A Randomized, Open-label, Cross-over, Placebo-device Study Investigating Critical and Over All Errors, Training/Teaching Time, and Preference Attributes of the ELLIPTA Dry Powder Inhaler (DPI) as Compared to HANDIHALER DPI Used in Combination With Either DISKUS DPI or TURBUHALER DPI, in Adult Patients With Chronic Obstructive Pulmonary Disease (COPD)
Phase: PHASE4
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: GlaxoSmithKline

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GlaxoSmithKline group of companies 
 
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TITLE PAGE 
Protocol Title: A randomized, open-label, cross-over, placebo-device study investigating 
critical and over all errors, training/teaching time, and preference attributes of the 
ELLIPTA dry powder Inhaler (DPI) as compared to HandiHaler DPI used in combination 
with either DISKUS DPI or Turbuhaler DPI, in adult patients with Chronic Obstructive 
Pulmonary Disease (COPD) 
Protocol Number: 206215 
Short Title: A clinical study assessing critical errors, training/teaching time, and 
preference attributes of the ELLIPTA dry powder inhaler, in comparison to combinations 
of dry powder inhalers used to provide triple therapy, in patients with COPD. 
Compound Number: GSK573719+GW642444+GW685698 (GSK2834425) 
 
Sponsor Name and Legal Registered Address:  
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual 
Regulatory Agency Identifying Number(s): Not Applicable 
Approval Date: 15-SEP-2016 
 
 
 
 
 
 
 
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.

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SPONSOR SIGNATORY: 
 
 
Steven Pascoe, MD 
Vice President, Respiratory Head Unit Physician  
 
Date 
 

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TABLE OF CONTENTS 
PAGE 
1. 
SYNOPSIS ............................................................................................................... 5 
2. 
SCHEDULE OF ACTIVITIES (SOA) ......................................................................... 8 
3. 
INTRODUCTION ...................................................................................................... 9 
3.1. 
Study Rationale ............................................................................................ 9 
3.2. 
Background .................................................................................................. 9 
3.3. 
Benefit/Risk Assessment ............................................................................ 11 
3.3.1. 
Risk Assessment ......................................................................... 11 
3.3.2. 
Benefit Assessment ..................................................................... 12 
3.3.3. 
Overall Benefit: Risk Conclusion .................................................. 12 
4. 
OBJECTIVES AND ENDPOINTS ........................................................................... 12 
5. 
STUDY DESIGN .................................................................................................... 13 
5.1. 
Overall Design ............................................................................................ 13 
5.2. 
Number of Participants ............................................................................... 14 
5.3. 
Participant and Study Completion ............................................................... 14 
5.4. 
Scientific Rationale for Study Design .......................................................... 15 
5.5. 
Dose Justification ........................................................................................ 15 
6. 
STUDY POPULATION ........................................................................................... 15 
6.1. 
Inclusion Criteria ......................................................................................... 15 
6.2. 
Exclusion Criteria ........................................................................................ 16 
6.3. 
Lifestyle Restrictions ................................................................................... 17 
6.3.1. 
Meals and Dietary Restrictions .................................................... 17 
6.3.2. 
Caffeine, Alcohol, and Tobacco ................................................... 17 
6.3.3. 
Activity ......................................................................................... 17 
6.4. 
Screen Failures........................................................................................... 17 
7. 
TREATMENTS ....................................................................................................... 17 
7.1. 
Treatments Administered ............................................................................ 18 
7.1.1. 
Medical Devices ........................................................................... 18 
7.2. 
Method of Treatment Assignment ............................................................... 19 
7.3. 
Blinding ....................................................................................................... 19 
7.4. 
Preparation/Handling/Storage/Accountability .............................................. 20 
7.5. 
Treatment Compliance ................................................................................ 20 
7.6. 
Concomitant Therapy.................................................................................. 20 
7.7. 
Treatment after the End of the Study .......................................................... 21 
8. 
DISCONTINUATION CRITERIA ............................................................................. 21 
8.1. 
Discontinuation of Study Treatment ............................................................ 21 
8.1.1. 
Liver Chemistry Stopping Criteria ................................................ 21 
8.1.2. 
QTc Stopping Criteria .................................................................. 21 
8.2. 
Withdrawal from the Study .......................................................................... 21 
8.3. 
Lost to Follow Up ........................................................................................ 21 
9. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 21 
9.1. 
Efficacy Assessments ................................................................................. 22 

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9.1.1. 
Assessment of Errors in Use of Device ........................................ 22 
9.1.1.1. 
Assessment of ELLIPTA error in use .......................... 23 
9.1.1.2. 
Assessment of DISKUS-HandiHaler in Sub 
Study 1, or Turbuhaler-HandiHaler in Sub 
Study 2, for error in use .............................................. 23 
9.1.1.3. 
Time Taken to Use Device ......................................... 24 
9.1.2. 
Assessments of Preference ......................................................... 24 
9.2. 
Adverse Events........................................................................................... 25 
9.2.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 25 
9.2.2. 
Method of Detecting AEs and SAEs ............................................. 25 
9.2.3. 
Follow-up of AEs and SAEs ......................................................... 25 
9.2.4. 
Regulatory Reporting Requirements for SAEs ............................. 26 
9.2.5. 
Cardiovascular and Death Events ................................................ 26 
9.3. 
Safety Assessments ................................................................................... 26 
9.4. 
Pharmacokinetics ....................................................................................... 26 
9.5. 
Pharmacodynamics .................................................................................... 27 
9.6. 
Genetics ..................................................................................................... 27 
9.7. 
Biomarkers ................................................................................................. 27 
9.8. 
Health Economics OR Medical Resource Utilization and Health 
Economics .................................................................................................. 27 
10. STATISTICAL CONSIDERATIONS ........................................................................ 27 
10.1. 
Hypotheses ................................................................................................. 27 
10.2. 
Sample Size Determination ........................................................................ 27 
10.3. 
Populations for Analyses ............................................................................ 28 
10.4. 
Statistical Analyses ..................................................................................... 29 
10.4.1. 
Efficacy Analyses ......................................................................... 29 
10.4.2. 
Safety Analyses ........................................................................... 30 
10.4.3. 
Other Analyses ............................................................................ 30 
10.4.4. 
Interim Analyses .......................................................................... 30 
11. REFERENCES ....................................................................................................... 31 
12. APPENDICES ........................................................................................................ 32 
12.1. 
Appendix 1: Abbreviations and Trademarks ................................................ 32 
12.2. 
Appendix 2: Inhaler Specific Errors for the inhalers used in the study ......... 33 
12.3. 
Appendix 3: Inhaler Preference Questionnaires .......................................... 36 
12.4. 
Appendix 4: Study Governance Considerations .......................................... 38 
12.5. 
Appendix 5: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 42 
 

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1. 
SYNOPSIS 
Protocol Title: A randomized, open-label, cross-over, placebo-device study investigating 
critical and over all errors, training/teaching time, and preference attributes of the 
ELLIPTA dry powder Inhaler (DPI) as compared to HandiHaler DPI used in combination 
with either DISKUS DPI or Turbuhaler DPI, in adult patients with Chronic Obstructive 
Pulmonary Disease (COPD) 
Short Title: A clinical study assessing critical errors, training/teaching time, and 
preference attributes of the ELLIPTA dry powder inhaler, in comparison to combinations 
of dry powder inhalers used to provide triple therapy, in patients with COPD. 
Rationale: This study is designed to assess the benefits of delivering triple therapy using 
a single ELLIPTATM DPI (Closed Triple therapy) versus delivering triple therapy using 
two different types of inhalers (open triple therapy) to patients with Chronic Obsttructive 
Pulmonay Disease (COPD). It will assess the proportion of COPD subjects who make 
critical errors when using a single ELLIPTA™ DPI versus those using combinations of 
commercially available and commonly used DPIs:  DISKUS used in combination with 
HandiHaler, or Turbuhaler used in combination with HandiHaler. This study would also 
assess training/teaching time and preference attributes for closed triple therapy as 
compared to the open triple therapy. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
To compare the number of critical 
errors  made by COPD patients, after a 
subject has read the respective patient 
information leaflet(s) (PIL), for each 
treatment option tested  
 
