Clinical trial NCT02184611
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: lung function Umeclidinium GSK573719 anticholinergic novel dry powder inhaler long-acting muscarinic receptor antagonist Chronic Obstructive Pulmonary Disease
Sponsor: GlaxoSmithKline
Start date: 2016-05-09; Completion date: 2017-11-08
Enrollment: 308 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Studies to date provides substantial evidence for the effectiveness for UMEC 62.5 microgram (mcg) as a long term maintenance therapy for the treatment of COPD; this study further evaluates the efficacy and safety of UMEC 62.5 mcg administered once-daily (OD) for 24 weeks via a NDPI compared with placebo in Asian subjects with COPD. Over approximate 27 weeks of entire study duration, 10 study clinic visits will be conducted on an outpatient basis. Pre-screening visit will be conducted for the informed consent form, review demography, COPD history and COPD concomitant medications. Subjects meeting the eligibility criteria at screening will complete a 7 to 14 day Run-in period and will be provided with albuterol/salbutamol as rescue medication on an "as-needed" basis. Further, subjects will be randomized to the UMEC 62.5 mcg or matching placebo in a 1:2 ratio for 24 week treatment period. A follow up for adverse event assessment will be scheduled approximately 7 days after the treatment period or the Early Withdrawal Visit.

Detailed description:

Arms: arm 1: Subjects meeting the eligibility criteria will complete a 7 to 14 day run-in period and will be randomized to receive UMEC Inhalation Powder 62.5 mcg OD over a period of 24 weeks arm 2: Subjects meeting the eligibility criteria will complete a 7 to 14 day run-in period and will be randomized to receive matching placebo of UMEC Inhalation Powder OD over a period of 24 weeks
Interventions: intervention 1: Umeclidinium bromide intervention 2: Placebo
Intervention descriptions: intervention 1: Blended with lactose and magnesium stearate dry white powder of umeclidinium 62.5 mcg to be inhaled via a NDPI intervention 2: Blended with lactose and magnesium stearate dry white powder to be inhaled via a NDPI

Protocol documents:
Prot_000.pdf: 
2013N159587_03
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AC4117410
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A 24- week randomised, double-blind and placebo-controlled 
study to evaluate the efficacy and safety of 62.5 mcg 
Umeclidinium Inhalation Powder delivered once-daily via a 
Novel Dry Powder Inhaler in subjects with Chronic Obstructive 
Pulmonary Disease
Compound Number:
GSK573719
Development Phase:
III
Effective Date:
11-NOV-2015
Protocol Amendment Number:  03
Author (s):
 (CMD, China);
 (Clinical Statistician, UK); 
 
(CMD, China); 
 (CMD, China)
Copyright 2015 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2013N159587_00
2013-NOV-13
Original
2013N159587_01
2014-APR-03
Amendment No.: 01
To update eligibility criteria, revise some minor errors
2013N159587_02
2014-MAY-09
Amendment No. 02
To define variables used in statistical assessment to meet authority’s requirement.
2013N159587_03
2015-NOV-11
Amendment No. 03

Removed Thailand and Taiwan from involved countries/areas.

Changed randomization ratio from 1:1 to 2:1.

Updated sample size based on the latest difference and SD. Updated analysis plan.

Dispense of rescue sulbutamol was moved up from V1 to V0.

Updated wordings in cardiovascular events, death events, liver stop/follow, and 
AE/SAE according to the latest protocol template.

Developed a China specific requirement on SAE collection period.

Pharmacogenetic research sections removed.

Updated the 12-Lead ECG Exclusion Criteria and 12-Lead ECG Withdrawal 
Criteria.

Novel Dry Powder Inhaler (NDPI) has been replaced with ELLIPTA.

Some minor revisions.


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SPONSOR INFORMATION PAGE
Clinical Study Identifier: AC4117410
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Sponsor Contact Address
GlaxoSmithKline Research & Development Limited
Iron Bridge Road 
Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK
Telephone:  
 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate
company (or designee). Where applicable, the details of the Sponsor and contact person 
will be provided to the relevant regulatory authority as part of the clinical trial 
submission.
Sponsor Medical Monitor Contact Information: 
Asia
 MD
GlaxoSmithKline
No. 1 Building, 917 Halei Road
Shanghai, China
Telephone: 
 MD
GlaxoSmithKline
No. 1 Building, 917 Halei Road
Shanghai, China
Telephone: 
Backup Global Medical Monitor
 MD
GlaxoSmithKline
Ocean Center, Block A, 
56 Dongsihuan Zhonglu,
Chaoyang District, 
Beijing, 100025, China
Telephone: 
  
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Sponsor Serious Adverse Events (SAE) Contact Information:
Case management Group, GCSP - Stockley Park, UK
Email: 
Fax: 
Regulatory Agency Identifying Number:
Regulatory Agency Identifying Number:  NA
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol AC4117410
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Signature
Date


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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS...........................................................................................10
PROTOCOL SUMMARY...............................................................................................12
1.
INTRODUCTION....................................................................................................15
1.1.
Background ................................................................................................15
1.2.
Rationale ....................................................................................................15
1.3.
Summary of Risk Management...................................................................16
2.
OBJECTIVE(S) and Endpoints...............................................................................20
3.
INVESTIGATIONAL PLAN.....................................................................................21
3.1.
Study Design ..............................................................................................21
3.2.
Discussion of Design ..................................................................................23
3.2.1.
Dose Selection ............................................................................24
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA.......................................25
4.1.
Number of Subjects ....................................................................................25
4.2.
Inclusion Criteria.........................................................................................25
4.3.
Exclusion Criteria........................................................................................26
4.4.
Randomization Criteria ...............................................................................29
4.5.
Withdrawal Criteria .....................................................................................30
4.6.
Pre-Screen and Screen Failures.................................................................31
4.7.
Run-in Failures ...........................................................................................32
4.8.
Premature Discontinuation..........................................................................32
4.9.
The Follow-up Phone Contact.....................................................................33
5.
STUDY TREATMENTS..........................................................................................34
5.1.
Investigational Product and Other Study Treatment....................................34
5.1.1.
Storage........................................................................................35
5.1.2.
Study Drug Return.......................................................................35
5.2.
Treatment Assignment................................................................................35
5.3.
Blinding.......................................................................................................36
5.4.
Product Accountability ................................................................................36
5.5.
Treatment Compliance................................................................................37
5.6.
Concomitant Medications and Non-Drug Therapies....................................37
5.6.1.
Permitted Medications and Non-Drug Therapies..........................37
5.6.2.
Prohibited Medications and Non-Drug Therapies.........................38
5.6.2.1.
Traditional or herbal medicines...................................39
5.7.
Treatment after the End of the Study ..........................................................39
5.8.
Treatment of Study Investigational product Overdose.................................39
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................39
6.1.
Critical Baseline Assessments....................................................................43
6.2.
Efficacy.......................................................................................................44
6.2.1.
Primary Efficacy Endpoints ..........................................................44
6.2.2.
Secondary Efficacy Endpoints .....................................................44
6.2.3.
Other Endpoints...........................................................................44


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6.2.4.
Spirometry and Reversibility Testing............................................45
6.2.4.1.
Spirometry..................................................................45
6.2.4.2.
Bronchodilator Responsiveness Testing.....................45
6.2.4.3.
6-Hour Serial Spirometry ............................................46
6.2.5.
BDI/TDI........................................................................................46
6.2.6.
Diary Assessments......................................................................46
6.2.6.1.
Paper Diary ................................................................46
6.2.7.
COPD Exacerbations...................................................................47
6.3.
Safety .........................................................................................................47
6.3.1.
Vital Signs....................................................................................47
6.3.2.
12-Lead ECG...............................................................................48
6.3.3.
Clinical Laboratory Tests .............................................................48
6.3.4.
Liver chemistry stopping and follow up criteria.............................49
6.3.5.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........52
6.3.5.1.
Definition of AEs.........................................................52
6.3.5.2.
Definition of SAEs ......................................................53
6.3.5.3.
Recording of AEs and SAEs.......................................55
6.3.5.4.
Evaluating AEs and SAEs ..........................................55
6.3.5.5.
Follow-up of AEs and SAEs........................................56
6.3.6.
Cardiovascular Events.................................................................57
6.3.7.
Death Events...............................................................................57
6.3.8.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs...............................................57
6.3.9.
Pregnancy ...................................................................................58
6.3.10.
Medical Devices...........................................................................58
6.3.11.
Time Period and Frequency of Detecting AEs and SAEs.............60
6.3.12.
Prompt Reporting of Serious Adverse Events and Other 
Events to GSK.............................................................................60
6.3.12.1.
Regulatory Reporting Requirements for SAEs............63
6.4.
Health Outcome Assessments Not Included as Primary or Key 
Secondary Endpoints..................................................................................63
6.4.1.
St George’s Respiratory Questionnaire........................................63
6.4.2.
Healthcare Resource Utilisation...................................................64
6.4.3.
COPD Assessment Test (CAT)....................................................64
7.
DATA MANAGEMENT ...........................................................................................65
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................65
8.1.
Hypotheses.................................................................................................65
8.2.
Study Design Considerations......................................................................66
8.2.1.
Sample Size Assumptions ...........................................................66
8.2.2.
Sample Size Sensitivity................................................................67
8.2.3.
Sample Size Re-estimation..........................................................68
8.3.
Data Analysis Considerations .....................................................................68
8.3.1.
Analysis Populations....................................................................68
8.3.2.
Analysis Data Sets.......................................................................69
8.3.3.
Treatment Comparisons ..............................................................69
8.3.3.1.
Primary Comparisons of Interest ................................69
8.3.3.2.
Other Comparisons of Interest....................................69
8.3.4.
Interim Analysis ...........................................................................69
8.3.5.
Key Elements of Analysis Plan ....................................................69
8.3.5.1.
Efficacy Analyses .......................................................70


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8.3.5.2.
Safety Analyses..........................................................71
8.3.5.3.
Health Outcomes Analyses ........................................72
9.
STUDY CONDUCT CONSIDERATIONS ...............................................................72
9.1.
Posting of Information on Publicly Available Clinical Trial Registers............72
9.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................72
9.3.
Quality Control (Study Monitoring) ..............................................................73
9.4.
Quality Assurance.......................................................................................73
9.5.
Study and Site Closure ...............................................................................73
9.6.
Records Retention......................................................................................74
9.7.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication....................74
9.8.
Independent Data Monitoring Committee (IDMC) .......................................75
10. REFERENCES.......................................................................................................76
11. APPENDICES........................................................................................................79
11.1.
Appendix 1: Country Specific Requirements...............................................79
11.2.
Appendix 2:  12-Lead ECG Exclusion Criteria.............................................80
11.3.
Appendix 3: 12-Lead ECG Withdrawal Criteria ...........................................81
11.4.
Appendix 4: Liver Chemistry Stopping and Increased Monitoring 
Algorithm ....................................................................................................82
11.5.
Appendix 5: Protocol changes in Amendment 01........................................83
11.6.
Appendix 6: Protocol changes in Amendment 02........................................93
11.7.
Appendix 7: Protocol changes in Amendment 03........................................95


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LIST OF ABBREVIATIONS
Ach
Acetylcholine
AE
Adverse Event
ALT
Alanine Transaminase
AST
Aspartate Aminotransferase
ATS
America Thoracic Society
AV
Atrioventricular
BDI
Baseline Dyspnea Index
CI
Confidence Interval
CAT
COPD Assessment Test
CPK
Creatine Phosphokinase
COPD
Chronic Obstructive Pulmonary Disease
CRF
Case Report Form
EW
Early Withdrawal
ECG
Electrocardiogram
eCRF
Electronic Case Record Form
FEV1
Forced Expiratory Volume in One Second
FSH
Follicle Stimulating Hormone
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GSK
GlaxoSmithKline
IB
Investigator’s Brochure
ICS
Inhaled Corticosteroid
IEC
Independent Ethics Committee
IgM
Immunoglobulin M
IRB
Independent Review Board
ITT
Intent-to-Treat
IWRS
Interactive Web Response System
LABA
Long Acting Beta-Agonist 
LAMA
Long Acting Muscarinic Antagonist
LDH
Lactate Dehydrogenase
LTOT
Long Term Oxygen Therapy
Mcg
Micrograms
MDI
Metered Dose Inhaler
MedRA
Medical Dictionary for Regulatory Activities
mMRC
Modified Medical Research Council Dyspnea Scale
MMRM
Mixed Models Repeated Measures
MSDS
Material Safety Data Sheet
mV
Millivolt
NHANES III
National Health and Nutrition Examination Survey III
PGx
Pharmacogenetics
PDE4
Phosphodiesterase 4
PK
Pharmacokinetic
PP
Per Protocol


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RAMOS NG
Randomization And Medication Ordering System Next
Generation
RAP
Reporting and Analysis Plan
SAE
Serious Adverse Event
SD
Standard Deviation
SGRQ
St George’s Respiratory Questionnaire
SPM
Study Procedures Manual
TDI
Transitional Dyspnea Index
ULN
Upper Limit of Normal
UMEC
Umeclidinium
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
CAT
None
ELLIPTA


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PROTOCOL SUMMARY
Rationale
Chronic Obstructive Pulmonary Disease (COPD) is a major cause of poor health, 
resulting in millions of deaths annually worldwide and contributing significantly to health 
care costs and morbidity. As of 2001, COPD was the fifth leading cause of death and the 
eleventh leading cause of disability worldwide. By the year 2020, COPD is expected to 
be the third leading cause of death and the fifth leading cause of disability. It has been 
estimated that over a 30 year period in China (up to 2033), 65 million deaths will be 
attributable to COPD.
COPD is a preventable and treatable disease characterized by airflow limitation that is 
not fully reversible. The airflow limitation of COPD is primarily due to small airways 
disease and parenchymal destruction associated with an abnormal inflammatory response 
of the lungs. This is mainly caused by cigarette smoking, although in many countries, air 
pollution resulting from burning of wood and other biomass fuels has also been identified 
as a COPD risk factor. Chinese smokers account for about one third of all smokers 
worldwide. In China the prevalence of COPD was reported to be 8.2 % for those 40 
years of age and is expected to rise. 
Pharmacological management of chronic, stable COPD is primarily aimed at improving 
symptoms and quality of life, optimizing lung function, reducing exacerbations and 
improving exercise tolerance.  Inhaled bronchodilators, including beta2-agonists and 
anticholinergics, together with inhaled corticosteroids (ICS) are the mainstays of therapy 
in patients diagnosed with COPD. Inhaled bronchodilators are recommended as a 
standalone treatment for patients in GOLD group A and B with long acting 
bronchodilators recommended as disease progresses. This is often followed by use as an 
‘add on’ to steroid for more severe patients.
Anti cholinergic bronchodilators (muscarinic receptor antagonists) exert their 
bronchodilator activity by inhibiting the binding of neurotransmitter acetylcholine (Ach)
with muscarinic Ach receptors on airway smooth muscle. This blocks endogenous airway 
smooth muscle tone allowing bronchodilation and reducing mucus hypersecretion.
Treatment with muscarinic antagonists has been shown to significantly improve Forced 
Expiratory Volume in One Second (FEV1), resting and dynamic lung hyperinflation, 
symptoms, exercise capacity, health status, and reduce COPD exacerbations.  However, a 
significant number of subjects are thought to continue to have symptoms, as reported in a 
primary care, cross-sectional study.
Umeclidinium (UMEC) is an orally inhaled, potent, pan-active long acting muscarinic 
antagonist (LAMA) in development for use as an inhaled product in the treatment of 
COPD as a monotherapy once-daily product and also in combination with the long acting 
beta agonist (LABA), vilanterol, as a once-daily treatment of COPD.
Studies to date provide substantial evidence for the effectiveness for UMEC 62.5 mcg as 
a long term maintenance therapy for the treatment of COPD. The purpose of this 24-week 


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study is to further evaluate the efficacy and safety of UMEC 62.5 mcg administered 
once-daily in Asian subjects with COPD.
Objective(s)
The primary objective of the study is to evaluate the efficacy and safety of Umeclidinium 
Inhalation Powder at 62.5 mcg compared with placebo administered once- daily via an
ELLIPTATM over 24 weeks in subjects with COPD.
Study Design
This is a 24-week, phase III multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study. 
288 eligible subjects will be randomized to the UMEC 62.5 mcg and placebo treatment 
groups in a 2:1 ratio, approximately 192 subjects in active arm and 96 subjects in placebo 
arm. All treatments will be administered once-daily in the morning by inhalation using an
ELLIPTA.  
There will be a total of 10 study clinic visits conducted on an outpatient basis. A pre-
screening visit (V0) will be conducted to sign the informed consent form (ICF), dispense 
the rescue medication and review demography, COPD history and concomitant 
medications. Once the ICF is signed the subject will be assigned a subject identifier. At 
Visit 0, any medications changes made by the investigator will be recorded. Subjects who 
meet the eligibility criteria at Screening (Visit 1) will complete a 7 to 14 day Run-in 
period. At the end of the Run-in period, subjects will be assessed and those who meet the 
randomisation criteria will enter a 24-week double-blind Treatment Period. Clinic visits 
(1 through 9) will be at Screening, Randomization (Day 1), Day 2, Day 28 (Week 4), Day 
56 (Week 8), Day 84 (Week 12), Day 112 (Week 16), Day 168 (Week 24) and Day 169.  
A follow-up contact for adverse event (AE) assessment will be conducted by telephone 
approximately 7 days after the Treatment period or the Early Withdrawal (EW) Visit.  
The total duration of subject participation, including follow-up will be approximately 27 
weeks. All subjects will be provided with albuterol/salbutamol for use on an “as-needed” 
basis throughout the Pre-screen, Run-in and study Treatment periods.
Study End-point Assessments
Primary
Clinic visit trough (pre-bronchodilator) FEV1 on Treatment Day 169 
Trough FEV1 on Treatment Day 169 is defined as the mean of the FEV1 values obtained 
23 and 24 hours after dosing on Treatment Day 168 (i.e. at Week 24). 


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Secondary

Transition Dyspnea Index (TDI) focal score at Week 24. 

Weighted mean clinic visit FEV1 over 0 to 6 hours post-dose at visit 2 (Day 1)
Others

Trough FEV1 and TDI focal score at other time points

Rescue albuterol/salbutamol use (percentage of rescue-free days and puffs/day)

Time to onset (defined as an increase of 100mL above baseline in FEV1) during 0-6hr 
post-dose on Treatment Day 1 (Visit 2)

Proportion of subjects achieving an increase in FEV1 of 12% and 200mL above 
baseline at any time during 0 to 6hr post-dose on Treatment Day 1 (Visit 2)

Proportion of subjects achieving an increase in FEV1 of 100mL above baseline in 
trough FEV1

Serial FEV1 over 0 to 6 hours post-dose (on day 1)

Serial and trough FVC

Proportion of responders to TDI. (a responder to TDI will be defined as a subject with 
TDI score of 1 unit or more)

Time to first COPD exacerbation 
Safety

Incidence of AEs

Vital signs (pulse rate, systolic and diastolic blood pressure)

12-lead electrocardiogram (ECG) parameters

Clinical chemistry and haematology parameters and routine urinalysis
Health- Related Quality of Life

St. George’s Respiratory Questionnaire (SGRQ)

COPD Assessment Test (CAT)

Healthcare resource utilisation


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1.
INTRODUCTION
1.1.
Background
Chronic Obstructive Pulmonary Disease (COPD) is a major cause of poor health, 
resulting in millions of deaths annually worldwide [GOLD,2015] and contributing 
significantly to health care costs and morbidity [Chapman, 2006; Jung, 2011; Lopez, 
2006]. As of 2001, COPD was the fifth leading cause of death and the eleventh leading 
cause of disability worldwide. By the year 2020, COPD is expected to be the third 
leading cause of death and the fifth leading cause of disability [Rennard, 2002]. It has 
been estimated that over a 30 year period in China (up to 2033), 65 million deaths will be 
attributable to COPD [Lin, 2008].
COPD is a preventable and treatable disease characterized by airflow limitation that is 
not fully reversible [Celli, 2004]. The airflow limitation of COPD is primarily due to 
small airways disease and parenchymal destruction associated with an abnormal 
inflammatory response of the lungs. This is mainly caused by cigarette smoking [Celli, 
2004], although in many countries, air pollution resulting from burning of wood and 
other biomass fuels has also been identified as a COPD risk factor.
Chinese smokers account for about one third of all smokers worldwide. In China the 
prevalence of COPD was reported to be 8.2% for those 40 years of age [Zhong, 2007] 
and is expected to rise. 
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. Pharmacological management of chronic, stable 
COPD is primarily aimed at improving symptoms and quality of life, optimizing lung 
function, reducing exacerbations and improving exercise tolerance [Celli, 2004; GOLD, 
2015]. 
1.2.
Rationale
Inhaled bronchodilators, including beta2-agonists and anticholinergics, together with 
inhaled corticosteroids (ICS) are the mainstays of therapy in patients diagnosed with 
COPD. Inhaled bronchodilators are recommended as a standalone treatment for patients 
in GOLD group A and B with long acting bronchodilators recommended as disease 
progresses. 
Dominant autonomic control of the airways is provided by the parasympathetic nerves, 
which control a variety of airway functions.  Release of the neurotransmitter 
acetylcholine (ACh) from parasympathetic nerves stimulates muscarinic receptors, 
causing bronchoconstriction and mucus secretion.  Anti cholinergic bronchodilators 
(muscarinic receptor antagonists) exert their bronchodilator activity by inhibiting the 
binding of ACh with muscarinic Ach receptors on airway smooth muscle. This blocks 
endogenous airway smooth muscle tone allowing bronchodilation and reducing mucus 
hypersecretion.


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Muscarinic receptor antagonists have been in use since 1975 and have become well 
established as safe and effective bronchodilators for the treatment of COPD [Decramer, 
2013; Niewoehner, 2005; Aaron, 2007].  Commonly used inhaled long acting muscarinic 
antagonists (LAMAs) are poorly absorbed orally, limiting the troublesome effects 
observed with the more systemically available atropine [Decramer, 2013]. 
Treatment with muscarinic antagonists has been shown to significantly improve Forced 
Expiratory Volume in One Second (FEV1), resting and dynamic lung hyperinflation, 
symptoms, exercise capacity, health status, and reduce COPD exacerbations [O'Donnell, 
1998; O'Donnell, 2004; Tashkin, 2008a; Tashkin, 2008b]. However, a significant number 
of subjects are thought to continue to have symptoms, as reported in a primary care, 
cross-sectional study [Dransfield, 2011].
Umeclidinium is an orally inhaled, potent, pan-active long acting muscarinic anatagonist 
(LAMA) for use as an inhaled product in the treatment of COPD as a stand-alone once-
daily product and with the long acting beta agonist (LABA), vilanterol, as a once-daily 
combination product for the treatment of COPD. Both Umeclidinium monotherapy and 
combination with vilanterol have been approved by FDA and EMA.
Studies to date provide substantial evidence for the effectiveness for UMEC 62.5 mcg as 
a long term maintenance therapy for the treatment of COPD. The purpose of this 24 week 
study is to further evaluate the efficacy and safety of UMEC 62.5 mcg administered 
once-daily in Asian subjects with COPD.
1.3.
Summary of Risk Management
GlaxoSmithKline (GSK) has assessed this study for potential risks that a subject may 
experience. The investigational product, UMEC, has an acceptable safety profile for 
clinical use and there are no significant associated risks. This conclusion is supported by 
the results of previously performed clinical studies with the products in healthy 
volunteers and subjects with COPD [GlaxoSmithKline Document Number 
RM2006/00835/11, Investigator’s Brochure (IB) 2015].
Subjects will be routinely monitored for safety throughout the duration of the study. 
Adverse effects associated with the use of LAMAs will be closely monitored. Stringent 
safety criteria outlining details for subject withdrawal is included in the protocol [Section 
4.5, Withdrawal Criteria]. A thorough summary and evaluation of the available 
preclinical data can be found in the investigators brochure [GlaxoSmithKline Document 
Number RM2006/00835/11, IB 2015]. Routine safety analysis of this study will be 
conducted by the company.
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK573719 can be found in the Investigator’s Brochure.  The following sectionoutlines 
the risk assessment and mitigation strategy for this protocol:


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Potential Risk of Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [e.g., GSK573719]
Cardiovascular effects such 
as cardiac arrhythmia, e.g. 
atrial fibrillation and 
tachycardia.
A potential class effect 
associated with anti-
muscarinic therapies.
The clinical significance of 
these arrhythmias is 
unknown. Clinical
experience with UMEC to 
date in completed studies 
has did not show any 
association with major
cardiovascular events. Data 
available to date in the IB 
for UMEC
[GlaxoSmithKlineDocument
Number RM2006/00835/11
effective date 10-AUG-
2015)
Exclusion criteria have 
been set for subjects with 
uncontrolled or severe 
cardiovascular disease
according to the PI’s 
opinion where the potential 
risk may outweight the 
benefit.
An abnormal and 
significant ECG finding 
from the 12-lead ECG 
conducted at Visit 1, 
including the presence of a 
paced rhythm on a 12-lead 
ECG which causes the 
underlying rhythm and 
ECG to be obscured will be 
excluded.  Specific ECG
findings that precluded 
subject eligibility are listed 
in Appendix 2:  The study 
investigator will determine 
the medical significance of 
any ECG abnormalities not 
listed in Appendix 3.
Narrow-angle glaucoma, 
urinary
No association has been 
found to date, in completed 
studies with UMEC on 
glaucoma or urinary
retention. However, 
glaucoma or urinary 
retention have been
observed with other
antimuscarinic agents, and 
could potentially be due to 
the pharmacology. Data 
available in the IB for 
UMEC [GlaxoSmithKline 
Document Number 
RM2006/00835/11 effective 
date 10-AUG-2015)
Exclusion criterion states 
that subjects with medical 
conditions such as narrow-
angle glaucoma, prostatic 
hypertrophy, or bladder
neck obstruction should 
only be included if, in the 
opinion of the study 
physician, the benefit
outweighs the risk.
Paradoxical bronchospasm 
Known effect associated 
If paradoxical 


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Potential Risk of Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
that may occur with an 
immediate increase in 
wheezing after dosing.
with inhalation therapy.
bronchospasm occurs 
following dosing with IP,
this treatment should be
discontinued immediately 
and
alternative therapy should 
be instituted
Pregnancy
There is no experience to 
date of pregnancy during the 
use of UMEC.
The study inclusion criteria
Ensure that female subjects
enrolled, who are of Child 
bearing potential, have a 
negative pregnancy test at 
screening, and agree to a 
reliable contraceptive
method, used consistently 
and correctly (i.e. in 
accordance with the 
approved product label and
the instructions of the 
physician for the duration 
of the study).
Severe hepatic impairment
UMEC has not been studied 
in severe hepatic 
impairment.
Exclusion criterion states 
that subjects with severe 
hepatic impairment should 
only be included if, in the 
opinion of the study 
physician, the benefit
outweighs the risk.
Study Procedures
Spirometry procedures
May cause difficulty 
breathing, changes in pulse 
rate and blood pressure, 
coughing, wheezing, chest 
tightness or fainting
Subjects will be monitored 
during the procedure for 
these effects and spirometry 
will be discontinued should 
these occur.
ECG lead placement
May cause skin irritation
It may be necessary to have 
small patches (about a 
centimetre in diameter) of 
hair on the chest shaved to 
properly attach electrodes 
to the chest.


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Potential Risk of Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
Other (if applicable)
Side effects of rescue 
salbutamol
Class effects associated with
SABAs
Subjects should call their 
study doctor if they 
experience any of these 
symptoms Adverse events 
(AEs) seen in clinical
studies to date are 
consistent for the beta2-
adrenergic class of
compounds.
Subjects’ condition may 
worsen since not on active 
treatment.
Subjects will be provided 
with rescue 
albuterol/salbutamol use
throughout the study.


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2.
OBJECTIVE(S) and Endpoints
Objectives
Endpoints
Primary Objectives

To evaluate the efficacy of 
Umeclidinium 62.5 mcg compared 
with placebo when administrated 
once-daily via the ELLIPTATM over a 
24-week treatment period in subjects 
with COPD
Primary Efficacy Endpoint: 

Clinic visit trough (pre-
bronchodilator) FEV1 on Treatment 
Day 169 
Trough FEV1 on Treatment Day 169 is 
defined as the mean of the FEV1 values 
obtained 23 and 24 hours after dosing on 
Treatment Day 168 (i.e. at Week 24). 
Secondary Efficacy Endpoint:
1. TDI focal score at Week 24. 
2. Weighted mean FEV1 over 0 to 6 
hours post-dose at visit 2 
(Randomisation visit)
Other Efficacy Endpoint:
1. Trough FEV1 and TDI focal score at 
other time points
2. Rescue albuterol/salbutamol use 
(percentage of rescue-free days and 
puffs/day)
3. Time to onset (defined as an increase 
of 100mL above baseline in FEV1) 
during 0-6hr post-dose on Treatment 
Day 1 (Visit 2)
4. Proportion of subjects achieving an 
increase in FEV1 of 12% and 
200mL above baseline at any time 
during 0 to 6hr post-dose on Treatment 
Day 1 (Visit 2)
5. Proportion of subjects achieving an 
increase in FEV1 of 100mL above 
baseline in trough FEV1
6. Serial FEV1 over 0 to 6 hours post-
dose at Visit 2(Day 1)
7. Serial and trough Forced Vital 
Capacity (FVC)
8. Proportion of responders to TDI. (a 
responder to TDI will be defined as a 


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Objectives
Endpoints
subject with TDI score of 1 unit or 
more)
9. Time to first COPD exacerbation 
Secondary Objectives

To evaluate the safety of 
Umeclidinium 62.5 mcg compared 
with placebo when administrated 
once-daily via ELLIPTA over a 24-
week treatment period in subjects 
with COPD
1. Incidence of AEs
2. Vital signs (pulse rate, systolic and 
diastolic blood pressure)
3. 12-lead ECG parameters
4. Clinical chemistry and haematology 
parameters and routine urinalysis

To evaluate health-related quality of 
life Umeclidinium 62.5 mcg 
compared with placebo when 
administrated once-daily via 
ELLIPTA over a 24-week treatment 
period in subjects with COPD
1. 1. St. George’s Respiratory 
Questionnaire (SGRQ)
2. COPD Assessment Test (CAT) 
3. Healthcare resource utilisation
3.
INVESTIGATIONAL PLAN
3.1.
Study Design
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct. 
This is a multicenter, randomized, double-blind, parallel group study to evaluate the 
efficacy and safety of umeclidinium 62.5 mcg administered once-daily via an ELLIPTA
compared with placebo over 24 weeks in subjects with COPD. Eligible subjects will be 
randomized 2:1 to receive one of the two following treatments:

Umeclidinium (GSK573719) 62.5 mcg Inhalation Powder administered QD via an
ELLIPTA in the morning

Placebo administered QD via an ELLIPTA in the morning


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There will be a total of 10 study clinic visits conducted on an outpatient basis. A pre-
screening visit (V0) will be conducted to sign the informed consent form (ICF), dispense 
rescue medication and review demography, COPD history and concomitant medications. 
Once the ICF is signed the subject will be assigned a subject identifier. At Visit 0, any 
medications changes made by the investigator will be recorded. Subjects who meet the 
eligibility criteria at Screening (Visit 1) will complete a 7 to 14 day run-in period 
followed by a 24 week treatment period. Clinic visits will be at Prescreening (visit 0), 
Screening, Randomization (Day 1), Day 2 and 4, 8, 12, 16, and 24 weeks, and 1 day after 
the Week 24 visit (Visit 0 to Visit 9, respectively). Additionally a safety Follow-Up 
assessment will be conducted by phone call approximately 7 days after the end of the 
study treatment (Visit 9 or Early Withdrawal, if applicable). The total duration of subject 
participation, including the Follow-Up, will be approximately 27 weeks. All subjects will 
be provided with albuterol/salbutamol for use on an “as-needed” basis throughout the 
pre-screen, run-in and study treatment periods.
Spirometry will be conducted at Screening and each on-treatment clinic visit.  Pre- and 
post-albuterol/salbutamol spirometry will be conducted at Screening (Visit 1) for 
determination of eligibility and calculation of reversibility. To further characterize 
bronchodilator responsiveness, post-ipratropium testing will be conducted following 
completion of post- salbutamol/albuterol spirometry. Baseline spirometry will be 
conducted at Visit 2 prior to randomization.  Pre-dose trough spirometry will be 
conducted at every on-treatment clinic visit after randomization.  Additionally, six hour 
post-dose serial spirometry will be conducted at Visit 2 (Day 1).
The Baseline Dyspnea Index (BDI) and Transition Dyspnea Index (TDI) will be used to 
measure the severity of breathlessness. It will be administered by study personnel trained 
on the proper administration of the set of questionnaires. The BDI and TDI should be 
obtained prior to performing any other study-related procedures including spirometry 
testing. The BDI will be administered at Visit 2 while TDI will be administered at Visits 
4, 6 and 8. 
Disease specific health status will be evaluated using the St. George’s Respiratory 
Questionnaire (SGRQ) and CAT. SGRQ and CAT will be administered at baseline (Day 
1- Visit 2) and Visits 4, 6 and 8. Vital signs (blood pressure and pulse rate), 12-lead 
ECGs and standard clinical laboratory tests (hematology and blood biochemistry) will be 
obtained at selected clinic visits.


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The occurrence of AEs will be evaluated throughout the study, beginning at Visit 2. 
SAEs will be collected over the same time period as for AEs. However, any SAEs 
assessed as related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant 
medication (e.g. Run-in medications, rescue medications provided by GSK), will be 
recorded from the time a subject consents to participate in the study up to and including 
any follow up contact (China sites should Section 11.1, Appendix 1)
Subjects will be provided with a diary for daily completion in the morning throughout the 
run-in period and 24-week treatment period. Subjects will use the diary to record daily 
use of supplemental albuterol/salbutamol. All unscheduled COPD-related visits to a 
physician’s office, urgent care facility, or emergency department, and COPD-related 
hospitalizations associated with the subject’s condition will be recorded on the COPD-
related healthcare resource utilisation assessment worksheet within the diary. 
For determination of subject disposition, subjects will be considered to have completed 
the study upon completion of Day 169 (Visit 9).  There is no plan to provide any of the 
active study treatments for compassionate use following study completion. 
The Modified Intent-to-Treat (ITT) population will be the primary population of interest, 
and is defined as all randomised subjects who have received at least one dose of the 
randomised study medication during the Treatment Period.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.
3.2.
Discussion of Design
A randomized, double-blind, placebo-controlled, parallel group study is a standard, well-
established design to evaluate the efficacy and safety of an investigational drug. A 
placebo arm is included in this study to allow for an absolute assessment of efficacy and 
safety of the active treatment. 
Duration of 24 weeks is considered adequate for assessment of lung function and 
symptoms in response to treatment intervention with bronchodilators, and is consistent 
with regulatory guidance on clinical studies in COPD.  The choice of a lung function 
endpoint, trough FEV1, as the primary efficacy endpoint is a robust, well established, and 
objective means of demonstrating bronchodilator efficacy and duration of effect at the 
end of 24 hours after dosing. Post-dose assessments of lung function on day 1 will 
provide for an assessment of treatment response over the 0 to 6 hour post-dose period 
which represents the beginning of the treatment effect.
A randomisation ratio of 2:1 will reduce the number of subjects randomised to placebo
arm, as well as to reduce drop-outs.


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3.2.1.
Dose Selection
Data from two dose ranging studies, AC4113073 and AC4113589, demonstrated 
significant improvements in lung function for UMEC as measured by FEV1 over 24 to 28 
hours. However, there was no clear dose differentiation over the range of once-daily 
doses tested (62.5 mcg and 1000 mcg). A third dose ranging study (AC4115321), 
evaluating lower doses of UMEC monotherapy once and twice daily in COPD, 
demonstrated a FEV1 dose response across the range of once-daily doses of UMEC tested 
(15.6 to 125 mcg) supporting the dose selection for Phase IIIa. This third study further 
substantiated the findings from the previous dose ranging study (AC4113073) by 
showing twice-daily doses did not provide added benefit over once-daily dose, supporting 
a once-daily dosing interval. Based on a favourable therapeutic index, two doses of 
UMEC were selected to be taken to Phase III, 62.5 mcg and 125 mcg.
Integrated analysis of Phase IIIa study lung function parameters and rescue medication 
data indicates that differences in response to the 125 mcg dose and the 62.5 mcg dose, 
were modest, were not always consistently observed and were not considered clinically 
meaningful. TDI score and SGRQ changes also did not show an advantage for the 125 
mcg dose versus 62.5 mcg and the sub-group analysis did not identify a group who 
benefited from UMEC 125 mcg versus the 62.5 mcg. Therefore, the 62.5 mcg is the most 
appropriate dose for the treatment of COPD patients.


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4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA
4.1.
Number of Subjects
Based on an early withdrawal rate of 18% of randomized subjects, approximately 288
study subjects will be randomized in 2:1 to the double blind medication, that means 192
subjects in active arm and 96 subjects in placebo arm, to ensure approximately 236 
subjects complete the 24 week treatment period.
4.2.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB/IB supplement(s).
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.   
Subjects eligible for enrolment in the study must meet all of the following criteria:
1.
Type of subject: outpatient, Asian ancestry.
2.
Informed Consent: A signed and dated written informed consent prior to study 
participation.
3.
Age:  40 years of age or older at Screening (Visit 1).
4.
Gender:  Male or female subjects are eligible to participate in the study.
A female is eligible to enter and participate in the study if she is of:
Non-child bearing potential (i.e. physiologically incapable of becoming pregnant, 
including any female who is post-menopausal or surgically sterile). Surgically sterile 
females are defined as those with a documented hysterectomy and/or bilateral 
oophorectomy or tubal ligation. Post-menopausal females are defined as being 
amenorrhoeic for greater than 1 year with an appropriate clinical profile, e.g. age 
appropriate, >45 years, in the absence of hormone replacement therapy.  However, in 
questionable cases, post-menopause status may be confirmed by analysis of a blood 
sample with Follicle Stimulating Hormone (FSH) >40MIU/ml and estradiol 
<40pg/ml (<140 pmol/L) as confirmatory.
OR
Child bearing potential, provided the subject has a negative pregnancy test at 
screening, and agrees to one of the following acceptable contraceptive methods used 
consistently and correctly (i.e. in accordance with the approved product label, and 
the instructions of the physician for the duration of the study – Screening to Follow-
Up contact):

Abstinence 

Oral contraceptive either combined or progestogen alone


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
Injectable progestogen

Implants of levonorgestrel

Estrogenic vaginal ring

Percutaneous contraceptive patches

Intrauterine device (IUD) or intrauterine system (IUS)

Male partner sterilization (vasectomy with documentation of azoospermia) prior 
to the female subject’s entry into the study and this male is the sole partner for 
that subject.

