       Treatment B
                                                                  (N=100)         (N=100)
        -------------------------------------------------------------------------------------------
        Day 14
          n                                                   x.xx                x.xx                    
          Responder          
  x.xx (x%)           x.xx (x%)                     
          Non-responder                                       x.xx (x%)           x.xx (x%)                     
          Active vs. Placebo
           Odds Ratio (95% CrI)                                x.xx (x.xx, x.xx)   x.xx (x.xx, x.xx)
           Pr Diff >1   
                     x.xx               x.xx
        Day 28
          n                                                   x.xx                x.xx                    
          Responder          
  x.xx (x%)           x.xx (x%)                     
          Non-responder                                       x.xx (x%)           x.xx (x%)                     
          Active vs. Placebo
           Odds Ratio (95% CrI)                                x.xx (x.xx, x.xx)   x.xx (x.xx, x.xx)
           Pr Diff >1   
                     x.xx               x.xx
        
        
        
 
 
 
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13.12.10. Example Shell 10
Protocol: XYZ100001                                                                    Page 1 of n
Population: Intent-to-Treat/Safety/Other study specific
Table X
Summary of severity of subsequent HCRU-defined exacerbation during 12-Week Treatment Period
Treatment
N
n
Mean
SD
Median
Min.
Max.
Placebo
30
30
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Trt A
30
30
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Trt B
30
30
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
 
 
 
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13.12.11. Example Shell 11
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
                        Mixed Model Repeated Measures Analysis of CAT Total Score
                                                                      
                                                               Treatment A       Treatment B
                                                                  (N=100)         (N=100)
        -------------------------------------------------------------------------------------------
        Day 28
          n                                                   x.xx               x.xx                    
          Adjusted mean score change (SE)                     x.xx (x)           x.xx (x)                     
          Active - Placebo
           Difference (SE)                                    x.xx (x.xx)        x.xx (x.xx)
           95% (CrI)                                          x.xx               x.xx
           Pr Diff >0  
                          x.xx               x.xx
        Day 56
          n                                                   x.xx                x.xx                    
          Adjusted mean score change (SE)                     x.xx (x)           x.xx (x)                     
          Active - Placebo
           Difference (SE)                                    x.xx (x.xx)        x.xx (x.xx)
           95% (CrI)                                          x.xx               x.xx
           Pr Diff >0  
                          x.xx               x.xx
        
           
 
 
 
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13.12.12. Example Shell 12
Protocol: ABC123456                                                                             Page 1 of 3
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
             Summary of COPD Related Unscheduled Healthcare Resource Utilization
                                                                        
                                                                        Treatment A    Treatment B
                                                                        (N=100)        (N=100)
        --------------------------------------------------------------------------------------------
          Unscheduled Healthcare Utilisation                Yes          97  (97%)      19  (19%)
                                                            No            3  ( 3%)      81  (81%)
          Number of Home Visits (day)                       n           100            100
                                                            0            90  (90%)      92  (92%)
                                                            1             4   (4%)       4   (4%)
                                                            2             0              0  
                                                            3             0              0
                                                            >3            0              2  (<1%)
                                                            Total [1]     4              4
          Number of Home Visits (night)                     n           100            100
                                                            0           100 (100%)     100 (100%)
                                                            1             0              0  
                                                            2             0              0
                                                            3             0              0
                                                            >3            0              0
                                                            Total [1]     0              0
[1] Total number of contacts across all subjects.
[2] Total number of days across all subjects.
 
 
 
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Protocol: ABC123456                                                                             Page 2 of 3
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
             Summary of COPD Related Unscheduled Healthcare Resource Utilization 
                                                                        