• 
The percentage of subjects making at least one 
critical error after reading the PIL(s)  
Secondary 
To compare the number of critical 
errors made by COPD patients after 
instruction from the Healthcare 
Professional (HCP) for each treatment 
option tested 
The percentage of subjects making at least one critical 
error after the:  
• first instruction from the HCP  
• second instruction from the HCP   
To compare the number of overall  
(critical and non-critical)  errors made 
by COPD patients, after a subject has 
read the PIL(S) or after Instruction from 
the HCP for each treatment option 
tested 
• 
The percentage of subjects making at least one 
overall error after reading the PIL(s)  
• 
The percentage of subjects making at least one 
overall error after the first instruction from the 
HCP 
• 
The percentage of subjects making at least one 
overall error after the second instruction from the 
HCP  

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Objectives 
Endpoints 
To compare the number of instructions 
(maximum of 2) from a HCP which is 
needed to demonstrate correct inhaler 
use  
The number of instructions (0, 1 or 2 times) from the 
HCP which are needed to demonstrate correct inhaler 
use  
To compare the Training/Teaching 
Time required to demonstrate correct 
inhaler use 
• The total amount of time taken to demonstrate 
correct inhaler use (T1+T2). 
• The amount of time taken to read the patient 
information leaflet and demonstrate correct 
inhaler use (T1)  
• The amount of time taken to be given instruction 
by the HCP (up to 2 times) on use of the inhaler 
and to demonstrate correct inhaler use (T2)  
Preference attributes for each 
treatment option tested  
Treatment preference, from questionnaire  for: 
• Number of steps required to take COPD 
medication 
• Over all treatment preference 
Overall Design: The study will be conducted as a multi-centre, randomized, open-label, 
placebo-device, cross-over study, with a 2x2 complete block design.  
It will comprise of two sub-studies: 
• 
Sub-study 1: Will compare ELLIPTA DPI to DISKUS-HandiHaler DPI combination  
• 
Sub-study 2: Will compare ELLIPTA DPI to Turbuhaler-HandiHaler DPI 
combination. 
The study has 2 visits (V0 and V1) and both can be completed on the same day. 
Each sub-study may run independently or in parallel of the other sub study. Each will 
start dependent on the availability of the placebo DPIs required for that sub-study. The 
data from the 2 sub studies may be reported independently and as each sub study 
completes. 

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Study Schematic 
 
 
Number of Participants: Sufficient patients with COPD will be screened to ensure 
approximately 160 participants will be randomized, such that approximately 144 
evaluable participants complete the study. Approximately 72 participants completing in 
each sub study.  
Treatment Groups and Duration: Duration is a single visit and subjects are randomised 
to receive treatments below; dependent on which sub-study they are included in.  
There is no active treatment and subjects will continue to take their own prescribed 
COPD medication for the duration of the study. 
Sub Study 1 Treatment Sequences 
Sequence 
Period 1 
Period 2 
Preference 
Questionnaire 
A 
ELLIPTA 
DISKUS + HandiHaler 
1 
B 
DISKUS + HandiHaler 
ELLIPTA 
2 
C 
ELLIPTA 
DISKUS + HandiHaler 
2 
D 
DISKUS + HandiHaler 
ELLIPTA 
1 

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Sub Study 2 Treatment Sequence 
Sequence 
Period 1 
Period 2 
Preference 
Questionnaire 
E 
ELLIPTA 
Turbuhaler + HandiHaler 
3 
F 
Turbuhaler + HandiHaler 
ELLIPTA 
4 
G 
ELLIPTA 
Turbuhaler + HandiHaler 
4 
H 
Turbuhaler + HandiHaler 
ELLIPTA 
3 
 
2. 
SCHEDULE OF ACTIVITIES (SOA) 
Visit Number 
V0 
V1 
Notes 
Study Day 
1 
1  
V0 can take place on the same day as V1. V1 
should be completed no later than 30 days 
after consent. 
Procedure: 
 
 
 
Screening Assessments 
 
 
Completed prior to randomisation 
Written informed consent 
X 
 
Informed consent may take place prior to V0 
for logistical reasons. Subjects should be 
included and randomised within 30 days of 
providing consent. 
Subject demography 
X 
 
Age, height, weight, year of birth, sex, ethnicity 
and geographic ancestry will be recorded 
Medical/disease history including 
Chronic Obstructive Pulmonary 
Disease (COPD) 
X 
 
Subject will have a medical history of COPD, 
previously confirmed by spirometry. 
Concomitant medication history 
including COPD Therapy History 
X 
 
Current concomitant medication will be 
recorded. A minimum COPD therapy history 
for the preceding 2 years from inclusion will be 
recorded 
Inclusion/exclusion criteria 
X 
 
All criteria must be meet prior to randomisation 
at V1 
Study Assessments 
 
 
Completed once a subject is included on study 
Randomisation 
 
X 
Randomised to treatment order and preference 
questionnaire  
Assess the number of inhaler 
errors (critical and overall) on each 
treatment after reading the Patient 
information leaflet (PIL) for Inhaler 
tested 
 
X 
No instruction is provided by the Health Care 
Professional (HCP) for this assessment. 
Assess the number of inhaler 
errors (overall and critical) on each 
treatment after each of 2  attempts 
following instruction by HCP 
 
 
If a subject cannot show correct use after 
reading the PIL, then the HCP has up to 2 
attempts to instruct the subject to attain this. 

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Visit Number 
V0 
V1 
Notes 
Teaching-Training Time for each 
inhaler includes the  following: 
• 
The amount of time taken to 
read the patient information 
leaflet and demonstrate 
inhaler use 
• 
The amount of time taken to 
be given instruction by the 
HCP on use of the inhaler and 
demonstrate inhaler use 
• 
The total amount of time 
taken to demonstrate inhaler 
use 
 
X 
• First assessment is attempt one, including 
time to read PIL and demonstrate use. 
• Second assessment will be time for HCP 
to correct errors and subject to show use 
for up to  2 more attempts 
• The Cumulative time for all assessments 
needed by subject and any HCP 
instruction to demonstrate no errors will 
also be captured. 
Preference Questionnaire  
 
X 
Subject will complete version of Preference 
Questionnaire they have been randomised to.   
SAE/AE assessment 
 
X 
Collected until completion of final study 
assessment at V1. 
3. 
INTRODUCTION 
3.1. 
Study Rationale 
Please note that Turbohaler and ACCUHALER are the names commonly used within the 
United Kingdom for these inhalers. However, in other regions and for the purposes of this 
study these inhalers are referred to as Turbuhaler and DISKUS respectively in this 
protocol. 
This study is designed to assess the benefits of delivering triple therapy using a single 
ELLIPTA TM Dry Powder Inhaler (DPI) (Closed Triple therapy) versus delivering triple 
therapy using two different types of inhalers (open triple therapy) to patients with COPD. 
It will assess the proportion of COPD subjects who make critical errors when using a 
single ELLIPTA DPI versus those using combinations of commercially available and 
commonly used DPIs:  DISKUS used in combination with HandiHaler, or Turbuhaler 
used in combination with HandiHaler. This study would also assess training/teaching 
time and preference attributes for closed triple therapy as compared to the open triple 
therapy. 
3.2. 
Background 
Chronic Obstructive Pulmonary Disease (COPD) is a progressive disease of the airways. 
Noxious particles or gases lead to a modification in subject’s airways which develop a 
chronic inflammatory response to these environmental factors. This leads to increasing 
airflow limitation, breathlessness and other symptoms. Despite being both treatable and 
preventable, COPD is a leading cause of morbidity and mortality worldwide. The 
economic and social burden of this disease has not been reduced and is increasing despite 
advances in diagnosis and treatment. [GOLD 2016] 

