Clinical trial NCT01957150
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: GlaxoSmithKline
Start date: 2014-01-28; Completion date: 2018-03-26
Enrollment: 283 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multi-center, randomized, double-blind, parallel-group study. The FF/VI inhalation powder once daily and VI inhalation powder once daily will be evaluated in subjects with COPD over 156 weeks. The primary objective of this study is to evaluate the effect of the inhaled corticosteroid FF on bone mineral density assessed at the total hip by comparing FF/VI treatment with VI treatment in subjects with moderate COPD.

Detailed description:

Arms: arm 1: Subjects will self administer FF/VI 100/25 mcg inhalation powder once daily for 156 weeks via the NDPI. arm 2: Subjects will self administer VI 25 mcg inhalation powder once daily for 156 weeks via the NDPI.
Interventions: intervention 1: Fluticasone Furoate/Vilanterol intervention 2: Vilanterol
Intervention descriptions: intervention 1: Dry white powder containing 100 mcg of Fluticasone Furoate blended with lactose per blister was administered by NDPI. Dry white powder containing 25 mcg of Vilanterol micronised drug (as the 'M' salt triphenylacetate) blended with lactose and magnesium stearate per blister was administered by NDPI. intervention 2: Dry white powder containing 25 mcg of Vilanterol micronised drug (as the 'M' salt triphenylacetate) blended with lactose and magnesium stearate per blister was administered by NDPI.

Protocol documents:
Prot_000.pdf: 
2012N150072_01
CONFIDENTIAL
The GlaxoSmithKline group of companies
HZC102972
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
Multi-centre, randomized, double-blind, parallel-group study 
evaluating the effect of Fluticasone Furoate/ Vilanterol (FF/VI) 
Inhalation Powder once daily compared with Vilanterol (VI) 
Inhalation Powder Once Daily on Bone Mineral Density (BMD) 
in subjects with Chronic Obstructive Pulmonary Disease 
(COPD)
Compound Number:
GW685698+GW642444
Effective Date:
14-AUG-2013
Protocol Amendment Number:  01
Subject: COPD, Bone Mineral Density, Fluticasone Furoate (FF), Vilanterol (VI), Novel 
Dry Powder Inhaler (NDPI)
Author:
Revision Chronology:
2012N150072_00
2013-JAN-07
Original
2012N150072_01
2013-AUG-14
Amendment No.: 01 This protocol 
amendment is being implemented to 
revise and clarify exclusion criteria 
concerning participation in pulmonary 
rehabilitation programs; clarify the 
description of DEXA procedures and 
clinical labs; correction of 
typographical errors.
Copyright 2013 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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SPONSOR INFORMATION PAGE
Clinical Study Identifier: 
HZC102972
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Sponsor Contact Address
GlaxoSmithKline Research &  Development Limited
Via 
2/4-37135
Verona, Italy
Telephone:  
GlaxoSmithKline Research & Development Limited
Addenbrooke’s Centre for Clinical Investigation (ACCI)
Addenbrooke’s Hospital
Hills Road
Cambridge, Cambridgeshire, CB2 2GG, UK
Telephone:  
GlaxoSmithKline Research & Development Limited
Iron Bridge Road 
Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK
Telephone:  
 
GlaxoSmithKline Research & Development Limited
2301 Renaissance Boulevard
Building #510
Post Office Box 61540
King of Prussia, Pennsylvania 19406
Telephone number: 
or
GlaxoSmithKline Research & Development Limited
1250 South Collegeville Road
Collegeville, PA 19426, USA
Telephone Number: 
GlaxoSmithKline Research & Development Limited
Five Moore Drive 
 
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P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone: 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate 
company (or designee). Where applicable, the details of the Sponsor and contact person 
will be provided to the relevant regulatory authority as part of the clinical trial 
submission.
Sponsor Medical Monitor Contact Information: 
 MD
GlaxoSmithKline
Five Moore Drive
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone: 
Sponsor Serious Adverse Events (SAE) Contact Information: 
Case Management Group, GCSP –Stockley Park, UK
Email: 
Fax: 
Regulatory Agency Identifying Number(s): FDA IND Numbers:  077855 and 050703; 
EudraCT #: 2012-004801-28
 
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INVESTIGATOR AGREEMENT PAGE
For protocol number HZC102972
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described clinical study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:  _____________________________
Investigator Signature
Date
 
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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS.............................................................................................9
PROTOCOL SUMMARY...............................................................................................11
1.
INTRODUCTION....................................................................................................13
1.1.
Background ................................................................................................13
1.2.
Rationale ....................................................................................................13
2.
OBJECTIVE(S) ......................................................................................................14
3.
INVESTIGATIONAL PLAN.....................................................................................14
3.1.
Study Design ..............................................................................................14
3.1.1.
Study Schematic..........................................................................15
3.2.
Discussion of Design ..................................................................................15
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA.......................................16
4.1.
Number of Subjects ....................................................................................16
4.2.
Inclusion Criteria.........................................................................................16
4.3.
Exclusion Criteria........................................................................................17
4.4.
Withdrawal Criteria .....................................................................................20
4.5.
Pre-Screen Failures and Screening Failures...............................................21
5.
STUDY TREATMENTS..........................................................................................22
5.1.
Investigational Product and Other Study Treatment....................................22
5.1.1.
Storage........................................................................................23
5.1.2.
Study Drug Return.......................................................................23
5.2.
Treatment Assignment................................................................................23
5.3.
Blinding.......................................................................................................24
5.4.
Product Accountability ................................................................................24
5.5.
Treatment Compliance................................................................................25
5.6.
Concomitant Medications and Non-Drug Therapies....................................25
5.6.1.
Permitted Medications and Non-Drug Therapies..........................25
5.6.2.
Prohibited Medications and Non-Drug Therapies.........................26
5.7.
Treatment after the End of the Study ..........................................................27
5.8.
Treatment of Study Treatment Overdose....................................................27
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................27
6.1.
Critical Baseline Assessments....................................................................31
6.2.
Safety .........................................................................................................31
6.2.1.
Primary Endpoint .........................................................................31
6.2.2.
Secondary Endpoints...................................................................31
6.2.3.
Other Endpoints...........................................................................31
6.2.4.
Bone Mineral Density...................................................................32
6.2.5.
Fractures .....................................................................................32
6.2.6.
COPD Exacerbations and Pneumonias .......................................32
6.2.7.
Liver chemistry stopping and follow up criteria.............................34
6.2.8.
Adverse Events............................................................................37
6.2.8.1.
Definition of an AE......................................................38
 
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6.2.8.2.
Definition of a SAE .....................................................39
6.2.9.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs.........................................................40
6.2.10.
Cardiovascular Events.................................................................40
6.2.11.
Death Events...............................................................................41
6.2.12.
Pregnancy ...................................................................................41
6.2.13.
Time Period and Frequency of Detecting AEs and SAEs.............41
6.2.14.
Prompt Reporting of Serious Adverse Events and Other 
Events to GSK.............................................................................41
6.2.14.1.
Regulatory reporting requirements for SAEs ..............43
6.2.15.
SpirometryTesting........................................................................43
6.2.15.1.
Reversibility Testing ...................................................44
6.2.16.
Laboratory Assessments .............................................................44
6.2.17.
Oropharyngeal Examination.........................................................45
6.2.18.
Diary Card - Medical Problems/Medications Taken......................45
6.2.19.
12-lead ECG Assessment............................................................45
6.2.20.
Smoking Cessation Counselling ..................................................46
6.3.
Pharmacogenetic Research........................................................................46
7.
DATA MANAGEMENT ...........................................................................................47
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................47
8.1.
Hypotheses.................................................................................................47
8.2.
Study Design Considerations......................................................................47
8.2.1.
Sample Size Assumptions ...........................................................47
8.2.2.
Sample Size Sensitivity................................................................48
8.2.3.
Sample Size Re-estimation..........................................................48
8.3.
Data Analysis Considerations .....................................................................48
8.3.1.
Analysis Populations....................................................................48
8.3.2.
Analysis Data Sets.......................................................................48
8.3.3.
Treatment Comparisons ..............................................................48
8.3.3.1.
Primary Comparisons of Interest ................................48
8.3.4.
Interim Analysis ...........................................................................49
8.3.5.
Key Elements of Analysis Plan ....................................................49
8.3.5.1.
Efficacy Analyses .......................................................49
8.3.5.2.
Safety Analyses..........................................................49
8.3.5.2.1.
Extent of Exposure .................................49
8.3.5.2.2.
Adverse Events (AEs).............................49
8.3.5.2.3.
Deaths and SAEs ...................................49
8.3.5.2.4.
Fractures ................................................49
8.3.5.2.5.
COPD Exacerbations and 
Pneumonias ...........................................49
8.3.5.3.
Pharmacogenetic Analyses ........................................49
9.
STUDY CONDUCT CONSIDERATIONS ...............................................................50
9.1.
Posting of Information on Publicly Available Clinical Trial Registers............50
9.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................50
9.3.
Quality Control (Study Monitoring) ..............................................................51
9.4.
Quality Assurance.......................................................................................51
9.5.
Study and Site Closure ...............................................................................51
9.6.
Records Retention......................................................................................52
 
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9.7.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication....................52
9.8.
Independent Data Monitoring Committee (IDMC) .......................................53
10. REFERENCES.......................................................................................................54
11. APPENDICES........................................................................................................55
11.1.
Appendix 1: Laboratory Assessments.........................................................55
11.2.
Appendix 2: Pharmacogenetic Research ....................................................56
11.3.
Appendix 3: Country Specific Requirements...............................................61
11.4.
Appendix 4: Liver Chemistry Stopping and Followup Criteria......................62
11.5.
Appendix 5: Protocol Changes....................................................................63
 
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LIST OF ABBREVIATIONS
AE
Adverse Event
ALT
Alanine Transaminase
AM
Morning
ANCOVA
Analysis of Covariance
AST
Aspartate Transaminase
AUC
Area Under the Curve
ATS
American Thoracic Society
BMD
Bone Mineral Density
IB
Investigator’s Brochure
COPD
Chronic Obstructive Pulmonary Disease
eCRF
Electronic Case Report Form
DEXA
Dual Energy X-ray Absorptiometry
ECG
Electrocardiogram
EISR
Expedited Investigator Safety Report
FEV1
Forced Expiratory Volume in one Second
FF
Fluticasone Furoate
FF/VI
Fluticasone Furoate/ Vilanterol Inhalation Powder 
Combination
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GCP
Good Clinical Practice
GOLD
Global Initiative for Chronic Obstructive Lung Disease
GSK
GlaxoSmithKline
IEC
Independent Ethics Committee
ICF
Informed Consent Form
ICS
Inhaled Corticosteroid
IDMC
Independent Data Monitoring Committee
IRB
Institutional Review Board
ITT
Intent to Treat
IVRS
Interactive Voice Response System
L
Liter
LABA
Long Acting Beta Agonist
LDH
Lactate Dehydrogenase
LSLV
Last Subject Last Visit
LTOT
Long Term Oxygen Therapy
MAOI
Monoamine Oxidase Inhibitor
Mcg
Microgram
MDI
Metered Dose Inhaler
MEDDRA
Medical Dictionary for Regulatory Activities
mL
Milliliter
MSDS
Material Safety Data Sheet
NDPI
Novel Dry Powder Inhaler
OTC
Over the Counter
PD
Pharmacodynamics
PK
Pharmacokinetics
 
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PEF
Peak Expiratory Flow
PFT
Pulmonary Function Test
PGx
Pharmacogenetics
PM
Evening
PR
Pulse Rate
PRN
As needed
QD
Once Daily
RAMOS
Registration and Medication Ordering System
RAP
Reporting Analysis Plan
RNA
Ribonucleic Acid
SAE
Serious Adverse Event
SD
Standard Deviation
SPM
Study Procedures Manual
UC
Urine Cortisol
ULN
Upper Limit of Normal
VI
Vilanterol
WHO
World Health Organization
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
NONE
 
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PROTOCOL SUMMARY
Rationale
Chronic obstructive pulmonary disease (COPD) has been defined as a preventable and 
treatable disease with some significant extra-pulmonary effects that may contribute to the 
severity in individual patients. The pulmonary component of COPD is characterized by 
airflow limitation that is not fully reversible, which is usually progressive and associated 
with an abnormal inflammatory response of the lung to noxious particles or gases. COPD 
is a major cause of poor health, resulting in millions of deaths annually worldwide 
[GOLD, 2010] and contributing significantly to health care costs and morbidity 
[Chapman, 2006; Lopez, 2006]. According to the World Health Organization, COPD was 
the fifth leading cause of death worldwide in 2002 and is estimated to be the third leading 
cause by 2030 [WHO, 2010].
Currently published guidelines on COPD state that the goals of pharmacologic therapy 
should be to control symptoms, improve health status and exercise tolerance, and reduce 
the frequency of COPD exacerbations [GOLD, 2010]. Recent clinical research has 
indicated that an inhaled corticosteroid (ICS) combined with a long acting 2-agonist 
(LABA) is more effective than the individual components in managing stable COPD to 
reduce exacerbations and improve lung function and health status [Ferguson, 2008; 
Calverley, 2007; Kardos, 2007]. 
Although inhaled corticosteroids have demonstrated utility in patients with COPD, there 
is a potential safety concern with long-term use on bone demineralization.  These 
concerns, for the most part, are derived from the well-documented effects of oral 
corticosteroids on bone density and fracture; however the actual effects of inhaled 
corticosteroids are not clear and require further study.
Study HZC102972 will prospectively assess the effects of 3 years (156 weeks) exposure 
to fluticasone furoate/vilanterol (FF/VI) Fluticasone Furoate /Vilanterol (FF/VI) 
inhalation powder once daily versus VI once daily on bone mineral density in adult 
subjects with COPD at approximately 40 centres.
Objective(s)
The primary objective of this study is to evaluate the effect of the inhaled corticosteroid 
FF on bone mineral density (BMD) assessed at the total hip by comparing FF/VI 
treatment with VI treatment in subjects with moderate COPD. 
A secondary objective is to evaluate the effect of the inhaled corticosteroid FF on bone 
mineral density by gender by comparing FF/VI treatment with VI treatment in subjects
with moderate COPD.
Another secondary objective is to evaluate the effect of FF on bone mineral density as 
assessed at the lumbar spine (L1-L4) by comparing FF/VI treatment with VI treatment in 
subjects with moderate COPD.
 
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Study Design
This is a multi-center, randomized, double-blind, parallel-group study.  The FF/VI 
inhalation powder once daily and VI inhalation powder once daily will be evaluated in 
subjects with COPD over 156 weeks. Subjects will sign the informed consent form (ICF) 
at Visit 0 and will be assigned a subject identifier. See Table 3 for further details. 
Subjects who meet all study inclusion and none of the exclusion criteria will begin a 14 to 
21 day single-blind run-in period following Visit 1.  Baseline BMD measurements will be 
collected between Visits 1 and 2.  At Visit 2, eligible subjects will be randomized to 
double-blind study medication and entered into a 156-week treatment period.  
Randomisation will be stratified based upon gender.  During the treatment period, clinic 
visits will occur every 3 months. BMD determined by dual-energy x-ray absorptiometry 
(DEXA) scans will be conducted every 6 months following randomization. A safety 
Follow-up Visit 15 will occur 7 days after the last treatment study day as a telephone 
contact.  Subjects will be prescribed appropriate COPD therapy at the end of Treatment 
Visit 14 if required.  There are no plans to provide the study drug for compassionate use 
following study completion.
The target enrolment across approximately 40 study centres is approximately 280
randomized subjects, to achieve approximately 224 who complete the 156-week 
treatment period.  The total duration of subject participation will be approximately 159 to 
160 weeks.
Study Endpoints/Assessments
Primary

BMD measured at the total hip 
Secondary

BMD measurements by gender 

BMD measured at the lumbar spine (L1-L4)
Other

Adverse Event reporting 

Serious Adverse Event reporting

Incidence of fractures

Incidence of pneumonias

COPD exacerbations
 
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1.
INTRODUCTION
1.1.
Background
COPD has been defined as a preventable and treatable disease with some significant 
extra-pulmonary effects that may contribute to the severity in individual patients. The 
pulmonary component of COPD is characterized by airflow limitation that is not fully 
reversible, which is usually progressive and associated with an abnormal inflammatory 
response of the lung to noxious particles or gases. COPD is a major cause of poor health, 
resulting in millions of deaths annually worldwide [GOLD, 2010] and contributing 
significantly to health care costs and morbidity [Chapman, 2006; Lopez, 2006]. 
According to the World Health Organization, COPD was the fifth leading cause of death 
worldwide in 2002 and is estimated to be the third leading cause by 2030 [WHO, 2010].
Currently published guidelines on COPD state that the goals of pharmacologic therapy 
should be to control symptoms, improve health status and exercise tolerance, and reduce 
the frequency of COPD exacerbations [GOLD, 2010]. Recent clinical research has 
indicated that an inhaled corticosteroid (ICS) combined with a long acting 2-agonist 
(LABA) is more effective than the individual components in managing stable COPD to 
reduce exacerbations and improve lung function and health status [Ferguson, 2008; 
Calverley, 2007; Kardos, 2007]. 
Bronchodilators are considered key to the symptomatic management of COPD and 
current Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines 
recommend the use of long-acting inhaled bronchodilators in moderate to very severe 
COPD, because they are more efficacious and more convenient to use than short-acting 
bronchodilators.  The benefits of bronchodilators include not only the control of 
symptoms but improvements in lung function, hyperinflation, exercise performance, and 
health status.
Inhaled corticosteroids are considered the most effective anti-inflammatory treatments for 
all severities of COPD.  The benefits of ICS may include control of COPD symptoms, 
improvement in lung function, decrease in airway hyper-responsiveness and 
improvement in health status and reduction in exacerbations.
1.2.
Rationale
Although inhaled corticosteroids have demonstrated utility in patients with COPD, there 
is a potential safety concern with long-term use of ICS on bone demineralization.  These 
concerns, for the most part, are derived from the well-documented effects of oral 
corticosteroids on bone density and fracture; however the actual effects of inhaled 
corticosteroids are not clear and require further study.
Study HZC102972 will prospectively assess the effects of 3 years (156 weeks) exposure 
to FF/VI Fluticasone Furoate /Vilanterol (FF/VI) Inhalation Powder Once Daily versus 
VI Once Daily on bone mineral density in adult subjects with chronic obstructive 
pulmonary disease (COPD) at approximately 40 centres.
 
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2.
OBJECTIVE(S)
The primary objective of this study is to evaluate the effect of the inhaled corticosteroid 
FF on bone mineral density assessed at the total hip by comparing FF/VI treatment with 
VI treatment in subjects with moderate COPD. 
A secondary objective is to evaluate the effect of the inhaled corticosteroid Fluticasone 
Furoate (FF) on bone mineral density by gender by comparing FF/VI treatment with VI 
treatment in subjects with moderate COPD.
Another secondary objective is to evaluate the effect of FF on bone mineral density as 
assessed at the lumbar spine (L1-L4) by comparing FF/VI treatment with VI treatment in 
subjects with moderate COPD.
3.
INVESTIGATIONAL PLAN
3.1.
Study Design
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct. 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.
This is a multi-center, randomized, double-blind, parallel-group study.  The FF/VI 
inhalation powder once daily and VI inhalation powder once daily will be evaluated in 
subjects with COPD over 156 weeks. Subjects will sign the ICF at Visit 0 and will be 
assigned a subject identifier. See Table 3 for further details. Subjects who meet all study 
inclusion and none of the exclusion criteria will begin a 14 to 21 day single-blind run-in 
period following Visit 1.  Baseline BMD measurements will be collected between Visits 
1 and 2.  At Visit 2, eligible subjects will be randomized to double-blind study 
medication and entered into a 156-week treatment period.  Randomisation will be 
stratified based upon gender.  During the treatment period, clinic visits will occur every 3 
months. BMD DEXA scans will be conducted every 6 months following randomization. 
A safety Follow-up Visit 15 will occur 7 days after the last treatment study day as a 
telephone contact.  Subjects will be prescribed appropriate COPD therapy at the end of 
Treatment Visit 14 if required.  There are no plans to provide the study drug for 
compassionate use following study completion.
Systemic corticosteroid therapies will not be allowed during the run-in period.  Subjects 
may take courses of systemic corticosteroids, where necessary, for treatment of a COPD 
exacerbation during the double-blind treatment period.
 
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3.1.1.
Study Schematic
FF/VI 100/25 once daily (N=140)
VI 25 once daily (N=140)
            │                          156 Week Treatment                                         │Follow-up
│__│_│___│___│___│___│___│___│___│___│___│___│___│___│_│
Visits
0     1   2       3       4       5      6      7       8       9      10     11    12     13     14  15
                             
Randomization
3.2.
Discussion of Design
The purpose of this study is primarily to assess the long-term safety effects of the FF 
component of the FF/VI inhalation powder on bone mineral density when administered to 
subjects with COPD over 156 weeks.  The American Thoracic Society (ATS)/European 
Respiratory Society definition of COPD defines the subject population that will be 
included in this study [Celli, 2004].  BMD at the total hip was chosen as the primary 
endpoint due to the important morbidity/mortality implications of hip fractures.  BMD at 
the lumbar spine (L1-L4) will be measured and assessed as a secondary endpoint.  
 