Double barrier method condom and an occlusive cap (diaphragm or 
cervical/vault caps) with a vaginal spermicidal agent 
(foam/gel/film/cream/suppository).
5.
COPD History:  An established clinical history of COPD in accordance with the 
definition by the American Thoracic Society/European Respiratory Society [Celli, 
2004] as follows:
Chronic obstructive pulmonary disease is a preventable and treatable disease state 
characterized by airflow limitation that is not fully reversible. The airflow limitation 
is usually progressive and is associated with an abnormal inflammatory response of 
the lungs to noxious particles or gases, primarily caused by cigarette smoking. 
Although COPD affects the lungs, it also produces significant systemic 
consequences. 
6. Tobacco Use and Smoking History:  Current or former cigarette smokers with a 
history of cigarette smoking of 10 pack-years [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)].  Former 
smokers are defined as those who have stopped smoking for at least 6 months prior to 
Visit 1.
Note: Pipe and/or cigar use cannot be used to calculate pack-year history. COPD 
patients who only use a pipe and/or cigar are not eligible.  
7. Severity of Disease: A pre and post-salbutamol/albuterol FEV1/FVC ratio of <0.70 
and a pre and post-salbutamol/albuterol FEV1 of 70% of predicted normal values 
calculated using National Health and Nutrition Examination Survey (NHANES) III 
reference equations at Visit 1 [Hankinson, 1999, Hankinson, 2010].
8. Dyspnea:  A score of ≥2 on the Modified Medical Research Council Dyspnoea Scale 
(mMRC) at Screening (Visit 1)
4.3.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
Subjects meeting any of the following criteria must not be enrolled in the study:


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1. Pregnancy: Women who are pregnant or lactating or are planning on becoming 
pregnant during the study.
2. Asthma:  A current diagnosis of asthma.
3. Other Respiratory Disorders: Known -1 antitrypsin deficiency, active lung 
infections (such as tuberculosis) and lung cancer are absolute exclusionary 
conditions. A subject, who in the opinion of the investigator has any other 
significant respiratory conditions in addition to COPD should be excluded. 
Examples may include clinically significant bronchiectasis, pulmonary 
hypertension, sarcoidosis or interstitial lung disease.
4. Other Diseases/Abnormalities:  Subjects with historical or current evidence of 
clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, 
immunological, endocrine (including uncontrolled diabetes or thyroid disease) or 
haematological abnormalities that are uncontrolled and/or a previous history of 
cancer in remission for <5 years prior to Visit 1 (localized carcinoma of the skin 
that has been resected for cure is not exclusionary).  Significant is defined as any 
disease that, in the opinion of the investigator, would put the safety of the subject 
at risk through participation, or which would affect the efficacy or safety analysis 
if the disease/condition exacerbated during the study.
5. Chest X-Ray:  A chest X-ray or computed tomography (CT) scan that reveals 
evidence of clinically significant abnormalities not believed to be due to the 
presence of COPD.  A chest X-ray must be taken at Visit 1 if a chest X-ray or CT 
scan is not available within 6 months prior to Visit 1.  
6. Contraindications: A history of allergy or hypersensitivity to any 
anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein 
or magnesium stearate or a medical condition such as of narrow-angle glaucoma, 
prostatic hypertrophy or bladder neck obstruction that, in the opinion of the study 
physician contraindicates study participation or use of an inhaled anticholinergic.
7. Hospitalization: Hospitalization for COPD or pneumonia within 12 weeks prior 
to Visit 1.
8. Lung Resection:  Subjects with lung volume reduction surgery within the 12 
months prior to Screening (Visit 1).
9. 12-Lead ECG:  An abnormal and significant ECG finding from the 12-lead ECG 
conducted at Visit 1, including the presence of a paced rhythm on a 12-lead 
electrocardiogram (ECG) which causes the underlying rhythm and ECG to be 
obscured.  Investigators will be provided with ECG reviews conducted by a 
centralized independent cardiologist to assist in evaluation of subject eligibility.  
Specific ECG findings that precluded subject eligibility are listed in Appendix 3:  
The study investigator will determine the medical significance of any ECG 
abnormalities not listed in Appendix 3.
10. Screening Labs: Significantly abnormal findings from clinical chemistry and 
haematology tests at Visit 1.
11. Medications Prior to Spirometry: Unable to withhold albuterol/salbutamol for 
the 4 hour period required prior to spirometry testing at each study visit.


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12. Medications Prior to Screening: Use of the following medications according to 
the following defined time intervals prior to Visit 1; (Table 1)
Table 1
Time Interval for Prohibited Medication Prior to Visit 1
Medication
Time Interval Prior to Visit 1
Depot corticosteroids
12 weeks
Systemic, oral, parenteral (intra-articular) corticosteroids
4 weeks
Antibiotics (for lower respiratory tract infection)
4 weeks
ICS/LABA combination products if ICS/LABA therapy is discontinued 
completely
30 days
Use of ICS at a dose >1000mcg/day of fluticasone propionate or 
equivalent1
30 days
Initiation or discontinuation of ICS use1
30 days
Phosphodiesterase 4 (PDE4) inhibitors (e.g.roflumilast)
14 days
Long-acting anticholinergics (e.g.,tiotropium and aclidinium, 
glycopyronium)
7 days
Theophyllines2
12 hours (stable dose of 
theophylline alone is allowed during 
the study but must be withheld 12 
hours prior to each study visit)
Oral leukotriene inhibitors (zafirlukast, montelukast, zileuton)
48 hours
Oral beta2-agonists 
Long- acting
Short –acting
48 hours
12 hours
Olodaterol and Indacaterol (inhaled long-acting beta2-agonist)
14 days
Salmeterol, formoterol, (inhaled long-acting beta2-agonist)
48 hours 
LABA/inhaled corticosteroid (ICS) combination products only if 
discontinuing LABA therapy and switching to ICS monotherapy3
48 hours for LABA component
Inhaled sodium cromoglycate or nedocromil sodium
24 hours 
Inhaled short acting beta2-agonists4
4 hours
Inhaled short-acting anticholinergics2 (e.g. ipratropium bromide)
4 hours
(stable dose of ipratropium alone is 
allowed during the study, provided that 
the subject is on a stable dose regimen 
from Screening (Visit 1 and remains so 
throughout the study) but must be 
withheld 4 hours prior to each study 
visit)
Inhaled short-acting anticholinergic/short-acting beta2-agonist 
combination products
4 hours


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Medication
Time Interval Prior to Visit 1
Any other investigational drug
30 days or 5 half lives, whichever is 
longer 
1.
Use of ICS is permitted provided the dose not exceed 1000mcg of fluticasone propionate or equivalent; ICS use 
not to be initiated or discontinued within 30 days prior to Visit 1
2.
Ipratropium bromide or theophylline is permitted, provided that the subject is on a stable dose from Screening 
(Visit 1) and remains on the stable dose throughout the study; however, Ipratropium bromide must be withheld for 
4 hours; theophylline must be withheld for 12 hours prior to and during each clinic visit. 
3.
The dose of ICS must be equivalent to that contained in the ICS/LABA combination product (the study procedures 
manual will have equivalence guidelines)
4.
Use of study provided albuterol/salbutamol is permitted during the study, except in the 4-hour period prior to 
spirometry testing
13. Oxygen: Use of long-term oxygen therapy (LTOT) described as oxygen therapy 
prescribed for greater than 12 hours a day. As-needed oxygen use (i.e., 12 hours 
per day) is not exclusionary.
14. Nebulized Therapy:  Regular use (prescribed for use every day, not for as-
needed use) of short-acting bronchodilators (e.g., albuterol/salbutamol) via 
nebulized therapy.
15. Pulmonary Rehabilitation Program: Participation in the acute phase of a 
pulmonary rehabilitation program within 4 weeks prior to Visit 1.  Subjects who 
are in the maintenance phase of a pulmonary rehabilitation program are not 
excluded.
16. Drug or Alcohol Abuse: A known or suspected history of alcohol or drug abuse 
within 2 years prior to Visit 1.
17. Affiliation with Investigator Site:  Is an investigator, sub-investigator, study 
coordinator, employee of a participating investigator or study site, or immediate 
family member of the aforementioned that is involved in this study.
18. Compliance: A subject will not be eligible if he/she has any infirmity, disability, 
illiteracy, disease, or geographical location which seems likely (in the opinion of 
the Investigator) to impair compliance with any aspect of this study protocol, 
including visit schedule and completion of daily diaries or questionnaires.
4.4.
Randomization Criteria
In order to be randomized to double-blind study drug the subject must continue to meet 
the inclusion/exclusion criteria above. In addition the following criteria must also be met
at Visit 2:
1. Pre-Dose 12-Lead ECG at Visit 2: There is no evidence of a significantly abnormal 
12-lead ECG finding at the pre-dose ECG at Visit 2. ECG reviews conducted by a 
centralized cardiologist will not be available at Visit 2 for evaluation of subject 
eligibility. Eligibility of the subject is based on Visit 1 (screening) overread ECG.
2. COPD Exacerbation: Subjects must not have experienced a COPD exacerbation 
(defined as worsening of symptoms of COPD requiring the use of any additional 


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treatment other than study medication or rescue salbutamol) or a lower respiratory 
tract infection during run-in or at Visit 2.
3. Inhaled Corticosteroids: Subjects using ICS must have maintained a regular use of a 
stable dose of ICS during the run-in period at a dose 1000 mcg/day fluticasone 
propionate or equivalent.
4. Prohibited Medications. Subjects must not have used any prohibited medication [as 
listed in Section 5.6.2] during the run in period or at Visit 2.
4.5.
Withdrawal Criteria
A subject will also be withdrawn from the study if any of the following withdrawal 
criteria are met:  
1. COPD exacerbation: Subjects who experience a COPD exacerbation during the 
treatment period requiring the use of any systemic/oral corticosteroids, with 
prescribed or non-prescribed (self administered) antibiotics, and/or emergency 
treatment or hospitalization need to be withdrawn from the study.  
Note: However, subjects who experience a COPD exacerbation requiring only the 
use of either prescribed or non-prescribed (self-administered) antibiotics may 
continue to participate in study.
If a subject is withdrawn due to a COPD exacerbation, the exacerbation section of 
the electronic Case Record Form (eCRF) should be completed.
2. Pneumonia : Presumptive diagnosis or radiographically confirmed. Pneumonia 
needing the treatment of oral antibiotics or/and systemic steroid and/or emergency 
treatment or hospitalisation.
3. Laboratory measurements: Demonstrate a clinically important change(s) in a 
laboratory parameter(s) as determined by the study investigator
4. ECG: An abnormal and significant ECG finding identified during the study.  
Specific ECG findings that would result in subject withdrawal are listed in 
Section 11.3. The study investigator will determine the medical significance of 
any ECG abnormalities not listed in Section 11.3.
5. Liver Chemistry: Meets any of the protocol-defined liver chemistry stopping 
criteria in Section 6.3.4
6. Pregnancy: Positive pregnancy test
A subject may voluntarily discontinue participation in this study at any time. The 
investigator may also, at his or her discretion, discontinue a subject from this study at any 
time. Every effort should be made by the investigator to keep the subject in the study.  
Subjects who are withdrawn from the study will not be replaced.
If study drug is permanently discontinued during the course of the study, the subject must 
be withdrawn from the study. A subject that is withdrawn early from the study after being 
randomised to treatment cannot be re-screened.


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The primary reason for subject withdrawal will be recorded in the electronic Case Report 
Form (eCRF). Primary reasons and sub-reasons for withdrawal will be categorised as 
follows:
1. adverse event
2. withdrew consent

subject relocated

frequency of visits

burden of procedures

other (specify)
3. lost to follow-up
4. protocol deviation
5. lack of efficacy

COPD exacerbation
6. subject reached protocol-defined stopping criteria

ECG abnormality

Laboratory abnormality

pregnancy
7. study closed/terminated
Specific regard should be given to distinguishing withdrawals due to an adverse event, 
lack of efficacy, and protocol deviation.  
In cases where contact cannot be made with the subject, the subject may be considered 
lost to follow-up after the site has attempted actions for contact, as detailed in the SPM.
4.6.
Pre-Screen and Screen Failures
A subject will be assigned a subject number at the time the informed consent is signed 
(V0).  
A subject who is assigned a subject number but does not have Visit 1 will be considered a 
pre-screen failure.  
Any subject who performs a Visit 1 procedure but does not continue in the study beyond 
Visit 1 or any subject who completes Visit 1 and enters the run-in period, but is 
subsequently found to be ineligible for the study based on procedures (e.g., laboratory, 
ECG, spirometry) conducted at Visit 1and is not randomized to the study treatment 
medication, is classified as a ‘screen failure’.
In addition, a subject who experienced an SAE as related to study participation between 
the date of informed consent and the planned date of Visit 1 will be assigned a subject 
numbers and considered a prescreening failure.


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The following information will be collected for subjects who are pre-screen failures:
1. Date of ICF signature
2. Details of COPD medications within 30 days of Visit 0
3. Summary Status of COPD exacerbation, Yes/No
4. Serious Adverse Events information, if applicable, only for any SAE considered 
as related to study participation (e.g., study treatment, protocol mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
concomitant medication
5. Demographic information including race, age and gender
6. Subject number
7. Investigator signature page
In addition to the information above, the following information will be collected for 
screen failures:
1. Date of screening visit
2. Reason subject failed screening
Subjects who are pre-screen failures or screen failures cannot be re-screened.
4.7.
Run-in Failures
Subjects who meet the eligibility criteria at Visit 1 and enter the run-in period, but are not 
randomized will be considered run-in failures. In addition to the information described in 
Section 4.6, the date of Visit 2 and the reason for the run-in failure will be recorded in the 
eCRF. 
4.8.
Premature Discontinuation
The definition of an early subject withdrawal (premature discontinuation) from the study 
will be any subject who is randomized to double-blind medication and, for any reason, is 
withdrawn prior to completion of the Visit 9 procedures.
A subject may voluntarily discontinue participation in the study at any time.  The 
investigator may also, at his/her discretion; discontinue the subject from participating in 
the study at any time. In addition, the investigator must make every effort to have the 
subject return to the clinic as soon as possible after discontinuation of study drug for an 
Early Withdrawal Visit. An Early Withdrawal Visit may occur at a regular scheduled 
clinic visit or between clinic visits.  The following evaluations and procedures should be 
completed and recorded in the eCRF. 
1. Concomitant medication assessment
2. AE/SAE assessment
3. COPD exacerbation assessment


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4. Physical examination (recorded in source documents only)
5. Vital signs
6. Collect and review paper diary
7. Collect used study medication( blinded study medication and rescue 
albuterol/salbutamol)
8. Assess compliance with investigational drug
9. 12-Lead ECG
10. Laboratory assessments (including chemistry, haematology, and pregnancy test 
for females of childbearing potential and routine urinalysis)
11. Evaluation of smoking status and smoking cessation counselling
12. Report subject’s early withdrawal from the study via Randomization And 
Medication Ordering System New Generation (RAMOS NG).
A follow- up contact as described in Section 4.9 should be conducted 72 days following 
completion of the Early Withdrawal Visit.
A subject that is withdrawn from the study after being randomised to treatment cannot be 
re-screened and subjects who are withdrawn from the study will not be replaced.
4.9.
The Follow-up Phone Contact
A follow-up contact will be conducted 72 days following completion of Visit 9 (or the 
Early Withdrawal Visit, if applicable).  The following procedures will be performed:
1. AE/SAE assessment
2. COPD exacerbation
3. Pregnancy information (if applicable)
4. Register visit in RAMOS NG
Subjects will be discharged from the study upon completion of the follow-up phone call.


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5.
STUDY TREATMENTS
5.1.
Investigational Product and Other Study Treatment
GlaxoSmithKline (GSK) will provide the investigational product for use in this study. 
The investigational product Umeclidinium Inhalation Powder (62.5 mcg), and Placebo 
Inhalation Powder will each be delivered via an ELLIPTA.  
Each ELLIPTA will be comprised of one or two foil, laminate, blister strip/s. 
Descriptions of the double-blind investigation product for this study are provided in 
Table 2 (Umeclidinium) and Table 3 (placebo).
The ELLIPTAs containing investigational product and placebo will be identical in 
appearance. Subjects will be instructed to take one inhalation each morning from their 
ELLIPTA.  Subject instructions and details on how to use the ELLIPTA are provided in 
the SPM.
All subjects will receive supplemental albuterol/salbutamol (MDI and/or nebules) to be 
used on an as-needed basis (rescue medication) throughout the study. 
Albuterol/salbutamol will be sourced from local commercial stock.  If not available 
locally, GSK will source centrally.
Ipratropium bromide MDI for additional responsiveness testing at Visit 1 will be sourced 
from local commercial stock.  If not available locally, then GSK will source centrally.
Table 2
Description of Umeclidinium Inhalation Powder ELLIPTA
Formulation
First strip
Umeclidinium bromide blended with lactose monohydrate and magnesium searate1
Dosage Form
ELLIPTA  with 30 doses (1 strip with 30 blisters )
Unit Dose Strengths
62.5 mcg
Physical Description
White powder
Route of Administration
Inhaled
1.
Magnesium stearate 0.6% w/w of total drug product
Table 3
Description of Placebo Inhalation Powder ELLIPTA
Formulation
First strip
Second strip
Lactose monohydrate blended with 
magnesium stearate1
Lactose monohydrate blended with 
magnesium stearate2
Dosage Form
ELLIPTA Inhaler with 30 doses (2 strips with 30 blisters per strip)
Unit Dose Strengths
Not applicable
Not applicable
Physical description
White powder
White powder
Route of Administration
Inhaled
1.
Magnesium stearate 0.6% w/w of total drug product
2.
Magnesium stearate 1.0% w/w of total drug product


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The contents of the label will be in accordance with all applicable regulatory 
requirements.
Under normal conditions of handling and administration, investigational product is not 
expected to pose significant safety risks to site staff.  A Material Safety Data Sheet 
(MSDS) describing the occupational hazards and recommended handling precautions will 
be provided to site staff if required by local laws or will otherwise be available from GSK 
upon request.
5.1.1.
Storage
All study medication should be stored up to 25°C (77°F).  Each ELLIPTA will be 
packaged in a foil pouch with a desiccant sachet.  The inhaler should not be used for 
more than 30 days after opening the foil pouch.  
The sites must maintain a daily temperature log for the investigational product. 
Investigational product must be stored in a secure area under the appropriate physical 
conditions for the product.  Access to and administration of the investigational product 
will be limited to the investigator and authorised site staff.  Investigational product must 
be dispensed or administered only to subjects enrolled in the study and in accordance 
with the protocol.
5.1.2.
Study Drug Return
At the end of the study, all study supplied study medication (used and unused) will be 
destroyed following local standard operating procedures  Details for both destruction and 
return of study medication are found in the SPM.
In addition, any ELLIPTA that fails to function properly must be identified and returned 
to GSK for testing.  Details of the failure will be documented in the eCRF.  If a subject’s 
inhaler fails to function properly, the subject should return to the clinic as soon as 
possible to obtain a new inhaler.  The site will obtain a new treatment pack number for 
the subject via RAMOS NG and dispense a new study medication kit from the site’s 
investigational product supply as instructed by RAMOS.
5.2.
Treatment Assignment
Subjects will be assigned to study treatment in accordance with the central randomization 
schedule. The randomisation code will be generated by GSK using a validated 
computerised system. Subjects will be randomised using RAMOS NG. This is an
internet-based system which will be used by the investigator or designee to register the 
subject (initially at pre-screening, and subsequently at each study visit), randomize the 
subject, and provide medication assignment information if and when required. Details on 
how to use RAMOS NG to register and randomize subjects are provided in the SPM.
Once a randomization number has been assigned to a subject, the same number cannot be 
reassigned to any other subject in the study.


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Following completion of the 7 to 14 day Run-In period eligible subjects will be 
randomized in 2:1 ratio to one of the following treatment regimes in equal proportions 

Umeclidinium Inhalation Powder 62.5 mcg once daily

Placebo Inhalation Powder once daily
Approximately 192 subjects will be randomised to active treatment and 96 subjects to 
placebo.
Study drug will be collected at Visit 8 or at the Early Withdrawal Visit (if applicable)
5.3.
Blinding
Investigational product taken during the 24-week treatment period will be double-blind. 
Neither the subject nor the study physician will know which study medication the subject 
is receiving.
The investigator or treating physician may unblind a subject’s treatment assignment only 
in the case of an emergency, when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the subject.  Whenever possible, the 
investigator must first discuss options with the GSK Medical Monitor or appropriate 
GSK study personnel before unblinding the subject’s treatment assignment.  If this is 
impractical, the investigator must notify GSK as soon as possible, but without revealing 
the treatment assignment of the unblinded subject, unless that information is important 
for the safety of subjects currently in the study.  The date and reason for the unblinding 
must be recorded in the appropriate data collection tool.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject 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 subject’s treatment assignment, may be sent to clinical investigators in 
accordance with local regulations and/or GSK policy. 
Subjects will be withdrawn if the treatment code becomes unblinded. The primary reason 
for discontinuation (the event or condition which led to the unblinding) will be recorded 
in the eCRF.
5.4.
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
investigational product dispensed and/or administered to study subjects, the amount 
returned by study subjects, and the amount received from and returned to GSK, when 
applicable.  Product accountability records must be maintained throughout the course of 
the study.


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5.5.
Treatment Compliance
Subject compliance with double-blind study medication will be assessed at Visits 3 
through to 8 by reviewing the dose counter on the ELLIPTA and at any unscheduled visit 
where study drug is returned,  Subjects should be 80% to 120% compliant on taking 
study medication between each pair of consecutive on-treatment visits. Subjects who fall 
outside this range should be re-educated on treatment compliance by their site. This re-
education should be documented in the subject’s source document.  If the double-blind 
study medication is prematurely discontinued during the course of study or medication 
compliance repeatedly falls outside of acceptable ranges, the study sponsor/site monitor 
must be contacted to discuss subject eligibility for continued participation in the study.
5.6.
Concomitant Medications and Non-Drug Therapies
All COPD medications used within 30 days prior to visit 0 and onward should be 
recorded in the eCRF including any changes. Beginning at visit 1 and throughout the rest 
of the study, all non COPD medications taken during the study will be recorded in the 
eCRF, including any changes. Study-provided albuterol/salbutamol should not be 
recorded in the eCRF. The minimum requirement includes but is not limited to drug 
name, dose, route and the dates of administration.  Medications initiated after completion 
of Visit 9 or the Early Withdrawal Visit will not be recorded in the eCRF with the 
exception of those used to treat a COPD exacerbation or SAE that occurs between Visit 9 
(or the Early Withdrawal Visit) and the follow-up contact.
5.6.1.
Permitted Medications and Non-Drug Therapies
The following relevant medications are permitted during this study.
1. Study-provided albuterol/salbutamol for use as relief medication throughout the 
Run-in and Treatment periods, except in the 4-hour period prior to spirometry 
testing
2. Theophylline is permitted, provided that the subject is on a stable dose from 
Screening (Visit 1) and remains on the stable dose throughout the study; however, 
theophylline must be withheld for 12 hours prior to and during each clinic visit.
3. Ipratropium bromide is permitted, provided that the subject is on a stable dose 
from Screening (Visit 1) and remains on the stable dose throughout the study, 
however, ipratropium bromide must be withheld for 4 hours prior to and during 
each clinic visit.
4. Inhaled corticosteroids at a dose 1000 mcg/day of fluticasone propionate or 
equivalent are permitted provided the dose remains consistent as defined in the 
SPM throughout the study. Any ICS product alone (e.g., fluticasone propionate) 
cannot be initiated or discontinued within 30 days prior to Visit 1
5.
If the subject is on an ICS/LABA product for at least 30 days to Visit 1, the 
subject may switch to an ICS product alone as long as it does not exceed
1000mcg/day of FP or equivalent, and the dose remains consistent, as defined in 
the SPM, throughout the study. The switch to ICS alone from an ICS/LABA 
product must occur at least 48 hours prior to screen visit. Discontinuation of the 


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ICS/LABA product completely in the absence of starting an ICS alone must occur 
at least 30 days prior to V1.
6.
Mucolytics such as acetylcysteine
7.
As-needed oxygen use (i.e., 12 hours per day)
8.
Medications for rhinitis (e.g., intranasal corticosteroids, antihistamines, cromolyn, 
nedocromil, nasal decongestants)
9.
Influenza vaccination
10. Pneumonia vaccination
11. Antibiotics for short term treatment of acute infection (≤2 weeks) 
12. Oral anticholinergic for overactive bladder
13. Pulmonary rehabilitation program in maintenance phase
14. Smoking cessation treatment, including a stable regimen of nicotine replacement
15. Use of positive airway pressure for sleep apnoea 
5.6.2.
Prohibited Medications and Non-Drug Therapies
Use of the medications listed in Table 4 is not permitted during the study and for the 
washout period indicated prior to Visit 1 refers to Table 1.
Table 4
Prohibited Medications
Depot corticosteroids
Systemic, oral or parenteral corticosteroids
LABA/ICS combination products 
Use of ICS at a dose >1000 mcg/day of fluticasone propionate or equivalent1
Initiation or discontinuation of ICS use1
PDE4 inhibitor (e.g.roflumilast)
Oral leukotriene inhibitors (e.g. zafirlukast, montelukast, zileuton)
Oral beta2-agonists
Inhaled long acting beta2-agonists (LABA, e.g., salmeterol,  formoterol, indacaterol, olodacterol)
Inhaled long acting anticholinergics (LAMA, eg; tiotropium, aclidinium, glycopyrronium)
Inhaled sodium cromoglycate or nedocromil sodium
Any other investigational medication
1.
Use of ICS is permitted provided the dose not exceed 1000mcg of fluticasone propionate or equivalent; ICS use 
not to be initiated or discontinued within 30 days prior to Visit 1
The following medications or treatments are also not allowed during the study:

LTOT (defined as oxygen therapy prescribed for greater than 12 hours per day)

Regular nebulized therapy

Initiation of pulmonary rehabilitation during the study


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5.6.2.1.
Traditional or herbal medicines
The following categories of traditional or herbal medicines are prohibited prior to Visit 1 
and at any time during the study:

Traditional or herbal medicines used for the treatment of COPD, including those 
with known effect of bronchodilation. 

Traditional or herbal medicines that have known effects on platelets and that 
increase the tendency to cause bleeding. 
5.7.
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the patient’s medical condition whether or not GSK is providing specific 
post study treatment.
GSK will not provide post-study treatment. Post-treatment COPD therapy should not be 
entered into the eCRF.
5.8.
Treatment of Study Investigational product Overdose
An overdose is defined as a dose greater than the total doses described above which 
results in clinical signs and symptoms. These should be recorded by the investigator on 
the AE/SAE pages.  In the event of an overdose of study medication, the investigator 
should use clinical judgment in treating the overdose and contact the study medical 
monitor.
GSK is not recommending specific treatment guidelines for overdose and toxicity 
management. The investigator is advised to refer to the relevant document(s) for detailed 
information regarding warnings, precautions, contraindications, adverse events, and other 
significant data pertaining to the study drug being used in this study. Such documents 
may include, but not be limited to, the IB or equivalent document provided by GSK
6.
STUDY ASSESSMENTS AND PROCEDURES
This Section provide an outline of the time and completing of all study procedures and a 
description of specific procedures.  A schedule of Time and Events is provided in Table 5


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Table 5
Time and Events Table
Detailed procedure and time window please reference to SPM.
Run-in
Double-blind treatment period
Visit
Visit
0
(Pre-
Screen)
Screenin
g Visit
(Visit 1)
Visit
2
Visit
3
Visit
4
Visit
5
Visit
6
Visit
7
Visit
8
Visit
9
Early 
With-
drawal 
(EW) Visit
Follow-Up 
(Phone 
contact)
Day
Day
-7 to -14
Day
1
Day
2
Day
282
Day
564
Day
844
Day
1124
Day
1684
Day
169 
(Visit 
8 +1 
day)
7±2 days after 
Visit 9 or EW
Week
-1
0
0
4
8
12
16
24
Written Informed Consent1
x
Demography/ COPD History
X
Medical History
X
Physical Examination
X
X
X
Smoking Status
X
X
X
Smoking Cessation Counselling
X
X
X
Chest X-ray2
X
Inclusion/exclusion criteria 
X
Randomization criteria
X
Screening spirometry (including post-
bronchodilator testing)3
X
mMRC questionnaire
X
Register visit in IWRS4 (RAMOS NG)
x
x
x
x
x
Diary Card Dispense or
Collection/Review
X
X
X
X
X
X
X
X
X
X


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Run-in
Double-blind treatment period
Visit
Visit
0
(Pre-
Screen)
Screenin
g Visit
(Visit 1)
Visit
2
Visit
3
Visit
4
Visit
5
Visit
6
Visit
7
Visit
8
Visit
9
Early 
With-
drawal 
(EW) Visit
Follow-Up 
(Phone 
contact)
Day
Day
-7 to -14
Day
1
Day
2
Day
282
Day
564
Day
844
Day
1124
Day
1684
Day
169 
(Visit 
8 +1 
day)
7±2 days after 
Visit 9 or EW
Week
-1
0
0
4
8
12
16
24
Efficacy assessments
Trough Spirometry5
X
X
X
X
X
X
X
Serial Spirometry6
X
COPD exacerbation assessment
x
X
X
X
X
X
X
X
X
X
X
X
Baseline Dyspnea Index (BDI)
X
Transition Dyspnea Index (TDI)
X
X
X
SGRQ
X
X
X
X
COPD Assessment Test (CAT)
X
X
X
X
Healthcare resource utilization7
Safety Assessments
12-Lead ECG8
X
X8
X8
X8
X
Vital Signs (blood pressure and pulse 
rate )9
X
X
X
X
X
X
X
X
X
X
Adverse Event 
X
X
X
X
X
X
X
X
X
X
Serious Adverse Event /Con-Med 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Routine urine
X
X
X
Urine Pregnancy Test
X
X
X
X
X
X
Clinical Laboratory tests10
X
X
X
X
Medication


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Run-in
Double-blind treatment period
Visit
Visit
0
(Pre-
Screen)
Screenin
g Visit
(Visit 1)
Visit
2
Visit
3
Visit
4
Visit
5
Visit
6
Visit
7
Visit
8
Visit
9
Early 
With-
drawal 
(EW) Visit
Follow-Up 
(Phone 
contact)
Day
Day
-7 to -14
Day
1
Day
2
Day
282
Day
564
Day
844
Day
1124
Day
1684
Day
169 
(Visit 
8 +1 
day)
7±2 days after 
Visit 9 or EW
Week
-1
0
0
4
8
12
16
24
COPD and Concurrent Medication 
Assessment
x
X
X
X
X
X
X
X
X
X
X
Dispense/collect rescue 
salbutamol/albuterol
X
X
X
X
X
X
X
X
X
X
X
Dispense double-blind study drug
X
X
X
X
X
Collect double-blind study drug
X
X
X
X
X
X
Assess double-blind study drug 
compliance
X
X
X
X
X
X
1.
Written informed consent must be obtained prior to performing any Visit 1 procedures or initiating any alterations in a subject’s medications. Subjects will be assigned a 
study number at the time the ICF is signed. Visit 0 and Visit 1 may occur on the same day if applicable.
2.
To be performed only if there is no chest X-ray or CT scan available within 6 months prior to Visit 1 
3.
Spirometry to be conducted as follows: pre-bronchodilator testing following by post-albuterol/salbutamol testing, followed by post-ipratropium testing. Post 
albuterol/salbutamol testing conducted 10 to 30 min after subject self-administration of 4 puffs of albuterol/salbutmol via MDI with a spacer.  Subject will then self 
administer 4 puffs of ipratropium bromide via MDI and spacer, followed by spirometry testing 30 to 60 min later. 
4.
IWRS stands for Interactive Web Response System.
5.
Trough spirometry obtained twice: at 23 and 24 hours after the previous day’s morning dose.
6.
6 hr serial spirometry: Performed post-dose at 15 and 30 min and 1, 3 and 6 hours. At Visit 2 (Day 1), pre-dose measurements will be obtained -30min and -5min pre-dose.
7.
Healthcare resource utilization will be collected and entered in the e-CRF as required during the study, collection of this data to be aided by the subject documentation in 
the paper diary of any contact with the doctor or nurse about their lung condition which was unrelated to study participation.
8.
ECG conducted pre-dose and 10 and 45 minutes post-dose
9.
Vital signs to be measured pre-dose and 10 and 45 minutes post-dose at visit 2, and measured only pre- dose at other visits (prior to spirometry).
10. Haematology, and clinical chemistry.


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6.1.
Critical Baseline Assessments
No study related procedures may be performed until the informed consent form 
document has been signed by the subject or legal deputy. A pre-screening visit may 
be required in order to administer the informed consent before any changes are made to 
the subject’s current medication regimen. The informed consent must be signed before 
any changes are made to the subject’s current medication regimen. The informed consent 
may be given at the screening visit if the subject does not take or has not taken any 
protocol excluded medications. 
Visit 0: During the pre-screening visit (Visit 0) each subject will have the following 
information collected:

Demographic history (including gender, ethnic origin, age, height and weight)

COPD history

COPD exacerbation assessment

Review of COPD medication
Visit 1: The following critical baseline assessments will be conducted at the screening 
visit, Visit 1:

Medical history including COPD (comprised of date of diagnosis and COPD type 
[emphysema and/or chronic bronchitis]), and smoking history, COPD 
exacerbations history, smoking status and previous and/or current medical 
conditions

Pre-and post-albuterol/salbutamol and post-ipratropium bromide spirometry

Cardiovascular medical history/risk factors 

12-Lead ECG 

Review of concomitant medications

Physical examination

Pulse rate and blood pressure measurements 

Chest x-ray (or historical CT-Scan obtained within 6 months of Screening or Visit 
1)

Clinical laboratory assessments (including chemistry, hematology, and routine 
urinalysis )

mMRC dyspnea scale (The subject’s degree of dyspnea to different levels of 
activity will be rated using a 0 to 4 point mMRC scale).

Urine pregnancy test

SAE assessment

Inclusion/ exclusion criteria


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The following critical baseline assessments will be conducted at Visit 2, as specified in 
Table 5;

Pre-dose spirometry

Baseline Dyspnea Index (BDI)

CAT

SGRQ
6.2.
Efficacy
6.2.1.
Primary Efficacy Endpoints
The primary efficacy endpoint is:

Clinic visit trough (pre-bronchodilator) FEV1 on Treatment Day 169. 
Trough FEV1 on Treatment Day 169 is defined as the mean of the FEV1 values obtained 
23 and 24 hours after dosing on Treatment Day 168 (i.e. at Week 24).
6.2.2.
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:

TDI Focal score at Week 24

Weighted mean clinic visit FEV1 over 0 to 6 hours post-dose at visit 2 (Day 1)
6.2.3.
Other Endpoints
Other endpoints include:

Trough FEV1 and mean TDI score at other time points

Rescue albuterol/salbutamol use (percentage of rescue-free days and puffs/day)

Time to onset (defined as an increase of 100mL in FEV1 above baseline) during 0
to 6h post-dose on Treatment Day 1 (Visit2)

Proportion of subjects achieving an increase in FEV1 of ≥12% and ≥200mL, 
above baseline at any time point during 0 to 6h post-dose on Treatment Day 1 
(Visit 2)

Proportion of subjects achieving an increase in FEV1 of ≥100mL above baseline 
in trough FEV1

Serial FEV1 over 0 to 6 hours post-dose at Visit 2 ( Day 1)

Serial and Trough FVC 

Proportion of responders to TDI.  A responder to TDI will be defined as a subject 
who reported a TDI score of 1 unit or more.

Time to first COPD exacerbation


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6.2.4.
Spirometry and Reversibility Testing
6.2.4.1.
Spirometry
Spirometry measurements will be performed using equipment that meets or exceeds the 
minimum performance recommendations of the America Thoracic Society (ATS) [Miller, 
2005].  All sites will use standardized spirometry equipment provided by an external 
vendor.
Subjects should wear nose clips while performing spirometry manoeuvres. For FEV1 and 
FVC determinations, at least 3 acceptable spirometry efforts (with no more than 8) should 
be obtained.  Acceptable spirometry efforts should have a satisfactory start of test and 
end of test (i.e., a plateau in the volume-time curve) and be free from artifacts due to 
cough, early termination, poor effort, obstructed mouthpiece, equipment malfunction, or 
other reasons [Miller, 2005; Pelligrino, 2005].
The largest FEV1 and FVC from the 3 acceptable efforts should be recorded, even if they 
do not come from the same effort

Spirometry must be performed as detailed in Table 5, initiated between 8.00am 
and 12.00pm (noon)

After completing BDI/TDI, SGRQ and CAT assessments

At Visit1 after withholding COPD medication as indicated in the exclusion 
criteria [Section 4.3]

At Visit 3 through to visit 8 after withholding the morning dose of the double-
blind study medication

At all visits, after withholding the albuterol/salbutamol rescue medication for ≥4 
hours

At all clinic visits after refraining from:
o
smoking for 1 hour  
o
drinks with high levels of caffeine such as tea and coffee for at least 2 hours 
Details regarding the spirometric procedures are provided in the manual provided by the 
central spirometry vendor.
Post-dose measurements should be made as close as to the scheduled time points as 
possible (see Table 5 for timings).  Details regarding allowable time windows can be 
found in the SPM.  
6.2.4.2.
Bronchodilator Responsiveness Testing
At Visit 1, both pre-and post-albuterol/salbutamol spirometry will be obtained. A pre-
and post-albuterol/salbutamol FEV1 ≤70% of predicted normal and FEV1/FVC ratio of 
<0.70 are required for subject eligibility. Additionally, to further characterize the 
bronchodilator responsiveness, post-ipratropium spirometry testing will be obtained 
following completion of the post-albuterol/salbutamol spirometry. 


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Bronchodilator responsiveness testing will be completed as follows:
Following pre-albuterol/salbutamol spirometry (three acceptable spirometry efforts 
should be obtained), the subject will then self-administer 4 puffs of albuterol/salbutamol 
via MDI using a spacer.  Three acceptable spirometry efforts should be obtained 
approximately 10 to 30 minutes after albuterol/salbutamol administration.
Following completion of post-albuterol/salbutamol spirometry, the subject will self-
administer 4 puffs of ipratropium via MDI using a spacer. Three acceptable spirometry 
efforts should be obtained approximately 30 to 60 minutes after ipratropium 
administration.
6.2.4.3.
6-Hour Serial Spirometry
All subjects will be required to perform the 6-hour serial spirometry on Day 1, Visit 2, at 
15 and 30 min, 1, 3 and 6h post-dose.  Pre-dose measurements will be obtained at 30min 
and 5 min prior to the dose of study medication.
Post-dose measurements should be made as close as to the scheduled time points as 
possible (see Table 5 for timings).  Details regarding allowable time windows can be 
found in the SPM.
6.2.5.
BDI/TDI
The BDI is used to measure the severity of dyspnea in patients at baseline.  The TDI 
measures changes in the patient’s dyspnea from baseline.  The BDI and TDI should be 
performed prior to spirometry testing.
The interviewer should be a physician, nurse, respiratory therapist, or cardiopulmonary 
technician.  The interviewer must be blinded to other parameters evaluated for the 
patient.  It is recommended that the same person conduct all interviews for each patient 
throughout the study. 
A worksheet will be provided to record the comments from the subject which were used 
to complete the BDI.  This worksheet will then be referred to at subsequent visits for 
completion of the TDI.
Additional instructions for completion of the BDI/TDI are provide in the SPM.
6.2.6.
Diary Assessments
6.2.6.1.
Paper Diary
Subjects will use paper diary to record the following information:

Any medical problems experienced and any medications used to treat those 
medical problems. These entries will be reviewed by the study coordinator at 
each study visit and recorded in the eCRF as an adverse events/concomitant 
medication or COPD exacerbations as appropriate.


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
The date and time of the morning dose of study medication taken on the days 
prior to Visit 4, Visit 5, Visit 6, Visit 7, and Visit 8

Supplemental albuterol/salbutamol used over the previous 24 hours. 
Subjects will be asked to bring the paper diary to each clinic visit. The study coordinator 
will review the paper diary at each clinic visit for completeness, legibility and 
consistency with subject-reported AEs.  Signs and symptoms of COPD recorded on the 
diary card will not be considered AEs and will not be collected in the eCRF. Additional 
details for completion of the diary cards are provided in the SPM.
6.2.7.
COPD Exacerbations
A COPD exacerbation will be defined as an acute worsening of symptoms of COPD 
requiring the use of any treatment beyond study medication or rescue 
albuterol/salbutamol. This includes requiring the use of antibiotics, systemic 
corticosteroids, and/or emergency treatment or hospitalization. COPD exacerbations will 
be recorded on the COPD exacerbation page of the eCRF. 
Subjects who experience an exacerbation during treatment or run-in period requiring the 
use of any systemic/oral corticosteroids, with/without either prescribed or non-prescribed 
(self administered) antibiotics, and/or emergency treatment or hospitalisation will be 
withdrawn from the study and will not be allowed to re-screen. However, subjects who 
experience a COPD exacerbation/lower respiratory tract infection requiring only the use 
of antibiotics, either prescribed or non-prescribed (self-administered), may continue to 
participate in study.
COPD exacerbations are associated with the disease under study and will not be recorded 
as AEs unless the exacerbation meets the definition of a “serious” AE as defined in 
Section 6.3.5.2 of this protocol.  Exacerbations that meet the definition of “serious” AEs 
will be recorded on the appropriate eCRF section and should be reported to GSK for all 
study subjects regardless of whether or not they are randomized to study medication.
6.3.
Safety
Safety endpoints include:

Incidence of adverse events

Vital signs (pulse rate and systolic and diastolic blood pressure)

12-Lead ECG parameters

Clinical Chemistry and haematology parameters and routine urinalysis
6.3.1.
Vital Signs
Vital signs measurements will include pulse rate and systolic and diastolic blood 
pressure.  Vital signs will be obtained after subjects have rested for approximately 5 


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minutes and before performing ECG and spirometry testing. A single set of values will be 
obtained.
Vital signs will be performed using equipment provided by investigational sites and will 
be obtained at visits and time points as detailed in Table 5.
Additional details of procedures related to vital signs are provided in the SPM.
6.3.2.
12-Lead ECG
A 12-lead ECG measurement and rhythm strip (10 seconds) will be obtained after 
measurement of vital signs and before spirometry testing. After vital signs are obtained 
subjects should be placed in the supine position for the ECG measurements.
ECG measurements will be taken at various visits and time points as detailed in Table 5
The investigator, a designated sub-investigator, or other appropriately trained site 
personnel will be responsible for performing 12-lead ECG assessments.  The investigator 
must provide his/her dated signature on the original paper tracing, attesting to the 
authenticity of the ECG machine interpretation.
ECG data 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 ECG measurements required for the study and an 
interpretation of ECGs findings. A hard copy of these results will be sent to the 
investigator.  The investigator must provide his/her dated signature on the confirmed 
report, attesting to his/her review of the independent cardiologist’s assessment.
Additional details of all 12-lead ECG procedures are provided in the SPM.
6.3.3.
Clinical Laboratory Tests
Routine, non fasting clinical laboratory (haematology and chemistry and urinalysis) tests 
will be performed as detailed in Table 5.  At the discretion of the investigator, additional 
samples may be taken for safety reasons. All samples will be measured at a designated 
central laboratory. 
A urine pregnancy test will be performed for all females of child bearing potential as 
detailed in Table 5.
The study clinical laboratory tests including analytes for clinical chemistry and 
haematology are shown below in Table 6.