                                                                        Treatment A    Treatment B
                                                                        (N=100)        (N=100)
        --------------------------------------------------------------------------------------------
          Number of Office/Practice Visits                  n           911            899
                                                            0           846  (93%)     808  (90%)
                                                            1            42   (5%)      58   (6%)
                                                            2            13   (1%)      23   (3%)
                                                            3             7  (<1%)       8  (<1%)
                                                            >3            3  (<1%)       2  (<1%)
                                                            Total [1]   103            140
          Number of Urgent Care/Outpatient Visits           n           911            899
                                                            0           886  (97%)     882  (98%)
                                                            1            15   (2%)      10   (1%)
                                                            2             3  (<1%)       2  (<1%)
                                                            3             3  (<1%)       3  (<1%)
                                                            >3            4  (<1%)       2  (<1%)
                                                            Total [1]    54             37
          Number of Emergency Room Visits                   n           911            899
                                                            0           906 (>99%)     893 (>99%)
                                                            1             5  (<1%)       5  (<1%)
                                                            2             0              1  (<1%)
                                                            3             0              0
                                                            >3            0              0
                                                            Total [1]     5              7
[1] Total number of contacts across all subjects.
[2] Total number of days across all subjects.
 
 
 
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Protocol: ABC123456                                                                             Page 3 of 3
Population: Intent-to-Treat/Safety/Other study specific
                                                Table 2.159
             Summary of COPD Related Unscheduled Healthcare Resource Utilization
                                                                        
                                                                        Treatment A    Treatment B
                                                                        (N=100)        (N=100)
        --------------------------------------------------------------------------------------------
          Number of Days in Intensive Care                  n           911            899
                                                            0           910 (>99%)     894 (>99%)
                                                            1             0              0
                                                            2             0              1  (<1%)
                                                            3             0              0
                                                            >3            1  (<1%)       4  (<1%)
                                                            Total [2]    12             40
          Number of Days in General Ward                    n           911            899
                                                            0           896  (98%)     878  (98%)
                                                            1             0              2  (<1%)
                                                            2             1  (<1%)      1  (<1%)
                                                            3             0              0
                                                            >3           14   (2%)      18   (2%)
                                                            Total [2]   119            258
[1] Total number of contacts across all subjects.
[2] Total number of days across all subjects.
 
 
 
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13.12.13. Example shell 13
Protocol: XYZ100001                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific 
       
Figure X
Median (range) Absolute Neutrophil Count by Time and Treatment
 
 
 
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13.12.14. Example Shell 14
Protocol: XYZ100001                                                                             Page 1 of n
Population: Intent-to-Treat/Safety/Other study specific
Table X
Summary of Baseline COPD Maintenance Therapy
Therapy category
Treatment A
(N=81)
Treatment B
(N=79)
Any medication at baseline
70 (86%)
50 (63%)
Monotherapy
X (x%)
X (x%)
  LAMA only
x  (x%)
x  (x%)
Dual therapy                          
x (x%)
x (x%)
  ICS/LABA
x  (x%)
x  (x%)
  Dual bronchodilator
xx (xx%)
xx (xx%)
Triple therapy
X (x%)
    X (x%)
  LAMA/ICS/LABA
x  (x%)
    0
 
 
 
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13.12.15. Example Shell 15
Protocol: XYZ100001                                                                             Page 1 of n
Population: Intent-to-Treat/Safety/Other study specific
Table X
Summary of On-Treatment COPD Maintenance (Step-up) Therapy
Therapy category
Treatment A
(N=81)
Treatment B
(N=79)
Any Step-up Therapy
70 (86%)
50 (63%)
 
 
 
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13.12.16. Example shell 16
Protocol: XYZ100001                                                                             Page 1 of n
Population: Intent-to-Treat/Safety/Other study specific
Table X
Summary of OCS use 
Treatment A
(N=81)
Treatment B
(N=79)
OCS use for index exacerbation
81 (100%)
79 (100%)
  Total number of Days of OCS use
    Mean
Xx
xx
    SD
Xx
xx
    Median
Xx
xx
    Min.
Xx
xx
    Max.
Xx
xx
On-treatment OCS use
xx (xx%)
xx (xx%)
  Total number of Days of OCS use
    Mean
Xx
xx
    SD
Xx
xx
    Median
Xx
xx
    Min.
Xx
xx
    Max.
Xx
xx
 
 
 