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The current treatment goals for COPD are to reduce and relieve symptoms and thereby 
improve exercise tolerance and health status, whilst reducing risk by preventing disease 
progression, preventing and treating exacerbations, and reducing mortality 
Smoking cessation, inhaled pharmacological therapy, primarily long and short term 
bronchodilators (beta2-agonists and anti-cholinergics) and inhaled corticosteroids, and 
other non pharmacological interventions are currently used to achieve the treatment 
goals. 
The current GOLD treatment guidelines, place patients in 4 groups from A to D, 
dependent on severity of symptoms and assessment of risk; with Group A patients having 
the fewest symptoms and a low risk as assessed by degree of airflow limitation and/or 
exacerbation history. COPD patients in Group A may just need a short acting 
bronchodilator as needed to relieve symptoms. However, as disease progresses, other 
inhaled therapies are added on to maintain control, such that COPD patients  in Group D, 
who have many symptoms and a high risk of exacerbations and/or high airflow 
limitation, may need multiple  inhaled therapies (inhaled corticosteroids (ICS), long-
acting beta2-agonist (LABA) and long-acting anticholinergic (LAMA)).  
Currently, subjects requiring triple therapy can be prescribed ICS/LABA and LAMA in 
separate inhalers. The specific ICS/LABA and LAMA prescribed determine whether the 
inhaler types (and thereby the inhalation techniques) and the dosing regimens are similar 
or different. Use of different inhaler types with different inhalation techniques and dosing 
regimens can add to treatment complexity, and also increase the potential for errors in 
inhaler use that reduce or preclude drug delivery to the site of action in the lungs 
[Cochrane, 2000, Van der Palen, 1999]. Fixed-dose combination inhalers that minimise 
the number of inhalers required would simplify treatment, improve adherence, reduce 
errors in inhaler use, and potentially lead to better outcomes [GOLD 2016]. 
The skill and ability of the COPD patient to use the prescribed inhaler/s correctly coupled 
with adequate training in inhaler technique are also critical to ensure effective drug 
delivery [Cochrane, 2000, Melani, 2011]. For any prescribed inhaler, the patient needs to 
follow all the steps in the patient leaflet correctly in order to ensure optimal drug 
delivery. In this regard, the time needed for a primary care nurse or physician, or a 
community pharmacist to train a patient in correct use of an inhaler at the time of initial 
prescription, and for any subsequent retraining becomes important. Given the time 
demands on healthcare professionals, a device which is simple to use and requires 
minimal time to train would be desirable [Bonini, 2015]. Further, patients may prefer 
easy-to-use inhalers having fewer steps to deliver drug; this has the potential to improve 
compliance and thereby impact outcomes. 
ELLIPTA DPI has been designed to be simple for patients to use. In COPD patients’ 
naïve to Ellipta and comparator inhalers, data has shown that patients make fewer critical 
and overall errors when using ELLIPTA as compared to other common DPIs tested [Van 
Der Palen, 2016(a)]. ELLIPTA DPI was also shown to be preferred by patients for a 
number of attributes, including number of steps and training time required to receive 
therapy [Van Der Palen, 2016(b), Van Der Palen, 2016(c), Komase, 2014]. ELLIPTA is 
already available to deliver a LABA/ICS combination (BREO ELLIPTA), LAMA 

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(INCRUSE ELLIPTA), and LAMA/LABA combination (ANORO ELLIPTA).  Closed 
triple therapy (ICS/LAMA/LABA) is currently being assessed in clinical studies to 
deliver all 3 active treatments from a single ELLIPTA DPI. 
3.3. 
Benefit/Risk Assessment 
The study involves use of placebo inhalers (placebo ELLIPTA, placebo DISKUS, 
placebo Turbuhaler and placebo HandiHaler) that do not contain active treatments and 
subjects will continue to take their own prescribed COPD medication and other 
concomitant medication for the duration of the study.  
The placebo inhalers and placebo capsules for HandiHaler contain the excipients lactose 
or lactose blended with magnesium stearate. Excipients of the study inhaler are noted in 
Section 7.1. Subjects with a known hypersensitivity to any of these or severe milk protein 
allergy that could contraindicate study participation are excluded from the study (Section 
6). Subjects who meet the inclusion/exclusion criteria will continue their COPD treatment 
as prescribed by their healthcare provider during their participation in the study.  Subjects 
should continue to follow up with their regular physician for their COPD healthcare 
during the study. 
The study procedures include reading of the inhaler patient information leaflets and 
demonstration of inhaler use by the study subjects and instruction  in correct-inhaler use 
by the site staff. 
3.3.1. 
Risk Assessment 
Potential Risk of 
Clinical 
Significance 
Summary of 
Data/Rationale for Risk 
Mitigation Strategy 
Paradoxical 
bronchospasm, 
which may occur 
with an immediate 
increase in 
wheezing after 
inhaling. 
As with other inhalation 
therapy, paradoxical 
bronchospasm may occur 
with an immediate increase 
in wheezing after dosing. 
From post-marketing data, 
paradoxical bronchospasm 
has been reported at a 
frequency of <1/10,000 
including isolated reports. 
This should be treated immediately with a fast 
and short acting inhaled bronchodilator. 
Investigators will be instructed to assess the 
subject’s condition to determine their eligibility 
to continue in the study and the need for 
alternative therapy. 
Allergic reaction 
due to 
hypersensitivity to 
placebo 
excipients. 
The placebo inhalers and 
placebo capsules (for 
HandiHaler) contain the 
excipients lactose and 
lactose blended with 
magnesium stearate. There 
are known allergies to these 
ingredients. 
Subjects with a known hypersensitivity to any 
of these, or severe milk protein allergy that 
could contraindicate study participation are 
excluded from the study (Section 6.2). If an 
allergic reaction occurs, it should be treated 
immediately with a fast and short acting 
inhaled bronchodilator. Investigators will be 
instructed to assess the subject’s condition to 
determine their eligibility to continue in the 
study and the need for alternative therapy 

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3.3.2. 
Benefit Assessment 
As this is a placebo study, no benefit to the subject is expected. No active treatment is 
being administered. The subjects will continue to receive their own COPD therapy as 
prescribed. 
3.3.3. 
Overall Benefit: Risk Conclusion 
The overall potential risk identified is minimal, due to the nature of the study. 
4. 
OBJECTIVES AND ENDPOINTS 
The study will compare critical errors, training time, and patient preference for closed 
triple therapy received from a single ELLIPTA inhaler versus open triple therapy 
received from HandiHaler in combination with either DISKUS or Turbuhaler. These 
comparisons will be performed as separate sub studies and the endpoints and objectives 
listed here will be the same for the treatment comparisons in each sub study: 
• 
Sub study 1: ELLIPTA (Treatment option 1) versus the combination of 
DISKUS-HandiHaler  (Treatment Option 2) 
• 
Sub study 2: ELLIPTA ((Treatment option 1)  versus the combination of 
Turbuhaler-HandiHaler (Treatment Option 3) 
Objectives 
Endpoints 
Primary 
To compare the number of critical 
errors a made by COPD patients, after 
a subject has read the respective 
patient information leaflet(s) (PIL), for 
each treatment option tested  
 
• 
The percentage of subjects making at least one 
critical error after reading the PIL(s)  
Secondary 
To compare the number of critical 
errors made by COPD patients after 
instruction from the Healthcare 
Professional (HCP) for each treatment 
option tested 
The percentage of subjects making at least one critical 
error after the:  
• first instruction from the HCP  
• second instruction from the HCP d  
To compare the number of overall a 
(critical and non-critical)  errors made 
by COPD patients, after a subject has 
read the PIL(S) or after Instruction from 
the HCP for each treatment option 
tested 
• 
The percentage of subjects making at least one 
overall error after reading the PIL(s)  
• 
The percentage of subjects making at least one 
overall error after the first instruction from the 
HCP 
• 
The percentage of subjects making at least one 
overall error after the second instruction from the 
HCP d 