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Table 6
Study Clinical Laboratory Tests
CHEMISTRY
HEMATOLOGY 
OTHER
Albumin 
Hemoglobin
Hepatitis B surface antigen1
Alkaline phosphatase 
Hematocrit
Hepatitis C virus antibody1
Alanine amino-transferase (ALAT or SGPT)
Platelet count
Urine pregnancy test (in clinic)2
Aspartate amino-transferase (ASAT or SGOT)
WBC count
Routine Urinalysis: 
Bilirubin, direct
Neutrophils, absolute
pH
Bilirubin, indirect
Neutrophils, segs (%)
Protein
Bilirubin, total
Neutrophils, bands (%)
Glucose
Calcium
Basophils (%)
Blood, Bilirubin, and White Cell 
Count
Chloride
Eosinophils (%)
CO2 content/Bicarbonate
Eosinophils , absolute
Creatinine
Lymphocytes (%)
Creatine phosphokinase (CPK), total
Monocytes (%)
Gamma glutamyl transferase (GGT)
RBC count
Glucose
Phosphorus 
Potassium
Protein, total serum
Sodium
Urea nitrogen (BUN)
Uric Acid 
1.
Assessed at Visit 1 (Screening) only, result is not exclusionary
2.
Only females of child-bearing potential; refer to Time and Events Table for specific visit information
Additional details of the clinical laboratory procedures and procedures for sending 
samples to the central laboratory will be provided by the central laboratory for placement 
in the SPM.
6.3.4.
Liver chemistry stopping and follow up criteria
Liver chemistry stopping and follow up criteria have been designed to assure subject 
safety and evaluate liver event aetiology (in alignment with the FDA premarketing 
clinical liver safety guidance).  
Liver chemistry stopping criteria 1 to 5 are defined below:
1.
Alanine Transaminase (ALT) 3xUpper Limit of Normal (ULN) and bilirubin 
2xULN (>35% direct bilirubin) (or ALT 3xULN and INR>1.5, if INR measured)
NOTE: if serum bilirubin fractionation is not immediately available, study drug should be 
discontinued if ALT 3xULN and bilirubin 2xULN. Serum bilirubin fractionation 
should be performed if testing is available. If testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and 
suggesting liver injury.
2.
ALT 8xULN.
3.
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4.
ALT 3xULN if associated with symptoms (new or worsening) believed to be 
related to hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia).
5.
ALT 5xULN but <8 xULN and cannot be monitored weekly for 2 weeks
When any of the liver chemistry stopping criteria 1 to 5 is met, do the following:

Immediately withdraw investigational product for that subject.

Report the event to GSK within 24 hours of learning its occurrence

Complete the liver event CRF and SAE data collection tool if the event also meets 
the criteria for an SAE. All events of ALT 3xULN and bilirubin 2xULN 
(>35% direct) (or ALT 3xULN and INR>1.5, if INR measured); INR 
measurement is not required and the threshold value stated will not apply to 
patients receiving anticoagulants), termed ‘Hy’s Law’, must be reported as an 
SAE (excluding studies of hepatic impairment or cirrhosis). 
NOTE: if serum bilirubin fractionation is not immediately available, study drug should be 
discontinued if ALT 3xULN and bilirubin 2xULN. Serum bilirubin fractionation 
should be performed if testing is available. If testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and 
suggesting liver injury.

Complete the liver imaging and/or liver biopsy CRFs if these tests are performed

Perform liver event follow up assessments, and monitor the subject until liver 
chemistries resolve, stabilize, or return to baseline values as described below. 

Withdraw the subject from the study (unless further safety follow up is required) 
after completion of the liver chemistry monitoring as described below.

Do not restart with investigational product.
In addition, for criterion 1: 

Make every reasonable attempt to have subjects return to clinic within 24 hours
for repeat liver chemistries, liver event follow up assessments (see below), and 
close monitoring

A specialist or hepatology consultation is recommended

Monitor subjects twice weekly until liver chemistries (ALT, Aspartate 
Aminotransferase (AST), alkaline phosphatase, bilirubin) resolve, stabilize or 
return to within baseline values
For criteria 2, 3, 4 and 5:

Make every reasonable attempt to have subjects return to clinic within 24 to 72 
hrs for repeat liver chemistries and liver event follow up assessments (see below)

Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values; criterion 5 subjects 
should be monitored as frequently as possible.


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Subjects with ALT 5xULN and <8xULN which exhibit a decrease to ALT 3xULN, but 
<5xULN and bilirubin <2xULN without hepatitis symptoms or rash, and who can be 
monitored weekly for 4 weeks:

Notify the GSK medical monitor within 24 hours of learning of the abnormality to 
discuss subject safety

Can continue investigational product 

Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize or return to within baseline 

If at any time these subjects meet the liver chemistry stopping criteria, proceed as 
described above

If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within 
baseline values. 
For criteria 1 to 5, make every attempt to carry out the liver event follow up assessments
described below:

Viral hepatitis serology including:
Hepatitis A Immunoglobin M (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 

Blood sample for Pharmacokinetic (PK) analysis, obtained within 72 hours of last 
dose.  Record the date/time of the PK blood sample draw and the date/time of the 
last dose of investigational product prior to blood sample draw on the CRF. If the 
date or time of the last dose is unclear, provide the subject’s best approximation. 
If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. 
Instructions for sample handling and shipping are in the SPM. 

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 hepatitis or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever rash or eosinophilia as relevant on the AE report form


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
Record use of concomitant medications, acetaminophen, herbal remedies, other 
over the counter medications, or putative hepatotoxins, on the concomitant 
medications report form.

Record alcohol use on the liver event alcohol intake case report form
The following are required for subjects with ALT 3xULN and bilirubin 2xULN 
(>35% direct) but are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies.

Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with definite or likely acetaminophen use in 
the preceding week (James, 2009).
NOTE: not required in China.

Only in those with underlying chronic hepatitis B at study entry (identified by 
positive hepatitis B surface antigen):  quantitative hepatitis B DNA and hepatitis 
delta antibody.  NOTE:  if hepatitis delta antibody assay cannot be performed,, it 
can be replaced with a PCR of hepatitis D RNA virus (where needed) – as 
outlined in: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1153793/

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease.
An algorithm for liver chemistry stopping and follow-up criteria is provided in 
Appendix 4: 
6.3.5.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.
6.3.5.1.
Definition of AEs
An AE is any untoward medical occurrence in a patient or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.  
Events meeting the definition of an AE include:

Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be 
clinically significant in the medical and scientific judgement of the investigator.


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
Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study

Signs, symptoms, or the clinical sequelae of a suspected interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfill the definition of an AE or 
SAE. 
Events that do not meet the definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied, or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
subject’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition 
that leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
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.
6.3.5.2.
Definition of SAEs
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
A serious adverse event (SAE) is defined as any untoward medical occurrence that, at 
any dose:

results in death

is life-threatening
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.

Requires hospitalization or prolongation of existing hospitalization


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NOTE:  In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are AEs.  
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.

Results in disability/incapacity
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption.

Is a congenital anomaly/birth defect

Other situations:
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition.  These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.

Is associated with liver injury and impaired liver function defined as:
ALT 3xULN and total bilirubin* 2xULN (>35% direct), or
ALT 3xULN and INR** >1.5.
* Serum bilirubin fractionation should be performed if testing is available; if 
unavailable, measure urinary bilirubin via dipstick.  If fractionation is unavailable and 
ALT 3xULN and total bilirubin 2xULN, then the event is still to be reported as an 
SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.


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6.3.5.3.
Recording of AEs and SAEs

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s 
medical records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of 
the subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
6.3.5.4.
Evaluating AEs and SAEs
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is 
assessed as severe will not be confused with an SAE. Severity is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment 
and the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.


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
The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK.  However, it is very 
important that the investigator always make an assessment of causality for 
every event prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
6.3.5.5.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as may be indicated or as 
requested by GSK to elucidate as fully as possible the nature and/or causality of 
the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory 
tests or investigations, histopathological examinations or consultation with other 
health care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem 
findings, including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.


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6.3.6.
Cardiovascular Events
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 thrombosis

Deep Venous Thrombosis

Revascularisation
The CV CRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
CV Event data query prompting its completion. 
6.3.7.
Death Events
In addition, for all deaths, specific Death sections of the CRF will be required to be 
completed. These sections include questions regarding cardiovascular (including sudden 
cardiac death) and non-cardiovascular death. 
This information should be recorded within one week of when the death is first reported.
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
6.3.8.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
COPD exacerbations are associated with the disease to be studied and will not be 
recorded as AEs unless they meet the definition of an SAE as defined in Section 6.3.5.2. 
Exacerbations that meet the definition of an SAE will be recorded on the appropriate 
eCRF section and should be reported to GSK for all subjects regardless of whether or not 
they are randomized to blinded study medication.
Medications used to treat a COPD exacerbation will be recorded in the eCRF


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6.3.9.
Pregnancy
Details of all pregnancies in female subjects will be collected after the start of dosing and 
until follow up call using a clinical trial pregnancy form. To ensure subject safety, each 
pregnancy must be reported to GSK within 2 weeks of learning of its occurrence.  
Subject will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow up information on mother and infant, which will be forwarded to GSK.  
Generally, follow-up will not be required for longer than 6 to 8 weeks beyond the 
estimated delivery date.
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complications and elective terminations for medical reasons must be reported as an AE or 
SAE.  Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy, brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
reasonably related to the study treatment, must be promptly reported to GSK. 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.
6.3.10.
Medical Devices
Medical devices are being provided by GSK for use in this study (spacers for 
administration of albuterol/salbutamol and ipratropium bromide at screening).  GSK 
medical device incidents, including those resulting from malfunctions of the device, must 
be detected, documented, and reported by the investigator throughout the study.
Medical Device – this is any instrument, apparatus, appliance, material or other article, 
whether used alone or in combination, including the software necessary for its proper 
application intended by the manufacturer to be used for human beings for the purpose of:

diagnosis, prevention, monitoring, treatment or alleviation of disease;

diagnosis, monitoring, treatment, alleviation of or compensation for an injury or 
handicap;

investigation, replacement or modification of the anatomy or of a physiological 
process;

control of conception
and which does not achieve its principle action in or on the human body by 
pharmacological, immunological or metabolic means, but may be assisted in its function 
by such means. 
Note: if these means fulfill the main purpose of the product, it is a Medicinal Product. 
The term medical device includes in vitro diagnostic (IVD) devices. 


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The detection and documentation procedures described in this protocol apply to all GSK 
medical devices provided for use in the study.
Incident – 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 patient, or user or 
of other persons or to a serious deterioration in their state of health.  
Not all incidents lead to death or serious deterioration in health. The non-occurrence 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, it might lead to death or serious 
deterioration in health

A serious deterioration in state of health can include:

A life-threatening illness (a)

Permanent impairment of body function or permanent damage to a body structure 
(b)

A condition necessitating medical or surgical intervention to prevent (a) or (b)

Any indirect harm as a consequence of an incorrect diagnostic or IVD test results 
when used within the manufacturer’s instructions for use

Fetal distress, fetal death or any congenital abnormality or birth defects
Incidents include, for example:

Inhalation of an object that has accidentally entered a spacer device and resulted 
in tracheal obstruction.
Incidents do not include for example:

medical occurrences associated with metered-dose inhalers that do not fulfill the 
definition of a medical device (such events will be reported as medicinal product 
AEs)

non-serious medical occurrences which have no further safety implications for the 
subject or the device
Malfunction – A failure of a device to perform in accordance with its intended purpose 
when used in accordance with the manufacturer’s instructions.
Remedial Action – Any action other than routine maintenance or servicing of a device 
where such action is necessary to prevent recurrence of a reportable incident [this 
includes any amendment to the design to prevent recurrence].


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6.3.11.
Time Period and Frequency of Detecting AEs and SAEs

AEs and SAEs will be collected from the start of Study Treatment until the 
follow-up contact at the timepoints specified in the Time and Events Table.
(China sites should follow Section 11.1, Appendix 1)

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact. (China sites should follow 
Section 11.1, Appendix 1)

All SAEs will be recorded and reported to GSK within 24 hours as indicated in 
Section 6.3.12.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
6.3.12.
Prompt Reporting of Serious Adverse Events and Other Events 
to GSK
SAEs, pregnancies, medical device incidents, and liver function abnormalities meeting 
pre-defined criteria will be reported promptly by the investigator to GSK as described in 
the following table once the investigator determines that the event meets the protocol 
definition for that event.

Primary mechanism for reporting SAEs to GSK will be the electronic data 
collection tool

If the electronic system is unavailable for greater than 24 hours, the site will use 
the paper SAE data collection tool and fax it to the SAE contactor.

Site will enter the serious adverse event data into the electronic system as soon as 
it becomes available.

The investigator will be required to confirm review of the SAE causality by 
ticking the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of 
submission of the SAE.

After the study is completed at a given site, the electronic data collection tool 
(e.g., InForm system) will be taken off-line to prevent the entry of new data or 
changes to existing data

If a site receives a report of a new SAE from a study subject or receives updated 
data on a previously reported SAE after the electronic data collection tool has 


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been taken off-line, the site can report this information on a paper SAE form or to 
SAE contactor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.


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Table 7
Reporting of SAE and Other Events to GSK
Initial Reports
Follow-up Information on a 
Previous Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
“SAE” data 
collection tool
24 hours
Updated “SAE” 
data collection tool 
Pregnancy
2 Weeks
Pregnancy 
Notification Form
2 Weeks
Pregnancy Follow 
up Form
Device Incident 
24 hours
“Medical Device 
Incident Report 
Form”
24 hours
Updated “Medical 
Device Incident 
Report Form”
Liver chemistry 
abnormalities Phase 
III-IV:
ALT3xULN and
Bilirubin2xULN 
(>35% direct) (or 
ALT3xULN and
INR>1.5, if INR 
measured)***
24 hours*
SAE data 
collection tool.
**Liver Event CRF 
and liver imaging 
and/or biopsy 
CRFs if applicable
24 hours
Updated SAE data 
collection tool. 
**Updated Liver 
Event CRF
ALT8xULN; 
ALT3xULN with 
hepatitis or rash or 
3xULN and <5xULN 
that persists 4 
weeks
24 hours*
**Liver event CRF
24 hours 
**Updated Liver 
Event CRF
ALT5xULN plus 
bilirubin <2xULN
24 hours*
**Liver event CRF 
does not need 
completing unless 
elevations persist 
for 2 weeks or 
subject cannot be 
monitored weekly 
for 2 weeks
24 hours
ALT5xULN and 
bilirubin <2xULN that 
persists 2 weeks
24 hours*
**Liver event CRF 
24 hours
Updated liver event 
CRF
ALT3xULN and <5x 
ULN and bilirubin 
<2xULN
24 hours*
**Liver event CRF 
does not need 
completing unless 
elevations persist 
for 4 weeks or 
subject cannot be 
monitored weekly 
for 4 weeks


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1.
*GSK to be notified at onset of liver chemistry elevations to discuss subject safety.
2.
** Liver event documents should be completed as soon as possible.
3.
*** INR measurement is not required; if measured, the threshold value stated will not apply to patients receiving 
anticoagulants.
The method of recording, evaluating and follow-up of AEs and SAEs plus procedures for 
completing and transmitting SAE reports to GSK are provided in the SPM.  Procedures 
for post-study AEs/SAEs are provided in the SPM.
Procedures for documenting, transmitting and follow-up of medical device incidents 
along with the regulatory reporting requirements for medical devices are provided in the 
SPM.
6.3.12.1.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs and non-serious AEs related to 
study treatment (even for non- interventional post-marketing studies) is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and the safety 
of a product under clinical investigation are met.
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
The Named Safety Contact (NSC) is responsible for individual expedited reports 
submission to SFDA within 15 days from GSK first receipt (7 days for death case).
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
6.4.
Health Outcome Assessments Not Included as Primary or 
Key Secondary Endpoints
6.4.1.
St George’s Respiratory Questionnaire
The St. George’s Respiratory Questionnaire (SGRQ) will be completed by study subjects 
at study visits as shown in Table 5. 
The SGRQ [Jones, 1992] is a disease-specific questionnaire designed to measure the 
impact of respiratory disease and its treatment on the subject’s health-related quality of 
life. As well as producing an overall summary score, it is also possible to calculate scores 
for the individual domains of symptoms, activity and impacts.  It has been widely used in 
studies of COPD subjects and has been translated and validated for use in most major 


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languages.  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, 1991; Jones, 2002].  The 
SGRQ is self-completed by subjects, taking on average 20 minutes.
The SGRQ should be completed prior to spirometry.
Additional, instructions for completion of the SGRQ are provided in the SPM. 
6.4.2.
Healthcare Resource Utilisation
All unscheduled COPD-related visits to a Physician’s office, urgent care facility, or 
emergency department, and COPD-related hospitalisations associated with the subject’s 
condition will be recorded on the COPD-related healthcare resource use assessment 
worksheet within the diary, by the subject
At Visits 2 through 9 or at the Early Withdrawal Visit, the resource utilisation worksheet 
completed by the subject to record all health care contacts  since the last visit will be 
reviewed by the investigator (or designee). The investigator (or designee) should ask the 
subject if any of the health care contacts recorded on the worksheets were due to COPD 
exacerbation. The investigator can refer to his/her records to verify or supplement 
information given by the subject if necessary. 
If any unscheduled healthcare contact was due to a COPD exacerbation, then the COPD 
Exacerbation section of the eCRF must be completed.  
6.4.3.
COPD Assessment Test (CAT)
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 development of the CAT has involved well 
accepted methodologies used to develop psychometric tools [Jones, 2009a; Jones,
2009b]. The process of generating the CAT item pool was patient centred and also 
involved literature reviews and physician interviews [Jones, 2009b]. Following initial 
studies using this item pool in the US and Europe, a structured, rigorous scientific 
approach was used in the item reduction process to select the best items and generate the 
final 8-item questionnaire [Jones, 2009a]. The CAT has been validated in prospective 
studies conducted in the USA [Jones, 2009a] and China. 
The CAT is an 8-item questionnaire suitable for completion by all patients diagnosed 
with COPD. When completing the questionnaire, subjects rate their experience on a 6-
point scale, ranging from 0 to 5 with a maximum score of 40. The implications of CAT 
scores need to be considered in relation to an individual’s disease severity. Patients with 
more severe COPD (as defined by GOLD, 2015) would be expected to have higher CAT 
scores than patients with milder disease, although many studies have shown that the 
relationship between GOLD stage (measured by FEV1) and health status as perceived by 
physicians and patients is generally very weak. CAT was developed as a measure of 
health status to aid communication between physicians and patients and does not replace 
diagnostic spirometry. Research is currently ongoing to define ranges of CAT score in 


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relation to severity and to better understand the minimal clinically relevant change (often 
referred to as the Minimum Clinically Important Difference or MCID) in a CAT score 
from one visit to the next.
The CAT should be completed by all patients at the time points specified in the Time and 
Events Table. Patients should complete the 8 questions independently and without 
supervision.  The CAT should be administered before any other study procedures are 
performed (including concurrent medication assessment or adverse event assessment, 
etc.).
7.
DATA MANAGEMENT
For this study subject data will be entered into GSK defined electronic case report forms 
(eCRFs), transmitted electronically to GSK and combined with data provided from other 
sources in a validated data system.  
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.  Adverse events and concomitant medications 
terms will be coded using MedDRA and an internal validated medication dictionary, 
GSKDrug.  An appropriate medical dictionary that covers all approved drugs in the 
region will be referenced. eCRFs (including queries and audit trails) will be retained by 
GSK, and copies will be sent to the investigator to maintain as the investigator copy. In 
all cases, subject initials will not be collected or transmitted to GSK according to GSK 
policy.
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
8.1.
Hypotheses
The objective of this study is to assess the efficacy and safety of 24 weeks’ treatment 
with Umeclidinium 62.5 mcg Inhalation Powder compared with placebo, when 
administered once-daily in subjects with COPD. The primary endpoint is trough FEV1 at 
Day 169. The comparisons of interest for the primary analysis are described in Section 
8.3.3.1. 
For each test on each efficacy endpoint, the null hypothesis is that there is no difference 
between treatment groups.
H0: T1 – T2 = 0
The alternative hypothesis is there is a difference between treatment groups.
H1: T1 – T2 0


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8.2.
Study Design Considerations
8.2.1.
Sample Size Assumptions
The sample size calculation is based on the primary endpoint of trough FEV1 on 
Treatment Day 169 which will be analysed using a Mixed Models Repeated Measures
(MMRM) analysis.  The calculation uses an estimate of residual standard deviation (SD)
of 234 mL, based on the residual standard deviation from the MMRM analysis of the
meta-analyses from prior studies with UMEC in COPD (studies DB2113361, 
DB2113373, DB2113374).
Based on the Table 8 of effect sizes from previous studies, a true treatment difference of
115mL has been assumed:
Table 8
Effect Sizes from Previous Studies
Study
Comparison
Treatment Difference
DB2113373 (Day 169)
UMEC vs Placebo
0.115
AC4115408 (Day 85)
UMEC vs Placebo
0.127
UMEC ISE (Day 169) (DB2113361, 
DB2113373, DB2113374)
UMEC vs Placebo
0.133
DB2114634 (Day 169)
UMEC/VI vs Placebo
0.151
DB2114634 (China) (Day 169)
UMEC/VI vs Placebo
0.167
The sample size needs to include sufficient subjects to satisfy anticipated individual 
country requirements and the China subgroup is powered at 90% with a minimum of 100 
evaluable subjects on UMEC arm. Assuming a treatment difference of 115mL and a 
residual standard deviation of 234mL gives 132 evaluable subjects on UMEC and 66 
evaluable subjects on placebo is needed for China.
It is estimated that approximately 18% subjects will withdraw without providing a Week 
24 assessment. Although, in MMRM, all available post-baseline assessments up to 
endpoint for subjects in the Modified Intent-to-Treat Population are utilized in the 
analysis, data for subjects who withdraw prematurely from the study are not explicitly 
imputed. 
Allowing an 18% dropout, this would equate to 162 subjects randomised to UMEC and 
81 subjects randomised to placebo from China.
45 randomised subjects from Korea will be sufficient, equating to 30 subjects randomised 
to UMEC and 15 subjects randomised to placebo. With an 18% withdrawal rate, this 
gives 24 evaluable subjects on UMEC and 12 evaluable subjects on placebo (allowing a 
2:1 ratio).
We therefore require a total of approximately 192 randomised subjects on UMEC and 96
subjects randomised to placebo (total randomised 288).


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Allowing for 18% dropout, a study with 156 evaluable subjects in active treatment arm 
and 78 evaluable subjects in placebo arm will have 94% power assuming a true treatment 
difference of 115mL to show a statistically significant difference between UMEC 
62.5mcg and placebo in trough FEV1. The calculations use a two-sample t-test and a two-
sided 5% significance level. 
The minimal detectable effect for the final sample size of 156 evaluable subjects on 
UMEC vs 78 evaluable subjects on placebo is 63.6mL.
8.2.2.
Sample Size Sensitivity
If the standard deviation in this study is different from the expected value, the power to 
detect the planned difference in trough FEV1 will be affected.  Table 9 illustrates the 
power which would be obtained with different values of SD, assuming the sample size 
remains constant at 156 evaluable subjects on UMEC vs 78 evaluable subjects on 
placebo.
Table 9
Power Calculation for Treatment Differences
Parameter
SD
Treatment Difference
Power
Trough FEV1 (mL)
205
115mL
98%
240
115mL
93%
260
115mL
88%
If the SD for trough FEV1 increased to 260 mL, the study would have 88% power to 
show a statistically significant difference between UMEC and placebo assuming a true 
treatment difference of 115 mL. If the SD were as low as 205 mL then the study would 
have 98% power to show a statistically significant difference of 115 mL.
The true treatment difference for a statistically significant difference with 90% power 
will also be affected by changes in the SD; this is shown in Table 10.
Table 10
Treatment Differences Detected with 90% Power
Parameter
SD
Power
Treatment Difference
Trough FEV1 (mL)
205
90%
93 mL
240
90%
108 mL
260
90%
117 mL
If the SD increased to 260mL, the study would have 90% power to show a statistically 
significant difference between UMEC and placebo assuming a true treatment difference 
of 117mL.  If the SD were as low as 205mL then the study would have 90% power to 
show statistical significance for a true treatment difference of detect a difference of 
93mL.


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8.2.3.
Sample Size Re-estimation
No sample size re-estimation is planned for this study.
8.3.
Data Analysis Considerations
The analysis described below will be performed on all subjects enrolled from China and 
Korea and also a separate analysis will be performed on the subjects enrolled in China 
alone: A China subgroup analysis.
8.3.1.
Analysis Populations
Four subject populations will be identified.  
The All Subjects Enrolled Population will comprise all subjects, for whom a record 
exists on the study database, including screen failures and any subject who was not 
screened but experienced an SAE between the date of informed consent and the planned 
date of the Screening Visit. This population will be used for reporting subject disposition, 
reasons for withdrawal prior to randomization, and inclusion, exclusion and 
randomization criteria deviations and SAEs for non-randomized subjects.
The Screen and Run in Failure population will comprise all subjects in the All Subjects 
Enrolled Population who are recorded as screen failures or run-in failures in the 
electronic case report form (eCRF). It will be used for the tabulation of reasons for screen 
and run-in failure and for inclusion, exclusion and randomisation criteria failed.
The Modified Intent-to-treat (ITT) Population will comprise all subjects randomized to 
treatment who received at least one dose of randomized study medication in the treatment 
period.  Randomized subjects will be assumed to have received study medication unless 
definitive evidence to the contrary exists. Outcomes will be reported according to the 
randomized treatment allocation. This population will constitute the primary population 
for all data analyses and displays.  All scheduled data collected until the time of study 
discontinuation will be included in the Modified Intent-to-treat analysis for subjects who 
withdraw from the study.
The Per Protocol (PP) Population will comprise all subjects in the Modified ITT 
Population who are not identified as full protocol violators. Receipt of a study treatment 
other than the randomized treatment will be considered a protocol deviation from the 
time of receiving incorrect treatment onwards. Subjects identified as partial protocol 
violators will be included in the PP Population but will have their data excluded from PP 
analyses from the time of violation onwards. The definition of full and partial violations 
will be included in the Reporting and Analysis Plan (RAP)In addition, details of 
exclusions from the Per Protocol population/ analyses which are not considered to be 
protocol deviations, but may have a potential impact on the efficacy data will also be 
documented in the RAP. This population will be used for confirmatory analyses of the 
primary efficacy endpoints only, irrespective of how many subjects are in the PP 
population. 


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For the China subgroup analysis, four subject populations will be identified as above, but 
will include only those subjects enrolled in sites from China. More details will be 
provided in the RAP.
8.3.2.
Analysis Data Sets
Details of the analysis datasets will be given in the RAP
8.3.3.
Treatment Comparisons
8.3.3.1.
Primary Comparisons of Interest
The following treatment comparisons will be performed on trough FEV1 on Treatment 
Day 169:

Umeclidinium 62.5 mcg vs. placebo
8.3.3.2.
Other Comparisons of Interest
The comparisons listed in Section 8.3.3.1 will be performed on the following secondary 
endpoints:

Mean TDI focal score at Week 24

Weighted mean clinic visit FEV1 over 0 to 6 hours post-dose at Visit 2 
The same treatment comparisons will be performed for the other efficacy endpoints.
8.3.4.
Interim Analysis
No interim analysis is planned.
8.3.5.
Key Elements of Analysis Plan
Where possible, data from subjects who withdraw prematurely from the study will be 
included in any relevant analyses. Specific details for inclusion will be detailed in the 
RAP, but in general the minimum data required will be a baseline evaluation and at least 
one on-treatment evaluation. 
Data collected during a clinic visit will be reported by the visit at which the data were 
collected and will not be excluded from any analysis for being collected outside of an 
assessment window.
For the purposes of analyses, a completed subject is defined as anyone completing the 
last treatment visit (Visit 9).
It is anticipated that approximately 50 centres will participate in the study. Centres 
enrolling a small number of subjects may be pooled with another centre.  All 
amalgamations will be finalised and documented in the RAP prior to unblinding the 
treatment codes.  These amalgamations will be used wherever centre groupings are 
incorporated into the analysis.


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Baseline values for each endpoint will be those used from Visit 1 (screening) or pre-
treatment at Visit 2 (randomisation) and will be defined in the RAP.
An overall analysis will be carried out including all countries, and also a China subgroup 
analysis. 
8.3.5.1.
Efficacy Analyses
All efficacy data will be summarized using means, SDs and ranges for continuous data 
and frequencies and percentages for categorical data.
Primary Endpoint
Primary analysis:
The primary endpoint of change from baseline trough FEV1 on Day 169 will be analysed 
for the Modified Intent-to-treat Population using a mixed model repeated measures 
(MMRM) analysis [Siddiqui, 2009], including trough FEV1 recorded at each of Days 2, 
28, 56, 84, 112, 168 and 169.
Treatment group (categorical) will be fitted as the explanatory variable with baseline 
FEV1, day, country, day by baseline interaction and day by treatment interaction fitted as 
covariates. Baseline FEV1 is defined as the mean of the two assessments made pre-dose at 
Visit2. Day (nominal) will be fitted as a categorical variable and day by baseline and day
by treatment interaction terms will be included to allow treatment effects to be estimated 
at each day separately. The variance-covariance matrix will be assumed unstructured 
(based on previous experience, no issues are expected with fitting models with this matrix 
structure).
Estimated treatment differences for each treatment comparison will be presented together 
with 95% confidence intervals (CIs) for the difference and p-values.
This analysis will be repeated for the Per Protocol Population.
Sensitivity analyses – interactions:
An assessment of whether the effect of treatment on trough FEV1 is modified by each of 
the following factors will be performed: 
Center grouping, reversibility and ICS use. 
Separate models will be fitted for each factor, which are identical to the primary efficacy 
analysis model but including an additional term for the factor and treatment by factor 
interaction. If these interaction terms demonstrate statistical significance at the 10% level 
then further investigation and characterization of the interaction will be undertaken.
Further factors may also be considered for investigation and will be detailed in the RAP.
Secondary Endpoints
The analysis of the TDI focal score on Days 28, 84 and 168 will use the same 
methodology as that for the primary endpoint, but adjusting for BDI score instead of 
baseline FEV1.


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Weighted mean clinic visit FEV1 over 0 to 6 hours post-dose at Visit 2 (Day 1) will be 
analysed using analysis of covariance (ANCOVA). Treatment group (categorical) will be 
fitted as the explanatory variable with baseline FEV1, and country fitted as covariates. 
Baseline FEV1 is defined as the mean of the two assessments made pre-dose at Visit2. 
Estimated treatment differences for each treatment comparison will be presented together 
with 95% confidence intervals (CIs) for the difference and p-values.
Secondary endpoints will be analyzed for the Modified Intent-to-treat Population only.
Other Endpoints
Serial FEV1 at 15mins, 30mins, 1, 3 and 6 hours after dosing will be analysed using a 
repeated measures model, including baseline FEV1, country,  treatment, time, time by 
treatment interaction and time by baseline interaction fitted as covariates.  Baseline 
FEV1 is defined as the mean of the two assessments made pre-dose at Visit2.  This 
analysis will be performed for Day 1 only.
Time to onset of bronchodilation (defined as an increase of 100 mL in FEV1 above 
baseline on Treatment Day 1 (Visit2)) and time to first COPD exacerbation will be 
compared between treatment groups using Cox’s proportional hazards model.
Other endpoints will be analysed for the Modified Intent-to-treat Population only. Full 
details of the analyses to be performed will be provided in the RAP.
8.3.5.2.
Safety Analyses
AEs will be coded using the standard GSK dictionary, Medical Dictionary for Regulatory 
Activities (MedDRA), and grouped by body system. AEs with onset pre-treatment, 
during active treatment and post-treatment will be summarized separately. The number 
and percentage of subjects experiencing at least one AE of any type, AEs within each 
body system and AEs within each preferred term will be presented for each treatment 
group. Separate summaries will be provided for all AEs, drug related AEs, SAEs and 
AEs leading to withdrawal.
All SAEs will be tabulated and listed by treatment group. Deaths and SAEs will be 
documented in case narrative format.
Clinical laboratory evaluations (hematological and clinical chemistry), vital signs (pulse 
rate, systolic blood pressure and diastolic blood pressure) and 12-lead will be 
summarized by treatment group.  Pulse rate, systolic and diastolic blood pressure and 
derived ECG parameters  QTc(F), PR interval, and heart rate will be analyzed at each 
time point at which they were recorded (10 minutes and 45 minutes post-dose on Day 1, 
for vital signs pre-dose on Days 2, 28, 56, 84, 112, 168 and 169, for ECG pre-dose on 
Days 1, 84, and 168, and 10 minutes and 45 minutes post-dose on Day 1, 84 and 168) 
separately, using an ANCOVA model with predefined effects including baseline. 
Estimated treatment differences for all comparisons performed will be presented together 
with 95% CIs for the difference and p-values. The baseline value will be that recorded 
pre-treatment on Day 1.


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8.3.5.3.
Health Outcomes Analyses
Full details of the analysis to be performed will be given in the RAP.
9.
STUDY CONDUCT CONSIDERATIONS
9.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins.
9.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a study site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the ethical principles that are outlined in the Declaration of Helsinki 
2008, including, but not limited to:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review 
and favourable opinion/approval of study protocol and any subsequent 
amendments.

Subject informed consent.

Investigator reporting requirements.
GSK will provide full details of the above procedures, either verbally, in writing, or both.
Written informed consent must be obtained from each subject prior to participation in the 
study.


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9.3.
Quality Control (Study Monitoring)
In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK 
requirements.  When reviewing data collection procedures, the discussion will include 
identification, agreement and documentation of data items for which the CRF will serve 
as the source document.
GSK will monitor the study to ensure that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
9.4.
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of 
the study. In the event of an assessment, audit or inspection, the investigator (and 
institution) must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to 
all relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective and/or 
preventative actions to address any findings/issues identified.
9.5.
Study and Site Closure
Upon completion or termination of the study, the GSK monitor will conduct site closure 
activities with the investigator or site staff (as appropriate), in accordance with applicable 
regulations, GCP, and GSK Standard Operating Procedures.
GSK reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe non-
compliance.  If GSK determines that such action is required, GSK will discuss the 
reasons for taking such action with the investigator or head of the medical institution 
(where applicable).  When feasible, GSK will provide advance notice to the investigator 
or head of the medical institution of the impending action.
If a study is suspended or terminated for safety reasons, GSK will promptly inform all 
investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study.  GSK will also promptly inform the relevant regulatory authorities 
of the suspension/termination along with the reasons for such action.  Where required by 


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applicable regulations, the investigator or head of the medical institution must inform the 
IRB/IEC promptly and provide the reason(s) for the suspension/termination.
9.6.
Records Retention
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere) in a safe and secure location.  The records must 
be easily accessible when needed (e.g., for a GSK audit or regulatory inspection) and 
must be available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken.  The 
investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original.  In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required.  The investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions.
GSK will inform the investigator of the time period for retaining the site records in order 
to comply with all applicable regulatory requirements.  The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, GSK standard operating procedures, and/or institutional requirements.
The investigator must notify GSK of any changes in the archival arrangements, including, 
but not limited to archival of records at an off-site facility or transfer of ownership of the 
records in the event that the investigator is no longer associated with the site.
9.7.
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the investigator with the randomisation codes for their site only after 
completion of the full statistical analysis.
The results summary will be posted to the Clinical Study Register no later than eight 
months after the final primary completion date, the date that the final subject was 


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examined or received an intervention for the purposes of final collection of data for the 
primary outcome.  In addition, a manuscript will be submitted to a peer reviewed journal 
for publication no later than 18 months after the last subject’s last visit (LSLV).  When 
manuscript publication in a peer reviewed journal is not feasible, a statement will be 
added to the register to explain the reason for not publishing.
9.8.
Independent Data Monitoring Committee (IDMC)
There is no IDMC in this study.


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10.
REFERENCES
Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, et al, for 
the Canadian Thoracic Society/Canadian Respiratory Clinical Research Consortium.  
Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone–Salmeterol for 
Treatment of Chronic Obstructive Pulmonary Disease. A Randomized Trial.  Ann Intern 
Med. 2007;146:545-555.
Casaburi R, Mahler DA, Jones PW, Wanner A, San PG, ZuWallack RL, et al. A long-
term evaluation of once-daily inhaled ipratropium in chronic obstructive pulmonary 
disease. Eur Respir J. 2002;19:217-224. 
Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD: 
a summary of the ATS/ERS position paper. Eur Respir J. 2004; 23:932-946.
Chapman KR, Mannino DM; Soriano JB, Vermeire PA, Buist AS, Thun MJ, et al.
Epidemiology and costs of Chronic Obstructive Pulmonary Disease. Eur Respir J. 
2006;27:188-207. 
Decramer M, Maltais F, Fieldman G, Brooks J, Harris S, Mehta R, et al. Bronchodilation 
of umeclidinium, a new long acting muscurinic antagonist, in COPD patients. Resp 
Physiol Neurobiol 2013 185; 393-399.
Dransfield MT, Bailey W, Crater G, Emmett A, O’Dell DM, Yawn B. Disease severity 
and symptoms among patients receiving monotherapy for COPD. Prim Care Respir J. 
2011; Mar; 20(1):46-53. 
GOLD. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global 
Initiative for Chronic Obstructive Lung Disease (GOLD) 2015. Available from: 
http://www.goldcopd.org/.
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of 
the general US population. Am J Resp Crit Care Med. 1999;159:179-187.
HankinsonJL, Kawut SM, Shahar E, Smith LJ, MD, Hinckley Stukovsky K, and Barr 
RG. Performance of American Thoracic Society-Recommended Spirometry Reference 
Values in a Multiethnic Sample of Adults: The Multi-Ethnic Study of Atherosclerosis 
(MESA) Lung Study. Chest. 2010;137:138-45.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. 
Pharmacokinetics of Acetaminophen-Protein Adducts in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37(8): 1779-1784.
Jones P, Harding G, Wiklund I, Berry P, Leidy N. Improving the process and outcome of 
care in COPD: development of a standardised assessment tool. Primary Care Resp J. 
2009b; 18:208-215. 
Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and 
first validation of the COPD Assessment Test. Eur Respir J. 2009a;34:648-654. 


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Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure for 
chronic airflow limitation - the St George's Respiratory Questionnaire. Am Rev Respir 
Dis 1992;145:1321-1327.
Jones PW, Quirk FH, Baveystock CM, The St George's Respiratory Questionnaire.Respir 
Med. 1991 Sep;85 Suppl B:25-31; discussion 33-7.
Jones PW. Interpreting thresholds for a clinically significant changes in health status in 
asthma and COPD. Eur Respir J 2002; 19:398-404.
Jung JY, Kang YA, Park MS, Oh YM, Park EC, Kim HR, et al.  Chronic obstructive lung 
disease-related health care utilisation in Korean adults with obstructive lung disease. Int J 
Tuberc Lung Dis. 2011; 15(6):824-9. 
Lin HH, Maurray M, Cohen T, Colijn C, Ezzati M. Effects of smoking and solid-fuel use 
on COPD, lung cancer and tuberculosis in China: a time –based, multiple risk factor, 
modelling study. Lancet 2008 Oct 25; 372(9648):1473-83.
Lopez AD, Shibuya K, Rao C, Mathers CD, Hansell AL, Held LS, et al. Chronic 
obstructive pulmonary disease: current burden and future projections. Eur Respir J. 
2006;27:397-412. 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al.
Standardisation of spirometry. Eur Respir J, 2005; 26:319-338
Niewoehner DE, Rice K, Cote C, Paulson D, Cooper JA, Korducki L, et al. Prevention of 
exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily 
inhaled anticholinergic bronchodilator: a randomized trial.  Ann Intern Med. 
2005;143:317-326.
O'Donnell DE, Fluge T, Gerken F, Hamilton A, Webb K, Aguilania B, et al. Effects of 
tiotropium on lung hyperinflation, dyspnoea, and exercise tolerance in COPD. Eur Respir 
J. 2004;23:832-840. 
O'Donnell DE, Lam M, Webb KA. Measurement of Symptoms, Lung Hyperinflation, 
and Endurance during Exercise in Chronic Pulmonary Disease, Am J Respir Crit Care 
Med 1998; 20: 799-805
Pelligrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, et al. Interpretative 
straregies for lung function tests. Eur Respir J. 2005;26:948-968. 
Rennard SI, DeCramer M; Calverley PM,Pride NB, Soriano JB, Vermeire PA, et al. 
Impact of COPD in North America and Europe in 2000: subjects' perspective of 
confronting COPD International Survey. Eur Respir J. 2002;20:799-805
Siddiqui O, Hung HMJ, O’Neill. MMRM vs LOCF: A Comprehensive Comparison 
Based on Simulation Study and 25 NDA Datasets J Biopharm Stat 2009; 19: 227-46


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Tashkin DA, Littner M, Andrews CP, Tomlinson L, Rinehart M, Denis-Mize K.  
Concomitant treatment with nebulized formoterol and tiotropium in subjects with COPD: 
A placebo-controlled trial.  Respir. Med. 2008a; 102: 479–487
Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, et al; UPLIFT Study 
Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N 
Engl J Med. 2008b;359:1543-54.
Umeclidinium (GSK573719) Investigators Brochure, GSK Document Number 
RM2006/00835/11, Version 11, 10 August. IB: 2015.
Zhong NS, Wang C, Yao WZ, Chen P, Kang J. Prevalence of Chronic Obstructive 
Pulmonary Disease in China - a large population-based survey. Am J Respir Crit Care 
Med. 2007;176:753-760.