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4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA
4.1.
Number of Subjects
Approximately 400 male and female subjects will be screened to randomize 
approximately 280 subjects, to obtain at least 224 who complete 156 weeks of treatment.  
Approximately 40 centres in multiple countries will be required to recruit for the study.
4.2.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB.
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.   
Subjects eligible for enrolment in the study must meet all of the following criteria:
1. Informed consent: Subjects must give their signed and dated written informed 
consent to participate.
2. Gender: Male or female subjects. Female subjects must be post-menopausal or using 
a highly effective method for avoidance of pregnancy. The decision to include or 
exclude women of childbearing potential may be made at the discretion of the 
investigator in accordance with local practice in relation to adequate contraception.
3. Age: ≥ 40 years of age at Screening (Visit 1)
4. COPD diagnosis: Subjects with a clinical history of COPD in accordance with the 
following definition by the American Thoracic Society/European Respiratory Society 
[Celli, 2004]: COPD is a preventable and treatable disease characterized by airflow 
limitation that is not fully reversible.  The airflow limitation is usually progressive 
and is associated with an abnormal inflammatory response of the lungs to noxious 
particles or gases, primarily caused by cigarette smoking.  Although COPD affects 
the lungs, it also produces significant systemic consequences.
5. Tobacco use: Subjects with a current or prior history of ≥10 pack-years of cigarette 
smoking at screening (Visit 1).  Former smokers are defined as those who have 
stopped smoking for at least 6 months prior to Visit 1.  Number of pack years = 
(number of cigarettes per day/20) x number of years smoked
Note: Pipe and/or cigar use cannot be used to calculate pack year history.
6. Severity of Disease: Subject with a measured post-albuterol/salbutamol FEV1/FVC 
ratio of < 0.70 at Screening (Visit 1).  Subjects with a measured post-
 
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albuterol/salbutamol 50% ≤ FEV1 ≤ 70% of predicted normal values calculated using 
NHANES III reference equations [Hankinson, 1999] at Screening (Visit 1).
7. Native Hip: Have at least one evaluable native hip.
4.3.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
Subjects meeting any of the following criteria must not be enrolled in the study:
1. Pregnancy: Women who are pregnant or lactating or are planning on becoming 
pregnant during the study.
2. 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).
3. α1-antitrypsin deficiency: Subjects with α-1 antitrypsin deficiency as the underlying 
cause of COPD.
4. Other respiratory disorders: Subjects with tuberculosis, lung cancer, 
bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung
diseases or other active pulmonary diseases.
5. Lung resection or transplantation: Subjects with lung volume reduction surgery 
within the 12 months prior to Screening Visit 1 or having had a lung transplant.
6. Chest X-ray:  Subjects with a chest X-ray (or CT scan) that revealed evidence of 
clinically significant abnormalities not believed to be due to the presence of COPD.  
A chest X-ray should be taken at Screening Visit 1 if a chest X-ray or CT scan is not 
available within 12 months prior to Visit 1.
7. Poorly controlled COPD: Subjects with poorly controlled COPD, defined as the 
occurrence of the following in the 12 weeks prior to Screening Visit 1: Acute 
worsening of COPD that is managed by the subject with corticosteroids or antibiotics 
or that requires treatment prescribed by a physician or requires hospitalization.
8. Moderate or severe COPD exacerbation or lower respiratory tract infection: 
Subjects with 2 or more moderate or severe COPD exacerbations and/or a lower 
respiratory tract infection (including pneumonia) within the 12 months prior to 
Screening Visit 1 or experience a moderate or severe COPD exacerbation and/or a 
lower respiratory infection (including pneumonia) during the Run-In period.
NOTE: A moderate COPD exacerbation is defined as requiring systemic 
corticosteroids and/or antibiotics.  A severe COPD exacerbation is defined as 
requiring hospitalization. 
 
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9. Abnormal clinically significant laboratory finding: Subjects who have an 
abnormal, clinically significant finding in any liver chemistry, biochemical, or 
haematology tests at Screening Visit 1 or upon repeat prior to randomization.
10. Abnormal and clinically significant 12-lead ECG: Subjects who have an abnormal, 
clinically significant ECG finding at Screening Visit 1.
11. Non-Compliance during Run-In Period: Failure to demonstrate adequate 
compliance with run-in medication (< 80% compliant), the ability to withhold COPD 
medications, and to keep clinic visit appointments.
12. Bone disorders/conditions: Subjects with historical or current evidence of bone 
cancer, severe scoliosis, rheumatoid arthritis, metabolic bone diseases (other than 
osteoporosis) including hyper-or hypo-parathyroidism, Paget’s disease of bone, 
osteomalacia, or osteogenesis imperfecta. Removal of vertebrae between L1 and L4 
of the lumbar spine and/or presence of metal implants or devices, such as plates, rods, 
or screws in the lumbar spine and/or hip.
13. Immobility: Wheel chair bound or paraplegic.
14. Low vitamin D: Previously known low-serum 25-hydroxy vitamin D concentration 
(less than 10ng [25nmoles] per liter).
15. Other diseases/abnormalities: Serious, uncontrolled disease (including serious 
psychological disorders) likely to interfere with the study within the 3-year study.
16. Cancer: Subjects with carcinoma that has not been in complete remission for at least 
5 years. Carcinoma in situ of the cervix, squamous cell carcinoma and basal cell 
carcinoma of the skin would not be excluded if the subject has been considered cured 
within 5 years since diagnosis.
17. Drug/food allergy: Subjects with a history of hypersensitivity to any of the study 
medications (e.g. beta-agonists, corticosteroid) or components of the inhalation 
powder (e.g. lactose, magnesium stearate). In addition, patients with a history of 
severe milk protein allergy that, in the opinion of the study physician, contraindicates 
the subject’s participation will also be excluded. 
18. Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug 
abuse within the last 2 years.
 
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19. Prohibited medications prior to spirometry at Visit 1: Subjects who are medically 
unable to withhold the following medications prior to spirometry testing at Visit 1:
Medication
No use within the following 
time intervals prior to Visit 1 
Spirometry Testing 
Inhaled corticosteroids
48 hours
Inhaled ICS/LABA combination products
48 hours 
Long-acting anticholinergics (e.g., tiotropium)
48 hours
Theophylline preparations
48 hours
Oral leukotriene inhibitors (zafirlukast, montelukast, zileuton)
48 hours
Oral PDE-4 inhibitors (e.g. roflumilast)
48 hours
Oral beta-agonists 
     Long-acting
     Short-acting
48 hours
12 hours
Inhaled long acting beta2-agonist (LABA) - Indacaterol
48 hours
Other inhaled LABAs (e.g., salmeterol)
24 hours 
Inhaled sodium cromoglycate or nedocromil sodium
24 hours
Ipratropium/ albuterol (salbutamol) combination product
4 hours 
Inhaled short-acting beta2-agonists
4 hours 
Short-acting anti-cholinergics (e.g., ipratropium bromide)
4 hours
20. Additional medication: Use of the following medications within the following time 
intervals prior to Visit 1 or during the study (unless otherwise specified):
Medication
No use within the following time intervals prior to 
Screening Visit 1 or thereafter at any time during the 
study (unless otherwise specified)
Depot corticosteroids
12 weeks
Systemic, Oral, parenteral, intra-
articular corticosteroids1
30 days   
Any other investigational drug
30 days or 5 half lives whichever is longer.
1.
Subjects may take courses of systemic corticosteroids, where necessary, for treatment of an exacerbation 
during the double-blind treatment period.
21. COPD medications: Use of inhaled corticosteroids (ICS), long-acting beta2-agonists 
(LABA), or ICS/LABA combination products (other than the study-provided double-
 
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blind study medication) at Visit 2 (Randomization) or during the double-blind 
treatment period.
22. Oxygen therapy: Subjects receiving treatment with long-term oxygen therapy 
(LTOT) or nocturnal oxygen therapy required for greater than 12 hours a day.  
Oxygen prn use (i.e., ≤12 hours per day) is not exclusionary.
23. Non-compliance: Subjects at risk of non-compliance, or unable to comply with the 
study procedures.  Any infirmity, disability, or geographic location that would limit 
compliance for scheduled visits.
24. Questionable validity of consent: Subjects with a history of psychiatric disease, 
intellectual deficiency, poor motivation or other conditions that will limit the validity 
of informed consent to participate in the study
25. Affiliation with investigator site: Study investigators, sub-investigators, study 
coordinators, employees of a participating investigator or immediate family members 
of the aforementioned are excluded from participating in this study.
4.4.
Withdrawal Criteria
A subject may voluntarily discontinue participation in this study at any time.  The 
investigator may also, at his or her discretion, discontinue a subject from this study at any 
time.  Every effort should be made by the investigator to keep the subject in the study.  
The primary reason for subject withdrawal will be recorded in the electronic Case Report 
Form (eCRF).  Primary reasons for withdrawal will be categorised as:

adverse event

withdrew consent

lost to follow-up

protocol deviation

lack of efficacy

subject reached protocol-defined stopping criteria

study closed/terminated

investigator discretion
Subject compliance with double-blind study medication will be assessed from Visits 2 
through 14, by reviewing the dose counter on the NDPI.  Subjects must be ≥80% to 
≤120% compliant on taking study medication between each pair of on-treatment visits.  
Subjects who fall outside this range should be re-educated on treatment compliance by 
their site.  This re-education should be documented in the subject’s source document.  If 
the double-blind study medication is prematurely discontinued during the course of study 
or medication compliance repeatedly falls outside of acceptable ranges, the study 
sponsor/site monitor must be contacted to discuss subject eligibility for continued 
participation in the study.
 
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A subject will also be withdrawn from the study, in consultation with the medical
monitor and principal investigator, if any of the following stopping criteria are met:

Liver Chemistry: Meets any of the liver chemistry stopping criteria as defined 
in Section 6.2.7.

Pregnancy: Positive pregnancy test

Laboratory Measurements:  Demonstrate a clinically important change in a 
laboratory parameter(s).
If a subject is withdrawn due to an exacerbation, the exacerbation section and SAE 
section, if applicable, of the eCRF should be completed and the subject should be 
followed until resolution of exacerbation.
If a subject is withdrawn due to pneumonia, the AE/SAE section and the 
pneumonia/chest x-ray section of the eCRF should be completed and the subject should 
be followed until clinical resolution of the pneumonia.
4.5.
Pre-Screen Failures and Screening Failures
A subject will be assigned a subject number at the time the informed consent is signed.
A subject who is assigned a subject number but does not have Visit 1 will be considered a 
pre-screen failure.
Any subject who performs a Visit 1 procedure but does not continue in the study beyond 
Visit 1 or any subject who completes Visit 1 and enters the run-in period, but is 
subsequently found to be ineligible for the study (e.g. exclusionary laboratory, ECG, or 
spirometry findings) conducted prior to randomization to the study treatment medication 
(Visit 2), is classified as a ‘screen failure’.
The study interactive voice response system (IVRS) will be contacted to report pre-screen 
failures. The following information will be collected for subjects who are pre-screen 
failures:

Subject number

Date of ICF signature

Demographic information including race, age and gender

Details of COPD medications within 30 days of Visit 0

Details of COPD exacerbation (yes/no status), if applicable

Serious Adverse Event information, if applicable, only for an SAE considered as 
related to study participation (e.g. study treatment, protocol mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
concomitant medication

Investigator signature page
IVRS will be contacted to report screen failures, In addition to the information above, the 
following information will be collected for screen failures:

Date of screening visit

Reason for screen failure (screening failure and inclusion/exclusion criteria)
 
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5.
STUDY TREATMENTS
5.1.
Investigational Product and Other Study Treatment
GSK Clinical Trials Supplies will provide the investigational products for use in this 
study. All blinded study medication will be delivered via the NDPI. At each dispensing 
each subject will receive NDPI for once-daily administration. The contents of each 
treatment are described in Table 1 and Table 2.
The NDPI provides a total of 30 doses (60 blisters), with each actuation comprising the 
contents of one blister from each of the two internal foil strips simultaneously. The 
NDPIs containing randomized treatment will appear identical on the outside to the 
subject (and his/her caregiver) and the Investigator.
All subjects will receive supplemental albuterol/salbutamol (MDI and/or nebules) to be 
used on an as-needed basis throughout the study; for all sites this medication will be 
sourced locally where possible.
Following the 14 to 21 day, Run-In period, eligible subjects will be randomized (1:1) to 
one of the following two possible treatments, administered each morning for 156 weeks:

FF/VI Inhalation Powder 100/25mcg QD

VI Inhalation Powder 25mcg QD
Randomization in each treatment group will be stratified (1:1) according to gender.
A description of the investigational treatments is provided below:
Table 1
Description of FF/VI Inhalation Powder Novel Dry Powder Inhaler 
(NDPI)
Formulation
First strip: Fluticasone Furoate  
blended with lactose
Second strip: Vilanterol micronised 
drug (as the ‘M’ salt 
triphenylacetate) blended with 
lactose and magnesium stearate1
Dosage Form
Novel dry powder inhaler with 30 doses (2 strips with 30 blisters per strip)
Unit Dose Strengths
100mcg per blister
25mcg per blister
Physical description
Dry white powder
Dry white powder
Route of Administration
Inhaled
Inhaled
1.
Magnesium stearate 1% w/w of total drug product
Table 2
Description of VI Inhalation Powder Novel Dry Powder Inhaler (NDPI)
Formulation
First strip: lactose  
Second strip: Vilanterol micronised 
drug (as the ‘M’ salt 
triphenylacetate) blended with 
lactose and magnesium stearate1
Dosage Form
NDPI with 30 doses (2 strips with 30 blisters per strip)
Unit Dose Strengths
N/A 
25mcg per blister
Physical description
Dry white powder
Dry white powder
Route of Administration
Inhaled
Inhaled
1.
Magnesium stearate 1% w/w of total drug product
 
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The contents of the label will be in accordance with all applicable regulatory 
requirements. Under normal conditions of handling and administration, investigational 
product is not expected to pose significant safety risks to site staff. Take adequate 
precautions to avoid direct eye or skin contact and the generation of aerosols or mists. 
Notify the monitor of any unintentional occupational exposure. A Material Safety Data 
Sheet (MSDS) describing the occupational hazards and recommended handling 
precautions will be provided to site staff if required by local laws or will otherwise be 
available from GSK upon request.
Adequate precautions must be taken to avoid direct contact with the investigational 
product.  The occupational hazards and recommended handling procedures are provided 
in the Material Safety Data Sheet (MSDS).
5.1.1.
Storage
Investigational product must be stored in a secure area under the appropriate physical 
conditions for the product.  Access to and administration of the investigational product 
will be limited to the investigator and authorized site staff.  Investigational product must 
be dispensed or administered only to subjects enrolled in the study and in accordance 
with the protocol.
The NDPIs are packaged in a foil overwrap with enclosed desiccant.  The foil overwrap 
must not be opened until immediately prior to use.  Once the foil overwrap has been 
opened the NDPI has a 30 day in-use shelf life.
5.1.2.
Study Drug Return
At the end of the study, all study-supplied study medication (used and unused) will be 
destroyed following local standard operating procedures, except where it is suspected that 
the NDPI or NDPI packaging is defective. The NDPI and packaging should be returned 
to GSK.
Details for both destruction and return of study medication are found in the SPM.
In addition, any study inhaler that fails to function properly must be identified to GSK 
personnel for return to GSK for testing.  Details of the failure will be documented in the 
eCRF.  The subject should return the NDPI to the clinic as soon as possible and avoid 
missing any doses if possible.  The site should then call IVRS and obtain a new treatment 
pack number for this subject and dispense a new study medication kit from the site's 
investigational product supply as instructed by RAMOS, an Interactive Voice Response 
System (IVRS).
5.2.
Treatment Assignment
Subjects will be assigned to study treatment in accordance with the randomization 
schedule.  Once a randomization number has been assigned to a subject, the same number 
cannot be reassigned to any other subject in the study.
 
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Subjects will be stratified based on gender.
Subjects will be site-based randomized using RAMOS, an Interactive Voice Response 
System (IVRS).  This is a telephone based system that will be used by the investigator or 
designee to register the subject (initially at Visit 0, and subsequently at each study visit), 
randomize the subject and provide medication assignment information.  Details on how 
to use RAMOS to register and randomize subjects is provided in the SPM.
Following the 14-21 day, Run-In period, eligible subjects will be randomized (1:1) to one 
of the following 2 possible treatments, administered as one inhalation each morning:

Fluticasone Furoate /Vilanterol 100/25mcg once daily

Vilanterol 25mcg once daily
5.3.
Blinding
Study Medication taken during the 156-week treatment period will be double-blind. 
Neither the subject nor the study physician will know which study medication the subject 
is receiving.
The investigator or treating physician may unblind a subject’s treatment assignment only 
in the case of an emergency, when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the subject.  Whenever possible, the 
investigator must first discuss options with the GSK Medical Monitor or appropriate 
GSK study personnel before unblinding the subject’s treatment assignment.  If this is 
impractical, the investigator must notify GSK as soon as possible, but without revealing 
the treatment assignment of the unblinded subject, unless that information is important 
for the safety of subjects currently in the study.  The date and reason for the unblinding 
must be recorded in the appropriate data collection tool.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject with an SAE.  If the SAE requires that an expedited 
regulatory report be sent to one or more regulatory agencies, a copy of the report, 
identifying the subject’s treatment assignment, may be sent to clinical investigators in 
accordance with local regulations and/or GSK policy.
Subjects will be withdrawn if the treatment code becomes unblinded.  The primary reason 
for discontinuation (the event or condition which led to the unblinding) will be recorded 
in the eCRF.
5.4.
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
investigational product dispensed and/or administered to study subjects, the amount 
returned by study subjects, and the amount received from and returned to GSK, when 
applicable.  Product accountability records must be maintained throughout the course of 
the study.
 
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5.5.
Treatment Compliance
An initial supply of albuterol (salbutamol), a short-acting, beta2-agonist, will be provided 
to each subject to use as needed for symptomatic relief of COPD symptoms during both 
the Run-in and Treatment Periods.  The subject’s use of albuterol (salbutamol) will be 
assessed at each clinic visit and additional albuterol (salbutamol) will be dispensed to the 
subject as needed.
Subject compliance with the single-blind placebo NDPI during Run-In will be assessed at 
Visit 2 by reviewing the dose counter on the NDPI.
Subject compliance with double-blind study medication will be assessed at each 
treatment visit (from Visits 3 - Visit 14) and any unscheduled visit where study drug is 
returned by reviewing the dose counter on the NDPI.  Subjects must be ≥80% to ≤120% 
compliant on taking study medication between each pair of on-treatment visits.  Subjects 
who fall outside this range should be re-educated on treatment compliance by their site. 
This re-education should be documented in the subject’s source document.  If the double-
blind study medication is prematurely discontinued during the course of study or 
medication compliance repeatedly falls outside of acceptable ranges, the study 
sponsor/site monitor must be contacted to discuss subject eligibility for continued 
participation in the study.
5.6.
Concomitant Medications and Non-Drug Therapies
All COPD medications taken within 30 days prior to Visit 0 and during the run-in period 
will be recorded in the eCRF.  All COPD and non-COPD concomitant medications taken 
during the study will be recorded in the eCRF.  The minimum requirement includes, but 
is not limited to name of the medications, and the dates of the administration.
Note: Care is advised when co-administering with strong CYP 3A4 inhibitors (e.g. 
ketoconazole, ritonavir) as there is potential for an increased systemic exposure to both 
fluticasone furoate and vilanterol, which could lead to an increase in the potential for 
adverse reactions.
5.6.1.
Permitted Medications and Non-Drug Therapies
The following medications are permitted during the Screening and Treatment periods:
COPD Medications

Study supplied albuterol/salbutamol (MDI or nebules) for symptomatic relief during 
the Run-In and Double-Blind Treatment period

Mucolytics 

Oxygen for intermittent use or PRN therapy ≤ 12 hours per day is allowed. (Subjects 
requiring LTOT or nocturnal oxygen therapy required for greater than 12 hours a day 
are excluded from the study.)
 
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
Theophyllines (long and short-acting)

Short-acting anti-cholinergic agents

Long-acting anti-cholinergic agents

Short-acting beta2-agonists; i.e. albuterol

Beta2-agonist-anti-cholinergic combinations; i.e. Combivent

Subjects may take courses of systemic corticosteroids, where necessary, for treatment 
of an exacerbation.
Non-COPD Medications

Cardioselective beta-blockers (stable dose) and ophthalmic beta-blockers. 
(Administer with caution as they may block bronchodilatory effects of beta-agonists 
and produce severe bronchospasm).