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Objectives 
Endpoints 
To compare the number of instructions 
(maximum of 2) from a HCP which is 
needed to demonstrate correct inhaler 
usec 
The number of instructions (0, 1 or 2 times) from the 
HCP which are needed to demonstrate correct inhaler 
use  
To compare the Training/Teaching 
Time required to demonstrate correct 
inhaler use 
• The total amount of time taken to demonstrate 
correct inhaler use (T1+T2). 
• The amount of time taken to read the patient 
information leaflet and demonstrate correct 
inhaler use (T1) d 
• The amount of time taken to be given instruction 
by the HCP (up to 2 times) on use of the inhaler 
and to demonstrate correct inhaler use (T2) d 
Preference attributes for each 
treatment option tested b 
Treatment preference, from questionnaire  for: 
• Number of steps required to take COPD 
medication 
• Over all treatment preference 
a. 
Over all and critical errors for each inhaler tested, as well as an explanation of how these endpoints were 
defined, are listed in Appendix 2 
b. 
Preference Questionnaires for each sub-study are included in Appendix 3 
c. 
To show correct inhaler use a subject demonstrates the use of the inhaler without making any critical or non-
critical error 
d. 
 Endpoint will be treated as ‘other endpoint’ and not secondary for the statistical analysis 
5. 
STUDY DESIGN 
5.1. 
Overall Design 
The study will be conducted as a multi-centre, randomized, open-label, placebo-device, 
cross-over study, with a 2x2 complete block design.  
It will comprise of two sub-studies: 
• 
Sub-study 1: Will compare ELLIPTA DPI (Treatment option 1) to DISKUS-
HandiHaler DPI combination (Treatment option 2) 
• 
Sub-study 2: Will compare ELLIPTA DPI (Treatment option 1) to Turbuhaler-
HandiHaler DPI combination (Treatment option 3). 
The study has 2 visits (V0 and V1) and both can be completed on the same day. 
Each sub-study may run independently or in parallel of the other sub study. Each will 
start dependent on the availability of the placebo DPIs required for that sub-study. The 
data from the 2 sub studies will be reported independently and as each sub study 
completes and the data have been cleaned.  The database will be locked when all of the 
sub-studies have completed and data are cleaned. 

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The study subjects will be randomised to order of treatment and preference questionnaire 
in each of the 2 sub studies. This is shown in further detail in Figure 1. 
Figure 1 
Study Schematic 
 
 
 
5.2. 
Number of Participants 
Sufficient patients with COPD will be screened to ensure approximately 160 participants 
will be randomized, such that approximately 144 evaluable participants complete the 
study. An evaluable subject is defined in the intent to treat population in Section 10.3. 
Approximately 72 participants completing in each sub study.  
If participants prematurely discontinue the study, additional replacement participants may 
be recruited at the discretion of the Sponsor. 
5.3. 
Participant and Study Completion 
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last scheduled procedure shown in the Schedule of 
Activities. 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 

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5.4. 
Scientific Rationale for Study Design 
This design has been used in previous studies looking at critical errors and/or preference 
of inhalers in patients with COPD and naive to the inhalers tested. The cross-over design 
was chosen to allow the subjects to serve as their own control in their ability to use both 
the ELLIPTA DPI and the other combination DPIs. A single visit is suitable for assessing 
these endpoints and reduces inconvenience of multiple visits for subject included. 
Placebo inhalers are used to remove any bias due to treatment effect, avoid the need for 
wash-in/-out periods, and to avoid the need to withhold or discontinue current COPD 
medications, which may affect the subject’s clinical status (improvement or decline) and 
perceptions, as noted above. 
5.5. 
Dose Justification 
Not applicable as this is a placebo-only study. 
6. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
6.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
AGE 
1. ≥40 years of age at Visit 1 
TYPE OF SUBJECT AND DIAGNOSIS 
2. Diagnosis of COPD with a documented history of COPD, in accordance with the 
definition by the European Respiratory Society [Celli, 2004]. 
3. Current COPD Therapy: Currently receiving maintenance therapy with a fixed dose 
combination of a long-acting beta 2-agonist (LABA) and inhaled corticosteroid (ICS). 
Subject may also be receiving long-acting muscarinic antagonist (LAMA; also known 
as a long-acting anti-cholinergic). Subjects must be able to continue using their 
currently prescribed COPD maintenance inhaler therapy throughout the study and as 
needed short acting beta-adrenergic agonist (SABA) and/or short acting muscarinic 
antagonist (SAMA) for rescue use. 
4. Has been on current maintenance ICS/LABA COPD treatment for at least 4 weeks 
prior to V0 and evaluated as unlikely to change treatment within 4 weeks of Visit 1. 
SMOKING HISTORY 
5. Smoking History: Current or former (defined as subjects who have quit smoking for 
at least 3 months prior to V0/V1) cigarette smokers with a >10 pack-year smoking 
history [Number of pack years = (number of cigarettes per day ÷ 20) x number of 

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years smoked (e.g., 10 pack-years is equal to 20 cigarettes per day for 10 years, or 10 
cigarettes per day for 20 years]. 
SEX 
6. Males or 
Females who are not pregnant or not planning a pregnancy during the study or not 
lactating 
INFORMED CONSENT 
7. Capable of giving signed informed consent as described in Appendix 4 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
 
6.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
CONCURRENT CONDITIONS/MEDICAL HISTORY 
1. Asthma: Subjects with a current diagnosis of asthma. Subjects with a prior history of 
asthma are eligible if they have a current diagnosis of COPD. 
CONCOMITANT MEDICATIONS 
2. Recent experience with the ELLIPTA inhaler: Subjects who used any ELLIPTA 
inhaler (e.g., RELVAR ELLIPTA,  ANORO ELLIPTA, ARNUITY ELLIPTA, 
INCRUSE ELLIPTA, participated in a clinical study of GW685698, GW642444, 
GSK573719 [fluticasone furoate, vilanterol, umeclidinium bromide], or any 
combination thereof, or placebo in an ELLIPTA inhaler study) within 24 months 
prior to Visit 0. 
3. Recent experience with any capsule inhaler: Subjects who used any capsule system 
inhaler (e.g. Spiriva HandiHaler, Seebri/Ultibro Breezhaler, or participated in a 
clinical studies of these, including placebo inhalers) within 24 months prior to Visit 0. 
4. Dependent on which sub-study a subject is included on they should not have any 
recent experience, within 24 months of V0 of the following inhaler for the sub study 
included on: 
• 
Sub Study 1: DISKUS inhaler (e.g. Seretide DISKUS or placebo DISKUS) 
• 
Sub Study 2:Turbuhaler (e.g. Symbicort Turbuhaler or placebo Turbuhaler) 
RELEVANT HABITS 
5. Drug/alcohol abuse: Subjects with a known or suspected alcohol or drug abuse at 
Visit 1 which in the opinion of the investigator could interfere with the subject’s 
proper completion of the protocol requirement 

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CONTRAINDICATIONS  
6. Drug/Food Allergy: A history of hypersensitivity to any components of the study 
inhaler (e.g., lactose, magnesium stearate). In addition, subjects with a history of 
severe milk protein allergy that, in the opinion of the study physician, contraindicates 
participation will also be excluded. 
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA 
7. Investigational Product: Subjects who have received an investigational drug and/or 
medical device within 30 days of entry into this study (Screening/Visit 1), or within 
five drug half-lives of the investigational drug, whichever is longer 
8. Inability to Read: In the opinion of the investigator, any subject who is unable to read 
and/or would not be able to complete a questionnaire and understand verbal 
instructions. 
6.3. 
Lifestyle Restrictions 
There are no lifestyle restrictions. 
6.3.1. 
Meals and Dietary Restrictions 
There are no meals or dietary restrictions. 
6.3.2. 
Caffeine, Alcohol, and Tobacco 
There are no caffeine, alcohol, and tobacco restrictions, other than those for a subject’s 
inclusion and any local restrictions whilst the subject is in the clinic. 
6.3.3. 
Activity 
There are no restrictions on activity. 
6.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse events 
(SAEs). 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened. Rescreened participants should be assigned a new subject number. 
7. 
TREATMENTS 
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. 