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11.
APPENDICES
11.1.
Appendix 1: Country Specific Requirements
For sites located in China, SAEs should be recorded from the time the consent form is 
signed until the follow-up contact. 
The requirement on SAE collecting time period in Section 3.1, Section 4.6 and Section
6.3.11 is not appropriate for sites in China.


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11.2.
Appendix 2:  12-Lead ECG Exclusion Criteria
An abnormal and clinically significant finding that would preclude a subject from 
entering the trial is defined as a 12-lead tracing that is interpreted as, but not limited to, 
any of the following:

Sinus tachycardia 120 bpm
*Note: sinus tachycardia 120bpm should be confirmed by two additional readings 
at least 5 minutes apart

Sinus bradycardia <45bpm
*Note:  Sinus bradycardia <45bpm should be confirmed by two additional readings 
at least 5 minutes apart. 

Multifocal atrial tachycardia 

Supraventricular tachycardia (>100bpm)

Atrial fibrillation with rapid ventricular response (rate >120bpm)

Atrial flutter with rapid ventricular response (rate >120bpm)

Ventricular tachycardias (non sustained, sustained, polymorphic, or 
monomorphic)

Ventricular flutter

Ventricular fibrillation

Torsades de Pointes

Evidence of Mobitz type II second degree or third degree atrioventricular (AV) 
block

AV dissociation

Trifascicular Block

For subjects with QRS duration <120 ms: QTc(F) 450msec or an ECG that is 
unsuitable for QT measurements (e.g., poor defined termination of the T wave).

For subjects with QRS duration>120: QTc(F) 480msec or an ECG that is 
unsuitable for QT measurements (e.g., poor defined termination of the T wave).

Myocardial infarction (acute or recent) * Note: Evidence of an old (resolved) 
myocardial infarction is not exclusionary.


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11.3.
Appendix 3: 12-Lead ECG Withdrawal Criteria
An ECG finding that would result in subject withdrawal post-randomization is defined as 
a 12-lead tracing that is interpreted as, but not limited to, any of the following:

Sinus tachycardia 120 bpm
*Note: sinus tachycardia 120bpm should be confirmed by two additional readings 
at least 5 minutes apart

Sinus bradycardia <37bpm
*Note:  Sinus bradycardia <37 bpm should be confirmed by two additional readings 
at least 5 minutes apart. 

Increase in heart rate 40bpm relative to baseline 
*Note: increase in heart rate 40bpm should be confirmed by two additional 
readings at least 5 minutes apart 

Multifocal atrial tachycardia 

Supraventricular tachycardia (>100bpm)

Atrial fibrillation with rapid ventricular response (rate >120bpm)

Atrial flutter with rapid ventricular response (rate >120bpm)

Ventricular tachycardias (non sustained, sustained, polymorphic, or 
monomorphic)

Ventricular flutter

Ventricular fibrillation

Torsades de Pointes

Evidence of Mobitz type II second degree or third degree atrioventricular (AV) 
block

AV dissociation

Trifascicular Block

An increase in QTcF>60 msec from baseline ECG

Uncorrected QT>600 msec

For subjects with QRS duration <120 ms: QTc(F) 500 msec or an ECG that is 
unsuitable for QT measurements (e.g., poor defined termination of the T wave).

For subjects with QRS duration>120 ms: QTc(F) 530 msec or an ECG that is 
unsuitable for QT measurements (e.g., poor defined termination of the T wave).

Myocardial infarction (acute or recent) Note: Evidence of an old (resolved) 
myocardial infarction is not exclusionary


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11.4.
Appendix 4: Liver Chemistry Stopping and Increased 
Monitoring Algorithm
Liver Chemistry Increased Monitoring Algorithm with Continued Therapy for ALT 
3xULN but <8xULN


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11.5.
Appendix 5: Protocol changes in Amendment 01
This amendment applies all sites.
Summary of Amendment Changes with Rationale
The following revisions were made:

Author(s) updated.

Inclusion Criteria updated. Asian ancestry is required.

Exclusion criteria updated. Remove CYP3A4 washout, add exclusive compliance.

Pre-Screen and Screen Failures updated. Required information is clarified.

Permitted Medications and Non-Drug Therapies revised.

Prohibited medications updated. Remove cytochrome P450 3A4 strong inhibitor

Time and Events Table revised.

COPD exacerbation revised.

Clinical Laboratory Tests revised.

Data Analysis Considerations revised on population and key elements.

12-Lead ECG Exclusion Criteria updated. Added 2:1 AV block and non-sustained 
ventricular tachycardia.

12-Lead ECG withdrawal criteria updated: Added 2:1 AV block.

Some minor format revisions.
List of specific changes
Section: Authors
Author(s): 
 (CMD, China);
 (CMD, China); 
 (DM ); 
 (Clinical Statistician, UK); 
 (CMD, China)
 
Section 3.2 Discussion of Design
A randomized, double-blind, placebo-controlled, parallel group study is a standard, well-
established design to evaluate the efficacy and safety of an investigational drug. A 
PPD
PPD
PPD
PPD
PPD
PPD


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placebo arm is included in this study to allow for an absolute assessment of efficacy and 
safety of each of the active treatments.
Section 4.2 Inclusion Criteria
1. Type of subject: outpatient, Asian ancestry
Section 4.3 Exclusion Criteria
Table 1
Time Interval for Prohibited Medication Prior to Visit 1
Medication
Time Interval Prior to Visit 1
Depot corticosteroids
12 weeks
Systemic, oral, parenteral (intra-articular) corticosteroids
4 weeks
Antibiotics (for lower respiratory tract infection)
4 weeks
Cytochrome P450 3A4 strong inhibitors1
4 weeks
(Grapefruit is allowed up to 
Visit 1, then limited to no more than one 
glass of grapefruit juice (250 mL/8 
ounces) or one grapefruit per day)
ICS/LABA combination products if ICS/LABA therapy is discontinued 
completely
30 days
Use of ICS at a dose >1000mcg/day of fluticasone propionate or 
equivalent21
30 days
Initiation or discontinuation of ICS use21
30 days
Phosphodiesterase 4 PDE4 inhibitors (roflumilast)
14 days
Long-acting anticholinergics (e.g.,tiotropium and aclidinium, 
glycopyronium)
7 days
Theophyllines32
12 hours (stable dose of 
theophylline alone is allowed during 
the study but must be withheld 12 
hours prior to each study visit)
Oral leukotriene inhibitors (zafirlukast, montelukast, zileuton)
48 hours
Oral beta2-agonists 
Long- acting
Short –acting
48 hours
12 hours
Olodaterol and Indacaterol (inhaled long-acting beta2-agonist)
14 days
Salmeterol, formoterol, (inhaled long-acting beta2-agonist)
48 hours 
LABA/inhaled corticosteroid (ICS) combination products only if 
discontinuing LABA therapy and switching to ICS monotherapy43
48 hours for LABA component
Inhaled sodium cromoglycate or nedocromil sodium
24 hours 


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Medication
Time Interval Prior to Visit 1
Inhaled short acting beta2-agonists54
4 hours
Inhaled short-acting anticholinergics32 (e.g. ipratropium bromide)
4 hours
(stable dose of ipratropium alone is 
allowed during the study, provided that 
the subject is on a stable dose regimen 
from Screening (Visit 1 and remains so 
throughout the study) but must be 
withheld 4 hours prior to each study 
visit)
Inhaled short-acting anticholinergic/short-acting beta2-agonist 
combination products
4 hours
Any other investigational drug
30 days or 5 half lives, whichever is 
longer 
1.
See the study procedures manual (SPM) for a complete list of excluded cytochrome P450 inhibitors
2.
1.Use of ICS is permitted provided the dose not exceed 1000mcg of fluticasone propionate or equivalent; ICS use 
not to be initiated or discontinued within 30 days prior to Visit 1
3.
2.Ipratropium bromide or theophylline is permitted, provided that the subject is are on a stable dose from 
Screening (Visit 1) and remains on the stable dose throughout the study; however, Ipratropium bromide must be 
withheld for 4 hours; theophylline must be withheld for 12 hours prior to and during each clinic visit. 
4.
3.The dose of ICS must be equivalent to that contained in the ICS/LABA combination product (the study 
procedures manual will have equivalence guidelines)
5.
4.Use of study provided albuterol/salbutamol is permitted during the study, except in the 4-hour period prior to 
spirometry testing
Section 4.3: Exclusion Criteria 

Compliance: A subject will not be eligible if he/she has any infirmity, disability, 
illiteracy, disease, or geographical location which seems likely (in the opinion of 
the Investigator) to impair compliance with any aspect of this study protocol, 
including visit schedule and completion of daily diaries or questionnaires.


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Section 4.6: Pre-Screen and Screen Failures
The study interactive voice response system (IVRS) will be contacted to report pre-screen 
failures. The following information will be collected for subjects who are pre-screen 
failures:

Date of ICF signature

Details of COPD medications within 30 days of Visit 0

Details of COPD exacerbation, if applicable Summary Status of COPD 
exacerbation, Yes/No

Serious Adverse Events information, if applicable, only for any SAE considered 
as related to study participation (e.g., study treatment, protocol mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
concomitant medication

Demographic information including race, age and gender

Subject number

Investigator signature page
Section 5.6.1 Permitted Medications and Non-Drug Therapies
If the subject is on an ICS/LABA product for at least 30 days to Visit 1, the subject may 
switch to an ICS product alone as long as it does not exceed 1000mcg/day of FP or 
equivalent, and the dose remains consistent, as defined in the SPM, throughout the 
study. The switch to ICS alone from an ICS/LABA product must occur at least 48 hours 
prior to screen visit starting the study. Discontinuation of the ICS/LABA product 
completely in the absence of starting an ICS alone must occur at least 30 days prior to 
V1.
Section 5.6.2 Prohibited Medications and Non-Drug Therapies
Table 4
Prohibited Medications
Depot corticosteroids
Systemic, oral or parenteral corticosteroids
Cytochrome P450 3A4 strong inhibitors1
LABA/ICS combination products 
Use of ICS at a dose >1000 mcg/day of fluticasone propionate or equivalent21
Initiation or discontinuation of ICS use21
PDE4 inhibitor (e.g.roflumilast)
Oral leukotriene inhibitors (zafirlukast, montelukast, zileuton)
Oral beta2-agonists
Inhaled long acting beta2-agonists (LABA, e.g., salmeterol,  formoterol, indacaterol, olodacterol)
Inhaled long acting anticholinergics (LAMA, eg; tiotropium, aclidinium, glycopyrronium)
Inhaled sodium cromoglycate or nedocromil sodium
Any other investigational medication
1.
See the SPM for a complete list of excluded cytochrome P450 inhibitors
2.
1. Use of ICS is permitted provided the dose not exceed 1000mcg of fluticasone propionate or equivalent; ICS use 
not to be initiated or discontinued within 30 days prior to Visit 1


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Section 6 STUDY ASSESSMENTS AND PROCEDURES
Table 5
Time and Events Table
Run-in
Double-blind treatment period
Visit
Visit
0
(Pre-
Screen)
Screenin
g Visit
(Visit 1)
Visit
2
Visit
3
Visit
4
Visit
5
Visit
6
Visit
7
Visit
8
Visit
9
Early 
With-
drawal 
(EW) Visit
Follow-Up 
(Phone 
contact)
Day
Day
-7 to -14
Day
1
Day
2
Day
282
Day
564
Day
844
Day
1124
Day
1684
Day
169 
(Visit 
8 +1 
day)
7±2 days after 
Visit 9 or EW
Week
-1
0
0
4
8
12
16
24
Written Informed Consent1
x
Demography/ COPD History
X
Medical History
X
Physical Examination
X
X
X
Smoking Status
X
X
X
Smoking Cessation Counselling
X
X
X
Chest X-ray2
X
Inclusion/exclusion criteria 
X
Randomization criteria
X
Screening spirometry (including post-
bronchodilator testing)3
X
mMRC questionnaire
X
Register visit in IVSR
x
x
x
x
X
x
x
x
x
x
x
x
Diary Card Dispense orand
Collection/Review
X
X
X
X
X
X
X
X
X
X


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Section 6.2.7 COPD Exacerbations
Subjects who experience an exacerbation during treatment or run-in period requiring the 
use of any systemic/oral corticosteroids, with/without either prescribed or non-prescribed 
(self administered) antibiotics, and/or emergency treatment or hospitalisation during the 
run-in will be withdrawn from the study and will not be allowed to re-screen. However, 
subjects who experience a COPD exacerbation/lower respiratory tract infection requiring 
only the use of antibiotics, either prescribed or non-prescribed (self-administered), may 
continue to participate in study.
Section 6.3.3 Clinical Laboratory Tests
Routine, non fasting clinical laboratory (haematology and chemistry and urinalysis) tests 
will be performed as detailed in Table 5.  At the discretion of the investigator, additional 
samples may be taken for safety reasons. All blood samples will be measured at a 
designated central laboratory.
Section 6.3.3 Clinical Laboratory Tests
Table 6
Study Clinical Laboratory Tests
CHEMISTRY
HEMATOLOGY 
OTHER
Albumin 
Hemoglobin
Hepatitis B surface antigen1
Alkaline phosphatase 
Hematocrit
Hepatitis C virus antibody1
Alanine amino-transferase (ALAT or SGPT)
Platelet count
Urine pregnancy test (in clinic)2
Aspartate amino-transferase (ASAT or SGOT)
WBC count
Routine Urinalysis: 
Bilirubin, direct
Neutrophils, absolute
pH
Bilirubin, indirect
Neutrophils, segs (%)
Protein
Bilirubin, total
Neutrophils, bands (%)
Glucose
Calcium
Basophils (%)
Blood, Bilirubin, and White Cell 
Count
Chloride
Eosinophils (%)
CO2 content/Bicarbonate
Eosinophils , absolute
Creatinine
Lymphocytes (%)
Creatine phosphokinase (CPK), total
Monocytes (%)
Gamma glutamyl transferase (GGT)
RBC count
Glucose
Phosphorus 
Potassium
Protein, total serum
Sodium
Urea nitrogen (BUN)
Uric Acid 
1.
Assessed at Visit 1 (Screening) only, result is not exclusionary
2.
Only females of child-bearing potential; refer to Time and Events Table for specific visit information
Section 8.3 Data Analysis Considerations
The analysis described below will be performed on all subjects enrolled from China, 
Taiwan, Korea and Thailand and also a separate analysis will be performed on the 
subjects enrolled in China alone: A China subgroup analysis.


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Section 8.3.1 Analysis Population
ThreeFour subject populations will be identified.  
The All Subjects Enrolled Population will comprise all subjects, for whom a record 
exists on the study database, including screen failures and any subject who was not 
screened but experienced an SAE between the date of informed consent and the planned 
date of the Screening Visit. This population will be used for reporting subject disposition, 
reasons for withdrawal prior to randomization, and inclusion, exclusion and 
randomization criteria deviations and SAEs for non-randomized subjects.
The Screen and Run in Failure population will comprise all subjects in the All Subjects 
Enrolled Population who are recorded as screen failures or run-in failures in the 
electronic case report form (eCRF). It will be used for the tabulation of reasons for screen 
and run-in failure and for inclusion, exclusion and randomisation criteria failed. 
The Intent-to-treat (ITT) Population will comprise all subjects randomized to treatment 
who received at least one dose of randomized study medication in the treatment period.  
Randomized subjects will be assumed to have received study medication unless definitive 
evidence to the contrary exists. Outcomes will be reported according to the randomized 
treatment allocation. This population will constitute the primary population for all data 
analyses and displays.  Subjects will be included in the analysis of a particular outcome if 
they provided at least one on-treatment assessment of that outcome.
The Per Protocol (PP) Population will comprise all subjects in the ITT Population who 
are not identified as full protocol violators. Receipt of a study treatment other than the 
randomized treatment will be considered a full protocol violation. Subjects identified as 
partial protocol violators will be included in the PP Population but will have their data 
excluded from PP analyses from the time of violation onwards. The definition of full and 
partial violations will be included in the Reporting and Analysis Plan (RAP) and the 
decision to exclude a subject from the PP Population or a subject’s data from PP analyses 
will be made prior to breaking the blind. This population will be used for confirmatory 
analyses of the primary and secondary efficacy endpoints only, irrespective of how many 
subjects are in the PP population. 
For the China subgroup analysis, four subject populations will be identified as above, but 
will include only those subjects enrolled in sites from China. More details will be 
provided in the RAP.
Section 8.3.5 Key Elements of Analysis Plan
Where possible, data from subjects who withdraw prematurely from the study will be 
included in any relevant analyses. Specific details for inclusion will be detailed in the 
RAP, but in general the minimum data required will be a baseline evaluation and at least 
one on-treatment evaluation. 
Data collected during a clinic visit will be reported by the visit at which the data were 
collected and will not be excluded from any analysis for being collected outside of an 
assessment window.


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For the purposes of analyses, a completed subject is defined as anyone completing the 
last treatment visit (Visit 9).
It is anticipated that approximately 50 centres will participate in the study. Centres 
enrolling a small number of subjects may be pooled with another centre.  All 
amalgamations will be finalised and documented in the RAP prior to unblinding the 
treatment codes.  These amalgamations will be used wherever centre groupings are 
incorporated into the analysis.
Baseline values for each endpoint will be those used from Visit 1 (screening) or pre-
treatment at Visit 2 (randomisation) and will be defined in the RAP.
An overall analysis will be carried out including all countries, and also a China subgroup 
analysis. 
Section 11.3 Appendix 3:  12-Lead ECG Exclusion Criteria
An ECG finding that would preclude a subject from entering the trial is defined as a 12-
lead tracing that is interpreted as, but not limited to, any of the following:

Sinus tachycardia 110 bpm
*Note: sinus tachycardia 110bpm should be confirmed by two additional readings 
at least 5 minutes apart

Sinus bradycardia <45 bpm
*Note:  Sinus bradycardia <45 bpm should be confirmed by two additional readings 
at least 5 minutes apart. 

Multifocal atrial tachycardia 

Junctional tachycardia (heart rate >100 bpm)

Junctional escape complexes

Supraventricular tachycardia (>100 bpm)

Ventricular tachycardias (non-sustained, sustained, polymorphic, or 
monomorphic)

Atrial fibrillation with rapid ventricular response (rate >100 bpm)

Atrial flutter

Evidence of bigeminy, trigeminy or multifocal premature ventricular complexes

Ventricular flutter

Ventricular fibrillation

Torsades de Pointes

R on T phenomenon

Wide QRS tachycardia (diagnosis unknown)


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
Electrical alternans

Pacemaker

Idioventricular rhythm – heart rate <100 bpm

Evidence of Mobitz type II second degree or third degree atrioventricular (AV) 
block

2:1 AV block

AV dissociation

Bifascicular block

Trifascicular block

Left bundle branch block

For subjects without complete right bundle branch block: QTc(F) 450 msec 
or an ECG that is unsuitable for QT measurements (e.g., poor defined termination 
of the T wave).

For subjects with complete right bundle branch block: QTc(F) 480 msec or an 
ECG that is unsuitable for QT measurements (e.g., poor defined termination of 
the T wave).
*Note: All potentially exclusionary QT measurements should be confirmed by two 
additional readings at least 5 minutes apart.

Accessory pathway (Wolff-Parkinson-White, Lown-Ganong-Levine)

Myocardial infarction (acute or recent)
*Note:  Evidence of an old (resolved) myocardial infarction is not exclusionary.
Section 11.4 Appendix 4: 12-Lead ECG Withdrawal Criteria
An ECG finding that would result in subject withdrawal post-randomization is defined as 
a 12-lead tracing that is interpreted as, but not limited to, any of the following:

Sinus tachycardia 110 bpm
*Note: sinus tachycardia 110 bpm should be confirmed by two additional readings 
at least 5 minutes apart

Increase in heart rate ≥40 bpm relative to baseline 

An increase in QTc(F) >60 msec from baseline ECG

Sinus bradycardia <37 bpm
*Note:  Sinus bradycardia <37 bpm should be confirmed by two additional readings 
at least 5 minutes apart.

Multifocal atrial tachycardia 

Junctional tachycardia (heart rate >100 bpm)


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
Junctional escape complexes

Supraventricular tachycardia (>100 bpm)

Ventricular tachycardias (non-sustained, sustained, polymorphic, or 
monomorphic) 

Atrial fibrillation with rapid ventricular response (rate >100 bpm)

Atrial flutter

Evidence of bigeminy, trigeminy or multifocal premature ventricular complexes

Ventricular flutter

Ventricular fibrillation

Torsades de Pointes

R on T phenomenon

Wide QRS tachycardia (diagnosis unknown)

Electrical alternans

Pacemaker

Idioventricular rhythm – heart rate <100 bpm

Evidence of Mobitz type II second degree or third degree atrioventricular (AV) 
block

2:1 AV block

AV dissociation

Bifascicular block

Trifascicular block

Left bundle branch block

For subjects without complete right bundle branch block: QTc(F) >500 msec 
or an ECG that is unsuitable for QT measurements (e.g., poor defined termination 
of the T wave).

For subjects with complete right bundle branch block: QTc(F) 530 msec or an 
ECG that is unsuitable for QT measurements (e.g., poor defined termination of 
the T wave).
*Note: All potentially exclusionary QT measurements should be confirmed by two 
additional readings at least 5 minutes apart.

Accessory pathway (Wolff-Parkinson-White, Lown-Ganong-Levine)

QT >600 msec

Myocardial infarction (acute or recent)
*Note:  Evidence of an old (resolved) myocardial infarction is not exclusionary


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11.6.
Appendix 6: Protocol changes in Amendment 02
This amendment applies all sites.
Summary of Amendment Changes with Rationale
To provide detailed information on efficacy analyses following authority’s requirement.
List of specific changes
Section 8.3.5.1 Efficacy Analysis
All efficacy data will be summarized using means, SDs and ranges for continuous data 
and frequencies and percentages for categorical data.
Primary Endpoint
Primary analysis:
The primary endpoint of change from baseline trough FEV1 on Day 169 will be analysed 
for the Intent-to-treat Population using a mixed model repeated measures (MMRM) 
analysis [Siddiqui, 2009], including trough FEV1 recorded at each of Days 2, 28, 56, 84, 
112, 168 and 169.
Treatment group (categorical) will be fitted as the explanatory variable with appropriate 
predefined variables, including baseline FEV1, smoking status, day, country, day by 
baseline interaction and day by treatment interaction fitted as covariates. Baseline FEV1 is 
defined as the mean of the two assessments made pre-dose at Visit2. Visit (nominal) will 
be fitted as a categorical variable and visit by baseline and visit by treatment interaction 
terms will be included to allow treatment effects to be estimated at each visit separately. 
The variance-covariance matrix will be assumed unstructured (based on previous 
experience, no issues are expected with fitting models with this matrix structure).
Estimated treatment differences for each treatment comparison will be presented together 
with 95% confidence intervals (CIs) for the difference and p-values.
This analysis will be repeated for the Per Protocol Population.
Sensitivity analyses – interactions:
An assessment of whether the effect of treatment on trough FEV1 is modified by each of 
the following factors will be performed: 
Center grouping, smoking status, reversibility and ICS use. 
Separate models will be fitted for each factor, which are identical to the primary efficacy 
analysis model but including an additional term for the factor and treatment by factor 
interaction. If these interaction terms demonstrate statistical significance at the 10% level 
then further investigation and characterization of the interaction will be undertaken.
Further factors may also be considered for investigation and will be detailed in the RAP.


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Secondary Endpoints
The analysis of the mean TDI focal score on Days 28, 84 and 168 will use the same 
methodology as that for the primary endpoint, including all sensitivity analyses but 
adjusting for (at a minimum) BDI score instead of baseline FEV1.
Weighted mean clinic visit FEV1 over 0 to 6 hours post-dose at Visit 2 (Day 1) will be 
analysed using analysis of covariance (ANCOVA). Treatment group (categorical) will be 
fitted as the explanatory variable with appropriate predefined variables, including
baseline FEV1, smoking status and country fitted as covariates. Baseline FEV1 is defined 
as the mean of the two assessments made pre-dose at Visit2. 
Estimated treatment differences for each treatment comparison will be presented together 
with 95% confidence intervals (CIs) for the difference and p-values.
Secondary endpoints will be analyzed for the Intent-to-treat Population only.
Other Endpoints
Serial FEV1 at 15 mins, 30 mins, 1, 3 and 6 hours after dosing will be analysed using a 
repeated measures model, with predefined variables, including baseline FEV1, country, 
smoking status, treatment, time, time by treatment interaction and time by baseline 
interaction fitted as covariates. Baseline FEV1 is defined as the mean of the two 
assessments made pre-dose at Visit2. Treatment, time and a time by treatment interaction 
term will be included. This analysis will be performed for Day 1 only.
Time to onset of bronchodilation (defined as an increase of 100 mL in FEV1 above 
baseline on Treatment Day 1 (Visit2)) and time to first COPD exacerbation will be 
compared between treatment groups using Cox’s proportional hazards model.
Other endpoints will be analysed for the Intent-to-treat Population only. Full details of the 
analyses to be performed will be provided in the RAP.
Section 8.3.3.2 Other Comparisons of Interest
The comparisons listed in Section 8.3.3.1 8.3.3.2 will be performed on the following 
secondary endpoints:

Mean TDI focal score at Week 24

Weighted mean clinic visit FEV1 over 0 to 6 hours post-dose at Visit 2 
The same treatment comparisons will be performed for the other efficacy endpoints.


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11.7.
Appendix 7: Protocol changes in Amendment 03
This amendment applies all sites. Besides, a China specific requirement was 
developed based on authority requirement.
Summary of Amendment Changes with Rationale
The following revisions were made:

Removed Thailand and Taiwan from involved countries/areas.

Changed randomization ratio from 1:1 to 2:1. 

Updated sample size based on the latest difference and SD. Updated analysis plan. 

Dispense of rescue sulbutamol was moved up from V1 to V0.

Updated wordings in cardiovascular events, death events, pregnancy, liver 
stop/follow, and AE/SAE according to the latest protocol template.

Developed a China specific requirement on SAE collection period.

Pharmacogenetic  research sections removed.

Updated the 12-Lead ECG Exclusion Criteria and 12-Lead ECG Withdrawl 
Criteria. 

Novel Dry Powder Inhaler (NDPI) has been replaced with ELLIPTA.

Some minor revisions.


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List of specific changes
Novel Dry Powder Inhaler (NDPI) has been replaced with ELLIPTA in throughout the 
document
The IB version has been updated to IB2015 in throughout the document as velow:
GlaxoSmithKline Document Number RM2006/00835/08 RM2006/00835/11, IB
20122015.
Author (s):
 (CMD, China);
 (Clinical Statistician, UK); 
 
(CMD, China); 
 (CMD, China);
 (CMD, China)
Sponsor Medical Monitor Contact Information: 
Asia
 MD
GlaxoSmithKline
No.1 Building, 917 Halei Road
Shanghai, China
Telephone:
 MD
GlaxoSmithKline
No. 1 Building, 917 Halei Road
Shanghai, China
Telephone: 
 MD
GlaxoSmithKline
No. 1 Building, 917 Halei Road
Shanghai, China
Telephone: 
Regulatory Agency Identifying Number:
Regulatory Agency Identifying Number:  NA
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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FDA IND Number: 104, 479Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
CAT
ELLIPTA
Protocol Summary
Rationale
Studies to date provide substantial evidence for the effectiveness for UMEC 62.5 mcg as 
a long term maintenance therapy for the treatment of COPD. The purpose of this 24-week 
study is to further evaluate the efficacy and safety of UMEC 62.5 mcg administered 
once-daily in Asian subjects with COPD.
Study Design
288 Eeligible subjects will be randomized to the UMEC 62.5 mcg and placebo treatment 
groups in a 2:1 1:1 ratio, such that of the planned total number of 454 randomized 
subjects, subjects will be equally randomised to the active and placebo treatment group
(approximately 192 227 subjects in active arm and 96 subjects in placebo arm per arm). 
All treatments will be administered once-daily in the morning by inhalation using an
ELLIPTANDPI.
There will be a total of 10 study clinic visits conducted on an outpatient basis. A pre-
screening visit (V0) will be conducted to sign the informed consent form (ICF), dispense 
the rescue medication and review demography, COPD history and concomitant 
medications. Once the ICF is signed the subject will be assigned a subject identifier. At 
Visit 0, any medications changes made by the investigator will be recorded. Subjects who 
meet the eligibility criteria at Screening (Visit 1) will complete a 7 to 14 day Run-in 
period. At the end of the Run-in period, subjects will be assessed and those who meet the 
randomisation criteria will enter a 24-week double-blind Treatment Period. Clinic visits 
(1 through 9) will be at Screening, Randomization (Day 1), Day 2, Day 28 (Week 4), Day 
56 (Week 8), Day 84 (Week 12), Day 112 (Week 16), Day 168 (Week 24) and Day 169.  
A follow-up contact for adverse event (AE) assessment will be conducted by telephone 
approximately 7 days after the Treatment period or the Early Withdrawal (EW) Visit.  
The total duration of subject participation, including follow-up will be approximately 27 
weeks. All subjects will be provided with albuterol/salbutamol for use on an “as-needed” 
basis throughout the Pre-screen, Run-in and study Treatment periods.


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Study End-point Assessments
Secondary

(Transition Dyspnea Index (TDI) focal score at Week 24. 

Weighted mean clinic visit FEV1 over 0 to 6 hours post-dose at visit 2 (
Randomisation visit Day 1)
1.2 Rationale
Treatment with muscarinic antagonists has been shown to significantly improve Forced 
Expiratory Volume in One Second (FEV1), resting and dynamic lung hyperinflation, 
symptoms, exercise capacity, health status, and reduce COPD exacerbations [O'Donnell, 
1998; O'Donnell, 2004; Tashkin, 2008a; Tashkin, 2008b]. However, a significant number 
of subjects are thought to continue to have symptoms, as reported in a primary care, 
cross-sectional study [Dransfield, 2011].
Umeclidinium is an orally inhaled, potent, pan-active long acting muscarinic anatagonist 
(LAMA)LAMA in development for use as an inhaled product in the treatment of COPD 
as a stand-alone once-daily product and with the long acting beta agonist (LABA), 
vilanterol, as a once-daily combination product for the treatment of COPD. Both 
Umeclidinium monotherapy and combination with vilanterol have been approved by 
FDA and EMA.
Studies to date provide substantial evidence for the effectiveness for UMEC 62.5 mcg as 
a long term maintenance therapy for the treatment of COPD. The purpose of this 24 week 
study is to further evaluate the efficacy and safety of UMEC 62.5 mcg administered 
once-daily in Asian subjects with COPD.
1.3 Summary of Risk Management
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK573719 can be found in the Investigator’s Brochure.  The following section (Table 
1*) outlines the risk assessment and mitigation strategy for this protocol:
*The detail of the Table 1 refers to the protocol.
2 Objectives and Endpoints
The objectives and Endpoints are presented together in a table to ensure all endpoints are 
aligned with an objective as per required of template update.
2.1 Primary Objective
The primary objective of the study is to evaluate the efficacy and safety of Umeclidinium 
62.5 mcg compared with placebo when administered once-daily via the Novel Dry 
Powder Inhaler (NDPI) over a 24-week treatment period in subjects with COPD.
3.1 Study Design
This is a multicenter, randomized, double-blind, parallel group study to evaluate the 
efficacy and safety of umeclidinium 62.5 mcg administered once-daily via a ELLIPTA


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novel dry powder inhaler (NDPI) compared with placebo over 24 weeks in subjects with 
COPD. Eligible subjects will be randomized 2:11:1 to receive one of the two following 
treatments:

Umeclidinium (GSK573719) 62.5 mcg Inhalation Powder administered QD via a 
ELLIPTA NDPI in the morning

Placebo administered QD via a ELLIPTA NDPI in the morning
The schematic diagram in previous protocol has been replaced with the new diagram.
3.1 Study Design
There will be a total of 10 study clinic visits conducted on an outpatient basis. A pre-
screening visit (V0) will be conducted to sign the informed consent form (ICF), dispense 
rescue medication and review demography, COPD history and concomitant medications. 
Once the ICF is signed the subject will be assigned a subject identifier. At Visit 0, any 
medications changes made by the investigator will be recorded. Subjects who meet the 
eligibility criteria at Screening (Visit 1) will complete a 7 to 14 day run-in period 
followed by a 24 week treatment period. Clinic visits will be at Prescreening (visit 0), 
Screening, Randomization (Day 1), Day 2 and 4, 8, 12, 16, and 24 weeks, and 1 day after 
the Week 24 visit (Visit 0 to Visit 9, respectively). Additionally a safety Follow-Up 
assessment will be conducted by phone call approximately 7 days after the end of the 
study treatment (Visit 9 or Early Withdrawal, if applicable). The total duration of subject 
participation, including the Follow-Up, will be approximately 27 weeks. All subjects will 
be provided with albuterol/salbutamol for use on an “as-needed” basis throughout the 
pre-screen, run-in and study treatment periods.
The occurrence of adverse events will be evaluated throughout the study, beginning at 
Visit 2. SAEs will be collected over the same time period as for AEs. However, any 
SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated 


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procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant 
medication (eg Run-in medications, rescue medications provided by GSK), will be 
recorded from the time a subject consents to participate in the study up to and including 
any follow up contact (China sites should follow Section 11.1, Appendix 1).
The Modified Intent-to-Treat (ITT) population will be the primary population of interest, 
and is defined as all randomised subjects who have received at least one dose of the 
randomised study medication during the Treatment Period.
3.2 Discussion of Design
A randomisation ratio of 2:1 will reduce the number of subjects randomised to placebo
arm, as well as to reduce drop-outs.
4.1 Number of Subjects
Based on an early withdrawal rate of 1821% of randomized subjects, approximately 
288454 study subjects will be randomized in 2:1 to the double blind medication, that 
means 192 subjects in active arm and 96 subjects in placebo arm, to ensure 
approximately 236360 subjects complete the 24 week treatment period.
4.6 Pre-Screen and Screen Failure
The study interactive voice response system (IVRS) will be contacted to report pre-screen
failures. The following information will be collected for subjects who are pre-screen 
failures.
IVRS will be contacted to report screen failures. In addition to the information above, the 
following information will be collected for screen failures.
4.8 Premature Discontinuation

Report subject’s early withdrawal from the study via Randomization And 
Medication Ordring System New Generation (RAMOS NG).


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5.1 Investigational Product and Other Study Treatment
Table 2
Description of Umeclidinium Inhalation Powder ELLIPTA
Formulation
First strip
Umeclidinium bromide blended with lactose monohydrate and magnesium searate1
Dosage Form
ELLIPTA  with 30 doses (1 strip with 30 blisters )
Unit Dose Strengths
62.5 mcg
Physical Description
White powder
Route of Administration
Inhaled
1.Magnesium stearate 0.6% w/w of total drug product
Formulation
First strip
Second strip1
GSK573719 blended with lactose and 
magnesium stearate
N/A
Dosage Form
Ellipta  with 30 doses (1 strip with 30 blisters )
Unit Dose Strengths
62.5 mcg per blister
N/A
Physical Description
Dry white powder
NA
Route of Administration
Inhaled
NA
1.
Umeclidinium Inhalation Powder Ellipta will only contain one strip
N/A= not applicable
Table 3
Description of Placebo Inhalation Powder ELLIPTA
Formulation
First strip
Second strip
Lactose monohydrate blended with 
magnesium stearate1
Lactose monohydrate blended with 
magnesium stearate2
Dosage Form
ELLIPTA Inhaler with 30 doses (2 strips with 30 blisters per strip)
Unit Dose Strengths
Not applicable
Not applicable
Physical description
White powder
White powder
Route of Administration
Inhaled
1.Magnesium stearate 0.6% w/w of total drug product
2.Magnesium stearate 1.0% w/w of total drug product
Formulation
First strip
Second strip
Lactose with magnesium stearate
Lactose with magnesium stearate
Dosage Form
Ellipta with 30 doses (2 strips with 30 blisters per strip)
Unit Dose Strengths
N/A
N/A
Physical description
Dry white powder
Dry white powder
Route of Administration
Inhaled
1.
N/A= not applicable
5.2 Treatment Assignment
Subjects will be assigned to study treatment in accordance with the central randomization 
schedule. The randomisation code will be generated by GSK using a validated 
computerised system RandAll version 2.5. Subjects will be randomised using RAMOS 


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NG IVRS, an Interactive Voice Response System (IVRS). This is a internet telephone-
based system which will be used by the investigator or designee to register the subject 
(initially at pre-screening, and subsequently at each study visit), randomize the subject, 
and provide medication assignment information if and when required. Details on how to 
use RAMOS NGIVRS to register and randomize subjects are provided in the SPM.
Following completion of the 7 to 14 day Run-In period eligible subjects will be 
randomized at 2:1 1:1 ratio to one of the following treatment regimes in equal proportions 

Umeclidinium Inhalation Powder 62.5 mcg once daily

Placebo Inhalation Powder once daily
Approximately 192 the same number of subjects will be randomised to active treatment 
(n=227) as and 96 subjects to placebo (n=227).
5.6.2 Prohibited Medications and Non-Drug Therapies
Table 4 Prohibited Medications
Oral leukotriene inhibitors (e.g. zafirlukast, montelukast, zileuton)


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6. Study Assessments and Procedures
Table 5 Time and Events Table
Run-in
Double-blind treatment period
Visit
Visit
0
(Pre-
Screen)
Screenin
g Visit
(Visit 1)
Visit
2
Visit
3
Visit
4
Visit
5
Visit
6
Visit
7
Visit
8
Visit
9
Early 
With-
drawal 
(EW) Visit
Follow-Up 
(Phone 
contact)
Day
Day
-7 to -14
Day
1
Day
2
Day
282
Day
564
Day
844
Day
1124
Day
1684
Day
169 
(Visit 
8 +1 
day)
7±2 days after 
Visit 9 or EW
Week
-1
0
0
4
8
12
16
24
Register visit in IVSR IWRS4 (RAMOS 
NG) 
x
x
x
x
x
x
x
x
x
x
x
x
Adverse Event /Con-Med Assessment
X
X
X
X
X
X
X
X
X
X
X
Serious Adverse Event /Con-Med 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
Medication
Dispense/collect rescue 
salbutamol/albuterol
X
X
X
X
X
X
X
X
X
X
X
4.IWRS stands for Interactive Web Response System.


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6.1 Critical Baseline Assessments
No study related procedures may be performed until the informed consent form document 
has been signed by the subject or legal deputy.
Visit 0: During the pre-screening visit (Visit 0) each subject will have the following 
information collected:

Demographic history (including gender, ethnic origin, age, height and weight)

COPD history

COPD exacerbation assessment

Review of COPD medication
6.3.4 Liver chemistry stopping and follow up criteria

Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with definite or likely acetaminophen use in 
the preceding week (James, 2009).
NOTE: not required in China.
6.3.5 Adverse Events (AE) and Serious Adverse Events (SAEs)
6.3.5.1 Definition of an AEs
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product. For marketed medicinal products, this 
also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.  
Events meeting the definition of an AE include:

Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be 
clinically significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study

Signs, symptoms, or the clinical sequelae of a suspected interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).


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“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfill the definition of an AE or 
SAE. Also “lack of efficacy” or “failure of expected pharmacological action” also 
constitutes an AE or SAE.
Events that do not meet the definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied, or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
subject’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition 
that leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
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.

The disease/disorder being studied, or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
subject’s condition.
6.3.5.2 Definition of a SAEs
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
A serious adverse event (SAE) is defined as any untoward medical occurrence that, at 
any dose:

results in death

is life-threatening
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.

Requires hospitalization or prolongation of existing hospitalization, or
NOTE:  In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are AEs.  
If a complication prolongs hospitalization or fulfills any other serious criteria, the 


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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.