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13.12.17. Example Shell 17
Protocol: ABC123456                                                                               Page 1 of x
Population: Safety
                                                 Table X
                                 Summary of Post-Inhalation Cough by Visit
Visit: VISIT 2 (RANDOMISATION)
                                                     GSK2269557 GSK2269557 GSK2269557 GSK2269557 GSK2269557
                                          Placebo    50 mcg     100 mcg    250 mcg    500 mcg    750 mcg
                                          (N=43)     (N=14)     (N=15)     (N=16)     (N=14)     (N=42)
----------------------------------------------------------------------------------------------------------
Did subject experience PI cough? [1]       
  n                                      20         10          12         15          12         35
  Yes                                     7  (35%)   4  (40%)    6  (50%)   3  (20%)    6  (50%)  12  (34%)
  No                                     13  (65%)   6   (60%)   6  (50%)  12  (80%)    6  (50%)  23  (66%)
Type of cough
   Single cough                           4  (57%)   2  (50%)   1  (17%)   1  (33%)   1  (17%)    2  (17%)
   Intermittent cough                     2  (29%)   2  (50%)   5  (83%)   1  (33%)   4  (67%)    5  (42%)
   Continuous cough                       1  (14%)   0          0          1  (33%)   1  (17%)    5  (42%)
Severity of cough
   Mild                                   5  (71%)   3  (75%)   3  (50%)   2  (67%)   1  (17%)    6  (50%)
   Moderate                               2  (29%)   1  (25%)   2  (33%)   1  (33%)   5  (83%)    4  (33%)
   Severe                                 0          0          1  (17%)   0          0           2  (17%)
Time to onset of PI cough (minutes)
   0-1                                    6  (86%)   3  (75%)   6 (100%)   3 (100%)   6 (100%)   12 (100%)
   >1-2                                   1  (14%)   1  (25%)   0          0          0           0
   >2-3                                   0          0          0          0          0           0
   >3-4                                   0          0          0          0          0           0
   >4-5                                   0          0          0          0          0           0
   >5                                     0          0          0          0          0           0
Duration of PI cough (minutes)
   <=1                                    6  (86%)   3  (75%)   5  (83%)   3 (100%)   5  (83%)   11  (92%)
   >1-2                                   1  (14%)   1  (25%)   1  (17%)   0          1  (17%)    1   (8%)
   >2-3                                   0          0          0          0          0           0
   >3-4                                   0          0          0          0          0           0
   >4-5                                   0          0          0          0          0           0
 
 
 
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   >5-10                                  x          x
   >10-30                                 x          x
   >30                                    x          x
Number of subjects reporting cough as
AE/SAE                                   2  (29%)   1  (25%)   4  (67%)   0          2  (33%)    3  (25%)
   Mild                                   x  (x%)    x
   Moderate                               x  (x%)    x
   Severe                                 x  (x%)    x
[1] Percentages are calculated using the number of subjects evaluated at visit as the denominator.
All other percentages are calculated using the number of subjects with a PI cough at visit as the denominator.
 
 
 
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13.12.18. Example shell 18
Protocol: ABC123456                                                                             Page 1 of x
Population: Intent-to-Treat/Safety/Other study specific
                                                 Figure X
Plot of Dose Response Model of Change from Baseline in FEV1 
[Footnote to describe the fitted model]
 
 
 
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13.12.19. Example Shell 19
Protocol: ABC123456                                                                             Page 1 of 3
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
             Summary of COPD Related Unscheduled Healthcare Resource Utilization
                                                                        
                                                                        Treatment A    Treatment B
                                                                        (N=100)        (N=100)
        --------------------------------------------------------------------------------------------
          Unscheduled Healthcare Utilisation                Yes          97  (97%)      19  (19%)
                                                            No            3  ( 3%)      81  (81%)
          Number of Home Visits (day)                       n           100            100
                                                            0            90  (90%)      92  (92%)
                                                            1             4   (4%)       4   (4%)
                                                            2             0              0  
                                                            3             0              0
                                                            >3            0              2  (<1%)
                                                            Total [1]     4              4
          Number of Home Visits (night)                     n           100            100
                                                            0           100 (100%)     100 (100%)
                                                            1            0              0  
                                                            2             0              0
                                                            3             0              0
                                                            >3            0              0
                                                            Total [1]     0              0
[1] Total number of contacts across all subjects.
[2] Total number of days across all subjects.
 