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7.1. 
Treatments Administered 
Study 
Treatment 
Name: 
 
ELLIPTA 
placebo DPI 
DISKUS 
placebo DPI 
HandiHaler DPI 
and placebo 
Capsules 
Turbuhaler 
placebo DPI 
Dosage 
formulation: 
 
Placebo DPI 
with two strips 
with 30 blisters 
per strip. 
 
First strip: 
lactose 
monohydrate 
Second strip: 
lactose 
monohydrate 
blended with 
magnesium 
stearate 
Placebo DPI 
with one blister 
strip containing 
lactose 
monohydrate. 
DPI with 
placebo 
capsules 
containing 
lactose 
monohydrate 
Placebo DPI 
containing 
lactose 
monohydrate 
Route of 
Administration 
Oral Inhalation 
Oral Inhalation 
Oral Inhalation 
Oral Inhalation 
Dosing 
instructions: 
As directed 
As directed 
As directed 
As directed 
Packaging and 
Labelling 
Study 
Treatment will 
be provided in 
the appropriate 
container and 
will be labelled 
as required per 
country 
requirement. 
Study 
Treatment will 
be provided in 
the appropriate 
container and 
will be labelled 
as required per 
country 
requirement. 
Study 
Treatment will 
be provided in 
the appropriate 
container and 
will be labelled 
as required per 
country 
requirement. 
Study 
Treatment will 
be provided in 
the appropriate 
container and 
will be labelled 
as required per 
country 
requirement. 
Manufacturer 
GSK 
GSK 
Boehringer 
Ingelheim 
 
AstraZeneca 
 
Device 
NA 
NA 
HandiHaler 
NA 
 
7.1.1. 
Medical Devices 
• 
Other medical device (not manufactured by or for GSK) provided for use in this 
study is HandiHaler Dry Powder Inhaler 

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• 
Any extra instructions for medical device will be provided in the Study Reference 
Manual. 
7.2. 
Method of Treatment Assignment 
All participants will be centrally randomized using an Interactive Web Response System 
(IWRS). Before the study is initiated, the log in information & directions for the IWRS 
will be provided to each site. 
Participants will be assigned in equal numbers to one of four sequences for the sub-study 
they are included on, in accordance with the randomization schedule generated by 
Clinical Statistics, prior to the start of the study and using validated internal software.  
The possible sequences for each sub study are shown in Table 1 and Table 2 
Table 1 
Sub Study 1 Treatment Sequences 
Sequence 
Period 1 
Period 2 
Preference 
Questionnaire 
A 
ELLIPTA 
DISKUS + HandiHaler 
1 
B 
DISKUS + HandiHaler 
ELLIPTA 
2 
C 
ELLIPTA 
DISKUS + HandiHaler 
2 
D 
DISKUS + HandiHaler 
ELLIPTA 
1 
 
Table 2 
Sub Study 2 Treatment Sequence 
Sequence 
Period 1 
Period 2 
Preference 
Questionnaire 
E 
ELLIPTA 
Turbuhaler + HandiHaler 
3 
F 
Turbuhaler + HandiHaler 
ELLIPTA 
4 
G 
ELLIPTA 
Turbuhaler + HandiHaler 
4 
H 
Turbuhaler + HandiHaler 
ELLIPTA 
3 
 
Study treatments will be dispensed at the study visit summarized in SOA 
7.3. 
Blinding 
This is an open-label study; however, the order of treatment and preference questionnaire 
answered by a participant will be assigned using an IWRS. The site will contact the 
IWRS prior to study treatment administration for each participant. The site will record the 
treatment assignment on the applicable case report form, if required. Potential bias will 
be reduced by randomising the order of treatment and the preference questionnaire 
version answered by subjects.  

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7.4. 
Preparation/Handling/Storage/Accountability 
• 
The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received and any 
discrepancies are reported and resolved before use of the study treatment. 
Details of transit and storage conditions for study treatments will be included in 
the SRM. 
• 
Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply study treatment. All study treatments must be 
stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized site staff. 
• 
The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records). 
• 
Further guidance and information for the final disposition of unused study 
treatment are provided in the Study Reference Manual.  
• 
Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.   
7.5. 
Treatment Compliance 
Participants receive study treatment only at the clinical site and they will receive study 
treatment directly under supervision of the investigator or designee. 
The date and time of each dose administered in the clinic will be recorded in the source 
documents. 
7.6. 
Concomitant Therapy 
A detailed history of previous and ongoing COPD medications, in particular any types of 
inhalers used to deliver these medications for the previous 24 months from V0, should be 
recorded in order to inform on the subject’s inclusion.  
This is a single visit study, and the subject should continue to take their usual COPD and 
other medications through the conduct of the study. 
However, any medication or vaccine (including over-the-counter or prescription 
medicines, vitamins, and/or herbal supplements) that the participant is receiving at the 
time of enrolment or receives during the study must be recorded along with: 
• 
reason for use 
• 
dates of administration including start and end dates 
• 
dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 

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7.7. 
Treatment after the End of the Study 
There is no active treatment; this is a single visit, placebo only study and participants will 
not receive any specific post study treatments. 
8. 
DISCONTINUATION CRITERIA 
8.1. 
Discontinuation of Study Treatment 
Not applicable as this is a single-visit study with no active treatment; all subjects will 
receive placebo treatment only.   
8.1.1. 
Liver Chemistry Stopping Criteria 
Not applicable as this is a single-visit study with no active treatment; all subjects will 
receive placebo treatment only. . 
8.1.2. 
QTc Stopping Criteria 
Not applicable as this is a single-visit study with no active treatment; all subjects will 
receive placebo treatment only.  
8.2. 
Withdrawal from the Study 
• 
A participant may withdraw from the study at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, compliance or administrative reasons. 
• 
If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent. 
• 
This is a single visit, placebo only study, if a subjects withdrawals during this 
single visit there are no assessments that would need to be completed following 
withdrawal. 
8.3. 
Lost to Follow Up 
Not applicable as this is a single visit study. 
9. 
STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timing are summarized in the SoA.  
• 
Protocol waivers or exemptions are not allowed  
• 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment. 
• 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 

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• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.  
• 
Procedures conducted as part of the participant’s routine clinical management (e.g., 
to confirm diagnosis of COPD) and obtained before signing of ICF may be utilized 
for screening provided the procedure met any protocol-specified criteria and was 
performed within the time frame defined in the SoA. 
• 
Prior to randomisation, at V1, all assessments to confirm inclusion at V0 will be 
completed. The details of these assessment are provided in the SoA  
9.1. 
Efficacy Assessments 
9.1.1. 
Assessment of Errors in Use of Device 
Within each sub-study, subjects will be randomised for the order of treatment.  One 
treatment will require subjects to demonstrate use of a single inhaler (ELLIPTA), while 
the other treatment will require the subject to demonstrate use of 2 inhalers (DISKUS-
HandiHaler in Sub Study 1 or Turbuhaler-HandiHaler in Sub Study 2). 
Subjects will be provided with the relevant section of the PIL, explaining correct use, for 
each inhaler they are to be tested on. The critical and over all errors per inhaler and how 
these have been defined are included in Appendix 2. 
The errors listed will be in aligned with the correct use information from the respective 
PILs, in a checklist for each inhaler and these will be provided to HCPs for scoring errors 
during the study conduct. The checklists will be provided in the Study Reference Manual. 
Figure 2 depicts the process flow for assessing inhaler use errors and further details are 
provided, for each treatment, in Section 9.1.1.1 and Section 9.1.1.2. 