Care is advised when co-administering with strong CYP 3A4 inhibitors (e.g. 
ketoconazole, ritonavir) as there is potential for an increased systemic exposure to 
both fluticasone furoate and vilanterol, which could lead to an increase in the 
potential for adverse reactions.

Antihistamines and nasal decongestants

Over-the-counter (OTC) cough suppressants (for short term treatment ≤7days)

Intranasal sodium cromoglycate or nedocromil sodium

Intranasal corticosteroids, provided the subject is on a stable daily dose for at least 4 
weeks prior to Visit 1 and remains on this dose throughout the study

Topical (≤1 % hydrocortisone in strength) or ophthalmic corticosteroids

Influenza and/or pneumonia vaccination

Tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs). Administer 
with caution as they may potentiate the effects of beta-agonists on the vascular 
system.

Diuretics. Caution is advised in the co-administration of beta-agonists with 
nonpotassium sparing diuretics.

Treatment(s) for smoking cessation

All medications for other disorders as long as the dose remains constant wherever 
possible.
5.6.2.
Prohibited Medications and Non-Drug Therapies
Medications prohibited at specific time intervals prior to Screening Visit 1 and at any 
time during the study are identified in Section 4.3 Exclusion Criteria.
If a subject’s current medication is going to be changed in order to participate in the 
study, then consent must be obtained prior to any medication change and the subject will 
 
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be required to return to the clinic to complete the Screening Visit 1 once the protocol 
specified time period has been completed.
5.7.
Treatment after the End of the Study
At the end of the treatment period (Visit 14 or Early Withdrawal), subjects can resume 
conventional COPD therapy as prescribed by the Investigator.  There are no plans to 
provide the study drug for compassionate use following study completion.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the patient’s medical condition whether or not GSK is providing specific 
post study treatment.
5.8.
Treatment of Study Treatment Overdose
An overdose is defined as a dose greater than what is instructed (see Section 5.1), which 
results in clinical signs and symptoms.  In the event of an overdose of study medication, 
the investigator should use clinical judgement in treating the overdose and contact the 
study medical monitor.  GSK is not recommending specific treatment guidelines for 
overdose and toxicity management.  The investigator should refer to the relevant 
document(s) for detailed information regarding warnings, precautions, contraindications, 
adverse events, and other significant data pertaining to the study drug(s) being used in 
this study.  Such documents may include, but not be limited to, the approved product 
labeling for albuterol (salbutamol), and the IB or equivalent document provided by GSK 
for double blind medications.
6.
STUDY ASSESSMENTS AND PROCEDURES
The Time and Events Table is provided in Table 3.  All study assessments should be 
conducted by the investigator or his/her qualified designee.  Please refer to the SPM for a 
suggested order of assessments.
 
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Table 3
Time and Events Table
Double-Blind Treatment period
Visit Number
0
Pre-
screen1
1
Screen-
ing2
2
Random-
ization
3
4
5
6
7
8
9
10
11
12
13
14
Early 
With-
draw
15
Follow
-up
Day 1
13 
wks 
14
26 
wks 
14
39 
wks 
14
52 
wks 
14
65 
wks 
14
78 
wks 
14
91 
wks 
14
104 
wks 
14
117 
wks 
14
130 
wks 
14
143 
wks 
14
156 
wks 
14
Visit 
14/EW 
+ 7±2
Days
Days
Days
Days
Days
Days
Days
Days
Days
Days
Days
Days
Days
Assessments
Informed consent3
X
PGx Consent & 
Sampling4
X
Demography 
X
Medical History
X
Physical Exam
X
X
X
X
X
Spirometry Testing
X
X
X
X
X
X
X
X
X
Reversibility Testing
X
Smoking history/ 
smoking status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Smoking cessation 
counseling 
X
X
X
X
X
Register visit on 
IVRS5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety Assessments
BMD DEXA scans6
X
X
X
X
X
X
X
X
Oropharyngeal 
examination7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chest X-ray8
X
Lab Tests9 / Serum 
Pregnancy Test10
X
 
 
 
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Double-Blind Treatment period
Visit Number
0
Pre-
screen1
1
Screen-
ing2
2
Random-
ization
3
4
5
6
7
8
9
10
11
12
13
14
Early 
With-
draw
15
Follow
-up
Day 1
13 
wks 
14
26 
wks 
14
39 
wks 
14
52 
wks 
14
65 
wks 
14
78 
wks 
14
91 
wks 
14
104 
wks 
14
117 
wks 
14
130 
wks 
14
143 
wks 
14
156 
wks 
14
Visit 
14/EW 
+ 7±2
Days
Days
Days
Days
Days
Days
Days
Days
Days
Days
Days
Days
Days
12-lead ECG & 
Rhythm Strip
X
Exacerbation 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Event 
Assessment11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious Adverse 
Event Assessment12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Diary
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect/Review Diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Medication 
Assessments
Concurrent 
Medication 
Assessment13
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense albuterol 
(salbutamol)14
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect albuterol 
(salbutamol)14
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Single-Blind 
Medication
X
Dispense Double-
Blind Medication
X
X
X
X
X
X
X
X
X
X
X
X
Collect Blinded 
Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Other Assessment 
 
 
 
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Double-Blind Treatment period
Visit Number
0
Pre-
screen1
1
Screen-
ing2
2
Random-
ization
3
4
5
6
7
8
9
10
11
12
13
14
Early 
With-
draw
15
Follow
-up
Day 1
13 
wks 
14
26 
wks 
14
39 
wks 
14
52 
wks 
14
65 
wks 
14
78 
wks 
14
91 
wks 
14
104 
wks 
14
117 
wks 
14
130 
wks 
14
143 
wks 
14
156 
wks 
14
Visit 
14/EW 
+ 7±2
Days
Days
Days
Days
Days
Days
Days
Days
Days
Days
Days
Days
Days
Discharge from 
Study15
X
X
1.
Visit 0 and Visit 1 may occur on the same day if the subject does not take or has not taken any protocol excluded medications.
2.
Following Screening Visit 1, subjects enter a 14 to 21 day single-blind run-in period.
3.
Subjects will be assigned a subject number at the time ICF is signed. The ICF must be signed before any study procedures including medication exclusion period(s).  
4.
Saliva (2ml) sample is collected in the DNA self-collection kit.  This should ideally be taken as soon after randomization (Visit 2) as possible, but may be taken at any other visit 
after randomization if necessary.  PGx consent must be signed prior to PGx sampling.
5.
A telephone based IVRS system (RAMOS) which will be used by the investigator or designate to register the subject, randomize the subject and provide medication assignment 
information.
6.
Baseline BMD measurements will be collected between Visit 1 and Visit 2.
7.
If evidence of infection, culture swab may be taken and appropriate therapy should be instituted at Investigator discretion.  Subjects with culture-positive infection may continue 
in the study on appropriate anti-infective treatment at Investigator discretion.
8.
Chest X-ray must be taken if a Chest X-ray or CT scan is not available within the 12 months preceding Visit 1. Chest x-rays will be requested for suspected cases of pneumonia.
9.
Non-fasting and pre-dose. A blood sample for repeat analysis is collected only if any part of Screening lab needs to be repeated. Results of repeat labs should be received prior 
to Randomization at Visit 2.
10. Females of child-bearing potential only
11. Adverse events are to be collected from the start of blinded study medication (Visit 2) until the follow-up phone contact.
12. Serious adverse events are to be collected from the start of study drug (Visit 2) until the follow-up phone contact.  However, any SAEs assessed as related to study participation 
will be recorded from the time subjects sign informed consent.
13. All COPD medications taken within 30 days prior to Visit 0 will be collected.
14. Collect and re-dispense as needed after Visit 1.
15. Discharge from study on appropriate therapy.
 
 
 
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6.1.
Critical Baseline Assessments
No study related procedures may be performed until the informed consent form 
document has been signed by the subject.  A pre-screening visit (Visit 0) may be 
required in order to administer the informed consent before any changes are made to the 
subject’s current medication regimen. Selection and modification of subject’s 
medications prior to study participation is based on the physician’s judgment according to 
sound medical practice, principles, and each subject’s needs. A subject‘s treatment must 
not be changed merely for the purpose of enabling the subject’s participation in the study. 
The pre-screening visit and screening visit may occur on the same day if the subject does 
not take or has not taken any protocol excluded medications. During the pre-screening 
visit, each subject will have the following demographic information collected:

Demographic history (including gender, ethnic origin, date of birth)
During Screening Visit 1, each subject will undergo the following assessments:

Medical history (including COPD and smoking history)

Cardiovascular medical history/risk factors will be assessed at baseline.

Inclusion/Exclusion criteria assessment

Concomitant medication review

ECG and rhythm strip

Spirometry with reversibility testing

Physical exam (including vital signs)

Laboratory assessments (including chemistry, hematology, hepatitis, and pregnancy)
See Section 4.5 for information regarding Screening Failures. 
6.2.
Safety
6.2.1.
Primary Endpoint

BMD measured at the total hip 
6.2.2.
Secondary Endpoints

BMD measured at the lumbar spine (L1-L4)

BMD measurements by gender
6.2.3.
Other Endpoints

Adverse Event reporting 

Serious Adverse Event reporting
 
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
Incidence of fractures

Incidence of pneumonias

COPD exacerbations
6.2.4.
Bone Mineral Density
Effects on the skeletal system will be assessed by measuring bone mineral density 
(BMD) using dual energy x-ray absorptiometry (DEXA) with established methodology.  
DEXA measurements of the total hip and the L1-L4 regions of the spine will be 
completed at baseline, 26 weeks, 52 weeks, 78 weeks, 104 weeks, 130 weeks, and 156 
weeks or end of study treatment.
All DEXA scans will be conducted by qualified technicians and sent electronically for 
centralized analysis.  Quality assurance and calibration of DEXA equipment and 
densitometric measurements will be monitored by this facility to control for site-to-site 
variability in BMD measurements.
Acceptable DEXA measurements must be conducted prior to the first dose of 
randomized study medication.
Subjects with DEXA results meeting pre-defined criteria for clinically significant bone 
mineral density loss from the Screening scan or any visit scan after randomization will be 
counseled about the clinical implications of the scan results.
6.2.5.
Fractures
For any fractures that occur after the initiation of the double-blind study drug, the 
location of the fracture, and whether it is considered traumatic or non-traumatic must be 
recorded on the Fractures page of the eCRF. Severity of a fracture should be determined 
by the Investigator.  Details regarding the information to be captured for fractures will be 
provided in the SPM.
6.2.6.
COPD Exacerbations and Pneumonias
For the purpose of this study, exacerbation of COPD is defined by a worsening of 
symptoms requiring additional treatment as follows:
•
A mild COPD exacerbation: managed by subject with increased use of prn 
medications
•
A moderate COPD exacerbation: requires treatment with antibiotics and/or 
systemic corticosteroids
•
A severe COPD exacerbation: requires hospitalization
 
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Any subject experiencing worsening of symptoms should:
•
Contact his/her study investigator and/or research coordinator immediately, and 
report to the study clinic as required
•
If the subject is unable to contact his/her study investigator and/or research 
coordinator, they should contact their primary care physician (or other health care 
practitioner as required) and contact their study site as soon as possible
•
If the subject seeks emergent/acute care for worsening respiratory symptoms, 
he/she should inform the caring Health Care Provider (HCP) to contact the 
investigator as soon as possible.
Subjects with presence of worsening respiratory symptoms will be classified by the 
Investigator as having:
•
A mild/moderate/severe COPD exacerbation and/or pneumonia
OR
•
A lower respiratory tract infection (LRTI) [i.e. other than pneumonia]
•
Background variability of COPD
•
A non-respiratory related disease
•
Other respiratory related disease
The time period for collection of COPD exacerbations will begin from the time of Visit 2 
(Randomization) and will end when the 7±2day Follow-up period has been completed.
COPD exacerbations should not be recorded as an adverse event, unless they meet the 
definition of a Serious Adverse Event.  For the purposes of this study, COPD 
exacerbations will be collected and recorded on the exacerbation log in the eCRF.  
Exacerbations that meet the definition of an SAE, will be recorded on the appropriate 
eCRF section and should be reported to GSK for all subjects regardless of whether or not 
they are randomized to blinded study medication.
Subjects are excluded from participating if any of the following apply:
•
They have poorly controlled COPD, defined as the occurrence of the following in 
the 12 weeks prior to Screening Visit 1: Acute worsening of COPD that is 
managed by the subject with corticosteroids or antibiotics or that requires 
treatment prescribed by a physician or requires hospitalization.
•
They have 2 or more moderate or severe COPD exacerbations and/or a lower 
respiratory tract infection (including pneumonia) within the 12 months prior to
Screening Visit 1 or experience a moderate or severe COPD exacerbation and/or a 
lower respiratory infection (including pneumonia) during the Run-In period.
 
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The dates of onset and resolution of each COPD exacerbation should be based on when 
the Investigator and/or subject determines that the COPD symptoms initially started and 
then returned to pre-exacerbation levels.
If an exacerbation begins as mild, but becomes moderate or severe or begins as moderate 
and becomes severe, the exacerbation should be captured as one exacerbation and 
classified by its highest level of severity.
For the purpose of this study, pneumonia is defined as new auscultatory findings 
compatible with parenchymal lung infection and/or radiographic evidence of 
parenchymal/air space disease. All suspected cases of pneumonia are encouraged to be 
confirmed radiographically within 48 hours of diagnosis. All diagnoses of pneumonia 
(radiographically confirmed or unconfirmed) must be reported as an AE or SAE (if 
applicable). Information regarding chest X-ray-confirmed cases of pneumonia will be 
recorded in the eCRF. Details regarding the information to be captured for pneumonias 
will be provided in the SPM.
If, based upon these criteria, a subject’s symptoms do not fulfill the diagnosis of an 
exacerbation and/or pneumonia, then the investigator should use his/her clinical judgment 
to assess the subject’s symptoms (including increased volume of sputum production 
and/or change in the sputum color) for a diagnosis of LRTI (e.g. acute bronchitis), 
background variability of COPD, a non-respiratory related disease or other respiratory 
related disease.
Investigator judgment should be used in deciding whether to report the signs and 
symptoms (and/or determined diagnosis) as an AE/SAE in the eCRF. Medication(s) used 
to treat a COPD exacerbation and/or pneumonia are to be recorded in the eCRF.
6.2.7.
Liver chemistry stopping and follow up criteria
Phase III-IV liver chemistry stopping and follow up criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance).  
Phase III-IV liver chemistry stopping criteria 1-5 are defined below and in Appendix 4:
1. ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) (or ALT 3xULN and
INR>1.5, if INR measured)
NOTE: if serum bilirubin fractionation is not immediately available, withdraw study drug 
for that subject if ALT 3xULN and bilirubin 2xULN. Serum bilirubin fractionation 
should be performed if testing is available. If testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and 
suggesting liver injury.
2. ALT 8xULN.
3. ALT 5xULN but <8 xULN persists for 2 weeks
 
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4. ALT  3xULN if associated with symptoms (new or worsening) believed to be related 
to  hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
or jaundice) or hypersensitivity (such as fever, rash or eosinophilia).
5. ALT 5xULN but <8 xULN and cannot be monitored weekly for 2 weeks
When any of the liver chemistry stopping criteria 1-5 is met, do the following:

Immediately withdraw investigational product for that subject

Report the event to GSK within 24 hours of learning its occurrence

Complete the liver event CRF and SAE data collection tool if the event also meets 
the criteria for an SAE. All events of ALT 3xULN and bilirubin 2xULN (>35% 
direct) (or ALT 3xULN and INR>1.5, if INR measured); INR measurement is not 
required and the threshold value stated will not apply to patients receiving 
anticoagulants), termed ‘Hy’s Law’, must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis). 
NOTE: if serum bilirubin fractionation is not immediately available, withdraw study drug 
for that subject if ALT 3xULN and bilirubin 2xULN. Serum bilirubin fractionation 
should be performed if testing is available. If testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and 
suggesting liver injury.

Complete the liver imaging and/or liver biopsy CRFs if these tests are performed

Perform liver event follow up assessments, and monitor the subject until liver 
chemistries resolve, stabilize, or return to baseline values as described below. 

Withdraw the subject from the study after completion of the liver chemistry 
monitoring (unless further safety follow up is required).

Do not restart investigational product.  
In addition, for criterion 1:

Make every reasonable attempt to have subjects return to clinic within 24 hours for 
repeat liver chemistries, liver event follow up assessments (see below), and close 
monitoring

A specialist or hepatology consultation is recommended

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values
For criteria 2, 3, 4 and 5:

Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for 
repeat liver chemistries and liver event follow up assessments (see below)

Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values; criterion 5 subjects 
should be monitored as frequently as possible.
 
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Subjects with ALT 5xULN and <8xULN which exhibit a decrease to ALT x3xULN, 
but <5xULN and bilirubin <2xULN without hepatitis symptoms or rash, and who can be 
monitored weekly for 4 weeks:

Notify the GSK medical monitor within 24 hours of learning of the abnormality to 
discuss subject safety

Can continue investigational product 

Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize or return to within baseline 

If at any time these subjects meet the liver chemistry stopping criteria, proceed as 
described above

If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within baseline 
values.
For criteria 1-5, make every attempt to carry out the liver event follow up assessments
described below:

Viral hepatitis serology including:

Hepatitis A IgM antibody;

Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 

Hepatitis C RNA; 

Cytomegalovirus IgM antibody;  

Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  

Hepatitis E IgM antibody 

Blood sample for PK analysis, obtained within 72 hours of last dose.  Record the 
date/time of the PK blood sample draw and the date/time of the last dose of 
investigational product prior to blood sample draw on the CRF. If the date or time of 
the last dose is unclear, provide the subject’s best approximation. If the date/time of 
the last dose cannot be approximated OR a PK sample cannot be collected in the 
time period indicated above, do not obtain a PK sample. Instructions for sample 
handling and shipping are in the SPM. 

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin 2xULN.

Obtain complete blood count with differential to assess eosinophilia.

Record the appearance or worsening of clinical symptoms of hepatitis or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever rash or eosinophilia as relevant on the AE report form.
 
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
Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins, on the concomitant medications 
report form.

Record alcohol use on the liver event alcohol intake case report form.
The following are required for subjects with ALT 3xULN and bilirubin 2xULN (>35% 
direct) but are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies.

Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with definite or likely acetaminophen use in 
the preceding week [James, 2009]). NOTE: not required in China.

Only in those with underlying chronic hepatitis B at study entry (identified by 
positive hepatitis B surface antigen):  quantitative hepatitis B DNA and hepatitis 
delta antibody.  NOTE:  if hepatitis delta antibody assay cannot be performed,, it can 
be replaced with a PCR of hepatitis D RNA virus (where needed) – as outlined in: 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1153793/.

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease.
6.2.8.
Adverse Events
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
AEs will be collected from the start of double-blind Investigational Product and until the 
follow up contact.  
COPD exacerbations should not be recorded as an adverse event, unless they meet the 
definition of a Serious Adverse Event.  For the purposes of this study, COPD 
exacerbations will be collected and recorded on the COPD exacerbation log in the eCRF.  
The time period for collection of COPD exacerbations will begin from the time of Visit 2 
(Randomization) and will end when the 7-day Follow-up period has been completed.
The investigators and site staff should remain vigilant for the possible development of 
pneumonia in patients with COPD as the clinical features of such infections overlap with 
the symptoms of COPD exacerbations. Risk factors for pneumonia in patients with 
COPD receiving fluticasone furoate/vilanterol include current smokers, patients with a 
history of prior pneumonia, patients with a body mass index <25 kg/m2 and patients with 
an FEV1<50% predicted.  For all suspected cases of pneumonia, Investigators are 
encouraged to confirm the diagnosis (this includes obtaining a chest x-ray) and to initiate 
appropriate therapy as promptly as possible. All diagnoses of pneumonia 
(radiographically confirmed or unconfirmed) must be reported as an AE or SAE (if 
applicable).
All AEs and SAEs will be followed until resolution, until the condition stabilizes, until 
the event is otherwise explained, or until the subject is lost to follow-up.  Once resolved, 
 
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the appropriate AE/SAE CRF page will be updated.  The investigator will ensure that 
follow-up includes any supplemental investigations as may be indicated to elucidate the 
nature and/or causality of the AE or SAE.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care 
professionals.
6.2.8.1.
Definition of an AE
Any untoward medical occurrence in a patient or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.  For marketed medicinal products, this 
also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.
Events meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study

Signs, symptoms, or the clinical sequelae of a suspected interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE) unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae.
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfil the definition of an AE or 
SAE.  
Events that do not meet the definition of an AE include:

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital)

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen

The disease/disorder being studied, or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
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6.2.8.2.
Definition of a SAE
A serious adverse event is any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:  In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity, or
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption.
e.
Is a congenital anomaly/birth defect
f.
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.  Examples of such events are invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
g.
All events of possible drug-induced liver injury with hyperbilirubinaemia defined as 
ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 3xULN and 
INR>1.5, if INR measured) termed ‘Hy’s Law’ events (INR measurement is not 
required and the threshold value stated will not apply to patients receiving 
anticoagulants).
 