Results in disability/incapacity
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption.

Is a congenital anomaly/birth defect

Other situations:
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition.  These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.

Is associated with liver injury and impaired liver function defined as:
ALT 3xULN and total bilirubin* 2xULN (>35% direct), or
ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if 
unavailable, measure urinary bilirubin via dipstick.  If fractionation is unavailable and 
ALT 3xULN and total bilirubin 2xULN, then the event is still to be reported as an 
SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.

All events of possible drug-induced liver injury with hyperbilirubinaemia defined 
as ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 3xULN and 
INR>1.5, if INR measured) termed ‘Hy’s Law’ events (INR measurement is not 
required and the threshold value stated will not apply to patients receiving 
anticoagulants).
NOTE: bilirubin fractionation is performed if testing is available. If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick indicating 
direct bilirubin elevations and suggesting liver injury. If testing is unavailable and a 
subject meets the criterion of total bilirubin 2xULN, then the event is still reported 


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as an SAE. If INR is obtained, include values on the SAE form. INR elevations >1.5 
suggest severe liver injury.
6.3.5.3 Recording of AEs and SAEs

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s 
medical records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of 
the subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
6.3.5.4 Evaluating AEs and SAEs
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is 
assessed as severe will not be confused with an SAE. Severity is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment 
and the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out.

The investigator will use clinical judgment to determine the relationship.


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
Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK.  However, it is very 
important that the investigator always make an assessment of causality for 
every event prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
6.3.5.5 Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as may be indicated or as 
requested by GSK to elucidate as fully as possible the nature and/or causality of 
the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory 
tests or investigations, histopathological examinations or consultation with other 
health care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem 
findings, including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
6.3.6 Laboratory and Other Safety Assessment Abnormalities Reported as AEs and 
SAEs
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), 
including those that worsen from baseline, and felt to be clinically significant in the 
medical and scientific judgement of the investigator are to be recorded as AEs or SAEs. 
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject’s condition, are not to be reported as AEs or SAEs.


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6.3.6 6.3.7 Cardiovascular Events
Investigators will be required to fill out the specific CV event page of the CRF event 
specific data collection tools 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 thrombosis

Deep Venous Thrombosis

Revascularisation
This information should be recorded within one week of when the AE/SAE(s) are first 
reported. The CV CRFs are presented as queries in response to reporting of certain CV 
MedDRA terms. The CV information should be recorded in the specific cardiovascular 
section of the CRF within one week of receipt of a CV Event data query prompting its 
completion.
6.3.7 6.3.8 Death Events
In addition, for all deaths, specific Death sections of the CRF will be required to be 
completed. These sections include questions regarding cardiovascular (including sudden 
cardiac death) and non-cardiovascular death. will require a specific death data collection 
tool to be completed.  The death data collection tool includes questions regarding 
cardiovascular (including sudden cardiac death) and noncardiovascular death.
This information should be recorded within one week of when the death is first reported.
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
6.3.9 6.3.10 Pregnancy
Details of all pregnancies in female subjects will be collected after the start of dosing and 
until follow up call Any pregnancy that occurs during study participation must be 
reported using a clinical trial pregnancy form. To ensure subject safety, each pregnancy 
must be reported to GSK within 2 weeks of learning of its occurrence.  
Subject will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow up information on mother and infant, which will be forwarded to GSK.  


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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. The pregnancy must be followed up to 
determine outcome (including premature termination) and status of mother and child.
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complications and elective terminations for medical reasons must be reported as an AE or 
SAE.  Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy, brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
reasonably possibly related to the study treatment, must be promptly reported to GSK.
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.
6.3.11 6.3.12 Time Period and Frequency of Detecting AEs and SAEs

AEs and SAEs will be collected from the start of Study Treatment until the 
follow-up contact, at the timepoints specified in the Time and Events Table.
(China sites should follow Section 11.21, Appendix 21)

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact. (China sites should follow 
Section 11. 21, Appendix 21)

All SAEs will be recorded and reported to GSK within 24 hours as indicated in 
Section 6.3.12.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
AEs will be collected from the start of study treatment and until the follow up contact.  
SAEs will be collected over the same time period as stated above for AEs. However, any 
SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant 
medication, will be recorded from the time a subject consents to participate in the study 


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up to and including any follow up contact. All SAEs will be reported to GSK within 24 
hours, as indicated in Section 6.3.10.
6.3.12 6.3.13 Prompt Reporting of Serious Adverse Events and Other Events to GSK
SAEs, pregnancies, medical device incidents, and liver function abnormalities meeting 
pre-defined criteria will be reported promptly by the investigator to GSK as described in 
the following table once the investigator determines that the event meets the protocol 
definition for that event.

Primary mechanism for reporting SAEs to GSK will be the electronic data 
collection tool

If the electronic system is unavailable for greater than 24 hours, the site will use 
the paper SAE data collection tool and fax it to the medical monitor.

Site will enter the serious adverse event data into the electronic system as soon as 
it becomes available.

The investigator will be required to confirm review of the SAE causality by 
ticking the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of 
submission of the SAE.

After the study is completed at a given site, the electronic data collection tool 
(e.g., InForm system) will be taken off-line to prevent the entry of new data or 
changes to existing data

If a site receives a report of a new SAE from a study subject or receives updated 
data on a previously reported SAE after the electronic data collection tool has 
been taken off-line, the site can report this information on a paper SAE form or to 
medical monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
6.3.12.1 Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the investigator to GSK of SAEs and non-serious AEs 
related to study treatment (even for non- interventional post-marketing studies) is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a product under clinical investigation are met.
6.5 Pharmacogenetic Research
This section was removed with alignment with PGx team.


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8.2.1 Sample Size Assumption (TBD)
The sample size calculation is based on the primary endpoint of trough FEV1 on 
Treatment Day 169 which will be analysed using a Mixed Models Repeated Measuresd
(MMRM) analysis.  The calculation uses an estimate of residual standard deviation of 
234 221mL, (based on the residual standard deviation from the MMRM analysis of the
meta-analyses from prior studies with UMEC in COPD (studies DB2113361, 
DB2113373, DB2113374)  HZC113684 study in COPD in North East Asian subjects). 
The variability observed in the global IIIa UMEC/VI studies (239 mL) was similar to that 
in the 6 month global FF/VI IIIa studies (248 mL) and therefore we would expect the 
variability in the UMEC China study to be similar to that in the FF/VI study (Table 8).
Table 8
Studies for sample size calculation
Study
Duration
Centralised 
Spirometry
SD Trough FEV1 at 
Week 24 (mL) (mean 
23 & 24hr FEV1)
DB2113360
24 Weeks
Yes
252
DB2113361
24 Weeks
Yes
224
DB2113373
24 Weeks
Yes
239
DB2113374
24 Weeks
Yes
240
HZC113684
24 Weeks
Yes
221
HZC112206
24 Weeks
Yes
252
HZC112207
24 Weeks
Yes
243
A study with 104 evaluable subjects per arm will have 90% power to detect a 100mL 
treatment difference between an active treatment and placebo in trough FEV1.The 
calculations use a two-sample t-test and a two-sided 5% significance level. 
Based on the Table 8 of effect sizes from previous studies, a true treatment difference of 
115 mL has been assumed:
Table 8
Effect Sizes from Previous Studies
Study
Comparison
Treatment Difference
DB2113373 (Day 169)
UMEC vs Placebo
0.115
AC4115408 (Day 85)
UMEC vs Placebo
0.127
UMEC ISE (Day 169) (DB2113361, 
DB2113373, DB2113374)
UMEC vs Placebo
0.133
DB2114634 (Day 169)
UMEC/VI vs Placebo
0.151
DB2114634 (China) (Day 169)
UMEC/VI vs Placebo
0.167


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The sample size was increased in order needs to include sufficient subjects to satisfy 
anticipated individual country requirements and the China subgroup is powered at 90%
with a minimum of 100 evaluable subjects on UMEC arm gives 132 evaluable subjects 
on UMEC and 66 evaluable subjects on placebo is needed for China.
It is estimated that approximately 18% subjects will withdraw without providing a Week 
24 assessment. Although, in MMRM, all available post-baseline assessments up to 
endpoint for subjects in the Modified Intent-to-Treat Population are utilized in the 
analysis, data for subjects who withdraw prematurely from the study are not explicitly 
imputed. 
Allowing an 18% dropout, this would equate to 162 subjects randomised to  UMEC and 
81 subjects randomised to placebo from China.
45 randomised subjects from  Korea  will be sufficient, equating to 30 subjects 
randomised to UMEC and 15 subjects randomised to placebo. With an 18% withdrawal 
rate, this gives 24 evaluable subjects on UMEC and 12 evaluable subjects on placebo 
(allowing a 2:1 ratio). 
We therefore require a total of approximately 192 randomised subjects on UMEC and 96 
subjects randomised to placebo (total randomised 288).
Allowing for 18% dropout, a study with 156 evaluable subjects in active treatment arm 
and 78 evaluable subjects in placebo arm will have 94% power assuming a true treatment 
difference of 115mL to show a statistically significant difference between UMEC 
62.5mcg and placebo in trough FEV1. The calculations use a two-sample t-test and a two-
sided 5% significance level. 
The minimal detectable effect for the final sample size of 156 evaluable subjects on 
UMEC vs 78 evaluable subjects on placebo is 63.6mL.
China will have 90% power to detect a 100 mL treatment differences within the China 
subgroup, which will have 104 evaluable subjects per arm. Taiwan will include a total of 
60 randomised subjects, Korea 100 randomised subjects and 30 subjects for Thailand. 
Assuming a 21% withdrawal rate (see below), Taiwan would therefore provide 
approximately 24 evaluable subjects per arm, Korea would provide approximately 40 
evaluable subjects per arm and Thailand would provide approximately 12 evaluable 
subjects per arm. Therefore the total sample size would be 180 evaluable subjects per 
arm. 
It is estimated that approximately 21% subjects will withdraw without providing a Week 
24 assessment. Although, in MMRM, all available post-baseline assessments up to 
endpoint for subjects in the Intent-to-Treat Population are utilized in the analysis, data for 
subjects who withdraw prematurely from the study are not explicitly imputed. Hence, to 
account for a 21% withdrawal rate, approximately 227 subjects will be randomised in 
equal proportions in each of the two treatment groups. i.e. approximately 454 subjects 
will be randomised in total.


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8.2.2 Sample Size Sensitivity
If the standard deviation in this study is different from the expected value, the power to 
detect the planned difference in trough FEV1 will be affected.  Table 9 illustrates the 
power which would be obtained with different values of SD, assuming the sample size 
remains constant at 156 evaluable subjects on UMEC vs 78 evaluable subjects on placebo
180 evaluable subjects in each treatment group.
Table 9
Power Calculation for Treatment Differences
Parameter
SD
Treatment Difference
Power
Trough FEV1 (mL)
205
115100mL
98>99%
240
115100mL
9398%
260280
115100mL
8892%
If the SD for trough FEV1 increased to 260280 mL, the study would have 8892% power 
to show a statistically significant difference between UMEC and placebo assuming a true 
treatment difference detect a difference of 115100 mL between each treatment 
comparison. If the SD were as low as 205 mL then the study would have 98>99% power 
to show a statistically significant difference detect a difference of 115100 mL.
The true treatment difference for a statistically significant difference which can be 
detected with 90% power will also be affected by changes in the SD; this is shown in 
Table 10.
Table 10
Treatment Differences Detected with 90% Power
Parameter
SD
Power
Treatment Difference
Trough FEV1 (mL)
205
90%
9370 mL
240
90%
10882 mL
260280
90%
11796 mL
If the SD increased to 260280 mL, the study would have 90% power to show a 
statistically significant treatment difference of 117 mL detect a difference of 12896 mL 
between each treatment comparison.  If the SD were as low as 205 mL then the study 
would have 90% power to show statistical significance for a true treatment difference of 
93 mLdetect a difference of 70 mL.
8.3 Data Analysis Considerations
The analysis described below will be performed on all subjects enrolled from China and 
Korea, Taiwan, Korea and Thailand and also a separate analysis will be performed on the 
subjects enrolled in China alone: A China subgroup analysis.
8.3.1 Analysis Populations
The modified Intent-to-treat (ITT) Population will comprise all subjects randomized to 
treatment who received at least one dose of randomized study medication in the treatment 
period.  Randomized subjects will be assumed to have received study medication unless 


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definitive evidence to the contrary exists. Outcomes will be reported according to the 
randomized treatment allocation. This population will constitute the primary population 
for all data analyses and displays.  Subjects will be included in the analysis of a particular 
outcome if they provided at least one on-treatment assessment of that outcome. All 
scheduled data collected until the time of study discontinuation will be included in the 
Intent-to-treat analysis for subjects who withdraw from the study.
The Per Protocol (PP) Population will comprise all subjects in the Modified ITT 
Population who are not identified as full protocol violators. Receipt of a study treatment 
other than the randomized treatment will be considered a full protocol deviation. Receipt 
of a study treatment other than the randomized treatment will be considered a protocol 
deviation from the time of receiving incorrect treatment onwards. Subjects identified as 
partial protocol violators will be included in the PP Population but will have their data 
excluded from PP analyses from the time of violation onwards. The definition of full and 
partial violations will be included in the Reporting and Analysis Plan (RAP) and the 
decision to exclude a subject from the PP Population or a subject’s data from PP analyses 
will be made prior to breaking the blind. In addition, details of exclusions from the Per 
Protocol population/ analyses which are not considered to be protocol deviations, but 
may have a potential impact on the efficacy data will also be documented in the RAP.
This population will be used for confirmatory analyses of the primary and secondary
efficacy endpoints only, irrespective of how many subjects are in the PP population.
8.3.5 Key Elements of Analysis Plan
An overall analysis will be carried out including all countries/regions, and also a China 
subgroup analysis.
8.3.5.1 Efficacy Analyses
Primary Endpoint
The primary endpoint of change from baseline trough FEV1 on Day 169 will be analysed 
for the Modified Intent-to-treat Population using a mixed model repeated measures 
(MMRM) analysis [Siddiqui, 2009], including trough FEV1 recorded at each of Days 2, 
28, 56, 84, 112, 168 and 169.
Treatment group (categorical) will be fitted as the explanatory variable with baseline 
FEV1, smoking status, day, country/region, day by baseline interaction and day by 
treatment interaction fitted as covariates. Baseline FEV1 is defined as the mean of the two 
assessments made pre-dose at Visit2. VisitDay (nominal) will be fitted as a categorical 
variable and day visit by baseline and day visit by treatment interaction terms will be 
included to allow treatment effects to be estimated at each day visit separately. The 
variance-covariance matrix will be assumed unstructured (based on previous experience, 
no issues are expected with fitting models with this matrix structure).
Sensitivity analyses – Interactions:
Center grouping, smoking status, reversibility and ICS use.


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Secondary Endpoints
The analysis of the mean TDI focal score on Days 28, 84 and 168 will use the same 
methodology as that for the primary endpoint but adjusting for BDI score instead of 
baseline FEV1, including all sensitivity analyses but adjusting for (at a minimum) BDI 
score instead of baseline FEV1.
Weighted mean clinic visit FEV1 over 0 to 6 hours post-dose at Visit 2 (Day 1) will be 
analysed using analysis of covariance (ANCOVA). Treatment group (categorical) will be 
fitted as the explanatory variable with baseline FEV1, smoking status and country/region
fitted as covariates. Baseline FEV1 is defined as the mean of the two assessments made 
pre-dose at Visit2.
Estimated treatment differences for each treatment comparison will be presented together 
with 95% confidence intervals (CIs) for the difference and p-values.
Secondary endpoints will be analyzed for the Modified Intent-to-treat Population only.
Other Endpoints
Serial FEV1 at 15 mins, 30 mins, 1, 3 and 6 hours after dosing will be analysed using a 
repeated measures model, including baseline FEV1, country/region, smoking status,
treatment, time, time by treatment interaction and time by baseline interaction fitted as 
covariates. Baseline FEV1 is defined as the mean of the two assessments made pre-dose 
at Visit2.  Treatment, time and a time by treatment interaction term will be included. This 
analysis will be performed for Day 1 only.
Time to onset of bronchodilation (defined as an increase of 100 mL in FEV1 above 
baseline on Treatment Day 1 (Visit2)) and time to first COPD exacerbation will be 
compared between treatment groups using Cox’s proportional hazards model.
Other endpoints will be analysed for the Modified Intent-to-treat Population only. Full 
details of the analyses to be performed will be provided in the RAP.
10. REFERENCES
Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, et al, for 
the Canadian Thoracic Society/Canadian Respiratory Clinical Research Consortium.  
Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone–Salmeterol for 
Treatment of Chronic Obstructive Pulmonary Disease. A Randomized Trial.  Ann Intern 
Med. 2007;146:545-555.
Casaburi R, Mahler DA, Jones PW, Wanner A, San PG, ZuWallack RL, et al. A long-
term evaluation of once-daily inhaled ipratropium in chronic obstructive pulmonary 
disease. Eur Respir J. 2002;19:217-224. 
Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD: 
a summary of the ATS/ERS position paper. Eur Respir J. 2004; 23:932-946.


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Epidemiology and costs of Chronic Obstructive Pulmonary Disease. Eur Respir J. 
2006;27:188-207. 
Decramer M, Maltais F, Fieldman G, Brooks J, Harris S, Mehta R, et al. Bronchodilation 
of umeclidinium, a new long acting muscurinic antagonist, in COPD patients. Resp 
Physiol Neurobiol 2013 185; 393-399.
Dransfield MT, Bailey W, Crater G, Emmett A, O’Dell DM, Yawn B et al. Disease 
severity and symptoms among patients receiving monotherapy for COPD. Prim Care 
Respir J. 2011; Mar; 20(1):46-53. 
GOLD. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global 
Initiative for Chronic Obstructive Lung Disease (GOLD) 2015. Available from: 
http://www.goldcopd.org/.
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of 
the general US population. Am J Resp Crit Care Med. 1999;159:179-187.
HankinsonJL, Kawut SM, Shahar E, Smith LJ, MD, Hinckley Stukovsky K, and Barr 
RG. Performance of American Thoracic Society-Recommended Spirometry Reference 
Values in a Multiethnic Sample of Adults: The Multi-Ethnic Study of Atherosclerosis 
(MESA) Lung Study. Chest. 2010;137:138-45.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM et al. Pharmacokinetics of Acetaminophen-Protein Adducts in Adults with 
Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37(8): 
1779-1784.
Jones P, Harding G, Wiklund I, Berry P, Leidy N. Improving the process and outcome of 
care in COPD: development of a standardised assessment tool. Primary Care Resp J. 
2009b; 18:208-215. 
Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and 
first validation of the COPD Assessment Test. Eur Respir J. 2009a;34:648-654. 
Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure for 
chronic airflow limitation - the St George's Respiratory Questionnaire. Am Rev Respir 
Dis 1992;145:1321-1327.
Jones PW, Quirk FH, Baveystock CM, The St George's Respiratory Questionnaire.Respir 
Med. 1991 Sep;85 Suppl B:25-31; discussion 33-7.
Jones PW. Interpreting thresholds for a clinically significant changes in health status in 
asthma and COPD. Eur Respir J 2002; 19:398-404.
Jung JY, Kang YA, Park MS, Oh YM, Park EC, Kim HR, et al.  Chronic obstructive lung 
disease-related health care utilisation in Korean adults with obstructive lung disease. Int J 
Tuberc Lung Dis. 2011; 15(6):824-9. 


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Lin HH, Maurray M, Cohen T, Colijn C, Ezzati M et al.. Effects of smoking and solid-
fuel use on COPD, lung cancer and tuberculosis in China: a time –based, multiple risk 
factor, modelling study. Lancet 2008 Oct 25; 372(9648):1473-83.
Lopez AD, Shibuya K, Rao C, Mathers CD, Hansell AL, Held LS, et al. Chronic 
obstructive pulmonary disease: current burden and future projections. Eur Respir J. 
2006;27:397-412. 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al.
Standardisation of spirometry. Eur Respir J, 2005; 26:319-338
Niewoehner DE, Rice K, Cote C, Paulson D, Cooper JA, Korducki L, Cassino C, Kesten 
S et al. Prevention of exacerbations of chronic obstructive pulmonary disease with 
tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial.  Ann 
Intern Med. 2005;143:317-326.
O'Donnell DE, Fluge T, Gerken F, Hamilton A, Webb K, Aguilania B, Make B, 
Magnussen H et al. Effects of tiotropium on lung hyperinflation, dyspnoea, and exercise 
tolerance in COPD. Eur Respir J. 2004;23:832-840. 
O'Donnell DE, Lam M, Webb KA. Measurement of Symptoms, Lung Hyperinflation, 
and Endurance during Exercise in Chronic Pulmonary Disease, Am J Respir Crit Care 
Med 1998; 20: 799-805
Pelligrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, Coates, A, van der 
Grinten CPM, Gustafsson P, Hankinson J, Jensen R, Johnson DC, MacIntyre N, McKay 
R, Miller MR, Navajas D, Pedersen OF, Wanger J et al. Interpretative straregies for lung 
function tests. Eur Respir J. 2005;26:948-968. 
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Impact of COPD in North America and Europe in 2000: subjects' perspective of 
confronting COPD International Survey. Eur Respir J. 2002;20:799-805
Siddiqui O, Hung HMJ, O’Neill. MMRM vs LOCF: A Comprehensive Comparison 
Based on Simulation Study and 25 NDA Datasets J Biopharm Stat 2009; 19: 227-46
Tashkin DA, Littner M, Andrews CP, Tomlinson L, Rinehart M, Denis-Mize K et al.  
Concomitant treatment with nebulized formoterol and tiotropium in subjects with COPD: 
A placebo-controlled trial.  Respir. Med. 2008a; 102: 479–487
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UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive 
pulmonary disease. N Engl J Med. 2008b;359:1543-54.
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Zhong NS, Wang C, Yao WZ, Chen P, Kang J. Prevalence of Chronic Obstructive 
Pulmonary Disease in China - a large population-based survey. Am J Respir Crit Care 
Med. 2007;176:753-760.
11.1 Appendix 1: Pharmacogenetic Research
This section was removed with alignment with PGx team.
11.1 11.2 Appendix 12: Country Specific Requirements
For sites located in China, SAEs should be recorded from the time the consent form is 
signed until the follow-up contact. 
The requirement on SAE collecting time period in Section 3.1, Section 4.6 and Section
6.3.11 is not appropriate for sites in China.
No country specific requirements exist.
The 12-Lead ECG Exclusion and Withdrawal Criteria have been updated as below. The 
underlined sections are those have been updated from the last version. 
11.2 Appendix2:  12-Lead ECG Exclusion Criteria
An abnormal and clinically significant finding that would preclude a subject from 
entering the trial is defined as a 12-lead tracing that is interpreted as, but not limited to, 
any of the following:

Sinus tachycardia 120 bpm
*Note: sinus tachycardia 120bpm should be confirmed by two additional readings 
at least 5 minutes apart

Sinus bradycardia <45bpm
*Note:  Sinus bradycardia <45bpm should be confirmed by two additional readings 
at least 5 minutes apart. 

Multifocal atrial tachycardia 

Supraventricular tachycardia (>100bpm)

Atrial fibrillation with rapid ventricular response (rate >120bpm)

Atrial flutter with rapid ventricular response (rate >120bpm)

Ventricular tachycardias (non sustained, sustained, polymorphic, or 
monomorphic)

Ventricular flutter

Ventricular fibrillation

Torsades de Pointes


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
Evidence of Mobitz type II second degree or third degree atrioventricular (AV) 
block

AV dissociation

Trifascicular Block

For subjects with QRS duration <120 ms: QTc(F) 450msec or an ECG that is 
unsuitable for QT measurements (e.g., poor defined termination of the T wave).

For subjects with QRS duration>120: QTc(F) 480msec or an ECG that is 
unsuitable for QT measurements (e.g., poor defined termination of the T wave).

Myocardial infarction (acute or recent) * Note: Evidence of an old (resolved) 
myocardial infarction is not exclusionary.
An ECG finding that would preclude a subject from entering the trial is defined as a 12-
lead tracing that is interpreted as, but not limited to, any of the following:

Sinus tachycardia 110 bpm
*Note: sinus tachycardia 110bpm should be confirmed by two additional readings 
at least 5 minutes apart

Sinus bradycardia <45 bpm
*Note:  Sinus bradycardia <45 bpm should be confirmed by two additional readings 
at least 5 minutes apart. 

Multifocal atrial tachycardia 

Junctional tachycardia (heart rate >100 bpm)

Junctional escape complexes

Supraventricular tachycardia (>100 bpm)

Ventricular tachycardias (non-sustained, sustained, polymorphic, or 
monomorphic)

Atrial fibrillation with rapid ventricular response (rate >100 bpm)

Atrial flutter

Evidence of bigeminy, trigeminy or multifocal premature ventricular complexes

Ventricular flutter

Ventricular fibrillation

Torsades de Pointes

R on T phenomenon

Wide QRS tachycardia (diagnosis unknown)

Electrical alternans

Pacemaker


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
Idioventricular rhythm – heart rate <100 bpm

Evidence of Mobitz type II second degree or third degree atrioventricular (AV) 
block

2:1 AV block

AV dissociation

Bifascicular block

Trifascicular block

Left bundle branch block

For subjects without complete right bundle branch block: QTc(F) 450 msec 
or an ECG that is unsuitable for QT measurements (e.g., poor defined termination 
of the T wave).

For subjects with complete right bundle branch block: QTc(F) 480 msec or an 
ECG that is unsuitable for QT measurements (e.g., poor defined termination of 
the T wave).
*Note: All potentially exclusionary QT measurements should be confirmed by two 
additional readings at least 5 minutes apart.

Accessory pathway (Wolff-Parkinson-White, Lown-Ganong-Levine)

Myocardial infarction (acute or recent)
*Note:  Evidence of an old (resolved) myocardial infarction is not exclusionary.
11.3 Appendix 3: 12-Lead ECG Withdrawal Criteria
An ECG finding that would result in subject withdrawal post-randomization is defined as 
a 12-lead tracing that is interpreted as, but not limited to, any of the following:

Sinus tachycardia 120 bpm
*Note: sinus tachycardia 120bpm should be confirmed by two additional readings 
at least 5 minutes apart

Sinus bradycardia <37bpm
*Note:  Sinus bradycardia <37 bpm should be confirmed by two additional readings 
at least 5 minutes apart. 

Increase in heart rate 40bpm relative to baseline 
*Note: increase in heart rate 40bpm should be confirmed by two additional 
readings at least 5 minutes apart 

Multifocal atrial tachycardia 

Supraventricular tachycardia (>100bpm)

Atrial fibrillation with rapid ventricular response (rate >120bpm)


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
Atrial flutter with rapid ventricular response (rate >120bpm)

Ventricular tachycardias (non sustained, sustained, polymorphic, or 
monomorphic)

Ventricular flutter

Ventricular fibrillation

Torsades de Pointes

Evidence of Mobitz type II second degree or third degree atrioventricular (AV) 
block

AV dissociation

Trifascicular Block

An increase in QTcF>60 msec from baseline ECG

Uncorrected QT>600 msec

For subjects with QRS duration <120 ms: QTc(F) 500 msec or an ECG that is 
unsuitable for QT measurements (e.g., poor defined termination of the T wave).

For subjects with QRS duration>120 ms: QTc(F) 530 msec or an ECG that is 
unsuitable for QT measurements (e.g., poor defined termination of the T wave).

Myocardial infarction (acute or recent) Note: Evidence of an old (resolved) 
myocardial infarction is not exclusionary
An ECG finding that would result in subject withdrawal post-randomization is defined as 
a 12-lead tracing that is interpreted as, but not limited to, any of the following:

Sinus tachycardia 110 bpm
*Note: sinus tachycardia 110 bpm should be confirmed by two additional readings 
at least 5 minutes apart

Increase in heart rate ≥40 bpm relative to baseline 

An increase in QTc(F) >60 msec from baseline ECG

Sinus bradycardia <37 bpm
*Note:  Sinus bradycardia <37 bpm should be confirmed by two additional readings 
at least 5 minutes apart.

Multifocal atrial tachycardia 

Junctional tachycardia (heart rate >100 bpm)

Junctional escape complexes

Supraventricular tachycardia (>100 bpm)

Ventricular tachycardias (non-sustained, sustained, polymorphic, or 
monomorphic) 


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
Atrial fibrillation with rapid ventricular response (rate >100 bpm)

Atrial flutter

Evidence of bigeminy, trigeminy or multifocal premature ventricular complexes

Ventricular flutter

Ventricular fibrillation

Torsades de Pointes

R on T phenomenon

Wide QRS tachycardia (diagnosis unknown)

Electrical alternans

Pacemaker

Idioventricular rhythm – heart rate <100 bpm

Evidence of Mobitz type II second degree or third degree atrioventricular (AV) 
block

2:1 AV block

AV dissociation

Bifascicular block

Trifascicular block

Left bundle branch block

For subjects without complete right bundle branch block: QTc(F) >500 msec 
or an ECG that is unsuitable for QT measurements (e.g., poor defined termination 
of the T wave).

For subjects with complete right bundle branch block: QTc(F) 530 msec or an 
ECG that is unsuitable for QT measurements (e.g., poor defined termination of
the T wave).
*Note: All potentially exclusionary QT measurements should be confirmed by two 
additional readings at least 5 minutes apart.

Accessory pathway (Wolff-Parkinson-White, Lown-Ganong-Levine)

QT >600 msec

Myocardial infarction (acute or recent)
*Note:  Evidence of an old (resolved) myocardial infarction is not exclusionary
11.4 Appendix 4 
The algorithm was updated according to new protocol template.

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
AC4117410
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for a 24- week randomised,
double-blind and placebo-controlled study to evaluate the 
efficacy and safety of 62.5 mcg Umeclidinium Inhalation 
Powder delivered once-daily via a Novel Dry Powder Inhaler 
in subjects with Chronic Obstructive Pulmonary Disease
Compound Number 
:
GSK573719
Effective Date 
:
26-DEC-2017
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
performed on all subjects enrolled from China and Korea and on the subjects 
enrolled in China alone: A China subgroup analysis for Protocol AC4117410.

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
Author
Date
26-DEC-2017
Senior Statistician, Statistics & Programming, R&D 
China
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
AC4117410
2
RAP Team Approvals:
Approver
Date
Approval Method
23-DEC-2017
E-mail approved
Principal Statistician, Clinical Statistics
26-DEC-2017
E-mail approved
Clinical Research Physician, R&D China
Senior Clinical Research Physician, R&D China
04-DEC-2017
E-mail approved
26-DEC-2017
E-mail approved
Senior Programmer, R&D China
25-DEC-2017
E-mail approved
Senior Study Manager, R&D China
Senior Clinical Data Scientist, R&D China
26-DEC-2017
E-mail approved
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
25-DEC-2017
E-mail approved
Associate Director, Statistics & Programming, 
R&D China
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
AC4117410
3
TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNPOSIS.........................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................8
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................8
2.2.
Study Objective(s) and Endpoint(s)...............................................................8
2.3.
Study Design ..............................................................................................10
2.4.
Statistical Hypotheses.................................................................................10
3.
PLANNED ANALYSES ..........................................................................................11
3.1.
Interim Analyses .........................................................................................11
3.2.
Final Analyses ............................................................................................11
4.
ANALYSIS POPULATIONS ...................................................................................11
4.1.
Protocol Deviations.....................................................................................13
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................14
6.
STUDY POPULATION ANALYSES .......................................................................15
6.1.
Overview of Planned Analyses ...................................................................15
7.
PRIMARY STATISTICAL ANALYSES....................................................................17
7.1.
Primary Efficacy Analyses ..........................................................................17
7.1.1.
Overview of Planned Primary Efficacy Analyses..........................17
7.1.2.
Planned Primary Efficacy Statistical Analyses .............................18
7.1.3.
Planned Missing Data Sensitivity Statistical Analyses for 
Trough FEV1 ...............................................................................20
7.2.
Secondary Efficacy Analyses......................................................................20
7.2.1.
Overview of Planned Secondary Efficacy Analyses .....................20
7.2.2.
Planned Secondary Efficacy Statistical Analyses.........................21
7.2.2.1.
0-6 h Weighted Mean FEV1 on Day 1 ........................21
7.2.2.2.
TDI .............................................................................22
7.3.
Other Efficacy Analyses..............................................................................23
7.3.1.
Overview of Planned Other Efficacy Analyses .............................23
7.3.2.
Planned Other Efficacy Statistical Analyses.................................24
7.3.2.1.
Time to Onset and Time to First COPD 
Exacerbation ..............................................................24
7.3.2.2.
Proportion Endpoints..................................................25
7.3.2.3.
Serial FEV1/FVC and Trough FVC.............................26
7.3.2.4.
Rescue Salbutamol Use (mean puffs/days)................26
7.4.
Health Outcomes Analyses.........................................................................27
7.4.1.
Overview of Planned Health Outcomes Analyses ........................27
7.4.2.
Planned Health Outcomes Statistical Analyses............................28
8.
SAFETY ANALYSES .............................................................................................29
8.1.
Adverse Events Analyses ...........................................................................29
8.1.1.
Overview of Planned Adverse Events Analyses...........................29
8.2.
Clinical Laboratory Analyses.......................................................................30
8.2.1.
Overview of Planned Clinical Laboratory Analyses ......................30


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AC4117410
4
8.3.
Other Safety Analyses ................................................................................31
8.3.1.
Overview of Planned Other Safety Analyses................................31
8.3.2.
Planned Safety Statistical Analyses.............................................32
9.
REFERENCES.......................................................................................................33
10. APPENDICES........................................................................................................34
10.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................35
10.1.1.
Exclusion of Data from Modified Intent-to-treat Analyses.............35
10.1.2.
Exclusions of Data from Per Protocol Analyses ...........................35
10.1.2.1 Inclusion/exclusion/randomisation Criteria Deviations..................35
10.1.3.
Programmed Checks to Identify Non-medication 
Deviations....................................................................................36
10.1.4.
Programmed Checks to Identify Medication Deviations ...............38
10.2.
Appendix 2: Time & Events.........................................................................40
10.2.1.
Protocol Defined Time & Events ..................................................40
10.3.
Appendix 3: Assessment Windows .............................................................42
10.4.
Appendix 4: Treatment States and Phases.................................................43
10.4.1.
Treatment Phases .......................................................................43
10.4.2.
Treatment States .........................................................................43
10.4.2.1.
Treatment States for Concomitant Medications 
Data ...........................................................................43
10.4.2.2.
Treatment States for AE Data.....................................43
10.4.2.3.
Treatment States for COPD exacerbation ..................44
10.5.
Appendix 5: Data Display Standards & Handling Conventions....................45
10.5.1.
Study Treatment & Sub-group Display Descriptors......................45
10.5.2.
Baseline Definition & Derivations .................................................45
10.5.2.1.
Baseline Definitions....................................................45
10.5.2.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................45
10.5.3.
Reporting Process & Standards...................................................46
10.6.
Appendix 6: Derived and Transformed Data ...............................................48
10.6.1.
General........................................................................................48
10.6.2.
Study Population..........................................................................48
10.6.3.
Safety ..........................................................................................50
10.6.4.
Health- Related Quality of Life .....................................................53
10.6.5.
Efficacy........................................................................................54
10.7.
Appendix 7: Premature Withdrawals & Handling of Missing Data ...............58
10.7.1.
Premature Withdrawals................................................................58
10.7.2.
Handling of Missing Data.............................................................58
10.7.2.1.
Handling of Missing Responder..................................58
10.7.2.2.
Handing of Missing Dates...........................................59
10.7.2.3.
Handling of Partial Dates............................................59
10.7.2.4.
Handling of Missing Data for Statistical 
Analysis......................................................................60
10.8.
Appendix 8: Values of Potential Clinical Importance ...................................61
10.8.1.
Laboratory Values........................................................................61
10.8.2.
ECG.............................................................................................61
10.8.3.
Vital Signs....................................................................................61
10.9.
Appendix 9: Multicenter Studies..................................................................62
10.10. Appendix 10: Examination of Covariates, Subgroups & Other Strata..........63


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AC4117410
5
10.11. Appendix 11: Multiple Comparisons & Multiplicity .......................................64
10.12. Appendix 12: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................65
10.12.1. Statistical Analysis Assumptions..................................................65
10.13. Appendix 13 – Abbreviations & Trade Marks ..............................................67
10.13.1. Abbreviations...............................................................................67
10.13.2. Trademarks .................................................................................68
10.14. Appendix 14: List of Data Displays..............................................................69
10.14.1. Data Display Numbering..............................................................69
10.14.2. Mock Example Shell Referencing ................................................69
10.14.3. Deliverable [Priority].....................................................................69
10.14.4. Study Population Tables..............................................................70
10.14.5. Study Population Figures.............................................................75
10.14.6. Efficacy Tables ............................................................................76
10.14.7. Efficacy Figures ...........................................................................82
10.14.8. Safety Tables...............................................................................85
10.14.9. Safety Figures .............................................................................90
10.14.10.ICH Listings .................................................................................92
10.14.11.Non-ICH Listings..........................................................................95
10.15. Appendix 15: Example Mock Shells for Data Displays ................................98


CONFIDENTIAL
AC4117410
6
1.
REPORTING & ANALYSIS PLAN SYNPOSIS
Overview
Key Elements of the RAP
Purpose

This RAP describes the analysis to be performed on all subjects enrolled from 
China, Korea and also the subjects enrolled in China alone: a China subgroup 
analysis for study AC4117410.
Protocol

This RAP is based on the protocol amendment 03 [(Dated: 11/Nov/2015) of 
study AC4117410 (GSK Document Number. 2013N159587_03] and eCRF 
Version (1.3).
Primary 
Objective

Evaluate the efficacy of Umeclidinium Inhalation Powder at 62.5 mcg compared 
with placebo when administered once-daily via ELLIPTATM over a 24-week 
treatment period in subjects with COPD
Primary 
Endpoint

Change from baseline of clinic visit trough (pre-bronchodilator) FEV1 on 
Treatment Day 169
Trough FEV1 on Treatment Day 169 is defined as the mean of the FEV1 values 
obtained 23 and 24 hours after dosing on Treatment Day 168 (i.e. at Week 24).
[Note: This has been altered from the Protocol GSK Document Number 2013N159587_03
where the endpoint was not clarified change from baseline]
Study 
Design

24-week, phase III multicenter, randomized, double-blind, placebo-controlled,
parallel-group study.

Planned total number of approximately 288 randomized subjects will be 
randomised to UMEC 62.5 mcg and placebo treatment group in a 2:1 ratio.

A total of 10 study clinic visits are planned to be conducted on an outpatient 
basis but may be less if subjects withdraw from study.

The total duration of subject participation, including follow-up will be
approximately 27 weeks. 

All subjects will be provided with albuterol/salbutamol for use on an “as-needed”
basis throughout the Pre-screen, Run-in and study Treatment periods.
Planned 
Analyses

All decisions regarding final analysis, as defined in this RAP document, will be 
made prior to Database Freeze (unblinding) of the study data.
Analysis 
Populations

The All Subjects Enrolled Population will be used for reporting subject 
disposition, AE listing and treatment misallocations listing.

The Screen and Run in Failure population will be used for the tabulation of 
reasons for screen and run-in failure and for inclusion, exclusion and 
randomisation criteria failed.

The Modified Intent-to-treat (ITT) Population will constitute the primary 
population for all data analyses and displays. 

The Per Protocol (PP) Population will be used for confirmatory analyses of the 
primary endpoint only, irrespective of how many subjects are in the PP 
population.


CONFIDENTIAL
AC4117410
7
Overview
Key Elements of the RAP
Hypothesis
For each test on each efficacy endpoint: 

The null hypothesis is that there is no difference between Umeclidinium 62.5 
mcg and placebo.
     H0: T1 – T2 = 0

The alternative hypothesis is there is a difference between Umeclidinium 62.5 
mcg and placebo.
     H1: T1 – T2 0
Primary 
Analyses

The primary endpoint of change from baseline trough in FEV1 on Day 169 will 
be analysed for the Modified Intent-to-treat Population using a mixed model 
repeated measures (MMRM) analysis, including trough FEV1 recorded at each 
of Days 2, 28, 56, 84, 112, 168 and 169.
Secondary 
Analyses

The analysis of the mean Transition Dyspnea Index (TDI) focal score on Days 
28, 84 and 168 will use the same methodology as that for the primary endpoint.

Weighted mean clinic visit FEV1 over 0 to 6 hours post-dose at Visit 2 (Day 1) 
will be analysed using analysis of covariance (ANCOVA).