 
 
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Protocol: ABC123456                                                                             Page 2 of 3
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
             Summary of COPD Related Unscheduled Healthcare Resource Utilization 
                                                                        
                                                                        Treatment A    Treatment B
                                                                        (N=100)        (N=100)
        --------------------------------------------------------------------------------------------
          Number of Office/Practice Visits                  n           911            899
                                                            0           846  (93%)     808  (90%)
                                                            1            42   (5%)      58   (6%)
                                                            2            13   (1%)      23   (3%)
                                                            3             7  (<1%)       8  (<1%)
                                                            >3            3  (<1%)       2  (<1%)
                                                            Total [1]   103            140
          Number of Urgent Care/Outpatient Visits           n           911            899
                                                            0           886  (97%)     882  (98%)
                                                            1            15   (2%)      10   (1%)
                                                            2             3  (<1%)       2  (<1%)
                                                            3             3  (<1%)       3  (<1%)
                                                            >3            4  (<1%)       2  (<1%)
                                                            Total [1]    54             37
          Number of Emergency Room Visits                   n           911            899
                                                            0           906 (>99%)     893 (>99%)
                                                            1             5  (<1%)       5  (<1%)
                                                            2             0              1  (<1%)
                                                            3             0              0
                                                            >3            0              0
                                                            Total [1]     5              7
[1] Total number of contacts across all subjects.
[2] Total number of days across all subjects.
 
 
 
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Protocol: ABC123456                                                                             Page 3 of 3
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
             Summary of COPD Related Unscheduled Healthcare Resource Utilization
                                                                        
                                                                        Treatment A    Treatment B
                                                                        (N=100)        (N=100)
        --------------------------------------------------------------------------------------------
          Number of Days in Intensive Care                  n           911            899
                                                            0           910 (>99%)     894 (>99%)
                                                            1             0              0
                                                            2             0              1  (<1%)
                                                            3             0              0
                                                            >3            1  (<1%)       4  (<1%)
                                                            Total [2]    12             40
          Number of Days in General Ward                    n           911            899
                                                            0           896  (98%)     878  (98%)
                                                            1             0              2  (<1%)
                                                            2             1  (<1%)       1  (<1%)
                                                            3             0              0
                                                            >3           14   (2%)      18   (2%)
                                                            Total [2]   119            258
[1] Total number of contacts across all subjects.
[2] Total number of days across all subjects.
 
 
 
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13.12.20. Example Shell 20
Protocol: ABC123456                                                                             Page 1 of x
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
             Summary of Non-COPD Related Unscheduled Healthcare Resource Utilization
                                                                        
                                                                        Treatment A    Treatment B
                                                                        (N=100)        (N=100)
        --------------------------------------------------------------------------------------------
          Unscheduled Healthcare Utilisation                Yes          97  (97%)      19  (19%)
                                                            No            3  ( 3%)      81  (81%)
          Number of Days in Accident and emergency          n           100            100
                                                            0            90  (90%)      92  (92%)
                                                            1             4   (4%)       4   (4%)
                                                            2             0              0  
                                                            3             0              0
                                                            >3            0              2  (<1%)
                                                            Total         4              4
          Number of Days in General Ward                    n           100            100
                                                            0           100 (100%)     100 (100%)
                                                            1             0              0  
                                                            2             0              0
                                                           3             0              0
                                                            >3            0              0
                                                            Total         0              0
 
 
 
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13.12.21. Example Shell 21
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
Summary of Exacerbation Related Hospitalizations
                                                                      
                                                               Treatment A       Treatment B
                                                                  (N=100)         (N=100)
        -------------------------------------------------------------------------------------------
        Index exacerbation
          Participants with hospitalization                   x.xx               x.xx                    
          Number of hospitalizations          
  x.xx               x.xx                      
          Mean duration (days)                                x.xx               x.xx                      
          SD                                                  x.xx               x.xx
          Median duration (days)                              x.xx               x.xx
          Minimum duration (days)                            x.xx               x.xx
          Maximum duration (days)                             x.xx               x.xx                      
        Subsequent exacerbations
          Participants with hospitalization                   x.xx               x.xx                    
          Number of hospitalizations          
  x.xx               x.xx                      
          Mean duration (days)                                x.xx               x.xx                      
          SD                                                  x.xx               x.xx
          Median duration (days)                              x.xx               x.xx
          Minimum duration (days)                             x.xx               x.xx
          Maximum duration (days)                             x.xx               x.xx                              
        