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NOTE: bilirubin fractionation is performed if testing is available. If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick indicating 
direct bilirubin elevations and suggesting liver injury. If testing is unavailable and a 
subject meets the criterion of total bilirubin 2xULN, then the event is still reported 
as an SAE. If INR is obtained, include values on the SAE form. INR elevations >1.5 
suggest severe liver injury.   
6.2.9.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), 
including those that worsen from baseline, and felt to be clinically significant in the 
medical and scientific judgement of the investigator are to be recorded as AEs or SAEs. 
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject’s condition, are not to be reported as AEs or SAEs.
6.2.10.
Cardiovascular Events
Investigators will be required to fill out event specific data collection tools for the 
following AEs and SAEs:  

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thrombosis

Deep Venous Thrombosis

Revascularization
This information should be recorded within one week of when the AE/SAE(s) are first 
reported.
 
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6.2.11.
Death Events
In addition, all deaths, whether or not they are considered SAEs, will require a specific 
death data collection tool to be completed.  The death data collection tool includes 
questions regarding cardiovascular (including sudden cardiac death) and 
noncardiovascular death.
This information should be recorded within one week of when the death is first reported.
6.2.12.
Pregnancy
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form.  To ensure subject safety, each pregnancy must be reported to GSK 
within 2 weeks of learning of its occurrence.  The pregnancy must be followed up to 
determine outcome (including premature termination) and status of mother and child.  
Pregnancy complications and elective terminations for medical reasons must be reported 
as an AE or SAE.  Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy, brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to GSK.
6.2.13.
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
AEs will be collected from the start of study treatment and until the follow up contact.  
SAEs will be collected over the same time period as stated above for AEs. However, any 
SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant 
medication, will be recorded from the time a subject consents to participate in the study 
up to and including any follow up contact. All SAEs will be reported to GSK within 24 
hours, as indicated in Section 6.2.14. 
6.2.14.
Prompt Reporting of Serious Adverse Events and Other Events 
to GSK
SAEs, pregnancies, and liver function abnormalities meeting pre-defined criteria will be 
reported promptly by the investigator to GSK as described in the following table once the 
investigator determines that the event meets the protocol definition for that event.
 
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Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
“SAE” data 
collection tool
“CV events” 
and/or “death” 
data collection 
tool(s) if 
applicable
24 hours
Updated “SAE” 
data collection tool
“CV events” and/or 
“death” data 
collection tool(s) if 
applicable
Pregnancy
2 weeks
“Pregnancy 
Notification Form”
2 weeks
“Pregnancy Follow-
up Form”
Non-serious adverse 
events related to 
study treatment
5 calendar 
days
“Adverse 
Reaction” data 
collection tool
2 weeks
Updated “Adverse 
Reaction” data 
collection tool
Liver chemistry abnormalities for Phase I to IV:
ALT3xULN and
Bilirubin2xULN 
(>35% direct) (or 
ALT3xULN and
INR>1.5, if INR 
measured)1
24 hours2
“SAE” data 
collection tool.  
“Liver Event CRF” 
and “Liver 
Imaging” and/or 
“Liver Biopsy” 
CRFs, if 
applicable3
24 hours
Updated “SAE” 
data collection 
tool/“Liver Event” 
Documents3
Remaining liver chemistry abnormalities Phase III to IV:
ALT8xULN; 
ALT3xULN with 
hepatitis or rash or 
3xULN and <5xULN 
that persists4 weeks
24 hours2
“Liver Event” 
Documents 
(defined above) 3
24 hours
Updated “Liver 
Event” Documents3
ALT5xULN plus 
bilirubin <2xULN
24 hours2
“Liver Event” 
Documents 
(defined above) 
do not need 
completing unless 
elevations persist 
for 2 weeks or 
subject cannot be 
monitored weekly 
for 2 weeks3
24 hours
Updated “Liver 
Event” Documents, 
if applicable3
ALT5xULN and 
bilirubin <2xULN that 
persists 2 weeks
24 hours2
“Liver Event” 
Documents 
(defined above) 3
24 hours
Updated “Liver 
Event” Documents3
 
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ALT3xULN and <5x 
ULN and bilirubin 
<2xULN
24 hours2
“Liver Event” 
Documents 
(defined above) 
do not need 
completing unless 
elevations persist 
for 4 weeks or 
subject cannot be 
monitored weekly 
for 4 weeks3
24 hours
Updated “Liver 
Event” Documents, 
if applicable3
1.
INR measurement is not required; if measured, the threshold value stated will not apply to patients receiving 
anticoagulants.
2.
GSK must be contacted at onset of liver chemistry elevations to discuss subject safety
3.
Liver Event Documents (i.e., “Liver Event CRF” and “Liver Imaging CRF” and/or “Liver Biopsy CRF”, as 
applicable) should be completed as soon as possible.
The method of detecting, recording, evaluating and follow-up of AEs and SAEs plus 
procedures for completing and transmitting SAE reports to GSK are provided in the 
SPM.  Procedures for post-study AEs/SAEs are provided in the SPM.
6.2.14.1.
Regulatory reporting requirements for SAEs
Prompt notification of SAEs by the investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
6.2.15.
SpirometryTesting
Lung function will be measured by spirometry at Visits 1, 2, 4, 6, 8, 10, 12, and 14, or at 
Early Withdrawal using site available spirometry equipment that meets or exceeds the 
minimum performance recommendations of the ATS/ERS [Miller, 2005].  For Visits 2 
onward, FEV1 will be measured prior to administration of morning study medication.
 
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For each observation, at least 3 valid (with no more than 8) efforts will be obtained using 
ATS/ERS guidelines.  The largest FEV1 and FVC from the 3 acceptable efforts should be 
recorded, even if they do not come from the same effort.  Acceptable spirometry efforts 
should have a satisfactory start of test and end of test (i.e. a plateau in the volume-time 
curve) and be free from artifacts due to cough, early termination, poor effort, obstructed 
mouthpiece, equipment malfunction, or other reasons [Miller, 2005].  The subject’s 
position during spirometry measurements (sitting or standing) should remain constant for 
the duration of the study.
A post-albuterol (salbutamol) FEV1/FVC ratio of < 0.70 and predicted normal value of 
50% ≤ FEV1 ≤ 70% is required at Screening Visit 1.  
All predicted values will be taken from Hankinson [Hankinson, 1999].
The investigator will retain a printed copy of the spirometry data in the subject’s source 
documents.
6.2.15.1.
Reversibility Testing
At Visit 1, reversibility to albuterol (salbutamol) will be assessed.  To determine 
reversibility, the subject will self-administer 4 puffs (360mcg) of albuterol (salbutamol) 
without the use of a spacer or holding chamber.  Triplicate spirometry efforts will be 
performed immediately pre-albuterol (salbutamol) and within 30 minutes post-albuterol 
(salbutamol).  The highest FEV1 from three valid forced expiratory curves will be used to 
determine reversibility.
Reversibility is defined as an increase in FEV1 of ≥12% and ≥200mL following 
administration of albuterol (salbutamol).  Non-reversible is defined as a post-albuterol 
(salbutamol) increase in FEV1 of <200mL or a ≥200mL increase that is <12% from pre-
albuterol (salbutamol) FEV1.
6.2.16.
Laboratory Assessments
Routine, non-fasting clinical laboratory (hematology and biochemistry), will be 
performed in all subjects at the Screening Visit 1.  
For women of childbearing potential, a serum pregnancy test will be included in the 
laboratory panel collected at Visit 1 if applicable.  
At the discretion of the investigator, additional samples may be taken for safety reasons.  
If the subject has an abnormal laboratory finding for any analyte from the Screening Visit 
laboratory panel, which in the opinion of the Investigator does not preclude the subject 
from participating in the study, but for which the Investigator feels warrants 
treatment/correction with a non-excluded medication(s) (e.g., calcium supplement for 
hypocalcemia), a blood sample for repeat analysis of the analyte(s) should be collected 
prior to Visit 2 (Randomization). Results of repeat Screening labs should be received 
prior to Randomization at Visit 2.
 
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All protocol required laboratory assessments, as defined in Appendix 1 must be 
performed by the central laboratory. Laboratory assessments must be conducted in 
accordance with the Central Laboratory Manual and Protocol Time and Events Schedule.
Laboratory requisition forms must be completed and samples must be clearly labelled 
with the subject number, protocol number, site/center number, and visit date. Details for 
the preparation and shipment of samples will be provided by the central laboratory. 
Reference ranges for all safety parameters will be provided to the site by the central 
laboratory.
6.2.17.
Oropharyngeal Examination
Oropharyngeal examinations for clinical evidence of infection (i.e., Candida albicans) 
will be performed at each study visit as shown in the Time and Events Table. If there is 
evidence of infection, a culture swab may be taken and appropriate therapy should be 
instituted at the discretion of the Investigator. Subjects with culture-positive infection 
may continue in the study on appropriate anti-infective treatment at the discretion of the 
Investigator. The results of these assessments, and any relative pharmacotherapy, will be 
recorded in the subject’s clinic notes and in the eCRF. After randomization, all culture 
positive results must be reported as adverse events.
6.2.18.
Diary Card - Medical Problems/Medications Taken
Subjects will be instructed to record any medical problems they may have experienced 
and any medications used to treat those medical problems in their diaries from Screening 
(Visit 1) through the Follow-up Phone Contact.  
Subjects will be instructed on how to complete the diary and will be asked to return 
completed diaries at each clinic visit.  The study coordinator must review the diary at 
each clinic visit and will inquire about the diary data during the Follow-up Phone Contact 
as well.  If the subject does not mention an event which is recorded on the diary, he/she 
should be questioned for further information in order to determine if there was the 
occurrence of an AE.  Any confirmed AE and/or concurrent medication will be entered 
into the eCRF.
6.2.19.
12-lead ECG Assessment
A single 12-lead ECG and rhythm strip will be recorded prior to spirometry at the 
Screening Visit 1.
All ECG measurements will be performed with the subject resting in a supine position for 
approximately 5 minutes before each reading, which should be carried out after 
measurement of vital signs and before spirometry.
The investigator, a designated sub-investigator, or other appropriately trained site 
personnel, will be responsible for performing the 12-lead ECG recording on each study 
visit, if applicable.  The investigator must provide his/her dated signature on the original 
paper tracing, attesting to the authenticity of the ECG machine interpretation.
 
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6.2.20.
Smoking Cessation Counselling
During the Screening Visit 1, 6, 10, and 14 or EW visit (if necessary), subjects will be 
given smoking cessation counselling, which includes advice regarding the following:

the health effects that smoking may cause.

the health benefits that may result if they stop smoking.

if they do not feel capable of discontinuing smoking that their primary care physician 
may be able to discuss anti-smoking strategies with them. 

that they may discontinue smoking at any time during the study and will not have to 
be withdrawn from the study if they do so.  
6.3.
Pharmacogenetic Research
Information regarding pharmacogenetic research is included in Appendix 2.  The 
IEC/IRB and, where required, the applicable regulatory agency must approve the PGx 
assessments before these can be conducted at the site.  The approval(s) must be in writing 
and will clearly specify approval of the PGx assessments.  In some cases, approval of the 
PGx assessments can occur after approval is obtained for the rest of the study.  If so, then 
the written approval will clearly indicate approval of the PGx assessments is being 
deferred and the study, except for PGx assessments, can be initiated.  When PGx 
assessments will not be approved, then the approval for the rest of the study will clearly 
indicate this and therefore, PGx assessments will not be conducted.
 
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7.
DATA MANAGEMENT
For this study subject data will be entered into GSK defined eCRFs, transmitted 
electronically to GSK and combined with data (e.g. laboratory data, diary data) provided 
from other sources in a validated data system.
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.  Adverse events and concomitant medications 
terms will be coded using MedDRA and an internal validated medication dictionary, 
GSKDrug.  An appropriate medical dictionary that covers all approved drugs in the 
region will be referenced.  eCRFs (including queries and audit trails) will be retained by 
GSK, and copies will be sent to the investigator to maintain as the investigator copy. In 
all cases, subject initials will not be collected or transmitted to GSK according to GSK 
policy.
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
8.1.
Hypotheses
The null hypothesis for the primary measure is that the change in BMD assessed at the 
total hip is worse for the FF/VI combination product arm compared with the VI arm. The 
alternative hypothesis that the change in BMD assessed at the total hip is not worse for 
the FF/VI arm compared with the VI arm.
This is also the null and alternative hypothesis for the secondary measure of BMD 
assessed at the L1-L4 lumbar spine.
8.2.
Study Design Considerations
8.2.1.
Sample Size Assumptions
This study will evaluate non-inferiority in both males and females separately as key 
secondary measures.  56 subjects per gender per treatment would provide 80% power to 
demonstrate non-inferiority by comparing the lower boundary of a two-sided 95% 
confidence interval on the treatment difference to -1%/year assuming a true treatment 
difference of -0.3%/year.  In study SCO40041, approximately 20% of subjects did not 
provide post-baseline data, therefore 70 subjects per gender per treatment will be 
randomized (280 total subjects).  Randomization will be stratified by gender.
For the primary evaluation of BMD for the total hip, males and females will be 
combined, and will have >90% power to demonstrate non-inferiority by comparing the 
lower boundary of a two-sided 95% confidence interval on the treatment difference to      
-1%/year assuming a true treatment difference of -0.3%/year.
 
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8.2.2.
Sample Size Sensitivity
The following table presents the power of the study under different circumstances in 
terms of the standard deviation and the observed treatment difference in change from 
baseline in bone mineral density for the total hip.
True Treatment Difference between FF/VI and VI
SD
-0.2%/yr
-0.3%/yr
-0.4%/yr
1.3%/yr
>99%
99%
96%
1.4%/yr
>99%
98%
94%
1.5%/yr
>99%
97%
91%
8.2.3.
Sample Size Re-estimation
No sample size re-estimation is planned for this study.
8.3.
Data Analysis Considerations
8.3.1.
Analysis Populations
All Subjects Enrolled Population: This population will consist of all subjects, for whom a 
record exists on the study database, including screen failures and any subject who was 
not screened but signed the informed consent form. This population will be used for 
reporting subject disposition, reasons for withdrawal prior to randomisation, and 
inclusion, exclusion and randomisation criteria deviations and SAEs for non-randomised 
subjects.
(Modified) Intent-to-Treat (ITT) Population: This population will consist of all subjects 
who are randomised and receive at least one dose of study drug. The ITT Population will 
be the primary population for all analyses of safety and efficacy measures.
8.3.2.
Analysis Data Sets
The bone mineral density data will comprise the primary data set of interest.  Details of 
derived data in analysis datasets to be created will be provided in the Reporting and 
Analysis Plan (RAP).
8.3.3.
Treatment Comparisons
8.3.3.1.
Primary Comparisons of Interest
BMD measured for the total hip will be summarized by visit and as change from baseline 
at each visit for raw values, percent changes from baseline, t-scores, and z-scores.  The 
percent change from baseline in BMD for the total hip will be the primary endpoint, and 
analyzed using a repeated measures model with terms for treatment, time, time by 
treatment, baseline BMD, baseline BMI and gender.  Contrasts will be formed using the 
time by treatment variable to provide 95% confidence intervals for the treatment 
difference with the unit of percent change per year.  The 95% confidence interval will be 
compared to a lower bound of -1%/year in order to assess clinical non-inferiority.  Any 
 
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additional covariates for the model, along with other details, including model inclusion 
and exclusion criteria for those covariates, will be determined a priori in a detailed 
Reporting and Analysis Plan (RAP) that will be completed prior to unblinding of the 
study.
The percent change from baseline in BMD at the L1-L4 region of the spine will also by 
summarized and analyzed in the same manner as the BMD data for the total hip.
8.3.4.
Interim Analysis
No interim analysis is planned for this study.
8.3.5.
Key Elements of Analysis Plan
8.3.5.1.
Efficacy Analyses
No efficacy analyses are planned for this study
8.3.5.2.
Safety Analyses
8.3.5.2.1.
Extent of Exposure
The extent of exposure to study drug will be summarized by treatment group.
8.3.5.2.2.
Adverse Events (AEs)
AEs will be coded using the standard GSK dictionary, Medical Dictionary for Regulatory 
Activities (MedDRA), and grouped by body system. AEs occurring pre-treatment, during 
active treatment and post-treatment will be summarized separately. The number and 
percentage of subjects experiencing at least one AE of any type, AEs within each body 
system and AEs within each preferred term will be presented for each treatment group. 
Separate summaries will be provided for all AEs, drug related AEs, SAEs, and for AEs 
leading to withdrawal.
8.3.5.2.3.
Deaths and SAEs
All SAEs will be listed by treatment group. Deaths and SAEs will be documented in case 
narrative format.
8.3.5.2.4.
Fractures
The number and percent of patients experiencing a bone fracture during the study will be 
summarized.
8.3.5.2.5.
COPD Exacerbations and Pneumonias
The number of moderate or severe COPD exacerbations and the percent of patients 
experiencing moderate or severe COPD exacerbations will be summarized.
8.3.5.3.
Pharmacogenetic Analyses
See Appendix 2: Pharmacogenetic Research for details about the Pharmacogenetics 
Analysis Plan.
 
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9.
STUDY CONDUCT CONSIDERATIONS
9.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins.
9.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a study site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the ethical principles that are outlined in the Declaration of Helsinki 
2008, including, but not limited to:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments.

Subject informed consent.

Investigator reporting requirements.
GSK will provide full details of the above procedures, either verbally, in writing, or both.
Written informed consent must be obtained from each subject prior to participation in the 
study.
No study related procedures may be performed until the informed consent form 
document has been signed by the subject.  A pre-screening visit may be required in 
order to administer the informed consent before any changes are made to the subject’s 
current medication regimen. The pre-screening visit and screening visit may occur on the 
same day if the subject does not take or has not taken any protocol excluded medications.
In approving the clinical protocol the IEC/IRB and, where required, the applicable 
regulatory agency are also approving the optional assessments e.g., PGx assessments 
described in Appendix 2, unless otherwise indicated.  Where permitted by regulatory 
authorities, approval of the optional assessments can occur after approval is obtained for 
the rest of the study.  If so, then the written approval will clearly indicate approval of the 
optional assessments is being deferred and the study, except for the optional assessments, 
can be initiated.  When the optional assessments are not approved, then the approval for 
the rest of the study will clearly indicate this and therefore, the optional assessments will 
not be conducted.
 
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9.3.
Quality Control (Study Monitoring)
In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK 
requirements. When reviewing data collection procedures, the discussion will include 
identification, agreement and documentation of data items for which the CRF will serve 
as the source document.
GSK will monitor the study to ensure that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
9.4.
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of 
the study. In the event of an assessment, audit or inspection, the investigator (and 
institution) must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to 
all relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective and/or 
preventative actions to address any findings/issues identified.
9.5.
Study and Site Closure
Upon completion or termination of the study, the GSK monitor will conduct site closure 
activities with the investigator or site staff (as appropriate), in accordance with applicable 
regulations, GCP, and GSK Standard Operating Procedures.
GSK reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe non-
compliance.  If GSK determines that such action is required, GSK will discuss the 
reasons for taking such action with the investigator or head of the medical institution 
(where applicable).  When feasible, GSK will provide advance notice to the investigator 
or head of the medical institution of the impending action.
If a study is suspended or terminated for safety reasons, GSK will promptly inform all 
investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study.  GSK will also promptly inform the relevant regulatory authorities 
of the suspension/termination along with the reasons for such action.  Where required by 
 
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applicable regulations, the investigator or head of the medical institution must inform the 
IRB/IEC promptly and provide the reason(s) for the suspension/termination.
9.6.
Records Retention
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere) in a safe and secure location.  The records must 
be easily accessible when needed (e.g., for a GSK audit or regulatory inspection) and 
must be available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken.  The 
investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original.  In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required.  The investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions.
GSK will inform the investigator of the time period for retaining the site records in order 
to comply with all applicable regulatory requirements.  The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, GSK standard operating procedures, and/or institutional requirements.
The investigator must notify GSK of any changes in the archival arrangements, including, 
but not limited to archival of records at an off-site facility or transfer of ownership of the 
records in the event that the investigator is no longer associated with the site.
9.7.
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
 
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GSK aims to post a results summary to the GSK Clinical Study Register and other 
publicly available registers no later than 8 months after the last subject’s last visit (LSLV) 
[this applies to each data analysis phase for studies with multiple phases, e.g., primary 
analysis, follow up analysis etc]. In addition, the aim is to submit a manuscript to a peer-
reviewed journal for publication within 18 months of LSLV. GSK also aims to publish 
the full study protocol on the GSK Clinical Study Register at the time the results of the 
study are published as a manuscript in the scientific literature. 
When manuscript publication in a peer-reviewed journal is not feasible, further study 
information will be posted to the GSK Clinical Study Register to supplement the results 
summary. 
9.8.
Independent Data Monitoring Committee (IDMC)
There is no IDMC in this study.
 