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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There was one change to the originally planned statistical analysis specified in the 
protocol amendment 03 (Dated: 11-NOV-2015) of study AC4117410 (GSK Document 
Number 2013N159587_03). This change was made so that primary endpoint description 
is consistent across all documents. 
In the following section of the protocol, the primary endpoint is Clinic visit trough (pre-
bronchodilator) FEV1 on Treatment Day 169. 
PROTOCOL SUMMARY
OBJECTIVE(S) and Endpoints (Section 2)
Efficacy (Section 6.2)
Hypotheses （Section 8.1）
Sample Size Assumptions (Section 8.2.1)
In Efficacy Analyses Section (8.3.5.1), it is clarified that the primary endpoint is change 
from baseline trough in FEV1 on Day 169. 
Actually, the primary endpoint of this study is change from baseline in trough FEV1 on 
Day 169. The sample size calculation was based on this endpoint. To avoid any confusion, 
the primary endpoint has been defined as change from baseline in trough FEV1 on Day 
169 in this RAP. 
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives

To evaluate the 
efficacy of
Umeclidinium 62.5 
mcg compared
with placebo when 
administrated
once-daily via the 
ELLIPTATM over 
a 24-week 
treatment period in 
subjects with 
COPD
Primary Efficacy Endpoints:

Change from Baseline of Clinic visit trough (pre-bronchodilator) FEV1 on 
Treatment Day 169
Trough FEV1 on Treatment Day 169 is defined as the mean of the FEV1 
values obtained 23 and 24 hours after dosing on Treatment Day 168 (i.e. at 
Week 24).
Secondary Efficacy Endpoints: 

TDI focal score at Week 24 (Day 168)

Weighted mean clinic visit FEV1 over 0 to 6 hours post-dose at visit 2
(Randomization visit, Day 1)
Other Efficacy Endpoints: 

Trough FEV1 and TDI focal score at other time points

Rescue albuterol/salbutamol use (percentage of rescue-free days and 
puffs/day)

Time to onset (defined as an increase of 100mL above baseline in FEV1) 
during 0-6hr post-dose on Treatment Day 1 (Visit 2)

Proportion of subjects achieving an increase in FEV1 of ≥12% and ≥200mL 
above baseline at any time during 0 to 6hr post-dose on Treatment Day 1 
(Visit 2)


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Objectives
Endpoints

Proportion of subjects achieving an increase in FEV1 of ≥100mL above 
baseline in trough FEV1

Serial FEV1 over 0 to 6 hours post-dose (on Day 1)

Serial and trough Forced Vital Capacity (FVC)

Proportion of responders to TDI. (a responder to TDI will be defined as a 
subject with TDI score of 1 unit or more)

Time to first COPD exacerbation
Secondary Objectives

To evaluate the 
safety of
Umeclidinium 62.5 
mcg compared
with placebo when 
administrated
once-daily via 
ELLIPTA over a 
24-week treatment 
period in subjects
with COPD

Incidence of adverse events

Vital signs (pulse rate, systolic and diastolic blood pressure)

12-lead ECG parameters

Clinical chemistry and haematology parameters and routine urinalysis

To evaluate 
health-related 
quality of life 
Umeclidinium 62.5 
mcg compared 
with placebo when
administrated 
once-daily via
ELLIPTA over a 
24-week treatment
period in subjects 
with COPD

St. George’s Respiratory Questionnaire (SGRQ)

COPD Assessment Test (CAT)

Healthcare resource utilisation


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2.3.
Study Design
Overview of Study Design and Key Features
Design Features

Multicenter, randomized, double-blind, parallel group study to 
evaluate the efficacy and safety of umeclidinium 62.5 mcg 
administered once-daily via ELLIPTATM compared with 
placebo over 24 weeks in subjects with COPD.
Dosing

Umeclidinium (GSK573719) 62.5 mcg Inhalation Powder 
administered QD via a ELLIPTATM in the morning

Placebo administered QD via a ELLIPTATM I in the morning
Treatment Assignment

Eligible subjects will be randomized 2:1 to receive active drug 
or placebo
Interim Analysis

No interim analysis is planned.
2.4.
Statistical Hypotheses
The objective of this study is to assess the efficacy and safety of 24 weeks’ treatment
with Umeclidinium 62.5 mcg Inhalation Powder compared with placebo, when
administered once-daily in subjects with COPD. The primary endpoint is change from 
baseline of trough FEV1 at Day 169. The comparisons of interest for the primary analysis 
are Umeclidinium 62.5 mcg vs. placebo. 
For each test on each efficacy endpoint, the null hypothesis is that there is no difference
between treatment groups.
H0: T1 – T2 = 0
The alternative hypothesis is there is a difference between treatment groups.
H1: T1 – T2 ≠0


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3.
PLANNED ANALYSES
3.1.
Interim Analyses
No interim analysis is planned.
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All subjects have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management.
3.
All criteria for unblinding the randomisation codes have been met. 
4.
Randomisation codes have been distributed according to RandAll NG procedures.
4.
ANALYSIS POPULATIONS
Population for analysis to be performed on all subjects enrolled from China and Korea.
Population
Definition / Criteria
Analyses Evaluated
All Subjects 
Enrolled

Comprise of all subjects, for whom a 
record exists on the study database, 
including pre-screen/screen failures 
and any subject who was not screened 
but experienced an SAE between the 
date of informed consent and the 
planned date of the Screening Visit.

Reporting subject 
disposition, AE listing and 
treatment misallocations 
listing
Screen and 
Run in Failure

Comprise of all subjects in the All 
Subjects Enrolled Population who are 
recorded as screen failures or run-in 
failures in the electronic case report 
form (eCRF)

Tabulation of reasons for 
screen and run-in failure and 
for inclusion, exclusion and 
randomisation criteria failed
Modified Intent-
To-Treat

Comprise of all subjects randomized to 
treatment who received at least one 
dose of randomized study medication in 
the treatment period.

Randomized subjects will be assumed 
to have received study medication
unless definitive evidence to the 
contrary exists.

Outcomes will be reported according to 
the randomized treatment allocation.

All scheduled data collected until the 

Constitute the primary 
population for all data 
analyses and displays. 


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Population
Definition / Criteria
Analyses Evaluated
time of study discontinuation will be 
included in the Modified Intent-to-treat 
analysis for subjects who withdraw from 
the study.
Per-Protocol

Comprise all subjects in the Modified
ITT Population who are not identified as 
full protocol violators.

Subjects identified as partial protocol 
violators will be included in the PP 
Population but will have their data
excluded from PP analyses from the 
time of violation onwards.

The definition of full and partial 
violations will be included in Section 4.1
(Protocol Deviations) and Appendix 1
(Protocol Deviation Management and 
Definition for Per-Protocol Population).

The decision to exclude a subject from 
the PP Population or a subject’s data 
from PP analyses will be made prior to 
breaking the blind.

Confirmatory analyses of the 
primary efficacy endpoint
only, irrespective of how 
many subjects are in the PP 
population.
NOTES : 

Please refer to Appendix 14: List of Data Displays which details the population to be used for each display being 
generated.
Population for analysis to be performed on subjects enrolled in China alone: a China 
subgroup analysis.
Population
Definition / Criteria
Analyses Evaluated
China All 
Subjects Enrolled

Comprise of all subjects as defined in 
the above table in All Subjects 
Enrolled population, but will include
only those subjects at sites in China.  

The same as above table for 
All Subjects Enrolled 
Population.
China Screen and 
Run in Failure

Comprise of all subjects as defined in 
the above table in Screen and Run in 
Failure population, but will include
only those subjects at sites in China

The same as above table for 
Screen and Run in Failure 
Population.
China Modified
Intent-To-Treat 

Comprise of all subjects as defined in 
the above table in Modified Intent-To-
Treat Population, but will include only 
those subjects at sites in China. 
The same as above table for 
Modified Intent-To-Treat 
Population.
China Per-
Protocol

Comprise all subjects as defined in 
the above table in Per-Protocol 
Population, but will include only those 

The same as above table for 
Per-Protocol Population.


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Population
Definition / Criteria
Analyses Evaluated
subjects at sites in China.
NOTES : 
Please refer to Appendix 14: List of Data Displays which details the population to be used for each display being 
generated.
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.

A separate summary and listing of all inclusion/exclusion criteria deviations will also 
be provided. This summary will be based on data as recorded on the 
inclusion/exclusion page of the eCRF.


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
Table 1 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 1
Overview of Appendices
Section
Appendix
RAP Section 4 : Analysis Populations
Section 10.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions
Section 10.2
Appendix 2: Time and Events
Section 10.3
Appendix 3: Assessment Windows
Section 10.4
Appendix 4: Treatment States & Phases
Section 10.5
Appendix 5: Data Display Standards & Handling Conventions

Study Treatment & Sub-group Display Descriptors

Baseline Definitions & Derivations

Reporting Process & Standards
Section 10.6
Appendix 6: Derived and Transformed Data

General, Study Population & Safety

Efficacy
Section 10.7
Appendix 7: Premature Withdrawals & Handling of Missing Data

Premature Withdrawals

Handling of Missing Data
Section 10.8
Appendix 8: Values of Potential Clinical Importance
Section 10.9
Appendix 9: Multicentre Studies
Section 10.10
Appendix 10: Examination of Covariates and Subgroups
Section 10.11
Appendix 11: Multiple Comparisons and Multiplicity
Section 10.12
Appendix 12: Model Checking and Diagnostics for Statistical Analyses
Other RAP Appendices
Section 10.13
Appendix 13: Abbreviations & Trade Marks
Section 10.14
Appendix 14: List of Data Displays
Section 10.15
Appendix 15: Example Mock Shells for Data Displays


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population analyses will be based on the Modified Intent-To-Treat population
for the analysis on all countries overall and on China Modified Intent-To-Treat 
population for the analysis of China subgroup alone, unless otherwise specified.
Table 2 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 14: List of Data Displays. All the planned 
study population analyses will be done on all countries overall, and China subgroup alone
(with the exception of those displays specified by country).
Table 2
Overview of Planned Study Population Analyses
Endpoint/ Parameter/ Display Type
Data Displays Generated
Table
Figure
Listing
Subject Populations
Subject Populations
Y
Subject Disposition
Subject Disposition
Y
Reasons for Screen Failure/Run-in Failures
Y
Y
Subjects by Country and Centre
Y
Reasons for Subject Withdrawal
Y
Y
Subjects for Whom the Treatment Blind was Broken
Y
Planned and Actual Treatments
Y
Subjects Attending Each Clinic Visit
Y
Subjects Withdrawals over Time
Y
Protocol Deviations
Subjects with Inclusion/ Exclusion/Randomisation Criteria 
Deviations
Y
Y[1]
Important Protocol Deviations
Y
Y[1]
All Protocol Deviations
Y
Exclusions from the Per protocol Population
Y
Demography and Baseline Characteristics
Demographics Characteristics 
Y
Y
Race and Racial Combinations
Y
Y[2]
Race and Racial Combination Details
Y
Medical Condition
Medical Conditions (Current/Past)
Y
Y
Past Cholecystectomies
Y
Y
Family History of Cardiovascular Risk Factors
Y
Y
COPD History
Y
Y
COPD Exacerbation 
Y
Y
Smoking History and Status
Y
Y
Lung Function Test at Screening
Y
Y
GOLD Stage and Reversibility/Responsiveness
Y
Y
Scores for Modified Medical Research Council dyspnoea
Y
Y
Concomitant Medication


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Endpoint/ Parameter/ Display Type
Data Displays Generated
Table
Figure
Listing
COPD medications not given for an exacerbation taken 
pre-treatment
Y
COPD medications not given for an exacerbation taken 
on-treatment
Y
COPD medications not given for an exacerbation taken 
post-treatment
Y
Medications given for an exacerbation taken pre-treatment
Y
Medications given for an exacerbation taken on-treatment
Y
Medications given for an exacerbation taken post-
treatment
Y
Non-COPD medications taken pre-treatment
Y
Non-COPD medications taken on-treatment
Y
Non-COPD medications taken post-treatment
Y
Relationship between ATC Level 1, Ingredient and 
Verbatim Text
Y
COPD medications
Y
Non-COPD medications
Y
Treatment Compliance
Treatment compliance
Y
Y
NOTES :

Y = Yes display generated.

All summaries tables will be presented by treatment group and overall. 

COPD History and COPD Exacerbation will be listed together.

Screening lung function data, GOLD stage, reversibility to salbutamol and reversibility to salbutamol and 
ipratropium will be listed together. 

COPD and non-COPD medications will be listed separately. The COPD medications listing will indicate whether 
each medication was taken for an exacerbation. Both listings will indicate in which study phases each medication 
was taken (pre-treatment, ontreatment and/or post-treatment).
[1] Flag shall be provided to identify if the subject is excluded from PP Population or excluded from PP population 
analysis. 
[2] Listing of race.


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7.
PRIMARY STATISTICAL ANALYSES
7.1.
Primary Efficacy Analyses
7.1.1.
Overview of Planned Primary Efficacy Analyses
The primary efficacy analyses will be based on the Modified Intent-To-Treat population, 
for the analysis on all countries overall and on China Modified Intent-To-Treat 
population for the analysis on China subgroup alone, unless otherwise specified.
Table 3 provides an overview of the planned efficacy analyses, with full details of data 
displays being presented in Appendix 14: List of Data Displays. All the planned primary 
efficacy analyses will be done on all countries overall, and China subgroup alone (with 
the exception of those displays specified by country). 
Table 3
Overview of Planned Efficacy Analyses
Endpoints
Absolute
Change from Baseline
Stats 
Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Primary Efficacy Analyses
Baseline FEV1
Y[1]
Y
Trough FEV1 on Day 
169
Y[1]
Y[1]
Y
Y[1
]
Y
Y[1]
Y
Y
Trough FEV1 on Day 
169 (Using LOCF)
Y
Y
Y
Y
Trough FEV1 at other 
time points
Y
Y
Y
Y
Y
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.

All the tables will be presented by treatment group. 
[1]:  Will be repeated for PP population. 


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7.1.2.
Planned Primary Efficacy Statistical Analyses
Primary Statistical Analyses
Endpoint(s)

Change from baseline in trough FEV1
Model Specification

Mixed Models Repeated Measures (MMRM) model.

While missing data are not explicitly imputed in the primary MMRM analyses, there is an
underlying assumption that the data are missing at random. All available scheduled 
postbaseline assessments will be utilized and via modeling of the within-subject correlation
structure, the derived treatment differences will be adjusted to account for missing data.

The MMRM analysis for trough FEV1 will include on-treatment FEV1 measurements at Days 2, 
28, 56, 84, 112, 168 and 169. 

Terms fitted the model: 
Response
:trough FEV1 on each day or Change from baseline in 
trough FEV1 on each Day
Categorical
:Treatment, Smoking Status (screening), Country [1], 
Day
Continuous
:Baseline FEV1
Interaction
: baseline*Day, treatment*Day
Repeated
: Day (nominal)

The model will be fit with an unstructured variance-covariance matrix.

The Kenward and Roger method (KR) for approximating the denominator degrees of
freedom and correcting for bias in the estimated variance-covariance of the fixed effects will
be used. In the event the model fails to run using the KR method, then the residual method
will be used instead.

Baseline is defined in Section 10.5.2.1

Two models will be fitted; one with trough FEV1 on each Day and one with Change from 
baseline in trough FEV1 on each Day.
Model Checking & Diagnostics

Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Least-square (LS) means and LS mean change from baseline values for each treatment group 
will be presented with their associated standard errors.

Estimated treatment differences along with corresponding 95 % confidence intervals (CIs) and 
p-values for Days 2, 28, 56, 84,112, 168 and 169 will be presented for the treatment 
comparisons

The LS means from the model for change from baseline in trough FEV1 for each treatment on
Days 2, 28, 56, 84, 112, 168 and 169, along with the corresponding 95 % CIs, will be plotted.

The LS mean treatment differences, along with the corresponding 95 % CIs, for change from 
baseline in trough FEV1 on Days 2, 28, 56, 84, 112, 168 and 169 will be plotted for active 
treatment group versus placebo.

The type III tests of fixed effects and the covariance parameter estimates from the model will 


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Primary Statistical Analyses
be presented in two tables in the statistical appendix.
Example SAS Code
proc mixed data=dsetin;
class trtcd visit subjid smk country[1];
model endpoint=trtcd baseline smk country[1] day day*baseline day*trtcd / ddfm =kr;
repeated visit / subject=subjid type=un;
lsmeans trtcd*visit / cl diff e om=OMdset at (baseline)=(&blm.);
ods output lsmeans=lsmeans;
      ods output diffs=diffs; 
run;
[where OMdset is a dataset with a row for every subject-visit combination that contains all of the
covariates and blm is a macro variable containing the mean baseline for the subjects used in the
analysis. This is used to derive the LS means using coefficients which are based on the subjects
used in the analysis.]
Note: [1]: In China subgroup analysis, Country will be removed.  
Sensitivity and Supportive Statistical Analyses

The summaries, figures and analysis detailed in Section 7.1.1 (Overview of Planned Efficacy 
Analyses) and above primary statistical analyses, except for the summary figures (box plot and 
empirical distribution function plot, details please refer to Appendix 14), will be repeated for the 
PP population for the analysis on all countries overall and on China PP population for the 
analysis on China subgroup alone as the supportive analysis of primary efficacy analyses. 

An assessment of whether the effect of treatment on trough FEV1 is modified by smoking
status at screening, country [1] or baseline will be made by fitting separate repeated measures 
models, identical to the model described in the above primary statistical analyses, but also 
including additional terms for the treatment by smoking status interaction, treatment by country 
(for the all countries analysis only) interaction and treatment by baseline interaction 
respectively.

Additionally, an assessment will be made of whether the effect of treatment on trough FEV1 is 
modified by the following factors, 
ICS use at screening.
       Reversibility to salbutamol at screening.
Post-salbutamol percent predicted FEV1 at screening
This will be made by fitting separate repeated measures models, identical to the model
described in Primary Statistical Analyses of Section 7.1.2 but also including additional terms for 
the factor and the factor by treatment interaction.

If any interaction from these analyses is significant at the 10 % level, further investigation and 
characterisation of the interaction will be undertaken.

The interaction p-values from these analyses will be included in the statistical appendix.
Note: [1]: In China subgroup analysis, Country will be removed.  


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7.1.3.
Planned Missing Data Sensitivity Statistical Analyses for Trough 
FEV1
Missing Trough FEV1 on Day 169 will be imputed using LOCF. This only include post-
baseline measurements at on-treatment scheduled clinic visits.  
Sensitivity Statistical Analyses – LOCF
Endpoint(s)

Change from baseline in trough FEV1 on Day 169
Model Specification

Analysis of Covariance (ANCOVA) model using LOCF

Terms in the model:

Response: trough FEV1 or change from baseline in trough FEV1 on Day 169.

Categorical: treatment group, smoking status (screening), country[1]

Continuous: baseline FEV1 

Baseline is defined in Section 10.5.2.1

Two models will be fitted; one with trough FEV1 on Day 169 and one with Change from 
baseline in trough FEV1 on Day 169.
Model Results Presentation

Least-square (LS) means and LS mean change from baseline values for treatment group will 
be presented with their associated standard errors. 

The estimated treatment difference along with corresponding standard error, 95% CI and p-
value will be presented.
Example SAS Code
proc mixed data=dsetin;
class trtcd smk country[1]  ;
model endpoint=trtcd baseline smk country[1]  / ddfm =kr;
lsmeans trtcd / cl diff e;
ods output lsmeans=lsmeans;
ods output diffs=diffs;
run;
Note: [1]: In China subgroup analysis, Country will be removed.  
7.2.
Secondary Efficacy Analyses
7.2.1.
Overview of Planned Secondary Efficacy Analyses
The secondary efficacy analyses will be based on the Modified Intent-To-Treat 
population, for the analysis on all countries overall and on China Modified Intent-To-
Treat population for the analysis on China subgroup alone, unless otherwise specified.
Table 4 provides an overview of the planned efficacy analyses, with further details of 
data displays being presented in Appendix 14: List of Data Displays. All the planned 
secondary efficacy analyses will be done on all countries overall, and China subgroup
alone (with the exception of those displays specified by country). 


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Table 4
Overview of Planned Efficacy Analyses
Endpoint
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
0-6 h Weighted Mean 
FEV1 on Day 1
Y
Y
Y
Y
Y
Y
Baseline Dyspnea 
Index (BDI)
Y
Y
Transition Dyspnea 
Index (TDI)
Y
Y
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.

All the tables will be presented by treatment group.
7.2.2.
Planned Secondary Efficacy Statistical Analyses
7.2.2.1.
0-6 h Weighted Mean FEV1 on Day 1
Statistical Analyses
Endpoint(s)

0-6 h Weighted Mean FEV1
Model Specification

ANCOVA Model

The absolute and change from baseline value of 0-6 h weighted mean FEV1 on Day 1 will be 
analysed.

Terms fitted in the ANCOVA model will be include: 
Response
:Absolute value or change from baseline value of 0-
6 h weighted mean FEV1 on Day 1
Categorical
:Treatment, Smoking Status (Screening), Country[1]
Continuous
:Baseline FEV1

Baseline is defined in Section 10.5.2.1

Two models will be fitted; one with a response variable of change from baseline and one with 
the response variable as absolute value.
Model Checking & Diagnostics

Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

LS mean and LS mean change from baseline values for each treatment group will be 
presented with their associated standard errors. 

Estimated treatment differences along with corresponding 95 % CIs and p-values for Day 1 will 
be presented for the treatment comparisons.
Example SAS Code
proc mixed data=dsetin;


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Statistical Analyses
class trtcd subjid smk country[1];
model endpoint=trtcd baseline smk country[1] / ddfm =kr;
lsmeans trtcd / cl diff e om;
ods output lsmeans=lsmeans;
ods output diffs=diffs;
run;
Note: [1]: In China subgroup analysis, Country will be removed.  
7.2.2.2.
TDI
Statistical Analyses
Endpoint(s)

TDI
Model Specification

MMRM

The model will use all available TDI focal scores recorded on Days 28, 84 and 168.

Terms fitted in the model will be include:
Response
: TDI focal scores on each day
Categorical
:Treatment, Smoking Status (screening), Country[1], 
Day
Continuous
:BDI focal score
Interaction
: BDI focal score *Day, treatment*Day
Repeated
: Day (nominal)
Model Checking & Diagnostics

Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

LS means values for each treatment group will be presented with their associated standard 
errors. 

Estimated treatment differences along with corresponding 95 % CIs and p-values for Days 28, 
84 and 168 will be presented for the treatment comparisons.

The LS means from the model for TDI focal score for Days 28, 84 and 168, along with the 
corresponding 95 % CIs, will be plotted
The LS mean treatment differences, along with the corresponding 95 % CIs for Days 
28, 84 and 168 will be plotted for active treatment group versus placebo
Example SAS Code
Similar like the code in Section 7.1.2.


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7.3.
Other Efficacy Analyses
7.3.1.
Overview of Planned Other Efficacy Analyses
Other efficacy analyses will be based on the Modified Intent-To-Treat population, for the 
analysis on all countries overall and on China Modified Intent-To-Treat population for 
the analysis on China subgroup alone, unless otherwise specified.
Table 5 provides an overview of the planned other efficacy analyses, with further details 
of data displays being presented in Appendix 14: List of Data Displays. All the planned 
study population analyses will be done on all countries overall, and China subgroup alone 
(with the exception of those displays specified by country). 
Table 5
Overview of Planned Other Efficacy Analyses
Endpoint
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Time to Onset (an
increase of 100mL in
FEV1 above baseline)
during 0-6 h post-dose
on Day 1
Y
Y
Y
Y
Proportion Achieving 
Increase in FEV1 of 
≥12 % and ≥200 mL 
above Baseline at any 
Time During 0-6 h 
Post-dose on Day 1
Y
Y
Y
Proportion Achieving
Increase of ≥100 mL 
above Baseline in
Trough FEV1
Y
Y
Y
Serial FEV1
Y
Y
Y
Y
Y
Y
Y
Trough FVC
Y
Y
Y
Y
Y
Y
Serial FVC
Y
Y
Y
Y
Y
Y
Y
Rescue Salbutamol 
Use (Percentage of 
Rescue-Free Days)[1]
Y
Y
Y
Rescue Salbutamol 
Use (mean 
puffs/days)[1]
Y
Y
Y
Y
Y
Y
Proportion of 
Responders According 
to TDI Focal Score[2]
Y
Y
Y
Time to First COPD 
Exacerbation
Y
Y
Y
Y
On-Treatment COPD 
Exacerbations[3]
Y
Post-Treatment COPD 
Exacerbations[3]
Y


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NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.

All the tables will be presented by treatment group.

[1]: Absolute summary will be done on each at baseline, during each four weeks of treatment and over the entire 
24-week treatment period. The change from baseline values will also be summarised by treatment, for each four 
weeks of treatment and the entire 24-week treatment period.

[2]: A responder to TDI will be defined as a subject with TDI score of 1 unit or more

[3]: The number and percentage of subjects reporting 0, 1, 2 or >2 on-treatment COPD exacerbations and the total 
number of exacerbations will be presented by treatment group. The number and percentage of exacerbations with 
each outcome category, the number and percentage of exacerbations leading to withdrawal and the number and
percentage of exacerbations treated by oral/systemic corticosteroids, antibiotics, or which resulted in a visit to the 
emergency room or hospitalisation will also be presented. In addition, the exacerbation duration will be 
summarised.
7.3.2.
Planned Other Efficacy Statistical Analyses
7.3.2.1.
Time to Onset and Time to First COPD Exacerbation
Statistical Analyses
Endpoint(s)

Time to Onset (an increase of 100mL in FEV1 above baseline) during 0-6 h post-dose on Day 
1     

Time to First COPD Exacerbation
Model Specification

Cox’s proportional hazards model

Terms in the model:
Dependent variable: Time to Onset or time to first COPD exacerbation
Categorical: treatment group, smoking status (screening), and Country[1]. 

Use the ‘exact’ method for handling ties. (If the analysis will not run using the ‘exact’ method, 
then the ‘Efron’ method for handling ties will be used instead.)  
Model Checking & Diagnostics

Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Hazard ratios for each of the treatment comparisons with associated 95 % CIs and p-values, 
will be presented.

Kaplan-Meier survivor functions of the proportion of subjects with onset over time will be 
obtained for each treatment group separately and will be plotted on the same figure.

The median time to onset on Day 1 (taken from the Kaplan Meier analysis) will also be
presented in the summary table.
Example SAS code

Cox’s proportional hazards model


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Statistical Analyses
proc phreg data=dsetin ;
model timeto1*eventflag(0)=treatment smokehis country[1]
/ risklimits ties=exact;
run;

Kaplan-Meier survivor functions
proc lifetest data=wdw outsurv=survest;
time timeto1*eventflag(0);
strata treatment;
run;
quit;
Note: [1]: In China subgroup analysis, Country will be removed.  
7.3.2.2.
Proportion Endpoints
Statistical Analyses
Endpoint(s)

Proportion Achieving Increase in FEV1 of ≥12 % and ≥200 mL above Baseline at any Time During 0-6 
h Post-dose on Day 1    

Proportion Achieving Increase of ≥100 mL above Baseline in Trough FEV1   

Proportion of Responders According to TDI Focal Score   
Model Specification
Proportion Endpoints

Logistic Regression Model 

At each of Days 2, 28, 56, 84, 112, 168 and 169, the proportion of subjects who achieved an 
increase of 100 mL above baseline in trough FEV1 will be analysed using a separate logistic 
regression model.

At each visit, the proportion of responders according to TDI focal score will be analysed using 
a separate logistic regression model.

Terms in the model:
Dependent Variable
: Proportion
Categorical
:Treatment, Smoking Status (screening), Country[1]
Continuous
:Baseline FEV1 or BDI
Model Checking & Diagnostics

Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

For each treatment comparison, the odds ratio, 95 % CI and p-value will be presented.
Example SAS code
proc logistic data=fevaanal descending;
class treatment (ref='1') smokehis country[1] / param=ref;
model respond=treatment base smokehis country[1] / clodds=wald expb;
ods output logistic.oddsratios=odds1
(where=(index(effect,'TREATMENT')>0


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Statistical Analyses
or index(effect,'treatment')>0));
ods output logistic.parameterestimates=pval1
(keep=probchisq variable classval0
where=(variable in ('TREATMENT’,'treatment')));
run;
Note: [1]: In China subgroup analysis, Country will be removed.  
7.3.2.3.
Serial FEV1/FVC and Trough FVC 
Statistical Analyses
Endpoint(s)

Serial FEV1 (including post dose 15 and 30 min, 1, 3 and 6 h post-dose measurements on Day 
1)

Trough FVC (including Days 2, 28, 56, 84, 112, 168 and 169)

Serial FVC (including post dose 15 and 30 min, 1, 3 and 6 h post-dose measurements on Day 
1)
Model Specification, Checking, Results Presentation and SAS code

Similar to trough FEV1 in Section 7.1.2
Model Checking & Diagnostics

Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
7.3.2.4.
Rescue Salbutamol Use (mean puffs/days)
Statistical Analyses
Endpoint(s)

Rescue Salbutamol Use (mean puffs/days) (absolute and change from baseline value)
Model Specification
ANCOVA model

The mean number of puffs of rescue medication per day over each four weeks of treatment 
and the entire 24 week treatment period will be analyzed. 

Terms in model:
Response
: Rescue Salbutamol Use (mean puffs/days) (absolute or 
change from baseline value)
Fixed Categorical
:Treatment, Smoking Status, Country[1]
Fixed Continuous Covariates
:Baseline

Baseline is defined in Section 10.6.5 Rescue Use part.

Two models will be fitted; one with absolute value and one with change from baseline value.
Model Checking & Diagnostics

Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

LS means and LS mean change from baseline values for each treatment group will be
presented with their associated standard errors. 

Estimated treatment differences along with corresponding 95 % CIs and p-values will be 
presented for the treatment comparisons.
Example SAS code


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Statistical Analyses
proc mixed data=start;
by week;
class treatment smokehis country[1];
model endpoint=treatment baseline smokehis country[1];
lsmeans treatment / cl diff e om;
ods output lsmeans=lsmeans;
ods output diffs=diffs;
run;
Note: [1]: In China subgroup analysis, Country will be removed.  
7.4.
Health Outcomes Analyses
7.4.1.
Overview of Planned Health Outcomes Analyses
Health outcomes analyses will be based on the Modified Intent-To-Treat population, for 
the analysis on all countries overall and on China Modified Intent-To-Treat population 
for the analysis on China subgroup alone, unless otherwise specified.
Table 6 provides an overview of the planned health outcomes analyses, with further 
details of data displays being presented in Appendix 14: List of Data Displays. All the 
planned study population analyses will be done on all countries overall, and China 
subgroup alone (with the exception of those displays specified by country). 
Table 6
Overview of Planned Health Outcomes Analyses
Endpoint
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Baseline SGRQ (Total 
and each domain)
Y
Y[1]
SGRQ total score
Y
Y
Y
Y
Y
Y
Y
Y
SGRQ each domain 
score
Y
Y
Y
Proportion of 
responders according 
to SGRQ total score
Y
Y
Baseline COPD 
Assessment Test 
(CAT) score
Y
CAT score
Y
Y
Y[2]
Y
Y
Y
Y
Proportion of 
Responders according 
to CAT Score
Y
Y
Healthcare Resource 
Utilisation
Y
Y


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NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.

All the tables will be presented by treatment group.

[1]: Only total baseline score will be listed. 

[2]: Two scatter plots will be generated:
   Change from baseline CAT score at day 168 vs Change from baseline FEV1 at 168
   Baseline CAT scores versus baseline FEV1
7.4.2.
Planned Health Outcomes Statistical Analyses
Primary Statistical Analyses
Endpoint(s)

SGRQ

CAT score

Proportion of responders according to SGRQ total score
Model Specification, Checking, Results Presentation and SAS code
SGRQ, 
CAT score

Similar to trough FEV1 in Section 7.1.2
Proportion of responders according to SGRQ total score
Proportion of Responders according to CAT Score

Similar to proportion endpoint in Section 7.3.2.2


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8.
SAFETY ANALYSES
8.1.
Adverse Events Analyses
8.1.1.
Overview of Planned Adverse Events Analyses
The safety analyses will be based on the Modified Intent-To-Treat population, for the 
analysis on all countries overall and on China Modified Intent-To-Treat population for 
the analysis on China subgroup alone, unless otherwise specified.
In case of treatment misallocation, additional outputs for safety analyses may be provided, 
showing the subjects impacted by misallocation and the treatments they actually received.
Table 7 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 14: List of Data Displays. All the planned study 
population analyses will be done on all countries overall, and China subgroup alone (with 
the exception of those displays specified by country). 
Table 7
Overview of Planned Adverse Event Analyses
Endpoint
Absolute
Summary
Individual
T
F
L
Exposure
Exposure to Study Treatment
Y
Y
Adverse Events (AEs)
Overview of AE incidence
All AEs by SOC
Y
Y
Common AEs by Overall Frequency
Y
Y
All Drug-Related AEs by SOC
Y
Subject Numbers for Individual AEs
Y
Relationship Between AE SOCs, PT & Verbatim Text
Y
On-Treatment AEs by SOC
Y
Post-Treatment AEs by SOC
Y
On-Treatment AEs experienced by 3% (after rounding) or more of subjects in 
any treatment group 
Y
Common On-Treatment non-serious AEs[1]
Y
On-treatment Drug-Related AE’s
Y
On-treatment Non-Serious Drug Related Adverse Events
Y
All AEs
Y
Serious and Other Significant AEs
Fatal SAEs[1]
Y
Y
Non-Fatal SAEs
Y
Y
Pre-treatment fatal SAEs
Y
Pre-treatment non-fatal SAEs
Y
Y
On-treatment non-fatal SAEs
Y
Y
Post-treatment Non-fatal SAEs
Y
Y
SAEs by SOC
Y
Drug related serious AE
Y


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Endpoint
Absolute
Summary
Individual
T
F
L
Drug related SAEs by SOC
Y
Pre-treatment AEs leading to withdrawal from the study
Y
Y
On-treatment AEs leading to permanent discontinuation of study treatment or
withdrawal from the study
Y
Y
On-Treatment AE of Special Interest
Y
Y
Fatal SAE of Special Interest
Y
On-treatment Non-Fatal SAE of Special Interest
Y
Drug Related Fatal SAEs
Y
On-treatment Non-Fatal Drug Related SAEs
Y
Reasons for potential ELLIPTA malfunctions
Y

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.

All the tables will be presented by treatment group.
[1]: A cut-off of 3% for ‘common’ will be used, but for this purpose it should be applied without rounding, i.e. an event 
experienced by 2.8% subjects should not be included. This table also needs a ‘number of subjects with any event’ 
row which only counts subjects experiencing any event in the body of the table.
8.2.
Clinical Laboratory Analyses
8.2.1.
Overview of Planned Clinical Laboratory Analyses
The safety analyses will be based on the Modified Intent-To-Treat population, for the 
analysis on all countries overall and on China Modified Intent-To-Treat population for 
the analysis on China subgroup alone, unless otherwise specified.
Table 8 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 14: List of Data Displays. All the planned study 
population analyses will be done on all countries overall, and China subgroup alone (with 
the exception of those displays specified by country). 
Table 8
Overview of Planned Clinical Laboratory Analyses
Endpoint
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Chemistry
Laboratory Values
Clinical Chemistry
Y
Y
Clinical Chemistry values outside the normal range
Y
Y
Clinical Chemistry change from baseline value relative to 
the normal range 
Y
Clinical Chemistry maximum post-baseline value
Y
Y
Clinical Chemistry minimum post-baseline value
Y
Y
Hematology
Hematology
Y
Y
Hematology values outside the normal range
Y
Y


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Endpoint
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Hematology change from baseline value relative to the 
normal range 
Y
Hematology maximum post-baseline value
Y
Y
Hematology minimum post-baseline value
Y
Y
Urinalysis
Urinalysis data
Y
Y
Hepatobiliary (Liver)
Liver Event
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, PCI = Potential Clinical Importance

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
8.3.
Other Safety Analyses
8.3.1.
Overview of Planned Other Safety Analyses
The safety analyses will be based on the Modified Intent-To-Treat population, for the 
analysis on all countries overall and on China Modified Intent-To-Treat population for 
the analysis on China subgroup alone, unless otherwise specified.
Table 9 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 14: List of Data Displays. All the planned study 
population analyses will be done on all countries overall, and China subgroup alone (with 
the exception of those displays specified by country). 
Table 9
Overview of Planned Other Safety Analyses
Endpoint 
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Vital Signs
Pulse rate
Y
Y
Y
Y
Y
Y
Y
Systolic
Y
Y
Y
Y
Y
Y
Y
Diastolic blood 
pressure
Y
Y
Y
Y
Y
Y
Y
12-Lead ECG
QTc(F)
Y
Y
Y
Y
Y
Y
Y
QTc(B)
Y
Y
PR interval
Y
Y
Y
Y
Y
Heart Rate
Y
Y
Y
Y
Y
ECG interpretation
Y
ECG abnormalities
Y
Y


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NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.

All the tables will be presented by treatment group.
8.3.2.
Planned Safety Statistical Analyses
Primary Statistical Analyses
Endpoint(s)

Pulse rate

Systolic

Diastolic blood pressure

QTc(F)

PR interval

Heart Rate
Model Specification

ANCOVA model

The absolute and change from baseline value of each endpoint will be statistically analysed at 
each scheduled time point after the start of treatment separately.

Terms fitted in the ANCOVA model will be include:
Response
: Absolute value or change from baseline value at 
each scheduled time point. 
Fixed Categorical
:Treatment, Smoking Status(Screening), Country[1]
Fixed Continuous Covariates
:Baseline

Baseline is defined in Section 10.5.2.1.

Two models will be fitted; one with a response variable of change from baseline and one with 
the response variable as absolute value.
Model Checking & Diagnostics

Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Treatment group LS mean values and LS mean change from baseline values with associated 
standard errors will be presented for each scheduled on-treatment time point for each 
endpoint. 

LS mean treatment differences for comparisons will be presented with associated 95 % CIs.

LS mean change from baseline and associated 95 % CIs for pre-dose values at each 
scheduled time point by treatment group will be presented graphically.
Example SAS Code
Similar to the code in Section 7.2.2.2
Note: [1]: In China subgroup analysis, Country will be removed.  


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9.
REFERENCES
CPMP/EWP/562/98. Points to Consider on Clinical Investigation of Medicinal Products
in the Chronic Treatment of Patients with Chronic Obstructive Pulmonary Disease
(COPD). 19 May 1999
GlaxoSmithKline Document Number 2013N159587_03 Study ID AC4117410. A 24-
week randomised, double-blind and placebo-controlled study to evaluate the efficacy and 
safety of 62.5 mcg Umeclidinium Inhalatin Powder delivered once-daily via a Novel Dry 
Powder Inhaler in subjects with Chronic Obstructive Pulmonary Disease Effective Date: 
11-NOV-2015.
Global Strategy for the Diagnosis, Management and Prevention of COPD, Global
Initiative for Chronic Obstructive Lung Disease (GOLD) 2011. Available from:
http://www.goldcopd.org/.
ICH E1A. The Extent of Population Exposure to Assess Clinical Safety: For Drugs
intended for Long Term Treatment of Non-Life Threatening Conditions.
Siddiqui O, Hung HMJ, O'Neill, R. MMRM vs. LOCF: A Comprehensive Comparison
Based on Simulation Study and 25 NDA Datasets J Biopharm Stat 2009; 19:227-46.
St. George’s Respiratory Questionnaire Manual, Version 2.3, 2009.
Witek TJ, Jr., Mahler DA. Minimal important difference of the transition dyspnoea index
in a multinational clinical trial. Eur Respir J 2003; 21:267-272.