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Figure 2 
Assessment of errors in use for each DPI tested 
 
9.1.1.1. 
Assessment of ELLIPTA error in use 
Subject will be asked to read the patient instruction leaflet for ELLIPTA and then 
demonstrate ELLIPTA use.  Any errors (critical or non-critical) made by the subject 
while using the ELLIPTA will be recorded by the HCP on the checklist provided.  If the 
subject makes no errors, this will also be recorded by the HCP, and there will be no 
further assessments.  If the subject makes any error in the use of the ELLIPTA, the HCP 
will provide instruction in the correct use of the ELLIPTA to the subject.  The subject 
will then demonstrate ELLIPTA use again.  If the subject makes no errors, this will be 
recorded by the HCP and there will be no further assessments.  If the subject again makes 
errors in the use of the ELLIPTA any errors will be recorded by the HCP. The HCP will 
again provide instruction in the correct use for the final time, following which the subject 
will then demonstrate ELLIPTA use one final time. Any errors made during this 
demonstration will be recorded.  There will be no further assessments. In total, the HCP 
can provide instruction in the use of the inhaler up to two times.  
9.1.1.2. 
Assessment of DISKUS-HandiHaler in Sub Study 1, or Turbuhaler-
HandiHaler in Sub Study 2, for error in use 
Subjects will be provided with 2 inhalers and 2 PILs dependent on which sub study they 
are included in. 
Subjects should be tested on each DPI provided consecutively, they will be tested in the 
following order for each sub study. 
• 
Sub Study 1: DISKUS followed by HandiHaler 

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• 
Sub Study 2: Turbuhaler followed by HandiHaler 
Subjects will be asked to read the patient instruction leaflet for the first DPI (DISKUS or 
Turbuhaler) and then demonstrate first DPI use.  Any errors (critical or non-critical) made 
by the subject while using the first DPI will be recorded by the HCP on the checklists 
provided.  If the subject makes no errors, this will also be recorded by the HCP and there 
will be no further assessment for this first DPI.  If the subject makes any error in the use 
of the first DPI, the HCP will provide instruction in the correct use of the inhaler to the 
subject.  The subject will then demonstrate inhaler use again.  If the subject makes no 
errors, this will also be recorded by the HCP and there will be no further assessments for 
this DPI. If the subject again makes errors in the use of the DPI, the HCP will record the 
errors and provide instruction in correct use for the final time. The subject will then 
demonstrate use of first DPI for one final time. Any errors or correct use after this 
demonstration will be recorded, and there will be no further assessments for this DPI.  In 
total, the HCP can provide instruction in the use of the first DPI up to two times.  
This assessment will then be repeated with HandiHaler. 
9.1.1.3. 
Time Taken to Use Device 
Time taken to use the device will be recorded as follows: 
• 
T1: the time from when the subject starts to read the patient instruction leaflet until 
they have completed demonstration of device use (i.e., with no investigator support). 
• 
T2: the time from when the HCP starts to instruct subject until correct use is 
demonstrated (up to a maximum of two attempts only). 
• 
T1+T2:  the time from when the subject starts to read the patient information leaflet 
until correct use is demonstrated (up to a maximum of three attempts, once after 
reading the PIL and following instruction, up to 2 times, by HCP). 
The HCP will start recording (clock start) the time from when T1 begins and will stop 
when device use has been demonstrated.  The clock re-starts when T2 begins and stops 
once correct use has been demonstrated, or when three failed attempts have been made. 
Note:  T2 includes the time used by the investigator for re-instructing the Subjects 
throughout.  
For subjects who demonstrate correct inhaler use after reading the PIL, T2 will be 0. 
9.1.2. 
Assessments of Preference 
After completing the errors in use assessment for both treatments, the HCP will ask the 
subject questions from the assigned preference questionnaire.  The wording of the 
questionnaires is included in Appendix 3. 

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9.2. 
Adverse Events 
The definitions of an AE or SAE can be found in Appendix 5. 
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study (see Section 8).  
9.2.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• 
All SAEs will be collected from consent until the time point specified in the 
SoA (Section 2). 
• 
All AEs will be collected from randomisation until the time point specified in 
the SoA (Section 2). 
• 
Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (CRF) not the AE section. 
• 
All SAEs will be recorded and reported to the sponsor or designee within 24 
hours, as indicated in Appendix 5. The investigator will submit any updated 
SAE data to the sponsor within 24 hours of it being available. 
• 
Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify the sponsor. 
• 
The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 5. 
9.2.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence.  
9.2.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up). Further 
information on follow-up procedures is given in Appendix 5. 

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9.2.4. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met.  
• 
The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators. 
• 
Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary. 
• 
An investigator who receives an investigator safety report describing a SAE or 
other specific safety information eg, summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements. 
9.2.5. 
Cardiovascular and Death Events 
For any cardiovascular events and all deaths, whether or not they are considered SAEs, 
specific Cardiovascular (CV) and Death sections of the CRF will be required to be 
completed.  These sections include questions regarding cardiovascular (including sudden 
cardiac death) and non-cardiovascular death.  
The CV CRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary of 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.   
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. 
9.3. 
Safety Assessments 
There are no mandated safety assessments, other than monitoring for AEs and SAEs and 
this is described in Section 9.2. 
9.4. 
Pharmacokinetics 
PK parameters are not evaluated in this study. 

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9.5. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
9.6. 
Genetics 
Genetics are not evaluated in this study. 
9.7. 
Biomarkers 
Biomarkers are not evaluated in this study. 
9.8. 
Health Economics OR Medical Resource Utilization and 
Health Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study. 
10. 
STATISTICAL CONSIDERATIONS 
10.1. 
Hypotheses 
The primary purpose of this study is to assess the number of critical errors made by 
COPD patients, after a subject has read the patient information leaflet(s) (PIL) for each 
treatment option tested. This is a superiority study.  
There are two sub-studies and these will be analysed separately. There is no overlap of 
subjects and so these are considered independent. Hence there will be no adjustment for 
multiplicity. 
The primary endpoint is the percentage of subjects making at least one critical error after 
reading the PIL(s) on Treatment Option 1 compared with each of Treatment Option  2 
(Sub-study 1) and Treatment Option 3 (Sub-study 2). 
For each sub-study, the null hypotheses are no difference between treatment options: 
H0: p1=pi ;  i=2, 3 
The alternative hypothesis is that there is a difference between treatment options. 
HA: p1≠pi;  i=2,3  
10.2. 
Sample Size Determination 
The sample size calculation for each sub-study is based on the primary endpoint, the 
percentage of subjects making at least one critical error in each device combination 
(Ellipta or DISKUS - HandiHaler or Turbuhaler - HandiHaler) after reading the patient 
information leaflet(s).   