      
 
 
 
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13.12.22. Example Shell 22
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
Summary of Re-hospitalization Within 30 days of Index Exacerbation
                                                                        
                                                                        Treatment A    Treatment B
                                                                        (N=100)        (N=100)
        --------------------------------------------------------------------------------------------
          Re-hospitalization Within 30 days                 Yes          97  (97%)      19  (19%)
                                                            No            3  ( 3%)      81  (81%)
          
 
 
 
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13.12.23. Example Shell 23
Protocol: XYZ100001                                                                             Page 1 of n
Population: Intent-to-Treat/Safety/Other study specific
Table X
Summary of Subsequent Exacerbation Treatment
Treatment A
(N=81)
Treatment B
(N=79)
Subsequent exacerbation
70 (86%)
50 (63%)
OCS
X (x%)
X (x%)
Antibiotics                           
x (x%)
x (x%)
OCS and antibiotics
X (x%)
    X (x%)
 
 
 
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13.12.24. Example Shell 24
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
Summary of Time from Resolution of Index Exacerbation to Next Exacerbation
                                                                      
                                                               Treatment A       Treatment B
                                                                  (N=100)         (N=100)
        -------------------------------------------------------------------------------------------
          Subsequent exacerbation                             x.xx               x.xx                    
          
          Mean duration (days)                                x.xx               x.xx                      
          SD                                                  x.xx               x.xx
          Median duration (days)                              x.xx               x.xx
          Minimum duration (days)                             x.xx               x.xx
          Maximum duration (days)                             x.xx               x.xx                      
        
        
        
 
 
 
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13.12.25. Example Shell 25
Protocol: ABC123456                                                                             Page 1 of x
Population: Intent-to-Treat/Safety/Other study specific
                                                 Table X
Summary of ECG Abnormalities for Participants with Any Abnormal Clinically Significant ECG Interpretation
                                                                      
                                                               Treatment A       Treatment B
                                                                  (N=100)         (N=100)
        -------------------------------------------------------------------------------------------
        Visit 2 (Day 1)
         Abnormal – Clinically significant                        10 (10%)       15 (15%)
           Any finding                                             5 (50%)        5 (33%)
           ST depression                                           5 (50%)        5 (33%)
           Short PR Interval                                       0              5 (33%)
           T wave inversion                                        0              5 (33%)
           …….
Includes Scheduled, unscheduled and Early Withdrawal visits.
Participants may have more than one abnormality at each visit. 
 
 
 
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13.12.26. Example Shell 26
Protocol: ABC123456   
Page 1 of n
Population: Intent-to-Treat/Safety/Other study specific
Table X
Statistical Analysis of Change from Baseline in FEV1 (mL) (Dose Response Model)
Measured post-bronchodilator
Placebo
(N=xx)
DNX 5mg
(N=xx)
DNX 10mg
(N=xx)
DNX 25mg
(N=xx)
DNX 35mg
(N=xx)
DNX 50mg
(N=xx)
n [1]
xx
xx
xx
xx
xx
xx
Posterior Mean Change 
x.xx
x.xx
x.xx
x.xx
x.xx
x.xx
(SD)
(x.xxx) 
(x.xxx)
(x.xxx)
(x.xxx) 
(x.xxx) 
(x.xxx) 
Posterior Median Change
x.xx
x.xx
x.xx
x.xx
x.xx
x.xx 
95% Credible Interval 
(x.xx,x.xx)
(x.xx,x.xx)
(x.xx,x.xx)
(x.xx,x.xx)
(x.xx,x.xx)
(x.xx,x.xx)
Column vs. Placebo  
  Posterior Difference
x.xx
x.xx
x.xx
x.xx
x.xx
  80% Credible Interval
(x.xx, 
x.xx)
(x.xx, 
x.xx)
(x.xx, 
x.xx)
(x.xx, 
x.xx)
(x.xx, 
x.xx)
  Prob(Difference>0) 
xx%
xx%
xx%
xx%
xx%
  Predictive probability (%) [2] 
[only if required]
xx%
xx%
xx%
xx%
xx%
[1] Number of subjects with data contributing to the analysis.
[2] Predictive posterior probability of success at end of study, where success is Pr(Difference>0)>90%.
Note: Model fitted was a…..[insert as appropriate]. 
 