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10.
APPENDICES
Section
Appendix
RAP Section 4 : Analysis Populations
Section 10.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions
Section 10.2
Appendix 2: Time and Events
Section 10.3
Appendix 3: Assessment Windows
Section 10.4
Appendix 4: Treatment States & Phases
Section 10.5
Appendix 5: Data Display Standards & Handling Conventions

Study Treatment & Sub-group Display Descriptors

Baseline Definitions & Derivations

Reporting Process & Standards
Section 10.6
Appendix 6: Derived and Transformed Data

General, Study Population & Safety

Efficacy
Section 10.7
Appendix 7: Premature Withdrawals & Handling of Missing Data

Premature Withdrawals

Handling of Missing Data
Section 10.8
Appendix 8: Values of Potential Clinical Importance
Section 10.9
Appendix 9: Multicentre Studies
Section 10.10
Appendix 10: Examination of Covariates and Subgroups
Section 10.11
Appendix 11: Multiple Comparisons and Multiplicity
Section 10.12
Appendix 12: Model Checking and Diagnostics for Statistical Analyses
Other RAP Appendices
Section 10.13
Appendix 13: Abbreviations & Trade Marks
Section 10.14
Appendix 14: List of Data Displays
Section 10.15
Appendix 15: Example Mock Shells for Data Displays


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10.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
Protocol deviations identified in this section are those considered to affect the primary 
outcome of the study. All decisions on whether to exclude a subject or a subject’s data 
from analysis will be made prior to breaking the blind, with the exception of subjects 
receiving incorrect treatment container. If, after breaking the blind, the container was 
found to have contained the correct randomised treatment, no data will be excluded from 
analyses.
10.1.1.
Exclusion of Data from Modified Intent-to-treat Analyses
In general, all data recorded for subjects who were randomised and received at least one
dose of study medication will be included in Modified ITT analyses. The following 
deviations will result in exclusion of data from Modified ITT analyses:
If a 23 h or 24 h post-dose FEV1 or FVC assessment is actually performed after the
following day’s dose, the value will be excluded from Modified ITT analyses.
If a 15 or 30 min, 1, 3, or 6 h FEV1 or FVC assessment is actually performed before
dosing, the value will be excluded from Modified ITT analyses.
Derived endpoints will be calculated from remaining assessment values. Exclusion of a
value from Modified ITT analyses does not necessarily mean the subject will not have a 
value for the derived endpoints.
10.1.2.
Exclusions of Data from Per Protocol Analyses
Subjects with full protocol deviations identified below will be excluded from the PP
population. Subjects with partial protocol deviations will generally be included in the PP
population but have data excluded from PP analyses from the time of the deviation
onwards. The exception to this is a partial deviation which occurred prior to the start of
treatment– in this case the subject will be excluded from the PP population. Subjects
with time-point specific deviations will have only the affected data excluded from PP
analyses.
10.1.2.1
Inclusion/exclusion/randomisation Criteria Deviations
Failure of criteria will be considered a full protocol deviations as detailed in Table 10: 


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Table 10
Inclusion/exclusion/randomisation criteria deviations considered to
affect the primary outcome
Reason for exclusion
Full protocol deviation considered to affect primary outcome
Inclusion criterion
Type of subject
No
Informed consent
No
Age
Yes
Gender
No
COPD History
Yes
Tobacco Use and Smoking history
Yes
Severity of disease
Yes
Dyspnoea (mMRC)
Yes
Exclusion criterion
Pregnancy
No
Asthma
Yes
Other respiratory disorders
Yes
Other diseases/abnormalities
No
Chest X-ray
Yes
Contraindications
No
Hospitalisation
Yes
Lung resection
Yes
12-lead ECG
No
Screening labs
No
Medication prior to spirometry
Yes
Medication prior to screening
Yes
Oxygen
Yes
Nebulised therapy
No
Pulmonary rehabilitation
Yes
Drug or alcohol abuse
No
Affiliation with investigator site
No
Compliance
No
Randomisation criterion
Pre-dose 12-Lead ECG at Visit 2
No
COPD exacerbation
Yes
ICS
Yes
Prohibited Medications
Yes
10.1.3.
Programmed Checks to Identify Non-medication Deviations
The data checks identified in Table 11 will be performed to further identify protocol
deviations.


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Table 11
Programmed non-medication checks
Reason for exclusion
Check performed
Deviation Type
Age
(visit date – date of birth) < 40 at pre-
screening
Full
Smoking history
number of pack-years < 10 at screening[1]
or only use a pipe and/or cigar
Full
Severity of disease: FEV1/FVC
Pre-salbutamol or Post-salbutamol 
FEV1/FVC ≥0.7 or any one missing at 
screening
Full
Severity of disease: % predicted
Pre-salbutamol or Post-salbutamol 
FEVPDPC > 70% or any one missing at 
screening
Full
Dyspnea (mMRC)
mMRC < 2 at screening or missing
Full
COPD exacerbation during run-in
Exacerbation onset date between dates of 
screening and start of treatment
Full
Compliance with treatment
Overall compliance < 80 % or > 120 % or 
missing
Full
Incorrect treatment
At any point
Partial; data excluded 
from start of incorrect
treatment onwards
Blind broken[3]
At any point
Partial; data excluded 
from date of breaking of 
blind
COPD exacerbation during
treatment and not withdrawn
Exacerbation onset date between
treatment start and stop date +1 with
measurement of primary efficacy endpoint 
after onset date[2]
Partial; data excluded 
from date of onset 
onwards
Meet other withdrawn criteria
defined in the protocol but not 
withdrawn
Manual Review
Partial; data excluded 
from date of PD 
happened. 
Trough FEV1 outside window
23 h or 24 h FEV1 assessment outside 
window of 22.5-24.5h after previous
day’s dose
Time-point specific
Note: 
1.
Pipe and/or cigar use cannot be used to calculate pack-year history.
2.
Subject experiences an exacerbation during the treatment period requiring the use of any systemic 
or oral corticosteroids with prescribed or non-prescribed (self-administered) antibiotics, and/or 
requiring emergency treatment or hospitalisation. If subjects used either prescribed or non-
prescribed (self-administered) antibiotics only for the treatment of exacerbation, they were 
permitted to remain in the study under PI’s discretion according to the study protocol therefore the 
use of only antibiotics will not be defined as a protocol deviation.
3.
Subjects whose blind was broken by someone external to GSK (i.e. site staff).


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10.1.4.
Programmed Checks to Identify Medication Deviations
Medications will be classified into Respiratory Medication Class (RMC) as identified in
concomitant medications part of Section 10.6.3.
Following agreement of the correct classification, medications taken prior to or on-
treatment (i.e. medication start date on or before treatment stop date) in the intervals
identified in Table 12 will be reviewed to identify data which should be excluded from
analysis. If the disallowed medication started within the specified window prior to Visit 2 
the deviation will be considered full and the subject will be excluded from the PP
population. Otherwise the deviation will be considered partial and the subject’s data will
be excluded from PP analyses from the start of the disallowed medication onwards. 
Table 12
Programmed medication checks
RMC
Disallowed rule
Depot corticosteroids
Started on-treatment; stopped after 12 weeks prior to V1
Systemic, oral, parenteral and
intra-articular corticosteroids
Started on-treatment; stopped after 4 weeks prior to V1.
Antibiotics1
Stopped after 4 weeks prior to V1, and reason is LRTI1
ICS2
Started on-treatment; stopped after 30 days prior to V12
PDE4 inhibitors
Started on-treatment; stopped after 14 days prior to V1
Long-acting anticholinergics
Started on-treatment; stopped after 7 days prior to V1
Xanthines
Started on-treatment; stopped after 12 hours prior to each visit
Leukotriene receptor antagonists
Started on-treatment; stopped after 2 days prior to V1
Oral beta-2 agonists – long
acting3
Started on-treatment; stopped after 2 days prior to V1
Oral beta-2 agonists - short-acting
Started on-treatment; stopped after day of V1
Inhaled beta-2 agonists – long
acting3
Started on-treatment; stopped after 2 days prior to V1
Nedocromil or sodium
cromoglycate
Started on-treatment; stopped after 1 day prior to V1 and route is 
inhaled
Other investigational medication
for COPD
Started on-treatment; stopped after 30 days prior to V1
Any investigational medication
30 days or 5 half lives, whichever is longer
Oxygen
Greater than 12 hours a day
Herbal medicine for respiratory
diseases
Manual Review
1. All antibiotics will be identified; manual review to identify those with reason for administration of LRTI. 
After v1, antibiotics used for acute infection <=2weeks is permitted. 
2. All ICS will be identified; manual review to identify ICS:
Started but not as switch from ICS/LABA or not within allowed dose range
Dose>1000 mcg fluticasone propionate or equivalent
Stopped with no change to an alternative steroid in the same dose range within 14 days of stopping
Change dose before treatment or change of more than one dose range on the treatment
3. The definition of LABA has now changed and split in to three categories which are now:
'Long-acting beta-2 agonist – Group 1';


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'Long-acting beta-2 agonist – Group 2 (Olodaterol or Indacaterol)';
'Long-acting beta-2 agonist – Group 3 (Salmeterol and Formoterol)';
The final decision on exclusion will be made following manual review and will be
documented prior to unblinding.


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10.2.
Appendix 2: Time & Events
10.2.1.
Protocol Defined Time & Events


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10.3.
Appendix 3: Assessment Windows
Data are generally reported according to the nominal time of clinic visits and assessments
as specified in the protocol, and time windows for exclusion will not be defined. For
example, if a subject recorded values for the Week 4 visit that were actually made on the
21st day of treatment, they will be presented as Week 4 values in the summary tables.
For the 23 and 24 h post-dose trough FEV1 measurements, a time window of 22.5-24.5 h
is allowed for the actual time of an assessment relative to time of dosing. Values falling
outside of this window will not be used in the PP analysis of the primary endpoint, but
will still be included in all Modified ITT analyses.


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10.4.
Appendix 4: Treatment States and Phases
10.4.1.
Treatment Phases
Assessments and events will be classified according to the time of occurrence relative to
study treatment, unless otherwise specified.
Treatment Phase
Definition
Pre-Treatment 
Date < Study Treatment Start Date
On-Treatment
Study Treatment Start Date ≤Date ≤ Study Treatment Stop Date
Post-Treatment
Date > Study Treatment Stop Date
NOTES: 

If the study treatment stop date is missing then the assessment will be considered to be On-Treatment
10.4.2.
Treatment States
Assessments and events will be classified according to time of occurrence relative to the 
start and/or stop date of the study treatment.
10.4.2.1.
Treatment States for Concomitant Medications Data
Treatment State
Definition
Pre-Treatment
Medication start date < Study Treatment Start Date    
On-Treatment
Medication start date ≤ Study Treatment Stop Date and Medication stop date≥ Study 
Treatment Start Date
Post-Treatment
Medication stop date > Study Treatment Stop Date
NOTES: 

A medication will be classed in every period of the study in which it was taken.

For medications with partial start and stop dates or missing start/stop dates, the medication will be classed in
every period of the study in which it could have been taken.

If the study treatment stop date is missing then the medication will be considered to be On-Treatment.

The answers to the questions “Taken Prior to Study?” and “Ongoing?” which are recorded on the eCRF will also 
be taken into consideration to determine if the medication was started pre-treatment or continued post-treatment. 
In each case, should the answers suggest a different classification than the dates, the medication will be 
summarised in all possible classifications (pre/on/post) in which it could conceivably have been taken.
10.4.2.2.
Treatment States for AE Data
Treatment State
Definition
Pre-Treatment
AE Start Date < Study Treatment Start Date
On-Treatment
Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop +1
Post-Treatment
AE Start Date > Study Treatment Stop Date+1
Onset Time  
Since 1st Dose
(Days)
If Treatment Start Date ˃ AE Onset Date
= AE Onset Date - Treatment Start Date
If Treatment Start Date ≤ AE Onset Date 
= AE Onset Date - Treatment Start Date +1
Missing otherwise.


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Treatment State
Definition
Duration (Days) 
AE Resolution Date – AE Onset Date + 1
Drug-related
If relationship is marked ‘YES’ on Inform/CRF OR value is missing.
NOTES: 

If the study treatment stop date is missing then the AE will be considered to be On-Treatment.

If the AE onset date is missing or partial then the AE will be considered on-treatment unless there is evidence to 
the contrary (e.g. the month of the onset date is present and is less than the month of the first dose of study 
treatment).

AEs reported by subjects who did not receive treatment will be considered pre-treatment.

Any SAEs for screen failures, run-in failures or subjects who were randomised but did not receive treatment will 
be classified as pre-treatment SAEs.
10.4.2.3.
Treatment States for COPD exacerbation
Treatment State
Definition
Pre-Treatment
Exacerbations Onset Date < Study Treatment Start Date
On-Treatment
Study Treatment Start Date ≤ Exacerbations Onset Date ≤ Study Treatment Stop +1
Post-Treatment
Exacerbations Onset Date > Study Treatment Stop Date+1
Time to first on-
treatment 
exacerbation
= Exacerbation Onset Date of first on-treatment exacerbation - Treatment Start Date
+1
Missing otherwise.
Duration (Days) 
Exacerbation resolution date or date of death – Exacerbation Onset Date + 1
NOTES: 

If the study treatment stop date is missing then the exacerbation will be considered to be On-Treatment.

If the exacerbation onset date is missing or partial then the exacerbation will be considered on-treatment unless 
there is evidence to the contrary (e.g. the month of the onset date is present and is less than the month of the first 
dose of study treatment).

Exacerbations reported by subjects who did not receive treatment will be considered pre-treatment.


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10.5.
Appendix 5: Data Display Standards & Handling 
Conventions
10.5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order [1]
A
UMEC 62.5 mcg
UMEC 62.5 mcg
2
P
Placebo
Placebo
1
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.
10.5.2.
Baseline Definition & Derivations
10.5.2.1.
Baseline Definitions
For all endpoints (expect FEV1 and FVC) the baseline value will be the latest pre-dose 
assessment at schedule visit. Unless otherwise stated, the mean of replicate assessments 
at any given time point will be used as the value for that time point.
The baseline value for FEV1 and FVC is calculated from the values measured 30 min and
5 min pre-dose on Day 1. If the actual time of an assessment is after the time of dosing on 
Day 1, the value at that assessment will be set to missing prior to calculating baseline. If 
one of the values is missing then the baseline will be the single remaining value;
otherwise the baseline will be the mean of the two values.
10.5.2.2.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from 
Baseline
= On-treatment Value – Baseline
value
% Change from 
Baseline
= 100 x [(On-treatment Value –
Baseline value) / Baseline value]
Maximum 
Change from 
Baseline
= Calculate the change from 
baseline at each given timepoint 
   and determine the maximum 
change
NOTES :

Unless otherwise specified, the baseline definitions specified 
in Section 10.5.2.1 Baseline Definitions will be used for 
derivations for endpoints / parameters and indicated on 
summaries and listings.

If either the baseline or on-treatment value is missing then 
the change from baseline will be set to missing.

The change from baseline will not be calculated for baseline 
records or records prior to baseline


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10.5.3.
Reporting Process & Standards
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: uk1salx00175
HARP Area
: \arenv\arprod\gsk573719\ac4117410\final
QC Spreadsheet
: arenv\arprod\gsk573719\ac4117410\final\qc
Analysis Datasets 

Analysis datasets will be created according to Integrated Data Standards Library standards.
Generation of RTF Files

RTF files will be generated.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated:
o
4.03 to 4.23: General Principles
o
5.01 to 5.08: Principles Related to Data Listings
o
6.01 to 6.11: Principles Related to Summary Tables
o
7.01 to 7.13: Principles Related to Graphics 
Formats

All data will be reported according to the randomized treatment the subject received unless 
otherwise stated. However, there may be additional adhoc displays for individual subjects 
using the actual treatment received.

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.

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.

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. 
Unscheduled Visits

Unscheduled visits will not be included in summary tables except as part of a ‘worst case post-
baseline’ assessment.


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Reporting Standards

Unscheduled visits will not be included in figures.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.


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10.6.
Appendix 6: Derived and Transformed Data
10.6.1.
General
Multiple Measurements at One Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics 
but if listed, all data will be presented.

If there are two values within a time window 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.

Subjects having both High and Low values for Normal Ranges at any post-baseline visits 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 < Start of treatment date → Study Day = Ref Date – Start of treatment date

Ref Data ≥ Start of treatment date → Study Day = Ref Date – (Start of treatment date) + 1  
Date of Completion/Withdrawal
The date of completion/withdrawal will be derived as follows:

For subjects who complete the last on-treatment study visit, the date of
completion/withdrawal will be the date of that visit (Visit 9).

For subjects who withdraw from the study, the date of completion/withdrawal will be the 
latest of the date of the last attended scheduled clinic visit (excluding follow-up), the date of 
the EW visit (if present) and the last dose date.
10.6.2.
Study Population
Demographics
Age

Age will be calculated based on the Pre-screening visit date.

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows:
o
Any subject with a missing day will have this imputed as day ‘15’. 
o
Any subject with a missing date and month will have this imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)2


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Smoking Status
At Screening, subjects who were identified as former smokers but who last smoked within 
6 months prior to Screening will be re-classified as current smokers prior to summarizing.  
Subject listings will include original and re-classified status.
During the study, smoking status will be derived from smoking status at Screening and 
records of change in smoking status at visits.  A subject identified as a current smoker at 
Screening who stopped smoking during the study will be assessed as a former smoker 
only at visits which are at least 6 months after the date the subject last smoked. Former 
smokers who started smoking will be considered current smokers at all visits after the date 
the subject started smoking.
In order to assess the last time a subject smoked the partial date will be imputed to earliest 
date within the month or year e.g.  If a subject has only remembered the year they last 
smoked (-----2010) then impute to 01JAN2010. If a subject has remembered the month 
and year that they last smoked (--SEP2010) then impute to 01SEP2010.
Concomitant Medications
COPD concomitant medications will be grouped into the following RMCs based on pre-
defined code lists derived from ATC classifications:
Short-acting anticholinergic  
Short-acting beta-2 agonist
Long-acting anticholinergic
Long-acting beta-2 agonist - Group 1
Long-acting beta-2 agonist - Group 2 (Olodaterol or Indacaterol)
Long-acting beta-2 agonist - Group 3 (Salmeterol and Formoterol)     
Xanthine
PDE4 Inhibitors
Corticosteroid - Inhaled
Corticosteroid - Depot
Corticosteroid - Systemic, oral, parenteral and intra-articular
Corticosteroid - Other
Leukotriene Receptor Antagonist   
Nedocromil or Cromolyn Sodium
Mucolytics
Cytochrome P450 3A4 Strong Inhibitors
Oxygen
Antiinfectives (antibiotics, antifungals, antivirals, antiseptics)
Other medication given for exacerbation 
Other COPD medication
Other
COPD concomitant medications that were stopped more than 30 days prior to Screening 
and non COPD concomitant medications that were stopped prior to Screening will not be 
presented in any tables or listings.
For reporting purposes, the LABA groups will be combined in the concomitant
medication tables. 


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Treatment Compliance
The number of doses of study treatment taken by each subject from each inhaler will be 
calculated from the dose counter start and stop counts for each inhaler used. If a dose 
counter start count is missing then it will be assumed to be 30. If all dose counter stop 
counts are non-missing then the percentage compliance will be calculated as:
Compliance = sum of all (dose counter start – dose counter stop) x 100
               (exposure stop date – exposure start date +1)
If any dose counter stop is missing then the treatment compliance will be set to missing 
for that subject.
Overall compliance will be categorised as follows: 
< 80 %
80 % to < 95 %
95 % to 105 %
>105 % to 120 %
>120 %.
If a subject received a treatment other than the randomised treatment during the study, the 
compliance will still be calculated using data from all containers received and overall 
exposure start and stop dates.
10.6.3.
Safety
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = Overall Treatment Stop Date – Overall Treatment Start 
Date + 1

If there are any treatment breaks during the study, exposure data will be adjusted accordingly.

If overall treatment stop date is missing it will be imputed as follows:

For subjects who attended a Study Treatment Discontinuation visit, use the date of the 
Study Treatment Discontinuation visit

For subjects who attended the last on-treatment visit, use the Visit 8 (Week 24) date.

For subjects who died and did not attend a Study Treatment Discontinuation visit or the last 
on-treatment visit, use the date of death

For all other subjects, use the last recorded exposure start or stop date.

If a subject’s overall exposure start date is missing then it will be assumed to be their Day 1 visit 
date.

If a subject received a treatment other than the randomised treatment during the study, the
exposure will still be calculated based on overall exposure start and stop dates.


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Adverse Events

The most frequent on-treatment AEs will be defined as the on-treatment AEs experienced by 3 
% (after rounding) or more of subjects in any treatment group. 

AE groups of special interest have been defined as AEs which have specified areas of 
interest for UMEC. The following table presents the special interest AE groups and 
subgroups. The complete list, including the PTs which contribute to each of the groups will 
be provided by Global Clinical Safety and Pharmacovigilance (GCSP) using the MedDRA 
version current at the time of reporting. This will be finalized prior to unblinding.
Special Interest AE Group
Special Interest AE Subgroup
Cardiovascular effects
Cardiac Arrhythmia
Cardiac Failure
Cardiac Ischaemia
Hypertension
Stroke
Urinary Retention
Pneumonia
Anticholinergic syndrome
Gastrointestinal obstruction
Hypersensitivity
LRTI excluding pneumonia
Ocular effects (antimuscarinic)
Paradoxical bronchospasm
gallbladder disorders

A flag will be derived to identify on-treatment AEs of special interest. In order to ensure 
consistency with the umeclidinium Global ISS, all outputs will use the same MedDRA version 
(i.e. v 15.0) and the same list of special interest terms as was used for the umeclidinium Global 
ISS.

The AESI category designated as Pneumonia and LRTI will include lower respiratory tract 
infections and related diseases. Also, the category designated as “Anticholinergic Syndrome” 
will be referenced as “Anticholinergic Effects” since the Anticholinergic Syndrome SMQ which 
was used to located terms includes events that are often associated with anticholinergic or 
antimuscarinic medication, but are not necessarily diagnostic for anticholinergic syndrome.  
Laboratory Parameters

The baseline value for a parameter will be the most recent recorded value for that parameter 
before dosing on Day 1 at schedule visit.


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Laboratory Parameters

Laboratory data values will be classified as ‘low’, ‘normal’ or ‘high’ with reference to normal 
ranges.

An ‘any visit post-baseline’ classification will be derived, in which subjects will be counted in the 
‘low’ and ‘high’ categories if they reported a low or high value at any scheduled, unscheduled or 
EW visit made after the start of study treatment, up to a maximum of two weeks after the last 
dose of study treatment. Subjects who did not report a low or high value at any visit after the 
start of study treatment will be counted in the ‘normal’ category.

Change from baseline values will be classified relative to the normal range as ‘to low’, ‘to 
normal or no change’ or ‘to high’. Subjects who do not change categories or move from out-of-
range to normal will be classified as ‘to normal or no change’.

An ‘any visit post-baseline’ change classification will be derived, in which subjects will be 
counted in the ‘to low’ and ‘to high’ categories if they reported a change from a ‘normal’ baseline 
to a value below or above the normal range (respectively) at any scheduled, unscheduled or 
EW visit made after the start of study treatment, up to a maximum of 2 weeks after the last dose 
of study treatment. Subjects who did not report a change to a value outside the normal range at 
any visit after the start of study treatment will be counted in the ‘to normal or no change’ 
category.

If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the 
comment field) is present, the number of significant digits in the observed values will be used to 
determine how much to add or subtract in order to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits = ‘< x ‘ becomes x – 0.01
o
Example 2: 1 Significant Digit =  ‘> x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1    
Vital Signs

The baseline value for a vital sign endpoint will be the most recent recorded value for that 
endpoint before dosing on Day 1 at schedule visit.

The ‘maximum/minimum post-baseline’ value will be the maximum value for pulse rate and 
systolic blood pressure, or the minimum value for diastolic blood pressure, recorded at any 
scheduled, unscheduled or EW visit made after the start of study treatment.
12-Lead ECG

The baseline value for an ECG endpoint will be the most recent recorded value for that endpoint 
before dosing on Day 1 at schedule visit.

A ‘maximum post-baseline’ QTc(F), QTc(B), PR interval and heart rate value will be derived as 
the maximum value recorded at any scheduled, unscheduled or EW visit made after the start of 
study treatment.

QTc(F) values (including ‘maximum post-baseline’) will be categorised as follows:
≤450 msec
> 450 to ≤480 msec
> 480 to ≤500 msec


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12-Lead ECG
> 500 msec.

Change from baseline QTc(F) values (including change to ‘maximum post baseline’) will be 
categorised as follows:
< -60 msec
≥-60 to < -30 msec
≥-30 to < 0 msec
≥0 to < 30 msec
≥30 to < 60 msec
≥60 msec.

An ‘any time post-baseline’ ECG interpretation will be derived as the worst interpretation 
recorded at a scheduled, unscheduled or EW visit made after the start of study treatment.  
The order of severity from worst to best for ECG interpretation is: abnormal: clinically significant, 
abnormal: not clinically significant, normal, unable to interpret.

Any ECG abnormality recorded by a subject with an ECG interpretation of ‘abnormal: clinically 
significant’ after the start of study treatment will be included in an ‘any-time post-baseline’ 
record of ECG abnormalities. 

Any ECG abnormality recorded by a subject after the start of study treatment will be included in 
an ‘any-time post-baseline’ record of all ECG abnormalities.
10.6.4.
Health- Related Quality of Life
St. George’s Respiratory Questionnaire

The SGRQ contains 76 items grouped into three domains (Symptoms, Activity and Impacts).  
The domain score will be calculated as the sum of the weighted scores for the non-missing 
items within each domain, dividing by the maximum possible score for those non-missing items 
and multiplying by 100. The SGRQ total score will be calculated as the sum of the weighted 
scores from all 76 items and dividing by the maximum possible score for the SGRQ and 
multiplying by 100. This calculation is outlined in the developer's guide (St. George’s 
Respiratory Questionnaire Manual, 2009).

If a subject has more than one response to a given item at a particular time point then the 
response will be taken as the average of the responses prior to calculating domain and total 
scores.

If a subject has given both responses to a dichotomous question (yes/ no, true/false) the
response to that question will be set to missing.

If more than 25 % of items are missing from a domain, then the domain total will be set to 
missing. This equates to no more than two missed questions for the Symptom domain, no more 
than four missed questions for the Activity domain and no more than six missed questions for 
the Impacts domain. If any domain score is missing, then the total score will be set to missing.

If the language of the SGRQ conducted during the study is different to the language used at 
Day 1, all SGRQ scores will be set to missing.

The baseline SGRQ domain and total scores are those recorded on Day 1.

A subject will be considered a ‘responder’ according to his SGRQ total score at each visit if the 
difference from the visit score to the baseline score was -4 units or lower. A subject will be 


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St. George’s Respiratory Questionnaire
considered a ‘non-responder’ if the difference from the visit score to the baseline score was 
greater than -4 units.  .

For the classification of responders, subjects with missing SGRQ total scores will be handled as 
detailed in Section 10.7.2.1 (Handling of Missing Responder).
CAT

The CAT consists of eight items each formatted as a six-point differential scale: 0 (no 
impact) to 5 (high impact). A CAT score will be calculated by summing the non-missing
scores on the eight items. If one or two items are missing, then the score for those items is 
set as the average of the non-missing items. If more than two items are missing, then the 
CAT score will be set to missing.

The baseline CAT score will be that recorded on Day 1.

A subject will be a responder if their on-treatment CAT score has decreased at least 2 units 
from baseline CAT total score.

A subject will be considered a non-responder if their on-treatment CAT score has 
decreased by less than 2 units, has not changed, or has increased compared to baseline.

For the classification of responders will be handled as detailed in Section 10.7.2.1
(Handling of Missing Responder).
Healthcare Resource Utilisation

The total number of visits for each type of healthcare contact (telephone contacts, home visits 
(day), home visits (night), office/practice visits, urgent care/outpatient clinic visits, emergency 
room visits and the number of days in intensive care and in general hospital wards will be 
derived.
10.6.5.
Efficacy
Post-ipratropium FEV1

The difference between post-ipratropium FEV1 and pre-salbutamol FEV1 will be calculated.
Reversibility and GOLD Stage

A subject’s responsiveness to salbutamol at Screening will be classified as ‘Reversible’ or ‘Non-
reversible’ based on the difference between their pre-salbutamol assessment of FEV1 and their 
post-salbutamol assessment of FEV1 as follows:
o
Reversible, if they had an difference in FEV1 of ≥12 % and ≥200 mL, or
o
Non-reversible, if they had a difference in FEV1 of < 200 mL or a ≥200 mL difference that 
was <12 % of the pre-salbutamol FEV1.  

A subject’s responsiveness to salbutamol and ipratropium at Screening will be classified as 
‘Reversible’ or ‘Non-reversible’ based on the difference between their pre-salbutamol
assessment of FEV1 and their post-ipratropium assessment of FEV1 as follows:
o
Reversible, if they had a difference in FEV1 of ≥12 % and ≥200 mL, or
o
Non-reversible, if they had a difference in FEV1 of < 200 mL or a ≥200 mL difference that 


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was < 12 % of the pre-salbutamol FEV1.  

Subjects will be classified according to Global Initiative for Chronic Obstructive Lung Disease 
(GOLD) stage (GOLD classification, [GOLD, 2011]): defined using the post-salbutamol percent 
predicted FEV1 assessed at Screening (Visit 1). Subjects will be classified as:
o GOLD1: Mild FEV1 ≥80% predicted
o GOLD 2: Moderate 50% ≤FEV1 < 80% predicted
o GOLD3: Severe 30% ≤FEV1 < 50% predicted
o GOLD4: Very Severe FEV1 <30% predicted
Trough FEV1 and FVC

The trough value for FEV1 and FVC at each of Days 2, 28, 56, 84, 112, 168 and 169 is 
calculated from the values at the assessments made 23 h and 24 h after dosing on the previous 
day. If the actual time of an assessment is after the time of dosing on the current day, the value 
will not be used in the calculation of trough. For the PP population, a value will additionally be 
excluded from the trough calculation if the assessment is outside the time window of 22.5-24.5 
h after dosing on the previous day (see Section 10.1.2 (Exclusions of Data from Per Protocol 
Analyses)). If one of the values is missing or excluded then the trough will be the single 
remaining value; otherwise the trough will be the mean of the two values.
BDI/TDI

The baseline dyspnoea index (BDI) focal score will be calculated as the sum of the ratings 
recorded for each of the three individual scales (Baseline Functional Impairment, Baseline 
Magnitude of Task, Baseline Magnitude of Effort). Each of these scales has five possible scores 
ranging from 0 to 4 (with lower scores indicating more impairment), so the range of the BDI 
focal score is 0 to 12.  If a score is missing (or has a value of W, X or Y) for any of the three 
scales, then the BDI focal score will be set to missing.

The TDI focal score will be calculated as the sum of the ratings recorded for each of the three 
individual scales (Change in Functional Impairment, Change in Magnitude of Task, Change in 
Magnitude of Effort). Each of these scales has seven possible scores ranging from -3 (major 
deterioration) to +3 (major improvement), so the range of the TDI focal score is -9 to +9.  If a 
score is missing (or has a value of Z) for any of the three scales, then the TDI focal score will be 
set to missing.

A subject will be considered a ‘responder’ according to TDI at each visit if the TDI focal score 
was at least 1 unit at that visit.  A subject will be considered a ‘non-responder’ if the score was 
less than 1 unit.

For the classification of responders, subjects with missing TDI assessments will be handled as 
detailed in Section 10.7.2.1 (Handing of Missing Responder).
Weighted Mean FEV1 and FVC

Weighted mean FEV1 and FVC will be calculated over the nominal 0-6 h post dose period.  
Values from post-dose assessments which are actually before the time of dosing will be 
excluded from the calculation. 

The 0 h value is the average value obtained 30 min and 5 min pre-dose, and both the 0 h and 6 
h values must be present for a 0-6 h weighted mean to be calculated.

The 0-6 h weighted mean will be derived by calculating the area under the FEV1 or FVC/time 


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Weighted Mean FEV1 and FVC
curve over the nominal time points of 0 h (as defined above), 15 and 30 min, 1, 3 and 6 h, using 
the trapezoidal rule, and then dividing by the actual time between dosing and the 6 h 
assessment. For post-dose observations the actual time of assessment relative to the time of 
dosing will be used for the calculation.
Weighted Mean (0-6h) 


f
l
i
I
i
i
i
i
t
t
y
y
t
t













/
)
)(
(
2
1
1
1
1
1
where
yi represents the value of the endpoint at the ith timepoint,
ti represents the actual relative time at the ith timepoint,
tf represents the actual relative time at the first timepoint (tf = 0 as the pre-dose measurement is 
used),
tl represents the actual relative time at the last timepoint (the 6h timepoint),
I represents the number of timepoints used in the AUC calculation. 
If missing values are present in data required for the calculation of the weighted means, the 
following approach will be employed:

If more than a third of the observations are missing then the weighted mean will be set to 
missing for that subject. 

If an observation is missing between two non-missing observations, the value will be
interpolated between the two non-missing values.

If there are two or more missing points that occur consecutively then the weighted mean will be 
set to missing.

If the first time-point is missing then the weighted mean will be set to missing.

If the last time-point is missing then the weighted mean will be set to missing.
Rescue Use

For rescue use, ‘day’ refers to the period (24 hours) between one record of rescue use and the 
next in the database.

The total puffs of rescue for each day will be calculated as number of salbutamol puffs. If the
number of puffs are missing then the total puffs will be set to missing for that day.

Rescue use will be summarised over the periods defined in below table: 
Period
First day
Last day
Baseline
Latest of 6 days before Visit 2 
and day after Visit 1
Day of Visit 2
Week 1-4
Study day 2 (day after Visit 2)
Study day 29
Week 5-8
Study day 30
Study day 57


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Rescue Use
Week 9-12
Study day 58
Study day 85
Week 13-16
Study day 86
Study day 113
Week 17-20
Study day 114
Study day 141
Week 21-24
Study day 142
Earliest of Study day 169 and day before Visit 
9
Week 1-24
Study day 2 (day after Visit 2)
Earliest of Study day 169 and day before Visit 
9

For each summary period, the mean number of puffs per day and the percentage of rescue-free 
days will be calculated, provided at least half the days within the summary period have non-
missing values for the endpoint.

Any data recorded after study day 169 (but before Visit 9) will not be included in any 
summaries.
Time to Onset on Day 1

The time to onset on Day 1 is calculated as the time (both nominal and actual) that the first 
post-dose FEV1 during the 0-6 h post-dose period is ≥100 mL above baseline FEV1. Post-dose 
assessments that are actually pre-dose will be considered missing in the calculation.

Subjects who have at least one FEV1 assessment within the 0-6 h post-dose period but do not 
achieve a ≥100 mL increase from baseline over 0-6 h post-dose will be considered censored.
Increase in FEV1 of ≥12% and ≥200 mL above Baseline at any
Time During 0-6 h Post-dose on Day 1

A flag will be derived to identify whether or not a subject achieved an increase in FEV1 of ≥12% 
and ≥200 mL above baseline at any time during 0-6 h post-dose on Day 1. The flag will have 
values as follows:
o 1, if any FEV1 value recorded at 15 or 30 min, 1, 3 or 6 h was ≥12 % and ≥200 mL above 
baseline.
o 0, if no FEV1 value recorded at 15 or 30 min, 1, 3 or 6 h was ≥12 % and ≥200 mL above 
baseline.
Increase of ≥100 mL above Baseline in Trough FEV1

A flag will be derived to identify whether or not a subject achieved an increase of ≥100 mL 
above baseline in trough FEV1 at each of Days 2, 28, 56, 84, 112, 168 and 169. The flag will 
have values as follows:
o 1, if the trough FEV1 was ≥100 mL above baseline.
o 0, if the trough FEV1 was < 100 mL above baseline, or the trough FEV1 was missing with 
no subsequent non-missing trough FEV1 values.
o Missing, if the trough FEV1 was missing but subsequent trough FEV1 values were non-
missing.


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10.7.
Appendix 7: Premature Withdrawals & Handling of Missing 
Data
10.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as on 
completion of final on-treatment clinic visit (Visit 9). 

Withdrawn subjects will not be replaced in the study.

All available data from subjects 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.

In general, the minimum data required will be a baseline evaluation and at least 
one post-baseline evaluation.

If a subject withdraws at a scheduled treatment visit, then any data collected at 
that visit associated with scheduled visit procedures will be used (under the 
scheduled visit assignment) in all summaries and analyses wherever possible.

All other data collected as part of the early withdrawal at a scheduled visit, or at 
a standalone EW visit, will only be used in summary or analysis tables as part of 
the ‘worst case post baseline’ summary/analysis.

Early withdrawal data will be included in any relevant listing.
10.7.2.
Handling of Missing Data
Element
Reporting Detail
General

For efficacy endpoints, missing data is expected to arise mainly from subjects 
missing complete visits or time points.  

The amount of occasional missing data for covariates included in the statistical 
analysis is expected to be minimal. Missing data will not be directly imputed in 
primary analysis of each endpoint.

For analysis of trough FEV1 at Day 169, sensitivity analyses with LOCF will be 
produced for supportive analysis.
Outliers

Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
10.7.2.1.
Handling of Missing Responder
Element
Reporting Detail
Responder 

Subjects with missing data and a subsequent non-missing assessment will not 
be considered a responder or non-responder but will be left as missing.

Subjects with missing data and no subsequent assessments will be considered 
a non-responder.

No extra visits will be added and no imputation performed in the original dataset.

The analysis dataset will initially contain rows for each visit at which at least one 


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Element
Reporting Detail
derived variable (excluding baseline) is able to be calculated. For these rows, 
IMPFLAG will be 1 (not imputed).

For subjects who do not provide data at the final visit, additional rows will be 
created for each subsequent visit after their final visit (i.e. their time of 
withdrawal) with non-missing data which is planned to be included in the 
responder analysis. For these rows, IMPFLAG will be 0 (imputed) and 
responder status will be ‘Non-responder’.

If the final visit containing non-missing data does not provide enough data to 
calculate the derived variable on which the responder status is based (e.g. some 
domains of the SGRQ are present but not all, so the total score cannot be 
created), then IMPFLAG will be changed to 0 (imputed) and responder status 
will be ‘Non-responder’ on that row.

Apart from derived FEV1 and FVC, the listings should not contain any rows 
where all the derived variables are missing, except for the rows which are 
imputed. (The FEV1 listing may have a blank row between two non-missing 
rows because all FEV1 derived variables are missing but FVC derived variables 
are present – IMPFLAG should still be 1 for these rows.)

If the baseline value is missing, or there are no post-baseline non-missing 
assessments, no imputation will be performed

No visits will be imputed if they are between two visits with non-missing 
assessments
10.7.2.2.
Handing of Missing Dates
Element
Reporting Detail
General

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.
10.7.2.3.
Handling of Partial Dates
Element
Reporting Detail
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:
o If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month
o If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.
Adverse 
Events

Any partial dates for adverse events will be raised to data management. If the 
full date cannot be ascertained, the following assumptions will be made:
o If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month. 


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Element
Reporting Detail
o However, if these results in a date prior to Week 1 Day 1 and the event 
could possibly have occurred during treatment from the partial information, 
then the Week 1 Day 1 date will be assumed to be the start date. 
o
The AE will then be considered to start on-treatment (worst case).
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the 
month, unless this is after the stop date of study treatment; in this case 
the study treatment stop date will be used.

The recorded partial date will be displayed in listings.
10.7.2.4.
Handling of Missing Data for Statistical Analysis
Element
Reporting Detail
MMRM

Missing data will not be directly imputed in this analysis; however, all non-
missing data for a subject will be used within the analysis to estimate the 
treatment effect
ANCOVA

For analysis of trough FEV1 at Day 169, sensitivity analyses with LOCF to 
imputed missing data will be produced for supportive analysis.

Missing data will not be imputed for other analysis. 
Cox’s 
proportional
Analysis

Missing data will not be imputed.
Logistic 
regression
Analysis

Missing data will not be imputed.


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10.8.
Appendix 8: Values of Potential Clinical Importance
10.8.1.
Laboratory Values
Threshold values for liver function test results, which are considered values of potential 
clinical importance, are:

3 times the upper limit of normal (ULN) for Alanine Aminotransferase (ALT)

2 times the ULN for Total Bilirubin (BILT).
Graphical displays of liver function test results will be produced as described in Section 
8.2 (Clinical Laboratory Analyses) to identify any results above the thresholds.
Laboratory values will be flagged relative to the normal range. Clinical concern ranges 
will not be used. 
10.8.2.
ECG
Clinical concern ranges will not be used. 
10.8.3.
Vital Signs
Clinical concern ranges will not be used.


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10.9.
Appendix 9: Multicenter Studies
This study was randomized centrally within country. No strata were defined.
Country will be considered a fixed effect in all analyses on overall population. For 
primary efficacy analysis, interaction with treatment will be explored by fitting a model 
with an additional treatment by country interaction term; any interaction found to be 
statistically significant at the 10 % level will be further investigated and characterised. 
Center will not be included as a covariate in China subgroup statistical analyses.
All results will be produced for all countries combined.  In addition, summary statistics 
of demography, screening lung function, primary and secondary endpoints will be 
produced by country.


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10.10.
Appendix 10: Examination of Covariates, Subgroups & 
Other Strata
The details of covariates that will be used in statistical analyses have been clarified in 
Section 7.1 (Primary Statistical Analyses), Section 7.2 (Secondary Statistical Analyses) 
and Section 7.3 (Other Statistical Analyses).  
Consistency of treatment effect across covariates fitted in the primary efficacy endpoint 
analysis models will be examined by fitting separate models to examine treatment by 
baseline, treatment by country (not done for China alone sub-group analysis) and 
treatment by smoking status at screening interactions. Separate analysis models will also 
be fitted to examine treatment by ICS use, treatment by reversibility to salbutamol and 
treatment by percent predicted FEV1.
No formal statistical analysis of sub-groups of the study population for either the overall 
analysis or the China subgroup analysis will be performed.  