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10.
REFERENCES
Calverley PM, Anderson JA, Celli B. Salmeterol and fluticasone propionate and survival 
in chronic obstructive pulmonary disease. NEJM. 2007;356:775-89.
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.
Chapman KR, Mannino DM, Soriano JB, Vermeire PA, Buist AS, Thun MJ, Connell C. 
Epidemiology and costs of chronic obstructive pulmonary disease. Eur Respir J. 
2006;27:188-207.
Ferguson GT, Anzueto A, Fei R, Emmett A, Knobil K, Kalberg C.  Effect of fluticasone 
propionate/salmeterol (50/250g) or salmeterol (50 g) on COPD exacerbations. Resp 
Med. 2008;102:1099-1108.
GOLD. Global Initiative for Chronic Obstructive Lung Disease. Executive Summary: 
Global strategy for the diagnosis, management, and prevention of chronic obstructive 
pulmonary disease (Updated 2010).  http://www.gold.copd.org
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of 
the general US population.  Am J Resp Crit Care Med. 1999;159:179-187.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37: 1779-1784. 
Kardos P, Wencker M, Glaab T. Impact of Fluticasone Propionate/Salmeterol  versus 
salmeterol on exacerbations in severe chronic obstructive pulmonary disease. Am J Resp 
Crit Care Med. 2007;175:144-149.
Lopez AD, Shibuya K, Rao C, Mathers CD, Hansell AL, Held LS, Schmid V, Buist S. 
Chronic obstructive pulmonary disease: current burden and future projections. Eur Respir 
J. 2006;27:397-412.
Miller MR, Hankinson J, Brusasco Vet al. Standardisation of spirometry. Eur Respir J. 
2005;26:319-338.
WHO. Chronic Obstructive Pulmonary Disease (COPD). Burden of COPD. WHO. 2010.
 
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11.
APPENDICES
11.1.
Appendix 1: Laboratory Assessments
Refer to the Time and Events Table 3 for information regarding the timing of laboratory 
tests.
CHEMISTRY
HEMATOLOGY 
OTHER
Albumin 
Hemoglobin
Hepatitis B surface antigen1
Alkaline phosphatase 
Hematocrit
Hepatitis C virus antibody1
Alanine amino-transferase (ALAT or SGPT)
Platelet count
Fungal culture of oral mucosa (if 
visual evidence of candidiasis )
Aspartate amino-transferase (ASAT or 
SGOT)
WBC count
hCG qualitative (serum 
pregnancy)2 
Bilirubin, direct
Neutrophils, absolute
Bilirubin, indirect
Neutrophils, segs (%)
Bilirubin, total
Neutrophils, bands 
(%)
Calcium
Basophils (%)
Chloride
Eosinophils (%)
CO2 content/Bicarbonate
Eosinophils , absolute
Creatinine
Lymphocytes (%)
Creatine phosphokinase (CPK), total
Monocytes (%)
Gamma glutamyl transferase (GGT)
Glucose
Phosphorus 
Potassium
Protein, total serum
Sodium
Urea nitrogen (BUN)
Uric Acid 
1.
Assessed at Visit 1 (Screening) only, result is not exclusionary
2.
Only females of child-bearing potential; refer to Time and Events Table for specific visit information
 
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11.2.
Appendix 2: Pharmacogenetic Research
Pharmacogenetics – Background
Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary 
factors in populations.  There is increasing evidence that an individual's genetic 
background (i.e., genotype) may impact the pharmacokinetics (absorption, distribution, 
metabolism, elimination), pharmacodynamics (relationship between concentrations and 
pharmacologic effects or the time course of pharmacologic effects) and/or clinical 
outcome (in terms of efficacy and/or safety and tolerability).  Some reported examples of 
PGx associations with safety/adverse events include:
Drug
Disease
Gene Variant
Outcome
Abacavir
HIV 
[Hetherington, 2002; 
Mallal, 2002; 
Mallal, 2008]
HLA-B* 5701
Carriage of the HLA-B*5701 variant has been shown to 
increase a patient's risk for experiencing 
hypersensitivity to abacavir.  Prospective HLA-B*5701 
screening and exclusion of HLA-B*5701 positive 
patients from abacavir treatment significantly decreased 
the incidence of abacavir hypersensitivity.  Treatment 
guidelines and abacavir product labeling in the United 
States and Europe now recommend (US) or require 
(EU) prospective HLA-B*5701 screening prior to 
initiation of abacavir to reduce the incidence of abacavir 
hypersensitivity.  HLA-B*5701 screening should 
supplement but must never replace clinical risk 
management strategies for abacavir hypersensitivity.
Carbamazepin
e
Seizure, Bipolar 
disorders & 
Analgesia Chung, 
2010; Ferrell, 2008
HLA-B*1502
Independent studies indicated that patients carrying 
HLA-B*1502 are at higher risk of Stevens-Johnson 
Syndrome and toxic epidermal necrolysis and that this 
marker is prevalent in some populations, particularly 
with Asian ancestry.  Regulators, including the US FDA 
and the Taiwanese TFDA, have updated the 
carbamazepine drug label to indicate that patients with 
ancestry in genetically at risk populations should be 
screened for the presence of HLA-B*1502 prior to 
initiating treatment with carbamazepine.
Irinotecan
Cancer [Innocenti, 
2004; Liu, 2008; 
Schulz, 2009]
UGT1A1*28
Variations in the UGT1A1 gene can influence a 
patient’s ability to break down irinotecan, which can 
lead to increased blood levels of the drug and a higher 
risk of side effects. A dose of irinotecan that is safe for 
one patient with a particular UGT1A1 gene variation 
might be too high for another patient without this 
variation, raising the risk of certain side-effects, that 
include neutropenia following initiation of Irinotecan 
treatment.  The irinotecan drug label indicates that 
individuals who have two copies of the UGT1A1*28 
variant are at increased risk of neutropenia.  A genetic 
blood test is available that can detect variations in the 
gene.    
A key component to successful PGx research is the collection of samples during the 
conduct of clinical studies.
 
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Collection of whole blood samples, even when no a priori hypothesis has been identified, 
may enable PGx analysis to be conducted if at any time it appears that there is a potential 
unexpected or unexplained variation in response to FF/VI Inhalation Powder. 
Pharmacogenetic Research Objectives
The objective of the PGx research (if there is a potential unexpected or unexplained 
variation) is to investigate a relationship between genetic factors and response to FF/VI 
Inhalation Powder.  If at any time it appears there is potential variability in response in 
this clinical study or in a series of clinical studies with FF/VI Inhalation Powder, the 
following objectives may be investigated – the relationship between genetic variants and 
study treatment with respect to:

Relationship between genetic variants and the pharmacokinetics and/or 
pharmacodynamics of investigational product

Relationship between genetic variants and safety and/or tolerability of investigational 
product

Relationship between genetic variants and efficacy of investigational product
Study Population
Any subject who is enrolled in the clinical study, can participate in PGx research.  Any 
subject who has received an allogeneic bone marrow transplant must be excluded from 
the PGx research.
Subject participation in the PGx research is voluntary and refusal to participate will not 
indicate withdrawal from the clinical study or result in any penalty or loss of benefits to 
which the subject would otherwise be entitled.
Study Assessments and Procedures
Saliva samples can be taken for Deoxyribonucleic acid (DNA) extraction and used in 
PGx assessments.
No additional whole blood samples will be necessary for the PGx analysis. Saliva (2mL) 
is collected into the DNA self-collection kit. A single sample will be taken but can be 
duplicated if the first sample is unusable. It is recommended that the saliva sample be 
collected at Visit 2.  

The PGx sample is labelled (or “coded”) with a study specific number that can be 
traced or linked back to the subject by the investigator or site staff. Coded samples 
do not carry personal identifiers (such as name or social security number).  The 
saliva sample is taken on a single occasion unless a duplicate sample is required due 
to inability to utilize the original sample.  
The DNA extracted from the saliva sample may be subjected to sample quality control 
analysis.  This analysis will involve the genotyping of several genetic markers to confirm 
the integrity of individual samples.  If inconsistencies are noted in the analysis, then those 
samples may be destroyed.
 
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The need to conduct PGx analysis may be identified after a study (or a set of studies) of 
FF/VI Inhalation Powder has been completed and the clinical study data reviewed.  In 
some cases, the samples may not be studied. e.g., no questions are raised about how 
people respond to FF/VI Inhalation Powder.
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will use samples collected from the study for 
the purpose stated in this protocol and in the informed consent form.  
Subjects can request their sample to be destroyed at any time.
Subject Withdrawal from Study
If a subject who has consented to participate in PGx research and has had a sample taken 
for PGx research withdraws from the clinical study for any reason other than lost to 
follow-up, the subject will be given the following options:

Retain the sample for PGx research 

Destroy the PGx sample 
If a subject withdraws consent for PGx research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Screen and Baseline Failures
If a blood sample for PGx research has been collected and it is determined that the 
subject does not meet the entry criteria for participation in the clinical study, then the 
investigator should instruct the participant that their PGx sample will be destroyed. No 
forms are required to complete this process as it will be completed as part of the consent 
and sample reconciliation process.  In this instance a sample destruction form will not be 
available to include in the site files.
Pharmacogenetics Analyses
Pharmacogenetics Analyses
1.
Specific genes may be studied that encode the drug targets, or drug mechanism of 
action pathways, drug metabolizing enzymes, drug transporters or which may 
underpin adverse events, disease risk or drug response. These candidate genes may 
include a common set of ADME (Absorption, Distribution, Metabolism and 
Excretion) genes that are studied to determine the relationship between gene variants 
or treatment response and/or tolerance. 
In addition, continuing research may identify other enzymes, transporters, proteins or 
receptors that may be involved in response to FF/VI Inhalation Powder.  The genes that 
may code for these proteins may also be studied.
 
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2.
Genome-wide scans involving a large number of polymorphic markers (e.g., single 
nucleotide polymorphisms) at defined locations in the genome, often correlated with 
a candidate gene, may be studied to determine the relationship between genetic 
variants and treatment response or tolerance. This approach is often employed when 
a definitive candidate gene(s) does not exist and/or the potential genetic effects are 
not well understood. 
If applicable and PGx research is conducted, appropriate statistical analysis methods will 
be used to evaluate pharmacogenetic data in the context of the other clinical data. Results 
of PGx investigations will be reported either as part of the main clinical study report or as 
a separate report. Endpoints of interest from all comparisons will be descriptively and/or 
graphically summarized as appropriate to the data.  A detailed description of the analysis 
to be performed will be documented in the study reporting and analysis plan (RAP) or in 
a separate pharmacogenetics RAP, as appropriate.  
Informed Consent
Subjects who do not wish to participate in the PGx research may still participate in the 
clinical study.  PGx informed consent must be obtained prior to any saliva being taken for 
PGx research.
Provision of Study Results and Confidentiality of Subject’s PGx Data
GSK may summarize the PGx research results in the clinical study report, or separately, 
or may publish the results in scientific journals. 
GSK does not inform the investigator, subject, or anyone else (e.g., family members, 
study investigators, primary care physicians, insurers, or employers) of individual 
genotyping results that are not known to be relevant to the subject’s medical care at the 
time of the study, unless required by law. This is due to the fact that the information 
generated from PGx studies is generally preliminary in nature, and therefore the 
significance and scientific validity of the results are undetermined.
 
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References
Chung WH, Hung SL, Chen YT. Genetic predisposition of life-threatening antiepileptic-
induced skin reactions.  Expert Opin. Drug Saf. 2010; 9: 15-21.
Ferrell PB, McLeod HL.  Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson 
syndrome and toxic epidermal necrolysis: US FDA recommendations.  
Pharmacogenomics. 2008; 9: 1543-46.
Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, 
Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses 
AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. 
Lancet. 2002; 359:1121-2.
Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch 
L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ.  Genetic variants in the UDP-
glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J 
Clin Oncol 2004; 22: 1382-1388.
Liu CY, Chen PM, Chiou TJ, Liu JH, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, 
Wang WS.  UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities 
without affecting treatment outcome and survival in patients with metastatic colorectal 
carcinoma.  Cancer. 2008; 112: 1932-40.
Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte 
C, Maxwell D, James I.  Association between presence of HLA-B*5701, HLA-DR7, and 
HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir.  
Lancet. 2002; 359:727-32.
Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, Jägel-Guedes E, 
Rugina S, Kozyrev O, Cid JF, Hay P, Nolan D, Hughes S, Hughes A, Ryan S, Fitch N, 
Thorborn D, Benbow A; PREDICT-1 Study Team. HLA-B*5701 screening for 
hypersensitivity to abacavir. N Engl J Med. 2008; 358; 568-78
Schulz C, Heinemann V, Schalhorn A, Moosmann N, Zwingers T, Boeck S, Giessen C, 
Stemmler HJ. UGT1A1 gene polymorphism: Impact on toxicity and efficacy of 
irinotecan-based regimens in metastatic colorectal cancer.  World J. Gastroenterol. 2009; 
15: 5058-66.
 
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11.3.
Appendix 3: Country Specific Requirements
 
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11.4.
Appendix 4: Liver Chemistry Stopping and Followup Criteria
Phase III-IV Liver Safety Algorithms
ALT>3xULN
plus 
bilirubin >2x 
ULN (>35%
direct) (or plus
INR >1.5, if   
measured)*
No
Yes
Yes
•Instruct subject to stop investigational product (IP)
•Notify GSK within 24h and arrange clinical followup 
within 24-72h
•Perform liver chemistries and liver event follow up 
assessments (serology, PK sample etc as in protocol) 
•Complete liver event CRF, SAE data collection tool if 
appropriate, and liver imaging and/or biopsy CRFs if  
tests performed.
•Obtain weekly liver chemistries [**as far as possible in 
these subjects] until resolved, stabilised or returned to 
baseline 
•Withdraw subject from study after monitoring 
complete unless protocol has option to restart drug
•Instruct subject to stop investigational product (IP)
•Notify GSK and arrange clinical followup within 24h
•Perform liver chemistries and liver event follow up 
assessments (serology, PK sample etc as in protocol) 
•Report as SAE (excl. hepatic impairment or cirrhosis 
studies) and complete liver event CRF, SAE data 
collection tool, and liver imaging and/or biopsy CRFs if 
tests performed.
•Obtain twice weekly liver chemistries until resolved, 
stabilised or returned to baseline values
•Consultation with hepatologist/specialist recommended
•Withdraw subject from study after monitoring 
complete unless protocol has option to restart drug
Hepatitis 
symptoms
or rash?
No
Able to 
monitor 
weekly for 
4 weeks?
Yes
No**
Yes
Continue IP
Obtain twice 
monthly liver 
chemistries until 
normalised or 
back to baseline 
values
Yes
Yes
ALT<3xULN 
+ bilirubin 
<2xULN 
after ≤ 4 
wks?
Yes
ALT 
>5xULN 
but 
<8xULN
No
ALT  
>8xULN
Yes
ALT >5 
and 
<8xULN 
for > 2 
wks
Yes
No
ALT>3xULN 
but <5xULN + 
bilirubin 
<2xULN+no 
symptoms
No
Able to 
monitor 
weekly for 
> 2 wks?
No
No
Notify GSK within 24h 
to discuss subject 
safety; continue IP;
check liver chemistry 
weekly for 4 weeks
Yes
No
*INR value not applicable to subjects on anticoagulants
 
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11.5.
Appendix 5: Protocol Changes
This amendment applies to all study centers participating in HZC102972
Rationale
This protocol amendment is being implemented to revise and clarify exclusion criteria 
concerning participation in pulmonary rehabilitation programs; clarify the description of 
DEXA procedures and clinical labs; correction of typographical errors.
Section - Study Design 
Original Text:
The target enrolment across approximately 40 study centres is approximately 400
randomized subjects, to achieve approximately 280 who complete the 156-week 
treatment period.  
Amended Text:
The target enrolment across approximately 40 study centres is approximately 280
randomized subjects, to achieve approximately 224 who complete the 156-week 
treatment period.  
Section 4.2. Inclusion Criteria - #6
Original Text:
Severity of Disease: Subject with a measured pre- and post-albuterol/salbutamol 
FEV1/FVC ratio of < 0.70 at Screening (Visit 1).  
Amended Text:
Severity of Disease: Subject with a measured post-albuterol/salbutamol FEV1/FVC ratio 
of < 0.70 at Screening (Visit 1).  
Section 4.3. Exclusion Criteria  
Deleted Text (formerly criteria #23):
Pulmonary rehabilitation: Subjects who have participated in the acute phase of a 
Pulmonary Rehabilitation Program within 4 weeks prior to Screening Visit 1 or who will 
enter the acute phase of a Pulmonary Rehabilitation Program during the study. Subjects 
who are in the maintenance phase of a Pulmonary Rehabilitation Program are not 
excluded.
Section 4.4. Withdrawal Criteria – 3rd paragraph
Original Text:
 
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Subject compliance with double-blind study medication will be assessed at Visits 2 
through 14, by reviewing the dose counter on the NDPI.  
Amended Text:
Subject compliance with double-blind study medication will be assessed from Visits 2 
through 14, by reviewing the dose counter on the NDPI.
 
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Section 6. Time and Events – Table 3 
Original Text:
Collect Double-Blind 
Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Amended Text:
Collect albuterol 
(salbutamol)14
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Single-Blind 
Medication
X
Collect Blinded 
Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 6. Time and Events – Table 3 Footnotes
Original Text:
1.  Visit 0 and Visit 1 may occur on the same day.
3.  Subjects will be assigned a subject number at the time ICF is signed. The ICF must be signed before any study procedures including drug washout(s).
9.   Non-fasting and pre-dose. Visit 2: pre-dose lab only completed if any part of Screening lab needs to be repeated
Amended Text:
1.  Visit 0 and Visit 1 may occur on the same day if the subject does not take or has not taken any protocol excluded medications.
3.  Subjects will be assigned a subject number at the time ICF is signed. The ICF must be signed before any study procedures including medication exclusion period(s).
9.   Non-fasting and pre-dose. A blood sample for repeat analysis is collected only if any part of Screening lab needs to be repeated. Results of repeat labs should be received prior to 
      Randomization at Visit 2.
 
 
 
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Section 6.1. Critical Baseline Assessments and Section 9.2. Regulatory and Ethical 
Considerations, Including the Informed Consent Process
Original Text:
The informed consent may be given at the screening visit if the subject does not take or 
has not taken any protocol excluded medications. 
Amended Text:
The pre-screening visit and screening visit may occur on the same day if the subject does 
not take or has not taken any protocol excluded medications. 
Section 6.2.6. COPD Exacerbations and Pneumonias
Added Text:
COPD exacerbations should not be recorded as an adverse event, unless they meet the 
definition of a Serious Adverse Event.  For the purposes of this study, COPD 
exacerbations will be collected and recorded on the exacerbation log in the eCRF.  
Section 6.2.4. Bone Mineral Density – 4th paragraph
Original Text:
DEXA Assessments

At Screening, any subject with a T score < -1.5 (assessed from the L1-L4 regions of 
the spine or the total hip) will be counseled about the clinical implications of this 
value.

At any visit after randomization to double-blind treatment (Visit 2) through Visit 10, 
any subject with a bone mineral density loss of 8% from baseline (assessed from 
the L1-L4 regions of the spine or the total hip) will be counseled about the clinical 
implications of this value.

At any visit after 2 years (Visit 10), any subject with a bone mineral density loss of 
10% from baseline (assessed from the L1-L4 regions of the spine or the total hip) 
will be counseled about the clinical implications of this value.
Amended Text:
Subjects with DEXA results meeting pre-defined criteria for clinically significant bone 
mineral density loss from the Screening scan or any visit scan after randomization will be 
counseled about the clinical implications of the scan results.
Section 6.2.16. Laboratory Assessments – 3rd paragraph
 
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Original Text:
a blood sample for repeat analysis of the analyte(s) should be collected pre-dose at Visit 2 
(Randomization).
Amended Text:
a blood sample for repeat analysis of the analyte(s) should be collected prior to Visit 2 
(Randomization). Results of repeat Screening labs should be received prior to 
Randomization at Visit 2.
Section 11.1. Appendix 1: Laboratory Assessments – third column
Deleted Text:
Urine pregnancy test (in clinic/home test)2
 
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GlaxoSmithKline group of companies
HZC102972
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TITLE PAGE
Division:  Worldwide Development
Title:
Multi-centre, randomized, double-blind, parallel-group study 
evaluating the effect of Fluticasone Furoate/ Vilanterol (FF/VI) 
Inhalation Powder once daily compared with Vilanterol (VI) 
Inhalation Powder Once Daily on Bone Mineral Density (BMD) 
in subjects with Chronic Obstructive Pulmonary Disease 
(COPD)
Compound Number:
GW685698+GW642444
Development Phase
IV
Effective Date:
07-JAN-2013
Subject: COPD, Bone Mineral Density, Fluticasone Furoate (FF), Vilanterol (VI), Novel 
Dry Powder Inhaler (NDPI)
Author(s):
Copyright 2013 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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SPONSOR INFORMATION PAGE
Clinical Study Identifier:
HZC102972
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Sponsor Contact Address
GlaxoSmithKline Research & Development Limited
Via 
2/4-37135
Verona, Italy
Telephone:  
GlaxoSmithKline Research & Development Limited
Addenbrooke’s Centre for Clinical Investigation (ACCI)
Addenbrooke’s Hospital
Hills Road
Cambridge, Cambridgeshire, CB2 2GG, UK
Telephone:  
GlaxoSmithKline Research & Development Limited
Iron Bridge Road
Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK
Telephone:  
GlaxoSmithKline Research & Development Limited
2301 Renaissance Boulevard
Building #510
Post Office Box 61540
King of Prussia, Pennsylvania 19406
Telephone number: 
or
GlaxoSmithKline Research & Development Limited
1250 South Collegeville Road
Collegeville, PA 19426, USA
Telephone Number: 
GlaxoSmithKline Research & Development Limited
Five Moore Drive 
P.O. 13398
 
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Research Triangle Park, NC 27709-3398, USA
Telephone: 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate 
company (or designee). Where applicable, the details of the Sponsor and contact person 
will be provided to the relevant regulatory authority as part of the clinical trial 
submission.
Sponsor Medical Monitor Contact Information: 
 MD
GlaxoSmithKline
Five Moore Drive
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone: 
Sponsor Serious Adverse Events (SAE) Contact Information: 
Case Management Group, GCSP –Stockley Park, UK
Email: 
Fax: 
Regulatory Agency Identifying Number(s): FDA IND Numbers:  077855 and 050703; 
EudraCT #: 2012-004801-28
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
Required Standard Wording:

I confirm agreement to conduct the study in compliance with the protocol.