 
 
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13.12.27. Example Shell 27
Protocol: ABC123456                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific
                                                Table X
Summary of QTc(F) (msec) Categories
                                                                  Treatment A      Treatment B
                                                                  (N=100)          (N=100)
            ------------------------------------------------------------------------------------
            Screening                                           
              n                                                    xx               xx   
              <=450                                                xx  (xx%)        xx  (xx%) 
              >450 to <=480                                        xx  (xx%)        xx  (xx%)
              >480 to <=500                                        xx  (xx%)        xx  (xx%)
              >500                                                 xx  (xx%)        xx  (xx%)
            
            Day 1 (Baseline)                                          
              n                                                    xx               xx   
              <=450                                                xx  (xx%)        xx  (xx%) 
              >450 to <=480                                        xx  (xx%)        xx  (xx%)
              >480 to <=500                                        xx  (xx%)        xx  (xx%)
              >500                                                 xx  (xx%)        xx  (xx%)
             Day 14                                          
              n                                                    xx               xx   
              <=450                                                xx  (xx%)        xx  (xx%) 
              >450 to <=480                                        xx  (xx%)        xx  (xx%)
              >480 to <=500                                        xx  (xx%)        xx  (xx%)
              >500                                                 xx  (xx%)        xx  (xx%)
 
 
 
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13.12.28. Example Shell 28
Protocol: ABC123456                                                                             Page 1 of x
Population: Safety
                                                 Table X
                         Summary of Post-Inhalation Cough by Visit and Cough Type
                                                                      
          Visit 2 (Day 1)                             
          Type of cough: Single cough                        Treatment A       
                                                                (N=100)         
        -------------------------------------------------------------------------------------------
         
           Did subject experience event [1]?                           12 (24%)        
           Cough severity              
             Mild                                                    6 (50%)       
             Moderate                                                5 (42%)        
             Severe                                                  1 (8%)             
           Time to onset of PI cough (minutes)                      
             0-1                                                     2(17%)          
             >1-2                                                    3(25%)          
             >2-3                                                    4(33%)          
             >3-4                                                    3(25%)          
             >4-5                                                    0          
             >5                                                      0  
       
           Duration of PI cough (minutes)                      
             <=1                                                     7(58%)          
             >1  - 2                                                 2(17%)          
             >2  - 3                                                 3(25%)          
             >3  - 4                                                 0          
             >4  - 5                                                 0          
             >5  - 10                                                0          
             >10 - 30                                                0          
             >30                                                     0         
[1] Percentages are calculated using the number of subjects evaluated at visit as the denominator.
All other percentages are calculated using the number of subjects with particular cough type at visit as the 
denominator.
 
 
 
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Protocol: ABC123456                                                                             Page 2 of x
Population: Safety
                                                 Table X
                         Summary of Post-Inhalation Cough by Visit and Cough Type
                                                                      
          Visit 2 (Day 1)                                           
          Type of cough: Single cough                        Treatment A            
                                                              (N=100)         
        -------------------------------------------------------------------------------------------
   Number of subjects reporting cough as AE/SAE              4 (33%)  
      Mild                                                   2 (17%)
      Moderate                                               2 (17%)
      Severe                                                 0
 
 
 
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Protocol: ABC123456                                                                             Page 3 of x
Population: Safety
                                                 Table X
                           Summary of Post-Inhalation Cough by Visit and Cough Type
                                                                      
          Visit 2 (Day 1)                                           
          Type of cough: Intermittent cough                        Treatment A     
                                                                    (N=100)         
        -------------------------------------------------------------------------------------------
                      