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10.11.
Appendix 11: Multiple Comparisons & Multiplicity
There is no adjustment for multiplicity to be applied in this study for the analysis on all 
countries overall as there is only one primary endpoint (Clinic visit trough (pre-
bronchodilator) FEV1 on Treatment Day 169) and only one primary comparison
( UMEC62.5 mcg vs. placebo) of interest. Treatment comparisons for secondary and 
other endpoints will be considered exploratory. 
For China subgroup analysis, as the China subgroup analysis is powered, the inference on 
the primary endpoint on China subgroup is dependent on statistical significance having 
been achieved for the primary endpoint on the analysis on all countries overall. Treatment 
comparisons for secondary and other endpoints in China subgroup analysis will also be 
considered exploratory. 


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10.12.
Appendix 12: Model Checking and Diagnostics for 
Statistical Analyses
10.12.1.
Statistical Analysis Assumptions
Endpoint(s)

Trough FEV1

Trough FVC

TDI Focal Score

Serial FEV1

Serial FVC
Analysis

MMRM
O The Kenward and Roger method (KR) for approximating the denominator degrees of 
freedom and correcting for bias in the estimated variance-covariance of the fixed effects 
will be used.  
O In the event the model fails to run using the KR method, then the residual method 
will be used instead.
o
Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the 
fitted values (i.e. checking the normality assumption and constant variance assumption of 
the model respectively) to gain confidence that the model assumptions are reasonable.
Endpoint(s)

0-6 h weighted mean FEV1 on Day 1

Mean number of puffs of rescue medication per day over each treatment period

Pulse rate

Systolic

Diastolic blood pressure

QTc(F)

PR interval

Heart rate
Analysis

ANCOVA
Distributional assumptions underlying the model used for analysis will be examined by obtaining a 
normal probability plot of the residuals and a plot of the residuals versus the fitted values (i.e. 
checking the normality assumption and constant variance assumption of the model respectively) to 
gain confidence that the model assumptions are reasonable.
Endpoint(s)

Time to Onset (an increase of 100mL in FEV1 above baseline) during 0-6 h 
post-dose on Day 1

Time to First COPD Exacerbation
Analysis

Cox’s proportional hazards model
The proportional hazards assumption for this method of analysis will be examined by 
obtaining the Kaplan-Meier estimates of the survival function S(t) over time separately for 
treatment group.  Under the assumption of proportional hazard between the treatment 


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groups,  ln{−ln[S(t)]} for the two groups should be parallel to each other and the distance 
between them constant. If the curves are approximately parallel, then the proportional 
hazard assumption is not violated. If these curves cross each other or diverge greatly from 
the assumption of parallel lines, then the assumption is not met.
Endpoint(s)

Proportion Achieving Increase in FEV1 of ≥12 % and ≥200 mL above Baseline 
at any Time During 0-6 h Post-dose on Day 1

Proportion Achieving Increase of ≥100 mL above Baseline in Trough FEV1

Proportion of Responders According to TDI Focal Score
Analysis

Logistic regression model

Computation of confidence intervals for the odds ratios is based on the individual Wald tests.

BUD/FOR will be used as the reference level for treatment

Goodness-of-fit of the logistic model will be examined using the LACKFIT option for the model 
statement in SAS.  Index plots of the Pearson residuals and deviance criteria residuals will be 
plotted by using the IPLOTS option for the model statement in SAS.


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10.13.
Appendix 13 – Abbreviations & Trade Marks
10.13.1.
Abbreviations
Abbreviation
Description
AE
Adverse Event
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
IA
Interim Analysis
ICH
International Conference on Harmonisation
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
GUI
Guidance
MMRM
Mixed Model Repeated Measures
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
QC
Quality Control
QTcF
Frederica’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
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
GSK
GlaxoSmithKline


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10.13.2.
Trademarks
Trademarks of the 
GlaxoSmithKline 
Group of Companies
Trademarks not 
owned by the 
GlaxoSmithKline 
Group of Companies
HARP
SAS
RAMOS
S-PLUS
RANDALL


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10.14.
Appendix 14: List of Data Displays
10.14.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population (Overall Analysis)
1.1 to 1.37
1.1 to 1.1
Study Population (China Subgroup 
Analysis)
1.1 to 1.35
1.1 to 1.1
Efficacy(Overall Analysis)
2.1 to 2.56
2.1 to 2.21
Efficacy (China Subgroup Analysis)
2.1 to 2.49
2.1 to 2.21
Safety (Overall Analysis)
3.1 to 3.48
3.1 to 3.17
Safety (China Subgroup Analysis)
3.1 to 3.48
3.1 to 3.17
Section
Listings
ICH Listings
1 to 25
Other Listings
26 to 54
10.14.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required an example 
mock-up displays provided in Appendix 15: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Efficacy
NA
NA
EFF_L1
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / TST ID / Example Shell’ or ‘Programming Notes’ column as 
‘[Non-Standard] + Reference.’
10.14.3.
Deliverable [Priority]
Delivery [Priority] [1]
Description
SAC [1]
Final Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort.


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10.14.4.
Study Population Tables
Study Population Tables
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming 
Notes
Deliverable 
[Priority]
1.1.
1.1.
All Subjects 
Enrolled
DB2114634
5.01
Summary of Subject Populations
SAC
1.2.
1.2.
Modified ITT
DB2114634
5.09
Summary of Exclusions from the Per Protocol Analysis
SAC
1.3.
1.3.
Modified ITT
DB2114634
5.02
Summary of Attendance at Each Clinic Visit
SAC
1.4.
1.4.
Modified ITT
DB2114634
5.03
Summary of Subject Disposition
SAC[1]
1.5.
1.5.
Screen and 
Run-in Failure
DB2114634
5.04
Summary of Reasons for Screen Failures 
SAC
1.6.
1.6.
Screen and 
Run-in Failure
DB2114634
5.05
Summary of Reasons for Run-in Failures
SAC
1.7.
1.7.
Modified ITT
DB2114634
5.06
Summary of Number of Subjects by Country and Centre
For China subgroup, 
Country will be omitted 
from the title.
SAC
1.8.
1.8.
Screen and 
Run-in Failure
DB2114634
5.07
Summary of Inclusion/Exclusion/Randomisation Criteria 
Deviations for Screen or Run-in Failures
SAC
1.9.
1.9.
Modified ITT
DB2114634
5.08
Summary of Inclusion/Exclusion/Randomisation Criteria 
Deviations for Modified Intent-to-treat Subjects
SAC


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Study Population Tables
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming 
Notes
Deliverable 
[Priority]
1.10.
1.10.
Modified ITT
DB2114634
5.09
Summary of Important Protocol Deviations
Remove rows of Full 
Protocol Deviations, 
Partial Protocol 
Deviations and Time-
point Specific Protocol 
Deviations and 
summarize all PDs 
with DVIMPFL marked 
as "Y".
SAC
1.11.
1.11.
Modified ITT
DB2114634
5.10
Summary of Demographic Characteristics
SAC[1]
1.12.
NA
Modified ITT
DB2114634
5.11
Summary of Demographic Characteristics by Country
SAC
1.13.
1.12.
PP
DB2114634
5.12
Summary of Demographic Characteristics
SAC
1.14.
1.13.
Modified ITT
DB2114634
5.13
Summary of Race and Racial Combinations
SAC
1.15.
1.14.
Modified ITT
DB2114634
5.14
Summary of Race and Racial Combination Details
SAC
1.16.
1.15.
Modified ITT
DB2114634
5.15
Summary of Current Medical Conditions
SAC


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Study Population Tables
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming 
Notes
Deliverable 
[Priority]
1.17.
1.16.
Modified ITT
DB2114634
5.16
Summary of Past Medical Conditions
SAC
1.18.
1.17.
Modified ITT
DB2114634
5.17
Summary of Past Cholecystectomies
SAC
1.19.
1.18.
Modified ITT
DB2114634
5.18
Summary of Family History of Cardiovascular Risk 
Factors
SAC
1.20.
1.19.
Modified ITT
DB2114634
5.19
Summary of COPD History
SAC
1.21.
1.20.
Modified ITT
DB2114634
5.20
Summary of COPD Exacerbation History 
SAC
1.22.
1.21.
Modified ITT
DB2114634
5.21
Summary of Smoking History 
SAC
1.23.
1.22.
Modified ITT
DB2114634
5.22
Summary of Smoking Status
SAC
1.24.
1.23.
Modified ITT
DB2114634
5.23
Summary of Screening Lung Function Test Results
SAC
1.25.
NA
Modified ITT
DB2114634
5.24
Summary of Screening Lung Function Test Results by 
Country/Region
SAC


CONFIDENTIAL
AC4117410
73
Study Population Tables
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming 
Notes
Deliverable 
[Priority]
1.26.
1.24.
Modified ITT
DB2114634
5.25
Summary of GOLD Stage, Percentage of Reversible 
Subjects and ICS Use at Screening 
SAC
1.27.
1.25.
Modified ITT
DB2114634
5.26
Summary of mMRC Dyspnoea Scale
SAC
1.28.
1.26.
Modified ITT
DB2114634
5.27
Summary of COPD Concomitant Medications Not Given 
for an Exacerbation Taken Pre-treatment
SAC
1.29.
1.27.
Modified ITT
DB2114634
5.28
Summary of COPD Concomitant Medications Not Given 
for an Exacerbation Taken On-treatment
SAC
1.30.
1.28.
Modified ITT
DB2114634
5.29
Summary of COPD Concomitant Medications Not Given 
for an Exacerbation Taken Post-treatment
SAC
1.31.
1.29.
Modified ITT
DB2114634
5.30
Summary of Concomitant Medications Given for an 
Exacerbation Taken Pre-treatment
SAC
1.32.
1.30.
Modified ITT
DB2114634
5.31
Summary of Concomitant Medications Given for an 
Exacerbation Taken On-treatment
SAC
1.33.
1.31.
Modified ITT
DB2114634
5.32
Summary of Concomitant Medications Given for an 
Exacerbation Taken Post-treatment
SAC
1.34.
1.32.
Modified ITT
DB2114634
5.33
Summary of Non-COPD Concomitant Medications Taken 
Pre-treatment
SAC


CONFIDENTIAL
AC4117410
74
Study Population Tables
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming 
Notes
Deliverable 
[Priority]
1.35.
1.33.
Modified ITT
DB2114634
5.34
Summary of Non-COPD Concomitant Medications Taken 
On-treatment
SAC
1.36.
1.34.
Modified ITT
DB2114634
5.35
Summary of Non-COPD Concomitant Medications Taken 
Post-treatment 
SAC
1.37.
1.35.
Modified ITT
DB2114634
5.36
Summary of Overall Percentage Treatment Compliance
SAC


CONFIDENTIAL
AC4117410
75
10.14.5.
Study Population Figures
Study Population: Figures
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.1
1.1
Modified ITT
DB2114634
5.01
Subject Withdrawals over Time
SAC


CONFIDENTIAL
AC4117410
76
10.14.6.
Efficacy Tables
Efficacy: Tables
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming 
Notes
Deliverable 
[Priority]
2.1.
2.1
Modified ITT
DB2114634
6.01
Summary of Baseline FEV1 (L), Modified Intent-to-treat
SAC[1]
2.2.
NA
Modified ITT
DB2114634
6.02
Summary of Baseline FEV1 (L) by Country/Region, 
Intent-to-treat
SAC
2.3.
2.2
Modified ITT
DB2114634
6.03
Summary of Trough FEV1 (L), Modified Intent-to-treat
SAC[1]
2.4.
NA
Modified ITT
DB2114634
6.04
Summary of Trough FEV1 (L) by Country/Region,
Modified Intent-to-treat
SAC
2.5.
2.3
Modified ITT
DB2114634
6.05
Analysis of Trough FEV1 (L), Modified Intent-to-treat, 
Repeated Measures
SAC[1]
2.6.
2.4
PP
DB2114634
6.06
Summary of Baseline FEV1 (L), Per Protocol
SAC
2.7.
NA
PP
DB2114634
6.07
Summary of Baseline FEV1 (L) by Country/Region, Per 
Protocol
SAC
2.8.
2.5
PP
DB2114634
6.08
Summary of Trough FEV1 (L), Per Protocol
SAC
2.9.
NA
PP
DB2114634
6.09
Summary of Trough FEV1 (L) by Country/Region, Per 
Protocol
SAC
2.10.
2.6
PP
DB2114634
6.10
Analysis of Trough FEV1 (L), Per Protocol, Repeated 
Measures
SAC


CONFIDENTIAL
AC4117410
77
Efficacy: Tables
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming 
Notes
Deliverable 
[Priority]
2.11.
2.7
Modified ITT
HZC113684 
6.07
Summary of Trough FEV1 (L) at Day 169 LOCF
SAC
2.12.
2.8
Modified ITT
HZC113684 
6.08
Statistical Analysis of Trough FEV1 (L) at Day 169 using 
LOCF
SAC
2.13.
2.9
Modified ITT
DB2114634
6.11
Summary of 0-6 h Weighted Mean FEV1 (L)
SAC
2.14.
NA
Modified ITT
DB2114634
6.12
Summary of 0-6 h Weighted Mean (L) by Country/Region
SAC
2.15.
2.10
Modified ITT
DB2114634
6.13
Analysis of 0-6 h Weighted Mean FEV1 (L)
SAC
2.16.
2.11
Modified ITT
DB2114634
6.14
Summary of Time to Onset (an increase of 100mL in 
FEV1 above baseline) on Day 1
SAC
2.17.
2.12
Modified ITT
DB2114634
6.15
Analysis of Time to Onset (min) (an increase of 100mL in 
FEV1 above baseline) on Day 1
SAC
2.18.
2.13
Modified ITT
DB2114634
6.16
Summary and Analysis of Proportion of Subjects 
Achieving Increase in FEV1 of >= 12 % and >= 200 mL 
above Baseline at Any Time during 0-6 h Post-dose on 
Day 1
SAC
2.19.
2.14
Modified ITT
DB2114634
6.17
Summary and Analysis of Proportion of Subjects 
Achieving Increase in Trough FEV1 of >= 100 mL above 
Baseline
SAC
2.20.
2.15
Modified ITT
DB2114634
6.18
Summary of Serial FEV1 (L)
SAC


CONFIDENTIAL
AC4117410
78
Efficacy: Tables
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming 
Notes
Deliverable 
[Priority]
2.21.
2.16
Modified ITT
DB2114634
6.19
Summary of Change from Baseline in Serial FEV1 (L)
SAC
2.22.
2.17
Modified ITT
DB2114634
6.20
Analysis of Serial FEV1 (L) on Day 1
SAC
2.23.
2.18
Modified ITT
DB2114634
6.21
Summary of Baseline FVC (L)
SAC
2.24.
2.19
Modified ITT
DB2114634
6.22
Summary of Trough FVC (L)
SAC
2.25.
2.20
Modified ITT
DB2114634
6.23
Analysis of Trough FVC (L)
SAC
2.26.
2.21
Modified ITT
DB2114634
6.24
Summary of Serial FVC (L)
SAC
2.27.
2.22
Modified ITT
DB2114634
6.25
Summary of Change from Baseline in Serial FVC (L)
SAC
2.28.
2.23
Modified ITT
DB2114634
6.26
Analysis of Serial FVC (L) on Day 1
SAC
2.29.
2.24
Modified ITT
DB2114634
6.27
Summary of Percentage of Rescue-Free Days
SAC
2.30.
2.25
Modified ITT
DB2114634
6.28
Summary of Mean Number of Puffs of Rescue Medication 
per Day
SAC
2.31.
2.26
Modified ITT
DB2114634
6.29
Analysis of Mean Number of Puffs of Rescue Medication 
per Day
SAC


CONFIDENTIAL
AC4117410
79
Efficacy: Tables
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming 
Notes
Deliverable 
[Priority]
2.32.
2.27
Modified ITT
DB2114634
6.30
Summary of BDI Focal Score
SAC[1]
2.33.
NA
Modified ITT
DB2114634
6.31
Summary of BDI Focal Score by Country/Region
SAC
2.34.
2.28
Modified ITT
DB2114634
6.32
Summary of TDI Focal Score
SAC[1]
2.35.
NA
Modified ITT
DB2114634
6.33
Summary of TDI Focal Score by Country/Region
SAC
2.36.
2.29
Modified ITT
DB2114634
6.34
Analysis of TDI Focal Score, Repeated Measures
SAC[1]
2.37.
2.30
Modified ITT
DB2114634
6.35
Summary and Analysis of Proportion of Responders 
According to TDI
SAC
2.38.
2.31
Modified ITT
DB2114634
6.36
Summary of Baseline SGRQ Scores
SAC
2.39.
2.32
Modified ITT
DB2114634
6.37
Summary of SGRQ Total Score
SAC
2.40.
2.33
Modified ITT
DB2114634
6.38
Summary of SGRQ Symptoms Domain Score
SAC
2.41.
2.34
Modified ITT
DB2114634
6.39
Summary of SGRQ Activity Domain Score
SAC
2.42.
2.35
Modified ITT
DB2114634
6.40
Summary of SGRQ Impacts Domain Score
SAC


CONFIDENTIAL
AC4117410
80
Efficacy: Tables
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming 
Notes
Deliverable 
[Priority]
2.43.
2.36
Modified ITT
DB2114634
6.41
Analysis of SGRQ Total Score
SAC
2.44.
2.37
Modified ITT
DB2114634
6.42
Summary and Analysis of Proportion of Responders 
According to SGRQ Total Score
SAC
2.45.
2.38
Modified ITT
DB2114634
6.43
Summary of Healthcare Resource Utilisation
SAC
2.46.
2.39
Modified ITT
DB2114634
6.44
Summary of Baseline CAT Score
SAC
2.47.
2.40
Modified ITT
DB2114634
6.45
Summary of CAT Score 
SAC
2.48.
2.41
Modified ITT
DB2114634
6.41
Analysis of CAT Score
SAC
2.49.
2.42
Modified ITT
DB2114634
6.42
Summary and Analysis of Proportion of Responders 
According to CAT Score up to Week 24
SAC
2.50.
2.43
Modified ITT
DB2114634
6.46
Summary of On-treatment COPD Exacerbations
SAC
2.51.
2.44
Modified ITT
DB2114634
6.47
Summary of Post-treatment COPD Exacerbations
SAC
2.52.
2.45
Modified ITT
DB2114634
6.48
Summary and Analysis of Time to First On-treatment 
Exacerbation (days)
SAC
Stats Appendix
2.53.
2.46
Modified ITT
DB2114634
10.01
Type III Tests of Fixed Effects for Repeated Measures 
Analysis of Trough FEV1
SAC


CONFIDENTIAL
AC4117410
81
Efficacy: Tables
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming 
Notes
Deliverable 
[Priority]
2.54.
2.47
Modified ITT
DB2114634
10.02
Covariance Parameter Estimates for Repeated Measures 
Analysis of Trough FEV1
SAC
2.55.
2.48
Modified ITT
DB2114634
10.03
Significance Levels for Interactions of Treatment with 
Smoking Status, country and Baseline for Trough FEV1
SAC
2.56.
2.49
Modified ITT
DB2114634
10.04
Significance Levels for Interactions of Treatment with ICS 
Use, Reversibility, Percent Predicted FEV1 for Trough 
FEV1
SAC


CONFIDENTIAL
AC4117410
82
10.14.7.
Efficacy Figures
Efficacy: Figures
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.1.
2.1
Modified
ITT
DB2114634
6.01
Box Plot of Change from Baseline in Trough FEV1 (L) at Day 169
SAC
2.2.
2.2
Modified
ITT
DB2114634
6.02
Empirical Distribution Function Plot of Change from Baseline in 
Trough FEV1 (L) at Day 169
SAC
2.3.
2.3
Modified
ITT
DB2114634
6.03
Least Squares Mean (95% CI) Change from Baseline in Trough 
FEV1 (L), Modified Intent-to-treat
SAC
2.4.
2.4
Modified
ITT
DB2114634
6.04
Least Squares Mean (95% CI) Treatment Differences from 
Placebo in Change from Baseline in Trough FEV1 (L), Modified
Intent-to-treat
SAC
2.5.
2.5
PP
DB2114634
6.05
Least Squares Mean (95% CI) Change from Baseline in Trough 
FEV1 (L), Per Protocol
SAC
2.6.
2.6
PP
DB2114634
6.06
Least Squares Mean (95% CI) Treatment Differences from 
Placebo in Change from Baseline in Trough FEV1 (L), Per 
Protocol
SAC
2.7.
2.7
Modified
ITT
DB2114634
6.07
Kaplan-Meier Estimates of Time to Onset (min) on Day 1
SAC
2.8.
2.8
Modified
ITT
DB2114634
6.08
Least Squares Mean (95% CI) Change from Baseline in FEV1 (L) 
Over Time on Day 1
SAC
2.9.
2.9
Modified
ITT
DB2114634
6.09
Least Squares Mean (95% CI) Treatment Differences from 
Placebo in Change from Baseline in FEV1 (L) Over Time on Day 
1
SAC
2.10.
2.10
Modified
ITT
DB2114634
6.10
Least Squares Mean (95% CI) Change from Baseline in Trough 
FVC (L)
SAC


CONFIDENTIAL
AC4117410
83
Efficacy: Figures
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.11.
2.11
Modified
ITT
DB2114634
6.11
Least Squares Mean (95% CI) Treatment Differences from 
Placebo in Change from Baseline in Trough FVC (L)
SAC
2.12.
2.12
Modified
ITT
DB2114634
6.12
Least Squares Mean (95% CI) Change from Baseline in FVC (L) 
Over Time on Day 1
SAC
2.13.
2.13
Modified
ITT
DB2114634
6.13
Least Squares Mean (95% CI) Treatment Differences from 
Placebo in Change from Baseline in FVC (L) Over Time on Day 1
SAC
2.14.
2.14
Modified
ITT
DB2114634
6.14
Least Squares Mean (95% CI) TDI Focal Score
SAC
2.15.
2.15
Modified
ITT
DB2114634
6.15
Least Squares Mean (95% CI) Treatment Differences from 
Placebo in TDI Focal Score
SAC
2.16.
2.16
Modified
ITT
DB2114634
6.16
Empirical Distribution Function of Change from Baseline in SGRQ 
Total Score at Day 168
SAC
2.17.
2.17
Modified
ITT
DB2114634
6.17
Least Squares Means (95% CI) Change from Baseline in SGRQ 
Total Score
SAC
2.18.
2.18
Modified
ITT
DB2114634
6.18
Least Squares Mean (95% CI) Treatment Differences from 
Placebo in Change from Baseline in SGRQ Total Score
SAC
2.19.
2.19
Modified
ITT
DB2114634
6.19
Time to First On-treatment COPD Exacerbation (days)
SAC
2.20.
2.20
Modified
ITT
DB2114634
6.20
Scatter plot of Change from Baseline CAT scores versus 
Change from Baseline Trough FEV1 at Day 168
SAC


CONFIDENTIAL
AC4117410
84
Efficacy: Figures
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.21.
2.21
Modified
ITT
DB2114634
6.21
Scatter Plot of Baseline CAT scores versus Baseline FEV1
SAC


CONFIDENTIAL
AC4117410
85
10.14.8.
Safety Tables
Safety : Tables
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.1.
3.1
Modified 
ITT
DB2114634
Summary of Exposure
SAC
3.2.
3.2
Modified
ITT
DB2114634
7.02
Overview of Adverse Events
SAC[1]
3.3.
3.3
Modified
ITT
AE1
Summary of All Adverse Events by System Organ 
Class and Preferred Term
SAC
3.4.
3.4
Modified
ITT
AE3
Summary of Common Adverse Events by Overall 
Frequency
A common AE is one 
reported by 3% or more of 
subjects in any treatment 
group
SAC
3.5.
3.5
Modified
ITT
DB2114634
7.03
Summary of On-treatment Adverse Events
SAC
3.6.
3.6
Modified
ITT
DB2114634
7.04
Summary of Post-treatment Adverse Events
SAC
3.7.
3.7
Modified
ITT
DB2114634
7.05
Summary of On-treatment Adverse Events 
Reported by 3 % (after rounding) or More Subjects 
in Any Treatment Group
SAC
3.8.
3.8
Modified
ITT
DB2114634
7.06
Summary of On-treatment Common Non-serious 
Adverse Events 
A common AE is one 
reported by 3% or more of 
subjects in any treatment 
group.
SAC
3.9.
3.9
Modified
ITT
DB2114634
7.07
Summary of On-treatment Drug-related Adverse 
Events
SAC


CONFIDENTIAL
AC4117410
86
Safety : Tables
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.10.
3.10
Modified
ITT
DB2114634
7.07
Summary of On-treatment Non-Serious Drug 
Related Adverse Events
SAC
3.11.
3.11
Screen and 
Run-in 
Failure
DB2114634
7.09
Summary of Pre-treatment Fatal Serious Adverse 
Events, Screen and Run-in Failure
SAC
3.12.
3.12
Screen and 
Run-in 
Failure
DB2114634
7.10
Summary of Pre-treatment Non-Fatal Serious 
Adverse Events, Screen and Run-in Failure
SAC
3.13.
3.13
Modified
ITT
DB2114634
7.11
Summary of Pre-Treatment Non-Fatal Serious 
Adverse Events, Modified Intent-to-treat
SAC
3.14.
3.14
Modified
ITT
DB2114634
7.12
Summary of Fatal Serious Adverse Events
SAC[1]
3.15.
3.15
Modified
ITT
DB2114634
7.07
Summary of Serious Adverse Events by System 
Organ Class
SAC[1]
3.16.
3.16
Modified
ITT
DB2114634
7.07
Summary of Drug-Related Serious Adverse Events 
by System Organ Class
SAC
3.17.
3.17
Modified
ITT
DB2114634
7.13
Summary of On-treatment Non-Fatal Serious 
Adverse Events
SAC
3.18.
3.18
Modified
ITT
DB2114634
7.14
Summary of Post-treatment Non- Fatal Serious 
Adverse Events
SAC
3.19.
3.19
Screen and 
Run-in 
Failure
DB2114634
7.15
Summary of Pre-treatment Adverse Events 
Leading to Withdrawal from the Study
SAC


CONFIDENTIAL
AC4117410
87
Safety : Tables
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.20.
3.20
Modified
ITT
DB2114634
7.16
Summary of On-treatment Adverse Events Leading 
to Discontinuation of Study Treatment or 
Withdrawal from the Study
SAC
3.21.
3.21
Modified
ITT
DB2114634
7.17
Summary of On-treatment Adverse Events of 
Special Interest
SAC[1]
3.22.
3.22
Modified
ITT
DB2114634
7.18
Summary of Fatal Serious Adverse Events of 
Special Interest 
SAC
3.23.
3.23
Modified
ITT
DB2114634
7.19
Summary of On-treatment Non-Fatal Serious 
Adverse Events of Special Interest
SAC
3.24.
3.24
Modified
ITT
DB2114634
7.20
Summary of Fatal Drug Related Serious Adverse 
Events
SAC
3.25.
3.25
Modified
ITT
DB2114634
7.21
Summary of On-treatment Non-Fatal Drug Related 
Serious Adverse Events 
SAC
3.26.
3.26
Modified
ITT
DB2114634
7.22
Summary of Chemistry Data
SAC
3.27.
3.27
Modified
ITT
DB2114634
7.23
Summary of Change from Baseline in Chemistry 
Data
SAC
3.28.
3.28
Modified
ITT
DB2114634
7.24
Summary of Chemistry Data Outside the Normal 
Range
SAC
3.29.
3.29
Modified
ITT
DB2114634
7.25
Summary of Chemistry Changes from Baseline 
Relative to the Normal Range
SAC
3.30.
3.30
Modified
ITT
DB2114634
7.26
Summary of Haematology Data
SAC


CONFIDENTIAL
AC4117410
88
Safety : Tables
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.31.
3.31
Modified
ITT
DB2114634
7.27
Summary of Change from Baseline in 
Haematology Data
SAC
3.32.
3.32
Modified
ITT
DB2114634
7.28
Summary of Haematology Data Outside the 
Normal Range
SAC
3.33.
3.33
Modified
ITT
DB2114634
7.29
Summary of Haematology Changes from Baseline 
Relative to the Normal Range
SAC
3.34.
3.34
Modified
ITT
HZC113684
7.27
Summary of Urinalysis Data
SAC
3.35.
3.35
Modified
ITT
DB2114634
7.30
Summary of Vital Signs
SAC
3.36.
3.36
Modified
ITT
DB2114634
7.31
Summary of Change from Baseline in Vital Signs
SAC
3.37.
3.37
Modified
ITT
DB2114634
7.32
Statistical Analysis of Pulse Rate (bpm)
SAC
3.38.
3.38
Modified
ITT
DB2114634
7.33
Statistical Analysis of Systolic Blood Pressure 
(mmHg)
SAC
3.39.
3.39
Modified
ITT
DB2114634
7.34
Statistical Analysis of Diastolic Blood Pressure 
(mmHg)
SAC
3.40.
3.40
Modified
ITT
DB2114634
7.35
Summary of ECG Values
SAC
3.41.
3.41
Modified
ITT
DB2114634
7.36
Summary of Change from Baseline in ECG Values
SAC


CONFIDENTIAL
AC4117410
89
Safety : Tables
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.42.
3.42
Modified
ITT
DB2114634
7.37
Summary of QTc(F) (msec) Categories
SAC
3.43.
3.43
Modified
ITT
DB2114634
7.38
Summary of Change From Baseline in QTc(F) 
(msec) Categories
SAC
3.44.
3.44
Modified
ITT
DB2114634
7.39
Statistical Analysis of QTc(F) (msec)
SAC
3.45.
3.45
Modified
ITT
DB2114634
7.40
Statistical Analysis of PR Interval (msec)
SAC
3.46.
3.46
Modified
ITT
DB2114634
7.41
Statistical Analysis of ECG Heart Rate (bpm)
SAC
3.47.
3.47
Modified
ITT
DB2114634
7.42
Summary of ECG Result Interpretations
SAC
3.48.
3.48
Modified
ITT
DB2114634
7.44
Summary of All ECG Abnormalities 
SAC


CONFIDENTIAL
AC4117410
90
10.14.9.
Safety Figures
Safety : Figures
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming 
Notes
Deliverable 
[Priority]
3.1.
3.1
Modified
ITT
DB2114634
7.01
Scatter Plots of Maximum Post Baseline versus Baseline for 
Chemistry Parameters with an Upper Limit of Normal Range
SAC
3.2.
3.2
Modified
ITT
DB2114634
7.02
Box Plots of Change from Baseline to Maximum Post-baseline for 
Chemistry Parameters with an Upper Limit of Normal Range
SAC
3.3.
3.3
Modified
ITT
DB2114634
7.03
Scatter Plots of Minimum Post Baseline versus Baseline for 
Chemistry Parameters with a Lower Limit of Normal Range
SAC
3.4.
3.4
Modified 
ITT
DB2114634
7.04
Box Plots of Change from Baseline to Minimum Post-baseline for 
Chemistry Parameters with a Lower Limit of Normal Range
SAC
3.5.
3.5
Modified 
ITT
DB2114634
7.05
Scatter Plots of Maximum Post Baseline versus Baseline for 
Haematology Parameters with an Upper Limit of Normal Range
SAC
3.6.
3.6
Modified 
ITT
DB2114634
7.06
Box Plots of Change from Baseline to Maximum Post-baseline for 
Haematology Parameters with an Upper Limit of Normal Range
SAC
3.7.
3.7
Modified 
ITT
DB2114634
7.07
Scatter Plots of Minimum Post Baseline versus Baseline for 
Haematology Parameters with a Lower Limit of Normal Range
SAC
3.8.
3.8
Modified 
ITT
DB2114634
7.08
Box Plots of Change from Baseline to Minimum Post-baseline for 
Haematology Parameters with A Lower Limit of Normal Range
SAC
3.9.
3.9
Modified 
ITT
DB2114634
7.09
Trellis Display of Maximum Post-baseline versus Baseline for Liver 
Function Test Parameters
SAC
3.10.
3.10
Modified 
ITT
DB2114634
7.10
Least Squares Means Change from Baseline (95% CI) in Pre-dose 
Pulse Rate (bpm)
SAC


CONFIDENTIAL
AC4117410
91
Safety : Figures
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming 
Notes
Deliverable 
[Priority]
3.11.
3.11
Modified 
ITT
DB2114634
7.11
Least Squares Means Change from Baseline (95% CI) in Pre-dose 
Systolic Blood Pressure (mmHg)
SAC
3.12.
3.12
Modified 
ITT
DB2114634
7.12
Least Squares Means Change from Baseline (95% CI) in Pre-dose 
Diastolic Blood Pressure (mmHg)
SAC
3.13.
3.13
Modified 
ITT
DB2114634
7.13
Empirical Distribution Function Plot of Maximum Post-baseline 
QTc(F) (msec)
SAC
3.14.
3.14
Modified 
ITT
DB2114634
7.14
Empirical Distribution Function Plot of Change from Baseline in 
Maximum Post-baseline QTc(F) (msec)
SAC
3.15.
3.15
Modified 
ITT
DB2114634
7.15
Least Squares Means Change from Baseline (95% CI) in Pre-dose 
QTc(F) (msec)
SAC
3.16.
3.16
Modified 
ITT
DB2114634
7.16
Least Squares Means Change from Baseline (95% CI) in Pre-dose 
PR Interval (msec)
SAC
3.17.
3.17
Modified 
ITT
DB2114634
7.17
Least Squares Means Change from Baseline (95% CI) in Pre-dose 
Heart Rate (bpm)
SAC


CONFIDENTIAL
AC4117410
92
10.14.10. ICH Listings
ICH : Listings
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Study Population
1.
1.
Screen and 
Run in 
Failure
ES7
Listing of Reasons for Screen Failure / Run-in Failure
SAC
2.
2.
Modified ITT
DB2114634
5.01
Listing of Reasons for Withdrawal
SAC
3.
3.
Modified ITT
DB2114634
5.02
Listing of Planned and Actual Treatments
SAC
4.
4.
Modified ITT
DV2
Listing of Important Protocol Deviations
SAC
5.
5.
Modified ITT
DV2
Listing of Participants Excluded from PP population
SAC
6.
6.
Modified ITT
DB2114634
5.03
Listing of Inclusion, Exclusion or Randomisation 
Criteria Deviations
SAC
7.
7.
Modified ITT
DB2114634
5.04
Listing of Date of and Reason for Breaking Treatment 
Blind During the Study
SAC
8.
8.
Modified ITT
DB2114634
5.05
Listing of Demographic Characteristics
Birth date will be 
presented as ‘YYYY’
SAC
9.
9.
Modified ITT
DB2114634
5.06
Listing of Race
SAC
10.
10.
Modified ITT
DB2114634
5.17
Listing of COPD Concomitant Medications
SAC


CONFIDENTIAL
AC4117410
93
ICH : Listings
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
11.
11.
Modified ITT
DB2114634
5.18
Listing of Non-COPD Concomitant Medications
SAC
12.
12.
Modified ITT
DB2114634
5.07
Listing of Screening Lung Function Test Results
SAC
Efficacy
13.
13.
Modified ITT
DB2114634
6.01
Listing of Raw FEV1 (L) and FVC (L)
SAC
Safety
14.
14.
Modified ITT
DB2114634
7.01
Listing of Exposure
SAC
15.
15.
All Subjects 
Enrolled
DB2114634
7.02
Listing of Subject Numbers for Individual Adverse 
Events
SAC
16.
16.
All Subjects 
Enrolled
DB2114634
7.03
Listing of All Adverse Events
SAC
17.
17.
All Subjects 
Enrolled
AE2
Listing of Relationship Between Adverse Event 
System Organ Classes, Preferred Terms, and 
Verbatim Text
SAC
18.
18.
All Subjects 
Enrolled
DB2114634
7.04
Listing of Non-fatal Serious Adverse Events
SAC
19.
19.
All Subjects 
Enrolled
DB2114634
7.05
Listing of Fatal Adverse Events
SAC
20.
20.
All Subjects 
Enrolled
DB2114634
7.06
Listing of On-Treatment Drug Related SAEs 
SAC


CONFIDENTIAL
AC4117410
94
ICH : Listings
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
21.
21.
Modified ITT
DB2114634
7.07
Listing of Subject Numbers for On-treatment Adverse 
Events of Special Interest
SAC
22.
22.
All Subjects 
Enrolled
DB2114634
7.08
Listing of Adverse Events leading to Discontinuation 
of Study Treatment or Withdrawal from the Study
SAC
23.
23.
Modified ITT
DB2114634
7.09
Listing of Potential Investigational Product Inhaler 
Malfunctions Reported by Subjects
SAC
24.
24.
Modified ITT
DB2114634
7.10
Listing of Chemistry Values for Subjects with at Least 
One Value outside the Normal Range
SAC
25.
25.
Modified ITT
DB2114634
7.11
Listing of Haematology Values for Subjects with at 
Least One Value outside the Normal Range
SAC


CONFIDENTIAL
AC4117410
95
10.14.11. Non-ICH Listings
Non-ICH : Listings
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Study Population
26.
26.
All Subjects 
Enrolled
DB2114634
5.08
Listing of Reasons for Withdrawal- Subjects Randomised 
but Not in the Modified Intent-to-Treat Population
SAC
27.
27.
All Subjects 
Enrolled
DB2114634
5.10
Listing of Treatment Misallocations
SAC
28.
28.
Modified 
ITT
DB2114634
5.11
Listing of Medical Conditions
SAC
29.
29.
Modified 
ITT
DB2114634
5.12
Listing of Past Cholecystectomies
SAC
30.
30.
Modified 
ITT
DB2114634
5.13
Listing of Family History of Cardiovascular Risk Factors
SAC
31.
31.
Modified 
ITT
DB2114634
5.14
Listing of COPD History
SAC
32.
32.
Modified 
ITT
DB2114634
5.15
Listing of Smoking History and Smoking Status
SAC
33.
33.
Modified 
ITT
DB2114634
5.16
Listing of mMRC Dyspnoea Scale
SAC
34.
34.
Modified 
ITT
DB2114634
5.19
Relationship between ATC Level 1, Ingredient and 
Verbatim Text
SAC
35.
35.
Modified 
ITT
DB2114634
5.20
Listing of Treatment Compliance Data
SAC


CONFIDENTIAL
AC4117410
96
Non-ICH : Listings
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
36.
36.
All Subjects 
Enrolled 
DB2114634
5.21
Listing of All Protocol Deviations
SAC
Efficacy
37.
37.
Modified 
ITT
DB2114634
6.02
Listing of Derived FEV1 Endpoints
SAC
38.
38.
Modified 
ITT
DB2114634
6.03
Listing of Derived FVC Endpoints
SAC
39.
39.
Modified 
ITT
DB2114634
6.04
Listing of BDI/TDI
SAC
40.
40.
Modified 
ITT
DB2114634
6.05
Listing of SGRQ Scores
SAC
41.
41.
Modified 
ITT
DB2114634
6.06
Listing of Derived Rescue Endpoints
SAC
42.
42.
Modified 
ITT
DB2114634
6.07
Listing of CAT Scores
SAC
43.
43.
Modified 
ITT
DB2114634
6.08
Listing of COPD Exacerbations
SAC
44.
44.
Modified 
ITT
Non-Standard
EFF_L1 
Listing of Healthcare Resource Utilisation
SAC
Safety
45.
45.
Modified 
ITT
DB2114634
7.12
Listing of Immunology Data for subjects with at least one 
Reactive Result
SAC


CONFIDENTIAL
AC4117410
97
Non-ICH : Listings
IMCT
No.
China 
Subgroup
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
46.
46.
Modified 
ITT
DB2114634
7.13
Listing of Virology Data
SAC
47.
47.
Modified 
ITT
DB2114634
7.14
Listing of Urinalysis Data
SAC
48.
48.
Modified 
ITT
DB2114634
7.15
Listing of Vital Signs
SAC
49.
49.
Modified 
ITT
DB2114634
7.18
Listing of ECG Values for Subjects with Any Abnormal 
ECG Interpretation
SAC
50.
50.
Modified 
ITT
DB2114634
7.19
Listing of ECG Findings for Subjects with Any Abnormal 
ECG Interpretation
SAC
51.
51.
Modified 
ITT
DB2114634
7.20
Listing of Liver Event Results and Time of Event Relative 
to Treatment
SAC
52.
52.
Modified 
ITT
DB2114634
7.21
Listing of Liver Event Information for RUCAM Score
SAC
53.
53.
Modified 
ITT
DB2114634
7.22
Listing of Liver Biopsy Details
SAC
54.
54.
Modified 
ITT
DB2114634
7.23
Listing of Liver Imaging Details
SAC


CONFIDENTIAL
AC4117410
98
10.15.
Appendix 15: Example Mock Shells for Data Displays
Example 
: EFF_L1
Page 1 of n
Protocol
: AC4117410
Population
: ITT
Listing 41
Listing of Healthcare Resource Utilisation
Investigator at 
Centre/
Subject
Date
of Contact
Number of
office/practice 
visits
Number of urgent 
care/outpatient 
Visits
Number of 
emergency room 
visits
Number of days 
in intensive care
Number of days 
in general ward
Was this contact 
due to an 
exacerbation
21May2013
0
1
0
0
0
N
01MAY2013
1
0
0
0
11
Y
PPD