I acknowledge that I am responsible for overall study conduct. I agree to 
personally conduct or supervise the described clinical study.

I agree to ensure that all associates, colleagues and employees assisting in the 
conduct of the study are informed about their obligations. Mechanisms are in 
place to ensure that site staff receives the appropriate information throughout the 
study.
Investigator Name:  _____________________________
Investigator Signature
Date
 
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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS.............................................................................................9
PROTOCOL SUMMARY...............................................................................................11
1.
INTRODUCTION....................................................................................................14
1.1.
Background ................................................................................................14
1.2.
Rationale ....................................................................................................14
2.
OBJECTIVE(S) ......................................................................................................15
3.
INVESTIGATIONAL PLAN.....................................................................................15
3.1.
Study Design ..............................................................................................15
3.1.1.
Study Schematic..........................................................................16
3.2.
Discussion of Design ..................................................................................16
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA.......................................16
4.1.
Number of Subjects ....................................................................................16
4.2.
Inclusion Criteria.........................................................................................16
4.3.
Exclusion Criteria........................................................................................17
4.4.
Withdrawal Criteria .....................................................................................20
4.5.
Pre-Screen Failures and Screening Failures...............................................22
5.
STUDY TREATMENTS..........................................................................................22
5.1.
Investigational Product and Other Study Treatment....................................22
5.1.1.
Storage........................................................................................24
5.1.2.
Study Drug Return.......................................................................24
5.2.
Treatment Assignment................................................................................24
5.3.
Blinding.......................................................................................................25
5.4.
Product Accountability ................................................................................25
5.5.
Treatment Compliance................................................................................25
5.6.
Concomitant Medications and Non-Drug Therapies....................................26
5.6.1.
Permitted Medications and Non-Drug Therapies..........................26
5.6.2.
Prohibited Medications and Non-Drug Therapies.........................27
5.7.
Treatment after the End of the Study ..........................................................27
5.8.
Treatment of Study Treatment Overdose....................................................28
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................28
6.1.
Critical Baseline Assessments....................................................................32
6.2.
Safety .........................................................................................................32
6.2.1.
Primary Endpoint .........................................................................32
6.2.2.
Secondary Endpoints...................................................................32
6.2.3.
Other Endpoints...........................................................................32
6.2.4.
Bone Mineral Density...................................................................33
6.2.5.
Fractures .....................................................................................33
6.2.6.
COPD Exacerbations and Pneumonias .......................................33
6.2.7.
Liver chemistry stopping and follow up criteria.............................35
6.2.8.
Adverse Events............................................................................38
6.2.8.1.
Definition of an AE......................................................39
 
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6.2.8.2.
Definition of a SAE .....................................................40
6.2.9.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs.........................................................41
6.2.10.
Cardiovascular Events.................................................................41
6.2.11.
Death Events...............................................................................42
6.2.12.
Pregnancy ...................................................................................42
6.2.13.
Time Period and Frequency of Detecting AEs and SAEs.............42
6.2.14.
Prompt Reporting of Serious Adverse Events and Other 
Events to GSK.............................................................................42
6.2.14.1.
Regulatory reporting requirements for SAEs ..............44
6.2.15.
SpirometryTesting........................................................................44
6.2.15.1.
Reversibility Testing ...................................................45
6.2.16.
Laboratory Assessments .............................................................45
6.2.17.
Oropharyngeal Examination.........................................................46
6.2.18.
Diary Card - Medical Problems/Medications Taken......................46
6.2.19.
12-lead ECG Assessment............................................................46
6.2.20.
Smoking Cessation Counselling ..................................................46
6.3.
Pharmacogenetic Research........................................................................47
7.
DATA MANAGEMENT ...........................................................................................47
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................47
8.1.
Hypotheses.................................................................................................47
8.2.
Study Design Considerations......................................................................48
8.2.1.
Sample Size Assumptions ...........................................................48
8.2.2.
Sample Size Sensitivity................................................................48
8.2.3.
Sample Size Re-estimation..........................................................48
8.3.
Data Analysis Considerations .....................................................................48
8.3.1.
Analysis Populations....................................................................48
8.3.2.
Analysis Data Sets.......................................................................49
8.3.3.
Treatment Comparisons ..............................................................49
8.3.3.1.
Primary Comparisons of Interest ................................49
8.3.4.
Interim Analysis ...........................................................................49
8.3.5.
Key Elements of Analysis Plan ....................................................49
8.3.5.1.
Efficacy Analyses .......................................................49
8.3.5.2.
Safety Analyses..........................................................49
8.3.5.2.1.
Extent of Exposure .................................49
8.3.5.2.2.
Adverse Events (AEs).............................49
8.3.5.2.3.
Deaths and SAEs ...................................50
8.3.5.2.4.
Fractures ................................................50
8.3.5.2.5.
COPD Exacerbations and 
Pneumonias ...........................................50
8.3.5.3.
Pharmacogenetic Analyses ........................................50
9.
STUDY CONDUCT CONSIDERATIONS ...............................................................50
9.1.
Posting of Information on Publicly Available Clinical Trial Registers............50
9.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................50
9.3.
Quality Control (Study Monitoring) ..............................................................51
9.4.
Quality Assurance.......................................................................................51
9.5.
Study and Site Closure ...............................................................................52
9.6.
Records Retention......................................................................................52
 
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9.7.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication....................53
9.8.
Independent Data Monitoring Committee (IDMC) .......................................53
10. REFERENCES.......................................................................................................54
11. APPENDICES........................................................................................................55
11.1.
Appendix 1: Laboratory Assessments.........................................................55
11.2.
Appendix 2: Pharmacogenetic Research ....................................................55
11.3.
Appendix 3: Country Specific Requirements...............................................61
11.4.
Appendix 4: Liver Chemistry Stopping and Followup Criteria......................62
 
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LIST OF ABBREVIATIONS
AE
Adverse Event
ALT
Alanine Transaminase
AM
Morning
ANCOVA
Analysis of Covariance
AST
Aspartate Transaminase
AUC
Area Under the Curve
ATS
American Thoracic Society
BMD
Bone Mineral Density
IB
Investigator’s Brochure
COPD
Chronic Obstructive Pulmonary Disease
eCRF
Electronic Case Report Form
DEXA
Dual Energy X-ray Absorptiometry
ECG
Electrocardiogram
EISR
Expedited Investigator Safety Report
FEV1
Forced Expiratory Volume in one Second
FF
Fluticasone Furoate
FF/VI
Fluticasone Furoate/ Vilanterol Inhalation Powder 
Combination
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GCP
Good Clinical Practice
GOLD
Global Initiative for Chronic Obstructive Lung Disease
GSK
GlaxoSmithKline
IEC
Independent Ethics Committee
ICF
Informed Consent Form
ICS
Inhaled Corticosteroid
IDMC
Independent Data Monitoring Committee
IRB
Institutional Review Board
ITT
Intent to Treat
IVRS
Interactive Voice Response System
L
Liter
LABA
Long Acting Beta Agonist
LDH
Lactate Dehydrogenase
LSLV
Last Subject Last Visit
LTOT
Long Term Oxygen Therapy
MAOI
Monoamine Oxidase Inhibitor
Mcg
Microgram
MDI
Metered Dose Inhaler
MEDDRA
Medical Dictionary for Regulatory Activities
mL
Milliliter
MSDS
Material Safety Data Sheet
NDPI
Novel Dry Powder Inhaler
OTC
Over the Counter
PD
Pharmacodynamics
PK
Pharmacokinetics
 
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PEF
Peak Expiratory Flow
PFT
Pulmonary Function Test
PGx
Pharmacogenetics
PM
Evening
PR
Pulse Rate
PRN
As needed
QD
Once Daily
RAMOS
Registration and Medication Ordering System
RAP
Reporting Analysis Plan
RNA
Ribonucleic Acid
SAE
Serious Adverse Event
SD
Standard Deviation
SPM
Study Procedures Manual
UC
Urine Cortisol
ULN
Upper Limit of Normal
VI
Vilanterol
WHO
World Health Organization
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
None
 
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PROTOCOL SUMMARY
Rationale
Chronic obstructive pulmonary disease (COPD) has been defined as a preventable and 
treatable disease with some significant extra-pulmonary effects that may contribute to the 
severity in individual patients. The pulmonary component of COPD is characterized by 
airflow limitation that is not fully reversible, which is usually progressive and associated 
with an abnormal inflammatory response of the lung to noxious particles or gases. COPD 
is a major cause of poor health, resulting in millions of deaths annually worldwide 
[GOLD, 2010] and contributing significantly to health care costs and morbidity 
[Chapman, 2006; Lopez, 2006]. According to the World Health Organization, COPD was 
the fifth leading cause of death worldwide in 2002 and is estimated to be the third leading 
cause by 2030 [WHO, 2010].
Currently published guidelines on COPD state that the goals of pharmacologic therapy 
should be to control symptoms, improve health status and exercise tolerance, and reduce 
the frequency of COPD exacerbations [GOLD, 2010]. Recent clinical research has 
indicated that an inhaled corticosteroid (ICS) combined with a long acting 2-agonist 
(LABA) is more effective than the individual components in managing stable COPD to 
reduce exacerbations and improve lung function and health status [Ferguson, 2008; 
Calverley, 2007; Kardos, 2007]. 
Although inhaled corticosteroids have demonstrated utility in patients with COPD, there 
is a potential safety concern with long-term use on bone demineralization.  These 
concerns, for the most part, are derived from the well-documented effects of oral 
corticosteroids on bone density and fracture, however the actual effects of inhaled 
corticosteroids are not clear and require further study.
Study HZC102972 will prospectively assess the effects of 3 years (156 weeks) exposure 
to fluticasone furoate/vilanterol (FF/VI) versus VI on bone mineral density in adult 
subjects with COPD at approximately 40 centers.
Objective(s)
The primary objective of this study is to evaluate the effect of the inhaled corticosteroid 
FF on bone mineral density (BMD) assessed at the total hip by comparing FF/VI 
treatment with VI treatment in subjects with moderate COPD. 
A secondary objective is to evaluate the effect of the inhaled corticosteroid FF on bone 
mineral density by gender by comparing FF/VI treatment with VI treatment in subjects 
with moderate COPD.
Another secondary objective is to evaluate the effect of FF on bone mineral density as 
assessed at the lumbar spine (L1-L4) by comparing FF/VI treatment with VI treatment in 
subjects with moderate COPD.
 
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Study Design
This is a multi-center, randomized, double-blind, parallel-group study.  The FF/VI 
inhalation powder once daily and VI inhalation powder once daily will be evaluated in 
subjects with COPD over 156 weeks. Subjects will sign the informed consent form (ICF)
at Visit 0 and will be assigned a subject identifier. See Table 3 for further details. 
Subjects who meet all study inclusion and none of the exclusion criteria will begin a 14 to 
21 day single-blind run-in period following Visit 1.  Baseline BMD measurements will be 
collected between Visits 1 and 2.  At Visit 2, eligible subjects will be randomized to 
double-blind study medication and entered into a 156-week treatment period.  
Randomisation will be stratified based upon gender.  During the treatment period, clinic 
visits will occur every 3 months. BMD determined by dual-energy x-ray absorptiometry
(DEXA) scans will be conducted every 6 months following randomization. A safety 
Follow-up Visit 15 will occur 7 days after the last treatment study day as a telephone 
contact.  Subjects will be prescribed appropriate COPD therapy at the end of Treatment 
Visit 14 if required.  There are no plans to provide the study drug for compassionate use 
following study completion.
The target enrolment across approximately 40 study centres is approximately 400
randomized subjects, to achieve approximately 280 who complete the 156-week 
treatment period.  The total duration of subject participation will be approximately 159 to 
160 weeks.
Study Endpoints/Assessments
Primary

BMD measured at the total hip 
Secondary

BMD measurements by gender

BMD measured at the lumbar spine (L1-L4)
 
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Other

Adverse Event reporting 

Serious Adverse Event reporting

Incidence of fractures

Incidence of pneumonias

COPD exacerbations
 
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1.
INTRODUCTION
1.1.
Background
COPD has been defined as a preventable and treatable disease with some significant 
extra-pulmonary effects that may contribute to the severity in individual patients. The 
pulmonary component of COPD is characterized by airflow limitation that is not fully 
reversible, which is usually progressive and associated with an abnormal inflammatory 
response of the lung to noxious particles or gases. COPD is a major cause of poor health, 
resulting in millions of deaths annually worldwide [GOLD, 2010] and contributing 
significantly to health care costs and morbidity [Chapman, 2006; Lopez, 2006]. 
According to the World Health Organization, COPD was the fifth leading cause of death 
worldwide in 2002 and is estimated to be the third leading cause by 2030 [WHO, 2010].
Currently published guidelines on COPD state that the goals of pharmacologic therapy 
should be to control symptoms, improve health status and exercise tolerance, and reduce 
the frequency of COPD exacerbations [GOLD, 2010]. Recent clinical research has 
indicated that an inhaled corticosteroid (ICS) combined with a long acting 2-agonist 
(LABA) is more effective than the individual components in managing stable COPD to 
reduce exacerbations and improve lung function and health status [Ferguson, 2008; 
Calverley, 2007; Kardos, 2007]. 
Bronchodilators are considered key to the symptomatic management of COPD and 
current Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines 
recommend the use of long-acting inhaled bronchodilators in moderate to very severe 
COPD, because they are more efficacious and more convenient to use than short-acting 
bronchodilators.  The benefits of bronchodilators include not only the control of 
symptoms but improvements in lung function, hyperinflation, exercise performance, and 
health status.
Inhaled corticosteroids are considered the most effective anti-inflammatory treatments for 
all severities of COPD.  The benefits of ICS may include control of COPD symptoms, 
improvement in lung function, decrease in airway hyper-responsiveness and 
improvement in health status and reduction in exacerbations.
1.2.
Rationale
Although inhaled corticosteroids have demonstrated utility in patients with COPD, there 
is a potential safety concern with long-term use of ICS on bone demineralization.  These 
concerns, for the most part, are derived from the well-documented effects of oral 
corticosteroids on bone density and fracture, however the actual effects of inhaled 
corticosteroids are not clear and require further study.
Study HZC102972 will prospectively assess the effects of 3 years (156 weeks) exposure 
to versus VI on bone mineral density in adult subjects with chronic obstructive 
pulmonary disease (COPD) at approximately 40 centers.
 
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2.
OBJECTIVE(S)
The primary objective of this study is to evaluate the effect of the inhaled corticosteroid 
FF on bone mineral density assessed at the total hip by comparing FF/VI treatment with 
VI treatment in subjects with moderate COPD. 
A secondary objective is to evaluate the effect of the inhaled corticosteroid Fluticasone 
Furoate (FF) on bone mineral density by gender by comparing FF/VI treatment with VI 
treatment in subjects with moderate COPD.
Another secondary objective is to evaluate the effect of FF on bone mineral density as 
assessed at the lumbar spine (L1-L4) by comparing FF/VI treatment with VI treatment in 
subjects with moderate COPD.
3.
INVESTIGATIONAL PLAN
3.1.
Study Design
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct. 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.
This is a multi-center, randomized, double-blind, parallel-group study.  The FF/VI 
inhalation powder once daily and VI inhalation powder once daily will be evaluated in 
subjects with COPD over 156 weeks. Subjects will sign the ICF at Visit 0 and will be 
assigned a subject identifier. See Table 3 for further details. Subjects who meet all study 
inclusion and none of the exclusion criteria will begin a 14 to 21 day single-blind run-in 
period following Visit 1.  Baseline BMD measurements will be collected between Visits 
1 and 2.  At Visit 2, eligible subjects will be randomized to double-blind study 
medication and entered into a 156-week treatment period.  Randomisation will be 
stratified based upon gender. During the treatment period, clinic visits will occur every 3 
months. BMD DEXA scans will be conducted every 6 months following randomization. 
A safety Follow-up Visit 15 will occur 7 days after the last treatment study day as a 
telephone contact.  Subjects will be prescribed appropriate COPD therapy at the end of 
Treatment Visit 14 if required.  There are no plans to provide the study drug for 
compassionate use following study completion.
Systemic corticosteroid therapies will not be allowed during the run-in period.  Subjects 
may take courses of systemic corticosteroids, where necessary, for treatment of a COPD 
exacerbation during the double-blind treatment period.
 
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3.1.1.
Study Schematic
FF/VI 100/25 once daily (N=140)
VI 25 once daily (N=140)
           │                          156 Week Treatment                                         │Follow-up
│__│_│___│___│___│___│___│___│___│___│___│___│___│___│_│
Visits
0     1  2       3       4       5     6     7       8       9      10     11    12     13     14  15
                             
Randomization
3.2.
Discussion of Design
The purpose of this study is primarily to assess the long-term safety effects of the FF 
component of the FF/VI inhalation powder on bone mineral density when administered to 
subjects with COPD over 156 weeks.  The American Thoracic Society (ATS)/European 
Respiratory Society definition of COPD defines the subject population that will be 
included in this study [Celli, 2004].  BMD at the total hip was chosen as the primary 
endpoint due to the important morbidity/mortality implications of hip fractures.  BMD at 
the lumbar spine (L1-L4) will be measured and assessed as a secondary endpoint.  
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA
4.1.
Number of Subjects
Approximately 400 male and female subjects will be screened to randomize 
approximately 280 subjects, to obtain at least 224 who complete 156 weeks of treatment.  
Approximately 40 centres in multiple countries will be required to recruit for the study.
4.2.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB.
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.   
 
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Subjects eligible for enrolment in the study must meet all of the following criteria:
1. Informed consent: Subjects must give their signed and dated written informed 
consent to participate.
2. Gender: Male or female subjects. Female subjects must be post-menopausal or using 
a highly effective method for avoidance of pregnancy. The decision to include or 
exclude women of childbearing potential may be made at the discretion of the 
investigator in accordance with local practice in relation to adequate contraception.
3. Age: ≥ 40 years of age at Screening (Visit 1)
4. COPD diagnosis: Subjects with a clinical history of COPD in accordance with the 
following definition by the American Thoracic Society/European Respiratory Society 
[Celli, 2004]: COPD is a preventable and treatable disease characterized by airflow 
limitation that is not fully reversible.  The airflow limitation is usually progressive 
and is associated with an abnormal inflammatory response of the lungs to noxious 
particles or gases, primarily caused by cigarette smoking.  Although COPD affects 
the lungs, it also produces significant systemic consequences.
5. Tobacco use: Subjects with a current or prior history of ≥10 pack-years of cigarette 
smoking at screening (Visit 1).  Former smokers are defined as those who have 
stopped smoking for at least 6 months prior to Visit 1.  Number of pack years = 
(number of cigarettes per day/20) x number of years smoked
Note: Pipe and/or cigar use cannot be used to calculate pack year history.
6. Severity of Disease: Subject with a measured pre- and post-albuterol/salbutamol 
FEV1/FVC ratio of < 0.70 at Screening (Visit 1).  Subjects with a measured post-
albuterol/salbutamol 50% ≤ FEV1 ≤ 70% of predicted normal values calculated using 
NHANES III reference equations [Hankinson, 1999] at Screening (Visit 1).
7. Native Hip: Have at least one evaluable native hip.
4.3.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
Subjects meeting any of the following criteria must not be enrolled in the study:
1. Pregnancy: Women who are pregnant or lactating or are planning on becoming 
pregnant during the study.
2. 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).
3. α1-antitrypsin deficiency: Subjects with α-1 antitrypsin deficiency as the underlying 
cause of COPD.
 