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Based on the results from studies 201301 and 201330, a range of critical error rates (at 
least one critical error using each device after reading the patient information leaflet) for 
each of the treatment options (ELLIPTA, DISKUS - HandiHaler and Turbuhaler - 
HandiHaler) were explored.  
Using 10000 simulations, a total of 72 subjects in each sub-study will provide at least 
90% power to show a statistically significant difference between the critical error rate of 
each of the paired treatment options (Sub-study 1: Treatment option 1 vs. Treatment 
Option 2; Sub-study 2: Treatment option 1 vs. Treatment Option 3) assuming the 
following true critical error rates.   
Treatment Option 1: 
Treatment Option 2: 
Treatment Option 3: 
ELLIPTA Critical 
Error Rate 
DISKUS - HandiHaler 
Critical Error rate 
Turbuhaler - HandiHaler 
Critical Error rate 
11% 
>=37% 
>=37% 
10% 
>=35% 
>=35% 
9% 
>=34% 
>=34% 
8% 
>=32% 
>=32% 
7% 
>=31% 
>=31% 
6% 
>=29% 
>=29% 
 
The error rates for the combined treatment options were based on the studies 201301 and 
201330 and a conservative assumption that the critical error rate for the combined 
treatment was the same as the critical error rate for a single device i.e. subjects who made 
errors made them on both devices. 
Conditional logistic regression and a two-sided 5% significance level were used as the 
analysis method in the simulations. No withdrawal is expected in this single visit study 
however up to 80 subjects may be randomised to each sub-study to ensure we have 72 
evaluable subjects in each sub-study.  
10.3. 
Populations for Analyses 
All analysis will be performed by individual sub-study.  Each sub-study data may be 
analysed when the sub-study has completed and the data have been cleaned.  The 
database will be locked when all of the sub-studies have completed and data are cleaned. 
For purposes of analysis, the following populations are defined for each sub-study: 
Population 
Description 
All Subjects Enrolled  (ASE) 
 
• All participants who sign the ICF and for whom a record 
exists in 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 

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Population 
Description 
Randomised 
• All participants who were randomised. 
Intent-to-treat (ITT) 
• All randomised subjects, excluding those who were 
randomised in error and made at least one critical error 
assessment from one treatment option device. A subject 
who is recorded as a screen or run-in failure and also 
randomized will be considered to be randomized in error.  
Any other subject who receives a randomization number will 
be considered to have been randomized. 
• Displays will be based on the treatment to which the subject 
was randomized. 
Safety 
• This population will be the same as the Intent-to-treat 
population. 
 
10.4. 
Statistical Analyses 
10.4.1. 
Efficacy Analyses 
Endpoint 
Statistical Analysis Methods 
Primary 
The primary endpoint is the percentage of subjects making at least one 
critical error after reading the PIL(s). 
This endpoint will be analysed using conditional logistic regression with 
subject as fixed strata, and treatment option and period as fixed effects. The 
odds ratio, 95% CI and p-value will be presented for the comparison between 
treatment options.  It will be based on a two-sided hypothesis testing 
approach of superiority. 
Secondary 
The following endpoints will be analysed in the same way as for the primary 
endpoint if there are sufficient subjects making errors otherwise the data will 
be summarised only: 
• 
The percentage of subjects making at least one critical error after    the 
first instruction from the HCP  
• 
The percentage of subjects making at least one overall error after 
reading the PIL(s)  
• 
The percentage of subjects making at least one overall error after the 
first instruction from the HCP 
The number of instructions (0, 1 or 2 times) from the HCP which are needed 
to demonstrate correct inhaler use will be analysed using the Wilcoxon 
signed rank test. 
The total amount of time taken to demonstrate correct inhaler use (T1+T2) 

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Endpoint 
Statistical Analysis Methods 
will be analysed using Kaplan-Meier methods. 
Treatment preference from questionnaire will be analysed using a Cochran-
Mantel-Haelszel test, adjusted for study inhaler use sequence. 
 
Other 
Analysis of the following other endpoints will be defined in the Reporting and 
Analysis Plan. 
• 
The percentage of subjects making at least one critical error after the 
second instruction from the HCP 
• 
The percentage of subjects making at least one overall error after the 
second instruction from the HCP 
• 
The amount of time taken to read the patient information leaflet and 
demonstrate correct inhaler device use (T1)  
• 
The amount of time taken to be given instruction by the HCP on use of 
the inhaler and demonstrate correct inhaler use (T2) 
 
10.4.2. 
Safety Analyses 
All safety analyses will be performed on the Safety Population. 
Adverse events (AEs) will be coded using the standard GSK dictionary, Medical 
Dictionary for Regulatory Activities (MedDRA), and grouped by body system. 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, fatal 
AEs, non-fatal SAEs, AESIs and AEs leading to withdrawal.  
Deaths and SAEs, if applicable, will be documented in case narrative format.  
10.4.3. 
Other Analyses 
Any other analyses will be described in the reporting and analysis plan  
10.4.4. 
Interim Analyses 
No interim analyses are planned. 
The protocol consists of two sub-studies to assess the following treatment comparisons: 
ELLIPTA DPI (treatment option 1) versus the combination of DISKUS-HandiHaler 
(treatment option 2) in Sub-study 1 and ELLIPTA DPI (treatment option 1) versus the 
combination of Turbuhaler-HandiHaler (treatment option 3) in Sub-study 2.   
Sub-study 1 will report out independently of Sub-study 2. 
 

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11. 
REFERENCES 
Bonini M, Usmani O. The importance of inhaler devices in the treatment of COPD. 
COPD Research and Practice (2015) 1:9 
Celli BR, MacNee W. Standards of the diagnosis and treatment of patients with COPD: a 
summary of the ATS/ERS position paper. Eur Respir J. 2004;23:932-46. 
Cochrane M, Bala M, Downs K, Mauskopf J, Ben-Joseph R. Inhaled Corticosteroids for 
Asthma Therapy:Patient Compliance, Devices, and Inhalation Technique. CHEST 2000; 
117:542–550 
Global Initiative for Chronic Obstructive Lung Disease (GOLD 2016).  Global strategy 
for the diagnosis, management, and prevention of COPD (Updated 2016).  Available 
from http://www.goldcopd.org 
Komase Y, Asako A, Kobyyashi A, Sharma R. E Ease-of-use preference for the  
ELLIPTA® dry powder inhaler over a commonly used single-dose capsule dry powder 
inhaler by inhalation device-naïve Japanese volunteers aged 40 years or older. 
International Journal of COPD 2014:9 
Melani A, Bonavia M, Cilenti V, Cinti C, Lodi M, Martucci P. Inhaler mishandling 
remains common in real life and is associated with reduced disease control. Respiratory 
Medicine (2011) 105, 930-938 
 
Van der PalenJ, Klein J, Van Herwaarden ,Zielhuis, Seydel E. Multiple inhalers confuse 
asthma patients. Eur Respir J 1999; 14: 1034-1037 
Van Der Palen J, Thomas M, Chrystyn H, Sharma R, Imber V, Zhu C.-Q, BarnesN. . 
Inhaler Errors After Reading The Patient Information Leaflet In Patients With COPD: A 
Comparison Of Ellipta® With Five Inhaler Devices. Am J Respir Crit Care Med 193; 
2016:A6811 (a) 
Van Der Palen J, Thomas M, Chrystyn H, Sharma R, Svedsater H, Zhu C.-Q, Barnes N. 
Inhaler Preference In Patients With COPD: A Comparison Of Ellipta® With Five Inhaler 
Devices. Am J Respir Crit Care Med 193; 2016:A6813 (b) 
Van Der Palen J, Thomas M, Chrystyn H, Sharma R, Imber V , Zhu C.-Q, Svedsater H . 
Training And Time To Achieve Correct Inhaler Use: A Comparison Between Inhalers In 
Patients With COPD. Am J Respir Crit Care Med 193; 2016:A6811 (c) 

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12. 
APPENDICES 
12.1. 
Appendix 1: Abbreviations and Trademarks 
Abbreviations 
ASE 
All Subjects Enrolled   
COPD 
Chronic Obstructive Pulmonary Disease 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
CV 
Cardiovascular 
DPI 
Dry Powder Inhaler 
HCP 
Healthcare Professional 
ICS 
Inhaled Corticosteroids 
IEC 
Independent Ethics Committees 
IRB 
Institutional Review Boards 
ITT 
Intent-to-treat 
IWRS 
Interactive Web Response System 
LABA 
Long-Acting Beta2-Agonist 
LAMA 
Long-Acting Anticholinergic 
MedRA 
Medical Dictionary of Regulatory activities 
PIL 
Patient Instruction Leaflet 
SABA 
Short Acting Beta-Adrenergic Agonist 
SAE 
Serious Adverse Events 
SAMA 
Short Acting Muscarinic Antagonist 
SRM 
Study Reference Manual 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
ANORO ELLIPTA 
 