           Did subject experience event [1]?                           11 (22%)        
           Cough severity              
             Mild                                                    2 (18%)       
             Moderate                                                6 (55%)        
             Severe                                                  3 (27%)             
           Time to onset of PI cough (minutes)                      
             0-1                                                     1(9%)          
             >1-2                                                    4(36%)          
             >2-3                                                    6(55%)          
             >3-4                                                    0          
             >4-5                                                    0          
             >5                                                      0    
     
           Duration of PI cough (minutes)                      
             <=1                                                     0          
             >1  - 2                                                 3(27%)          
             >2  - 3                                                 6(55%)          
             >3  - 4                                                 1(9%)          
             >4  - 5                                                 0          
             >5  - 10                                                0          
             >10 - 30                                                1(9%)      
             >30                                                     0         
   
 
 
 
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Protocol: ABC123456                                                                             Page 4 of x
Population: Safety
                                                 Table X
                      Summary of Post-Inhalation Cough by Visit and Cough Type
                                                                      
          Visit 2 (Day 1)                                              
          Type of cough: Intermittent cough                      Treatment A              
                                                                  (N=100)         
        -------------------------------------------------------------------------------------------
   Number of subjects reporting cough as AE/SAE              5 (45%)  
      Mild                                                   1 (9%)
      Moderate                                               2 (18%)
      Severe                                                 2 (18%)
 
 
 
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Protocol: ABC123456                                                                             Page 5 of x
Population: Safety
                                                 Table X
                      Summary of Post-Inhalation Cough by Visit and Cough Type
                                                                      
          Visit 2 (Day 1)                                       
          Type of cough: Continuous cough                      Treatment A                   
                                                                  (N=100)         
        -------------------------------------------------------------------------------------------
                    
           Did subject experience event [1]?                            4 (8%)        
           Cough severity              
             Mild                                                    1 (25%)       
             Moderate                                                2 (50%)        
             Severe                                                  1 (25%)             
           Time to onset of PI cough (minutes)                      
             0-1                                                     3(75%)          
             >1-2                                                    1(25%)          
             >2-3                                                    0          
             >3-4                                                    0          
             >4-5                                                    0          
             >5                                                      0   
      
           Duration of PI cough (minutes)                      
             <=1                                                     0         
             >1  - 2                                                 0          
             >2  - 3                                                 0 
             >3  - 4                                                 1 (25%)                    
             >4  - 5                                                1 (25%)                   
             >5  - 10                                                0          
             >10 - 30                                                1 (25%)                   
             >30                                                     1 (25%)                   
   
 
 
 
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Protocol: ABC123456                                                                             Page 6 of x
Population: Safety
                                                 Table X
                        Summary of Post-Inhalation Cough by Visit and Cough Type
                                                                      
          Visit 2 (Day 1)                                      
          Type of cough: Continuous cough                      Treatment A                         
                                                                  (N=100)         
        -------------------------------------------------------------------------------------------
   Number of subjects reporting cough as AE/SAE              2 (50%)  
      Mild                                                   1 (25%)
      Moderate                                               1 (25%)
      Severe                                                 0
REPEAT FOR EACH VISIT
 
 
 
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13.12.29. Example Shell 29
Protocol: MID200879                                                                              Page 1 of 1
Population: Intent-to-Treat
                                                Listing X
                           Listing of Subjects who Received Incorrect Medication
                             Start      End                                              Actual
Randomized         Centre/   Date of    Date of    Duration                   Dispense   Treatment
Treatment          Subj      Dosing     Dosing     (Days)   Dispense Visit    Date       Dispensed
------------------------------------------------------------------------------------------------------------
GSK2269557 500 mcg 
  XXXXXXXXX  XXXXXXXXX    XX     Visit 3 (Week 0)  XXFEB2013  GSK2269557 500 mcg
                   
                                                              
                             XXXXXXXXX  XXXXXXXXX    XX     Visit 5 (Week 4)  XXMAR2013  GSK2269557 100 mcg
                             XXXXXXXXX  XXXXXXXXX    XX     Visit 6 (Week 8)  XXAPR2013  GSK2269557 500 mcg
 
 
 
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