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4. Other respiratory disorders: Subjects with tuberculosis, lung cancer, 
bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung 
diseases or other active pulmonary diseases.
5. Lung resection or transplantation: Subjects with lung volume reduction surgery 
within the 12 months prior to Screening Visit 1 or having had a lung transplant.
6. Chest X-ray:  Subjects with a chest X-ray (or CT scan) that revealed evidence of 
clinically significant abnormalities not believed to be due to the presence of COPD.  
A chest X-ray should be taken at Screening Visit 1 if a chest X-ray or CT scan is not 
available within 12 months prior to Visit 1.
7. Poorly controlled COPD: Subjects with poorly controlled COPD, defined as the 
occurrence of the following in the 12 weeks prior to Screening Visit 1: Acute 
worsening of COPD that is managed by the subject with corticosteroids or antibiotics 
or that requires treatment prescribed by a physician or requires hospitalization.
8. Moderate or severe COPD exacerbation or lower respiratory tract infection:
Subjects with 2 or more moderate or severe COPD exacerbations and/or a lower 
respiratory tract infection (including pneumonia) within the 12 months prior to 
Screening Visit 1 or experience a moderate or severe COPD exacerbation and/or a 
lower respiratory infection (including pneumonia) during the Run-In period.
NOTE: A moderate COPD exacerbation is defined as requiring systemic 
corticosteroids and/or antibiotics.  A severe COPD exacerbation is defined as 
requiring hospitalization.
9. Abnormal clinically significant laboratory finding: Subjects who have an 
abnormal, clinically significant finding in any liver chemistry, biochemical, or 
haematology tests at Screening Visit 1 or upon repeat prior to randomization.
10. Abnormal and clinically significant 12-lead ECG: Subjects who have an abnormal, 
clinically significant ECG finding at Screening Visit 1.
11. Non-Compliance during Run-In Period: Failure to demonstrate adequate 
compliance with run-in medication (< 80% compliant), the ability to withhold COPD 
medications, and to keep clinic visit appointments.
12. Bone disorders/conditions: Subjects with historical or current evidence of bone 
cancer, severe scoliosis, rheumatoid arthritis, metabolic bone diseases (other than 
osteoporosis) including hyper-or hypo-parathyroidism, Paget’s disease of bone, 
osteomalacia, or osteogenesis imperfecta. Removal of vertebrae between L1 and L4 
of the lumbar spine and/or presence of metal implants or devices, such as plates, rods, 
or screws in the lumbar spine and/or hip.
13. Immobility: Wheel chair bound or paraplegic.
14. Low vitamin D: Previously known low-serum 25-hydroxy vitamin D concentration 
(less than 10ng [25nmoles] per liter).
 
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15. Other diseases/abnormalities: Serious, uncontrolled disease (including serious 
psychological disorders) likely to interfere with the study within the 3-year study.
16. Cancer: Subjects with carcinoma that has not been in complete remission for at least 
5 years. Carcinoma in situ of the cervix, squamous cell carcinoma and basal cell 
carcinoma of the skin would not be excluded if the subject has been considered cured 
within 5 years since diagnosis.
17. Drug/food allergy: Subjects with a history of hypersensitivity to any of the study 
medications (e.g. beta-agonists, corticosteroid) or components of the inhalation 
powder (e.g. lactose, magnesium stearate). In addition, patients with a history of 
severe milk protein allergy that, in the opinion of the study physician, contraindicates 
the subject’s participation will also be excluded. 
18. Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug 
abuse within the last 2 years.
19. Prohibited medications prior to spirometry at Visit 1: Subjects who are medically 
unable to withhold the following medications prior to spirometry testing at Visit 1:
Medication
No use within the following 
time intervals prior to Visit 1 
Spirometry Testing 
Inhaled corticosteroids
48 hours
Inhaled ICS/LABA combination products
48 hours 
Long-acting anticholinergics (e.g., tiotropium)
48 hours
Theophylline preparations
48 hours
Oral leukotriene inhibitors (zafirlukast, montelukast, zileuton)
48 hours
Oral PDE-4 inhibitors (e.g. roflumilast)
48 hours
Oral beta-agonists 
     Long-acting
     Short-acting
48 hours
12 hours
Inhaled long acting beta2-agonist (LABA) - Indacaterol
48 hours
Other inhaled LABAs (e.g., salmeterol)
24 hours 
Inhaled sodium cromoglycate or nedocromil sodium
24 hours
Ipratropium/ albuterol (salbutamol) combination product
4 hours 
Inhaled short-acting beta2-agonists
4 hours 
Short-acting anti-cholinergics (e.g., ipratropium bromide)
4 hours
 
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20. Additional medication: Use of the following medications within the following time 
intervals prior to Visit 1 or during the study (unless otherwise specified):
Medication
No use within the following time intervals prior to 
Screening Visit 1 or thereafter at any time during the 
study (unless otherwise specified)
Depot corticosteroids
12 weeks
Systemic, Oral, parenteral, intra-
articular corticosteroids1
30 days   
Any other investigational drug
30 days or 5 half lives whichever is longer.
1.
Subjects may take courses of systemic corticosteroids, where necessary, for treatment of an exacerbation 
during the double-blind treatment period.
21. COPD medications: Use of inhaled corticosteroids (ICS), long-acting beta2-agonists 
(LABA), or ICS/LABA combination products (other than the study-provided double-
blind study medication) at Visit 2 (Randomization) or during the double-blind 
treatment period.
22. Oxygen therapy: Subjects receiving treatment with long-term oxygen therapy 
(LTOT) or nocturnal oxygen therapy required for greater than 12 hours a day.  
Oxygen prn use (i.e., ≤12 hours per day) is not exclusionary.
23. Pulmonary rehabilitation: Subjects who have participated in the acute phase of a 
Pulmonary Rehabilitation Program within 4 weeks prior to Screening Visit 1 or who 
will enter the acute phase of a Pulmonary Rehabilitation Program during the study. 
Subjects who are in the maintenance phase of a Pulmonary Rehabilitation Program 
are not excluded.
24. Non-compliance: Subjects at risk of non-compliance, or unable to comply with the 
study procedures.  Any infirmity, disability, or geographic location that would limit 
compliance for scheduled visits.
25. Questionable validity of consent: Subjects with a history of psychiatric disease, 
intellectual deficiency, poor motivation or other conditions that will limit the validity 
of informed consent to participate in the study
26. Affiliation with investigator site: Study investigators, sub-investigators, study 
coordinators, employees of a participating investigator or immediate family members 
of the aforementioned are excluded from participating in this study.
4.4.
Withdrawal Criteria
A subject may voluntarily discontinue participation in this study at any time.  The 
investigator may also, at his or her discretion, discontinue a subject from this study at any 
time.  Every effort should be made by the investigator to keep the subject in the study.  
 
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The primary reason for subject withdrawal will be recorded in the electronic Case Report 
Form (eCRF). Primary reasons for withdrawal will be categorised as:

adverse event

withdrew consent

lost to follow-up

protocol deviation

lack of efficacy

subject reached protocol-defined stopping criteria

study closed/terminated

investigator discretion
Subject compliance with double-blind study medication will be assessed at Visits 2 
through 14, by reviewing the dose counter on the NDPI.  Subjects must be ≥80% to 
≤120% compliant on taking study medication between each pair of on-treatment visits. 
Subjects who fall outside this range should be re-educated on treatment compliance by 
their site. This re-education should be documented in the subject’s source document. If 
the double-blind study medication is prematurely discontinued during the course of study 
or medication compliance repeatedly falls outside of acceptable ranges, the study 
sponsor/site monitor must be contacted to discuss subject eligibility for continued 
participation in the study.
A subject will also be withdrawn from the study, in consultation with the medical
monitor and principal investigator, if any of the following stopping criteria are met:

Liver Chemistry: Meets any of the liver chemistry stopping criteria as defined 
in Section 6.2.7.

Pregnancy: Positive pregnancy test

Laboratory Measurements:  Demonstrate a clinically important change in a 
laboratory parameter(s).
If a subject is withdrawn due to an exacerbation, the exacerbation section and SAE 
section, if applicable, of the eCRF should be completed and the subject should be 
followed until resolution of exacerbation.
If a subject is withdrawn due to pneumonia, the AE/SAE section and the 
pneumonia/chest x-ray section of the eCRF should be completed and the subject should 
be followed until clinical resolution of the pneumonia.
 
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4.5.
Pre-Screen Failures and Screening Failures
A subject will be assigned a subject number at the time the informed consent is signed.
A subject who is assigned a subject number but does not have Visit 1 will be considered a 
pre-screen failure.
Any subject who performs a Visit 1 procedure but does not continue in the study beyond 
Visit 1 or any subject who completes Visit 1 and enters the run-in period, but is 
subsequently found to be ineligible for the study (e.g. exclusionary laboratory, ECG, or 
spirometry findings) conducted prior to randomization to the study treatment medication
(Visit 2), is classified as a ‘screen failure’.
The study interactive voice response system (IVRS) will be contacted to report pre-screen 
failures. The following information will be collected for subjects who are pre-screen 
failures:

Subject number

Date of ICF signature

Demographic information including race, age and gender

Details of COPD medications within 30 days of Visit 0

Details of COPD exacerbation (yes/no status), if applicable

Serious Adverse Event information, if applicable, only for an SAE considered as 
related to study participation (e.g. study treatment, protocol mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
concomitant medication

Investigator signature page
IVRS will be contacted to report screen failures, In addition to the information above, the 
following information will be collected for screen failures:

Date of screening visit

Reason for screen failure (screening failure and inclusion/exclusion criteria)
5.
STUDY TREATMENTS
5.1.
Investigational Product and Other Study Treatment
GSK Clinical Trials Supplies will provide the investigational products for use in this 
study. All blinded study medication will be delivered via the NDPI. At each dispensing 
each subject will receive one NDPI for once-daily administration. The contents of each 
treatment are described in Table 1 and Table 2
The NDPI provides a total of 30 doses (60 blisters), with each actuation comprising the 
contents of one blister from each of the two internal foil strips simultaneously. The 
 
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NDPIs containing randomized treatment and dummy medication (placebo) will appear 
identical on the outside to the subject (and his/her caregiver) and the Investigator.
All subjects will receive supplemental albuterol/salbutamol (MDI and/or nebules) to be 
used on an as-needed basis throughout the study; for all sites this medication will be 
sourced locally where possible.
Following the 14 to 21 day, Run-In period, eligible subjects will be randomized (1:1) to 
one of the following two possible treatments, administered each morning for 156 weeks:

FF/VI Inhalation Powder 100/25mcg QD

VI Inhalation Powder 25mcg QD
Randomization in each treatment group will be stratified (1:1) according to gender.
A description of the investigational treatments is provided below:
Table 1
Description of FF/VI Inhalation Powder Novel Dry Powder Inhaler
(NDPI)
Formulation
First strip: Fluticasone Furoate  
blended with lactose
Second strip: Vilanterol micronised 
drug (as the ‘M’ salt 
triphenylacetate) blended with 
lactose and magnesium stearate1
Dosage Form
Novel dry powder inhaler with 30 doses (2 strips with 30 blisters per strip)
Unit Dose Strengths
100mcg per blister
25mcg per blister
Physical description
Dry white powder
Dry white powder
Route of Administration
Inhaled
Inhaled
1.
Magnesium stearate 1% w/w of total drug product
Table 2
Description of VI Inhalation Powder Novel Dry Powder Inhaler (NDPI)
Formulation
First strip: lactose  
Second strip: Vilanterol micronised 
drug (as the ‘M’ salt 
triphenylacetate) blended with 
lactose and magnesium stearate1
Dosage Form
NDPI with 30 doses (2 strips with 30 blisters per strip)
Unit Dose Strengths
N/A 
25mcg per blister
Physical description
Dry white powder
Dry white powder
Route of Administration
Inhaled
Inhaled
1.
Magnesium stearate 1% w/w of total drug product
The contents of the label will be in accordance with all applicable regulatory 
requirements. Under normal conditions of handling and administration, investigational 
product is not expected to pose significant safety risks to site staff. Take adequate 
precautions to avoid direct eye or skin contact and the generation of aerosols or mists. 
Notify the monitor of any unintentional occupational exposure. A Material Safety Data 
Sheet (MSDS) describing the occupational hazards and recommended handling 
precautions will be provided to site staff if required by local laws or will otherwise be 
available from GSK upon request.
 
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Adequate precautions must be taken to avoid direct contact with the investigational 
product. The occupational hazards and recommended handling procedures are provided 
in the Material Safety Data Sheet (MSDS).
5.1.1.
Storage
Investigational product must be stored in a secure area under the appropriate physical 
conditions for the product.  Access to and administration of the investigational product 
will be limited to the investigator and authorized site staff.  Investigational product must 
be dispensed or administered only to subjects enrolled in the study and in accordance 
with the protocol.
The NDPIs are packaged in a foil overwrap with enclosed desiccant.  The foil overwrap 
must not be opened until immediately prior to use.  Once the foil overwrap has been 
opened the NDPI has a 30 day in-use shelf life.
5.1.2.
Study Drug Return
At the end of the study, all study-supplied study medication (used and unused) will be 
destroyed following local standard operating procedures, except where it is suspected that 
the NDPI or NDPI packaging is defective. The NDPI and packaging should be returned 
to GSK.
Details for both destruction and return of study medication are found in the SPM.
In addition, any study inhaler that fails to function properly must be identified to GSK 
personnel for return to GSK for testing. Details of the failure will be documented in the 
eCRF. The subject should return the NDPI to the clinic as soon as possible and avoid 
missing any doses if possible. The site should then call IVRS and obtain a new treatment 
pack number for this subject and dispense a new study medication kit from the site's 
investigational product supply as instructed by RAMOS, an Interactive Voice Response 
System (IVRS).
5.2.
Treatment Assignment
Subjects will be assigned to study treatment in accordance with the randomization 
schedule. Once a randomization number has been assigned to a subject, the same number 
cannot be reassigned to any other subject in the study.
Subjects will be stratified based on gender.
Subjects will be site-based randomized using RAMOS, an Interactive Voice Response 
System (IVRS). This is a telephone based system that will be used by the investigator or 
designee to register the subject (initially at Visit 0, and subsequently at each study visit), 
randomize the subject and provide medication assignment information. Details on how 
to use RAMOS to register and randomize subjects is provided in the SPM.
 
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Following the 14-21 day, Run-In period, eligible subjects will be randomized (1:1) to one 
of the following 2 possible treatments, administered as one inhalation each morning and 
evening for 156 weeks:

Fluticasone Furoate /Vilanterol 100/25mcg once daily

Vilanterol 25mcg once daily
5.3.
Blinding
Study Medication taken during the 156-week treatment period will be double-blind. 
Neither the subject nor the study physician will know which study medication the subject 
is receiving.
The investigator or treating physician may unblind a subject’s treatment assignment only 
in the case of an emergency, when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the subject.  Whenever possible, the 
investigator must first discuss options with the GSK Medical Monitor or appropriate 
GSK study personnel before unblinding the subject’s treatment assignment.  If this is 
impractical, the investigator must notify GSK as soon as possible, but without revealing 
the treatment assignment of the unblinded subject, unless that information is important 
for the safety of subjects currently in the study.  The date and reason for the unblinding 
must be recorded in the appropriate data collection tool.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject with an SAE.  If the SAE requires that an expedited 
regulatory report be sent to one or more regulatory agencies, a copy of the report, 
identifying the subject’s treatment assignment, may be sent to clinical investigators in 
accordance with local regulations and/or GSK policy.
Subjects will be withdrawn if the treatment code becomes unblinded. The primary reason 
for discontinuation (the event or condition which led to the unblinding) will be recorded 
in the eCRF.
5.4.
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
investigational product dispensed and/or administered to study subjects, the amount 
returned by study subjects, and the amount received from and returned to GSK, when 
applicable.  Product accountability records must be maintained throughout the course of 
the study.
5.5.
Treatment Compliance
An initial supply of albuterol (salbutamol), a short-acting, beta2-agonist, will be provided 
to each subject to use as needed for symptomatic relief of COPD symptoms during both 
the Run-in and Treatment Periods.  The subject’s use of albuterol (salbutamol) will be 
assessed at each clinic visit and additional albuterol (salbutamol) will be dispensed to the 
subject as needed.
 
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Subject compliance with the single-blind placebo NDPI during Run-In will be assessed at 
Visit 2 by reviewing the dose counter on the NDPI.
Subject compliance with double-blind study medication will be assessed at each 
treatment visit (from Visits 3 - Visit 14) and any unscheduled visit where study drug is 
returned by reviewing the dose counter on the NDPI.  Subjects must be ≥80% to ≤120% 
compliant on taking study medication between each pair of on-treatment visits. Subjects 
who fall outside this range should be re-educated on treatment compliance by their site. 
This re-education should be documented in the subject’s source document.  If the double-
blind study medication is prematurely discontinued during the course of study or 
medication compliance repeatedly falls outside of acceptable ranges, the study 
sponsor/site monitor must be contacted to discuss subject eligibility for continued 
participation in the study.
5.6.
Concomitant Medications and Non-Drug Therapies
All COPD medications taken within 30 days prior to Visit 0 and during the run-in period 
will be recorded in the eCRF.  All COPD and non-COPD concomitant medications taken 
during the study will be recorded in the eCRF.  The minimum requirement includes, but 
is not limited to name of the medications, and the dates of the administration.
Note: Care is advised when co-administering with strong CYP 3A4 inhibitors (e.g. 
ketoconazole, ritonavir) as there is potential for an increased systemic exposure to both 
fluticasone furoate and vilanterol, which could lead to an increase in the potential for 
adverse reactions.
5.6.1.
Permitted Medications and Non-Drug Therapies
The following medications are permitted during the Screening and Treatment periods:
COPD Medications

Study supplied albuterol/salbutamol (MDI or nebules) for symptomatic relief during 
the Run-In and Double-Blind Treatment period

Mucolytics at constant dosage

Oxygen for intermittent use or PRN therapy ≤ 12 hours per day is allowed. (Subjects 
requiring LTOT or nocturnal oxygen therapy required for greater than 12 hours a day 
are excluded from the study.)

Theophyllines (long and short-acting)

Short-acting anti-cholinergic agents

Long-acting anti-cholinergic agents

Short-acting beta2-agonists; i.e. albuterol

Beta2-agonist-anti-cholinergic combinations; i.e. Combivent

Subjects may take courses of systemic corticosteroids, where necessary, for treatment 
of an exacerbation.
 
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Non-COPD Medications

Cardioselective beta-blockers (stable dose) and ophthalmic beta-blockers.
(Administer with caution as they may block bronchodilatory effects of beta-agonists 
and produce severe bronchospasm).

Care is advised when co-administering with strong CYP 3A4 inhibitors (e.g. 
ketoconazole, ritonavir) as there is potential for an increased systemic exposure to 
both fluticasone furoate and vilanterol, which could lead to an increase in the 
potential for adverse reactions.

Antihistamines and nasal decongestants

Over-the-counter (OTC) cough suppressants (for short term treatment ≤7days)

Intranasal sodium cromoglycate or nedocromil sodium

Intranasal corticosteroids, provided the subject is on a stable daily dose for at least 4 
weeks prior to Visit 1 and remains on this dose throughout the study

Topical (≤1 % hydrocortisone in strength) or ophthalmic corticosteroids

Influenza and/or pneumonia vaccination

Tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs). Administer 
with caution as they may potentiate the effects of beta-agonists on the vascular 
system.

Diuretics. Caution is advised in the co-administration of beta-agonists with 
nonpotassium sparing diuretics.

Treatment(s) for smoking cessation

All medications for other disorders as long as the dose remains constant wherever 
possible.
5.6.2.
Prohibited Medications and Non-Drug Therapies
Medications prohibited at specific time intervals prior to Screening Visit 1 and at any 
time during the study are identified in Section 4.3 Exclusion Criteria.
If a subject’s current medication is going to be changed in order to participate in the 
study, then consent must be obtained prior to any medication change and the subject will 
be required to return to the clinic to complete the Screening Visit 1 once the protocol 
specified time period has been completed.
5.7.
Treatment after the End of the Study
At the end of the treatment period (Visit 14 or Early Withdrawal), subjects can resume 
conventional COPD therapy as prescribed by the Investigator.  There are no plans to 
provide the study drug for compassionate use following study completion.
 
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The investigator is responsible for ensuring that consideration has been given to the post-
study care of the patient’s medical condition whether or not GSK is providing specific 
post study treatment.
5.8.
Treatment of Study Treatment Overdose
An overdose is defined as a dose greater than what is instructed (see Section 5.1), which 
results in clinical signs and symptoms.  In the event of an overdose of study medication, 
the investigator should use clinical judgement in treating the overdose and contact the 
study medical monitor. GSK is not recommending specific treatment guidelines for 
overdose and toxicity management.  The investigator should refer to the relevant 
document(s) for detailed information regarding warnings, precautions, contraindications, 
adverse events, and other significant data pertaining to the study drug(s) being used in 
this study.  Such documents may include, but not be limited to, the approved product 
labeling for albuterol (salbutamol), and the IB or equivalent document provided by GSK 
for double blind medications.
6.
STUDY ASSESSMENTS AND PROCEDURES
The Time and Events Table is provided in Table 3.  All study assessments should be 
conducted by the investigator or his/her qualified designee. Please refer to the SPM for a 
suggested order of assessments. 
 