SAS 
ARNUITY ELLIPTA 
 
Seebri  Breezhaler 
INCRUSE ELLIPTA 
 
Spiriva HandiHaler 
RELVAR ELLIPTA 
 
Symbicort Turbuhaler 
SERETIDE DISKUS 
 
Symbicort Turbohaler 
BREO ELLIPTA 
 
Ultibro Breezhaler 
SERETIDE ACCUHALER  
 
 
 

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12.2. 
Appendix 2: Inhaler Specific Errors for the inhalers used in 
the study 
There are no universally agreed checklists that define critical errors and over all errors for 
specific inhalers. The checklist and critical errors, for use in this study have been 
developed by GSK for each inhaler based upon: 
• 
A review of the patient information leaflet for each inhaler and the steps defined 
therein for correct use 
• 
The available literature which is exhaustive for a number of the commonly used 
inhalers  
• 
Review of these errors with a group of external inhaler experts  
The critical errors checklist are, therefore, as robust as possible. Furthermore, GSK has 
used selected sites with trained assessors to ensure as much consistency as possible in the 
valuation of errors in study subjects. 
Checklist of instructions for correct use will be based on the steps listed in the patient 
information leaflets/package insert for each device.  Some of the steps outlined in the 
patient information leaflets/package inserts require several actions to be identified and 
checked by the HCP.  
Critical Errors are identified in bold text in the list below.  A critical error is defined as 
an error that is most likely to result in no or significantly reduced medication being 
inhaled. 
These errors will be captured in a checklist provided for HCP assessment of DPI use. 
DISKUS/ACCUHALER 
Failed to open cover 
Lever is not pushed back  
Shook the device after dose preparation 
No exhalation before an inhalation 
Exhaled directly into mouthpiece 
No seal by the lips round the mouthpiece during the 
inhalation 
Inhalation manoeuvre: 
- 
steady 
- 
deep 
Did not hold breath 
Did not close the device (Note:  this is an error but one 
which does not affect the medication that is inhaled) 
Any other comments: [free text box] 
 

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ELLIPTA 
Failed to open cover 
Shook the device after dose preparation 
No exhalation before an inhalation 
Exhaled directly into mouthpiece 
No seal by the lips round the mouthpiece during the 
inhalation 
Inhalation manoeuvre: 
- 
long 
- 
steady 
- 
deep 
Blocked air inlet during inhalation manoeuvre 
Did not hold breath 
Did not close the device (Note:  this is an error but one 
which does not affect the medication that is inhaled) 
Any other comments: [free text box] 
 
TURBUHALER 
Failed to remove cap 
Did not hold device upright (±45% OK) during dose 
preparation 
Base not twisted fully backwards and forwards, no 
click heard 
Device tipped downwards after dose preparation 
Shook the device after dose preparation 
No exhalation before an inhalation 
Exhaled directly into mouthpiece 
No seal by the lips round the mouthpiece during the 
inhalation 
Inhalation manoeuvre: 
- 
forceful 
- 
deep 
Note to HCP:  it is important that the inhalation is 
forceful and deep from the start for this inhaler 
Blocked air inlet during inhalation manoeuvre 
Did not hold breath 
Did not close the device (Note:  this is an error but one 
which does not affect the medication that is inhaled) 
Any other comments: [free text box] 
 

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HANDIHALER 
Failed to remove capsule 
Failed to insert capsule into the chamber 
Did not completely close device capsule chamber 
(heard click when satisfactory) 
Did not pierce the capsule (HCP should check 
capsule was pierced) 
Shook the device after dose preparation  
No exhalation before an inhalation 
Exhaled directly into mouthpiece 
No seal by the lips round the mouthpiece during the 
inhalation 
Inhalation manoeuvre: 
- 
slow 
- 
deep  
Capsule did not rattle  
Blocked air inlet during inhalation manoeuvre 
Did not hold breath 
Did not check inside the capsule chamber if powder 
was left / did not make a second inhalation 
Any other comments: [free text box] 

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12.3. 
Appendix 3: Inhaler Preference Questionnaires 
Inhaler Preference Questionnaire Version 1 
Instructions: Please complete the following questions related to the treatments 
you used during this study. Check only one response for each question.  
1. Which treatment do you prefer based on the number of steps needed to take your 
COPD medication?  
□ DISKUS and HandiHaler  
□ ELLIPTA  
□ No preference  
 
2. Which treatment do you prefer for taking your COPD medication?  
□ DISKUS and HandiHaler  
□ ELLIPTA  
□ No preference  
 
Inhaler Preference Questionnaire Version 2 
Instructions: Please complete the following questions related to the treatments 
you used during this study. Check only one response for each question.  
1. Which treatment do you prefer based on the number of steps needed to take your 
COPD medication?  
□ ELLIPTA 
□ DISKUS and HandiHaler 
□ No preference  
 
2. Which treatment do you prefer for taking your COPD medication?  
□ ELLIPTA 
□ DISKUS and HandiHaler 
□ No preference  
 

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Inhaler Preference Questionnaire Version 3 
Instructions: Please complete the following questions related to the treatments 
you used during this study. Check only one response for each question.  
1. Which treatment do you prefer based on the number of steps needed to take your 
COPD medication?  
□ Turbuhaler and HandiHaler  
□ ELLIPTA  
□ No preference  
 
2. Which treatment do you prefer for taking your COPD medication?  
□ Turbuhaler and HandiHaler 
□ ELLIPTA  
□ No preference  
 
 
Inhaler Preference Questionnaire Version 4 
Instructions: Please complete the following questions related to the treatments 
you used during this study. Check only one response for each question.  
1. Which treatment do you prefer based on the number of steps needed to take your 
COPD medication?  
□ ELLIPTA  
□ DISKUS and HandiHaler 
□ No preference  
 
2. Which treatment do you prefer for taking your COPD medication?  
□ ELLIPTA  
□ DISKUS and HandiHaler 
□ No preference 

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12.4. 
Appendix 4: Study Governance Considerations 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with: 
• Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated.  
• 
Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.  
• 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC 
• Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations 
Financial Disclosure 
 Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
Informed Consent Process 
• 
The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study.  

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• 
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study centre.  
• 
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study.  
• 
A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative.  
Data Protection 
• 
Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred.  
• 
The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant.  
• 
The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities. 
Publication Policy 
• 
The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.  
• 
The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement. 
• 
Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements. 
Dissemination of Clinical Study Data 
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 

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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. 
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy. 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF.  
• 
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.  
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.  
• 
The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
• 
Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.  
• 
Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years after study completion 
unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor.  
Source Documents 
• 
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• 
Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 

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medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
• 
Definition of what constitutes source data can be found in source data agreement 
or source data verification form 
Study and Site Closure 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study treatment development 

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12.5. 
Appendix 5: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment. 
 
Events Meeting the AE Definition  
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
• 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE.  
• 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE. 
 
Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 

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assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 

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and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
 
Recording AE and SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
• 
The investigator will then record all relevant AE/SAE information in the CRF. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories:  
• 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities. 
• 
Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as 

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severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe. 
 
 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE. 
• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK. 
• 
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AE and SAE 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology. 

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• 
New or updated information will be recorded in the originally completed CRF. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
 
Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
• 
The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper SAE data collection tool (see next section). 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor by telephone. 
• 
Contacts for SAE reporting can be found in the SRM. 
 
SAE Reporting to GSK via Paper CRF 
• 
Facsimile transmission, or a scanned version sent by email, of the SAE paper CRF is 
the preferred method to transmit this information to the medical monitor. 
• 
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service. 
• 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
• 
Contacts for SAE reporting can be found in the SRM.