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Table 3
Time and Events Table
Double-Blind Treatment period
Visit Number
0
Pre-
screen1
1
Screen-
ing2
2
Random-
ization
3
4
5
6
7
8
9
10
11
12
13
14
Early 
With-
draw
15
Follow
-up
Day 1
13 
wks 
14
26 
wks 
14
39 
wks 
14
52 
wks 
14
65 
wks 
14
78 
wks 
14
91 
wks 
14
104 
wks 
14
117 
wks 
14
130 
wks 
14
143 
wks 
14
156 
wks 
14
Visit 
14/EW 
+ 7±2
Days
Days
Days
Days
Days
Days
Days
Days
Days
Days
Days
Days
Days
Assessments
Informed consent3
X
PGx Consent & 
Sampling4
X
Demography 
X
Medical History
X
Physical Exam
X
X
X
X
X
Spirometry Testing
X
X
X
X
X
X
X
X
X
Reversibility Testing
X
Smoking history/
smoking status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Smoking cessation 
counseling 
X
X
X
X
X
Register visit on 
IVRS5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety Assessments
BMD DEXA scans6
X
X
X
X
X
X
X
X
Oropharyngeal 
examination7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chest X-ray8
X
Lab Tests9 / Serum 
Pregnancy Test10
X
 
 
 
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Double-Blind Treatment period
Visit Number
0
Pre-
screen1
1
Screen-
ing2
2
Random-
ization
3
4
5
6
7
8
9
10
11
12
13
14
Early 
With-
draw
15
Follow
-up
Day 1
13 
wks 
14
26 
wks 
14
39 
wks 
14
52 
wks 
14
65 
wks 
14
78 
wks 
14
91 
wks 
14
104 
wks 
14
117 
wks 
14
130 
wks 
14
143 
wks 
14
156 
wks 
14
Visit 
14/EW 
+ 7±2
Days
Days
Days
Days
Days
Days
Days
Days
Days
Days
Days
Days
Days
12-lead ECG & 
Rhythm Strip
X
Exacerbation 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Event 
Assessment11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious Adverse 
Event Assessment12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Diary
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect/Review Diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Medication 
Assessments
Concurrent 
Medication 
Assessment13
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense albuterol 
(salbutamol)14
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Double-
Blind Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect Double-Blind 
Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Other Assessment 
Discharge from 
Study15
X
X
 
 
 
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1.
Visit 0 and Visit 1 may occur on the same day.
2.
Following Screening Visit 1, subjects enter a 14 to 21 day single-blind run-in period
3.
Subjects will be assigned a subject number at the time ICF is signed. The ICF must be signed before any study procedures including drug washout(s).  
4.
Saliva (2ml) sample is collected in the DNA self-collection kit.  This should ideally be taken as soon after randomization (Visit 2) as possible, but may be taken at any other visit 
after randomization if necessary.  PGx consent must be signed prior to PGx sampling.
5.
A telephone based IVRS system (RAMOS) which will be used by the investigator or designate to register the subject, randomize the subject and provide medication assignment 
information.
6.
Baseline BMD measurements will be collected between Visit 1 and Visit 2.
7.
If evidence of infection, culture swab may be taken and appropriate therapy should be instituted at Investigator discretion. Subjects with culture-positive infection may continue 
in the study on appropriate anti-infective treatment at Investigator discretion.
8.
Chest X-ray must be taken if a Chest X-ray or CT scan is not available within the 12 months preceding Visit 1. Chest x-rays will be requested for suspected cases of pneumonia.
9.
Non-fasting and pre-dose. Visit 2: pre-dose lab only completed if any part of Screening lab needs to be repeated
10. Females of child-bearing potential only
11. Adverse events are to be collected from the start of blinded study medication (Visit 2) until the follow-up phone contact.
12. Serious adverse events are to be collected from the start of study drug (Visit 2) until the follow-up phone contact.  However, any SAEs assessed as related to study participation 
will be recorded from the time subjects sign informed consent.
13. All COPD medications taken within 30 days prior to Visit 0 will be collected.
14. Collect and re-dispense as needed after Visit 1.
15. Discharge from study on appropriate therapy.
 
 
 
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6.1.
Critical Baseline Assessments
No study related procedures may be performed until the informed consent form 
document has been signed by the subject.  A pre-screening visit may be required in 
order to administer the informed consent before any changes are made to the subject’s 
current medication regimen. Selection and modification of subject’s medications prior to 
study participation is based on the physician’s judgment according to sound medical 
practice, principles, and each subject’s needs. A subject‘s treatment must not be changed 
merely for the purpose of enabling the subject’s participation in the study. The informed 
consent may be given at the screening visit if the subject does not take or has not taken 
any protocol excluded medications. During the pre-screening visit (Visit 0), each subject 
will have the following demographic information collected:

Demographic history (including gender, ethnic origin, date of birth)
During Screening Visit 1, each subject will undergo the following assessments:

Medical history (including COPD and smoking history)

Cardiovascular medical history/risk factors will be assessed at baseline.

Inclusion/Exclusion criteria assessment

Concomitant medication review

ECG and rhythm strip

Spirometry with reversibility testing

Physical exam (including vital signs)

Laboratory assessments (including chemistry, hematology, hepatitis, and pregnancy)
See Section 4.5 for information regarding Screening Failures.
6.2.
Safety
6.2.1.
Primary Endpoint

BMD measured at the total hip 
6.2.2.
Secondary Endpoints

BMD measured at the lumbar spine (L1-L4)

BMD measurements by gender
6.2.3.
Other Endpoints

Adverse Event reporting 

Serious Adverse Event reporting

Incidence of fractures
 
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
Incidence of pneumonias

COPD exacerbations
6.2.4.
Bone Mineral Density
Effects on the skeletal system will be assessed by measuring bone mineral density 
(BMD) using dual energy x-ray absorptiometry (DEXA) with established methodology.  
DEXA measurements of the total hip and the L1-L4 regions of the spine will be 
completed at baseline, 26 weeks, 52 weeks, 78 weeks, 104 weeks, 130 weeks, and 156 
weeks or end of study treatment.
All DEXA scans will be conducted by qualified technicians and sent electronically for 
centralized analysis.  Quality assurance and calibration of DEXA equipment and 
densitometric measurements will be monitored by this facility to control for site-to-site 
variability in BMD measurements.
Acceptable DEXA measurements must be conducted prior to the first dose of 
randomized study medication.
DEXA Assessments

At Screening, any subject with a T score < -1.5 (assessed from the L1-L4 regions of 
the spine or the total hip) will be counseled about the clinical implications of this 
value.

At any visit after randomization to double-blind treatment (Visit 2) through Visit 10, 
any subject with a bone mineral density loss of 8% from baseline (assessed from 
the L1-L4 regions of the spine or the total hip) will be counseled about the clinical 
implications of this value.

At any visit after 2 years (Visit 10), any subject with a bone mineral density loss of 
10% from baseline (assessed from the L1-L4 regions of the spine or the total hip) 
will be counseled about the clinical implications of this value.
6.2.5.
Fractures
For any fractures that occur after the initiation of the double-blind study drug, the 
location of the fracture, and whether it is considered traumatic or non-traumatic must be 
recorded on the Fractures page of the eCRF. Severity of a fracture should be determined 
by the Investigator.  Details regarding the information to be captured for fractures will be 
provided in the SPM.
6.2.6.
COPD Exacerbations and Pneumonias
For the purpose of this study, exacerbation of COPD is defined by a worsening of 
symptoms requiring additional treatment as follows:
 
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•
A mild COPD exacerbation: managed by subject with increased use of prn 
medications
•
A moderate COPD exacerbation: requires treatment with antibiotics and/or 
systemic corticosteroids
•
A severe COPD exacerbation: requires hospitalization
Any subject experiencing worsening of symptoms should:
•
Contact his/her study investigator and/or research coordinator immediately, and 
report to the study clinic as required
•
If the subject is unable to contact his/her study investigator and/or research 
coordinator, they should contact their primary care physician (or other health care 
practitioner as required) and contact their study site as soon as possible
•
If the subject seeks emergent/acute care for worsening respiratory symptoms, 
he/she should inform the caring Health Care Provider (HCP) to contact the 
investigator as soon as possible.
Subjects with presence of worsening respiratory symptoms will be classified by the 
Investigator as having:
•
A mild/moderate/severe COPD exacerbation and/or pneumonia
OR
•
A lower respiratory tract infection (LRTI) [i.e. other than pneumonia]
•
Background variability of COPD
•
A non-respiratory related disease
•
Other respiratory related disease
The time period for collection of COPD exacerbations will begin from the time of Visit 2 
(Randomization) and will end when the 7±2day Follow-up period has been completed.
Exacerbations that meet the definition of an SAE, will be recorded on the appropriate 
eCRF section and should be reported to GSK for all subjects regardless of whether or not 
they are randomized to blinded study medication.
Subjects are excluded from participating if any of the following apply:
•
They have poorly controlled COPD, defined as the occurrence of the following in 
the 12 weeks prior to Screening Visit 1: Acute worsening of COPD that is 
managed by the subject with corticosteroids or antibiotics or that requires 
treatment prescribed by a physician or requires hospitalization.
 
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•
They have 2 or more moderate or severe COPD exacerbations and/or a lower 
respiratory tract infection (including pneumonia) within the 12 months prior to 
Screening Visit 1 or experience a moderate or severe COPD exacerbation and/or a 
lower respiratory infection (including pneumonia) during the Run-In period.
The dates of onset and resolution of each COPD exacerbation should be based on when 
the Investigator and/or subject determines that the COPD symptoms initially started and 
then returned to pre-exacerbation levels.
If an exacerbation begins as mild, but becomes moderate or severe or begins as moderate 
and becomes severe, the exacerbation should be captured as one exacerbation and 
classified by its highest level of severity.
For the purpose of this study, pneumonia is defined as new auscultatory findings 
compatible with parenchymal lung infection and/or radiographic evidence of 
parenchymal/air space disease. All suspected cases of pneumonia are encouraged to be 
confirmed radiographically within 48 hours of diagnosis. All diagnoses of pneumonia 
(radiographically confirmed or unconfirmed) must be reported as an AE or SAE (if 
applicable). Information regarding chest X-ray-confirmed cases of pneumonia will be 
recorded in the eCRF. Details regarding the information to be captured for pneumonias 
will be provided in the SPM.
Definitions for COPD exacerbations and pneumonia are given above. If, based upon 
these criteria, a subject’s symptoms do not fulfill the diagnosis of an exacerbation and/or 
pneumonia, then the investigator should use his/her clinical judgment to assess the 
subject’s symptoms (including increased volume of sputum production and/or change in 
the sputum color) for a diagnosis of LRTI (e.g. acute bronchitis), background variability 
of COPD, a non-respiratory related disease or other respiratory related disease.
Investigator judgment should be used in deciding whether to report the signs and 
symptoms (and/or determined diagnosis) as an AE/SAE in the eCRF. Medication(s) used 
to treat a COPD exacerbation and/or pneumonia are to be recorded in the eCRF.
6.2.7.
Liver chemistry stopping and follow up criteria
Phase III-IV liver chemistry stopping and follow up criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance).  
Phase III-IV liver chemistry stopping criteria 1-5 are defined below and in Appendix 4:
1. ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) (or ALT 3xULN and
INR>1.5, if INR measured)
NOTE: if serum bilirubin fractionation is not immediately available, withdraw study drug
for that subject if ALT 3xULN and bilirubin 2xULN. Serum bilirubin fractionation 
should be performed if testing is available. If testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and 
suggesting liver injury.
 
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2. ALT 8xULN.
3. ALT 5xULN but <8 xULN persists for 2 weeks
4. ALT  3xULN if associated with symptoms (new or worsening) believed to be related 
to hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
or jaundice) or hypersensitivity (such as fever, rash or eosinophilia).
5. ALT 5xULN but <8 xULN and cannot be monitored weekly for 2 weeks
When any of the liver chemistry stopping criteria 1-5 is met, do the following:

Immediately withdraw investigational product for that subject

Report the event to GSK within 24 hours of learning its occurrence

Complete the liver event CRF and SAE data collection tool if the event also meets 
the criteria for an SAE. All events of ALT 3xULN and bilirubin 2xULN (>35% 
direct) (or ALT 3xULN and INR>1.5, if INR measured); INR measurement is not 
required and the threshold value stated will not apply to patients receiving 
anticoagulants), termed ‘Hy’s Law’, must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis). 
NOTE: if serum bilirubin fractionation is not immediately available, withdraw study drug
for that subject if ALT 3xULN and bilirubin 2xULN. Serum bilirubin fractionation 
should be performed if testing is available. If testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and 
suggesting liver injury.

Complete the liver imaging and/or liver biopsy CRFs if these tests are performed

Perform liver event follow up assessments, and monitor the subject until liver 
chemistries resolve, stabilize, or return to baseline values as described below. 

Withdraw the subject from the study after completion of the liver chemistry 
monitoring (unless further safety follow up is required).

Do not restart investigational product.  
In addition, for criterion 1:

Make every reasonable attempt to have subjects return to clinic within 24 hours for 
repeat liver chemistries, liver event follow up assessments (see below), and close 
monitoring

A specialist or hepatology consultation is recommended

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values
For criteria 2, 3, 4 and 5:

Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for 
repeat liver chemistries and liver event follow up assessments (see below)
 
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
Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values; criterion 5 subjects 
should be monitored as frequently as possible.
Subjects with ALT 5xULN and <8xULN which exhibit a decrease to ALT x3xULN, 
but <5xULN and bilirubin <2xULN without hepatitis symptoms or rash, and who can be 
monitored weekly for 4 weeks:

Notify the GSK medical monitor within 24 hours of learning of the abnormality to 
discuss subject safety

Can continue investigational product 

Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize or return to within baseline 

If at any time these subjects meet the liver chemistry stopping criteria, proceed as 
described above

If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within baseline 
values. 
For criteria 1-5, make every attempt to carry out the liver event follow up assessments
described below:

Viral hepatitis serology including:

Hepatitis A IgM antibody;

Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 

Hepatitis C RNA; 

Cytomegalovirus IgM antibody;  

Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  

Hepatitis E IgM antibody 

Blood sample for PK analysis, obtained within 72 hours of last dose.  Record the 
date/time of the PK blood sample draw and the date/time of the last dose of 
investigational product prior to blood sample draw on the CRF. If the date or time of 
the last dose is unclear, provide the subject’s best approximation. If the date/time of 
the last dose cannot be approximated OR a PK sample cannot be collected in the 
time period indicated above, do not obtain a PK sample. Instructions for sample 
handling and shipping are in the SPM. 

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin 2xULN.

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
Record the appearance or worsening of clinical symptoms of hepatitis or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever rash or eosinophilia as relevant on the AE report form.

Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins, on the concomitant medications 
report form.

Record alcohol use on the liver event alcohol intake case report form.
The following are required for subjects with ALT 3xULN and bilirubin 2xULN (>35% 
direct) but are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies.

Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with definite or likely acetaminophen use in 
the preceding week [James, 2009]). NOTE: not required in China.

Only in those with underlying chronic hepatitis B at study entry (identified by 
positive hepatitis B surface antigen):  quantitative hepatitis B DNA and hepatitis 
delta antibody.  NOTE:  if hepatitis delta antibody assay cannot be performed,, it can 
be replaced with a PCR of hepatitis D RNA virus (where needed) – as outlined in: 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1153793/.

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease.
6.2.8.
Adverse Events
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
AEs will be collected from the start of double-blind Investigational Product and until the 
follow up contact.  
COPD exacerbations should not be recorded as an adverse event, unless they meet the 
definition of a Serious Adverse Event.  For the purposes of this study, COPD 
exacerbations will be collected and recorded on the COPD exacerbation log in the eCRF.  
The time period for collection of COPD exacerbations will begin from the time of Visit 2 
(Randomization) and will end when the 7-day Follow-up period has been completed.
The investigators and site staff should remain vigilant for the possible development of 
pneumonia in patients with COPD as the clinical features of such infections overlap with 
the symptoms of COPD exacerbations. Risk factors for pneumonia in patients with 
COPD receiving fluticasone furoate/vilanterol include current smokers, patients with a 
history of prior pneumonia, patients with a body mass index <25 kg/m2 and patients with 
an FEV1<50% predicted.  For all suspected cases of pneumonia, Investigators are
encouraged to confirm the diagnosis (this includes obtaining a chest x-ray) and to initiate 
appropriate therapy as promptly as possible. All diagnoses of pneumonia 
(radiographically confirmed or unconfirmed) must be reported as an AE or SAE (if 
applicable).
 
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All AEs and SAEs will be followed until resolution, until the condition stabilizes, until 
the event is otherwise explained, or until the subject is lost to follow-up.  Once resolved, 
the appropriate AE/SAE CRF page will be updated.  The investigator will ensure that 
follow-up includes any supplemental investigations as may be indicated to elucidate the 
nature and/or causality of the AE or SAE.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care 
professionals.
6.2.8.1.
Definition of an AE
Any untoward medical occurrence in a patient or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.  For marketed medicinal products, this 
also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.
Events meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study

Signs, symptoms, or the clinical sequelae of a suspected interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE) unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae.
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfil the definition of an AE or 
SAE.  
Events that do not meet the definition of an AE include:

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital)

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen
 
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
The disease/disorder being studied, or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition
6.2.8.2.
Definition of a SAE
A serious adverse event is any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:  In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity, or
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption.
e.
Is a congenital anomaly/birth defect
f.
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.  Examples of such events are invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
g.
All events of possible drug-induced liver injury with hyperbilirubinaemia defined as 
ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 3xULN and 
INR>1.5, if INR measured) termed ‘Hy’s Law’ events (INR measurement is not 
 
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required and the threshold value stated will not apply to patients receiving 
anticoagulants).
NOTE: bilirubin fractionation is performed if testing is available. If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick indicating 
direct bilirubin elevations and suggesting liver injury. If testing is unavailable and a 
subject meets the criterion of total bilirubin 2xULN, then the event is still reported 
as an SAE. If INR is obtained, include values on the SAE form. INR elevations >1.5 
suggest severe liver injury.   
6.2.9.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), 
including those that worsen from baseline, and felt to be clinically significant in the 
medical and scientific judgement of the investigator are to be recorded as AEs or SAEs.
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject’s condition, are not to be reported as AEs or SAEs.
6.2.10.
Cardiovascular Events
Investigators will be required to fill out event specific data collection tools for the 
following AEs and SAEs:  

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thrombosis

Deep Venous Thrombosis

Revascularization
This information should be recorded within one week of when the AE/SAE(s) are first 
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6.2.11.
Death Events
In addition, all deaths, whether or not they are considered SAEs, will require a specific 
death data collection tool to be completed.  The death data collection tool includes 
questions regarding cardiovascular (including sudden cardiac death) and 
noncardiovascular death.
This information should be recorded within one week of when the death is first reported.
6.2.12.
Pregnancy
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form.  To ensure subject safety, each pregnancy must be reported to GSK 
within 2 weeks of learning of its occurrence.  The pregnancy must be followed up to 
determine outcome (including premature termination) and status of mother and child.  
Pregnancy complications and elective terminations for medical reasons must be reported 
as an AE or SAE.  Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy, brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to GSK.
6.2.13.
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
AEs will be collected from the start of study treatment and until the follow up contact.  
SAEs will be collected over the same time period as stated above for AEs. However, any 
SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant 
medication, will be recorded from the time a subject consents to participate in the study 
up to and including any follow up contact. All SAEs will be reported to GSK within 24 
hours, as indicated in Section 6.2.14. 
6.2.14.
Prompt Reporting of Serious Adverse Events and Other Events 
to GSK
SAEs, pregnancies, and liver function abnormalities meeting pre-defined criteria will be 
reported promptly by the investigator to GSK as described in the following table once the 
investigator determines that the event meets the protocol definition for that event.
 
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Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
“SAE” data 
collection tool
“CV events” 
and/or “death” 
data collection 
tool(s) if 
applicable
24 hours
Updated “SAE” 
data collection tool
“CV events” and/or 
“death” data 
collection tool(s) if 
applicable
Pregnancy
2 weeks
“Pregnancy 
Notification Form”
2 weeks
“Pregnancy Follow-
up Form”
Non-serious adverse 
events related to 
study treatment
5 calendar 
days
“Adverse 
Reaction” data 
collection tool
2 weeks
Updated “Adverse 
Reaction” data 
collection tool
Liver chemistry abnormalities for Phase I to IV:
ALT3xULN and
Bilirubin2xULN 
(>35% direct) (or 
ALT3xULN and
INR>1.5, if INR 
measured)1
24 hours2
“SAE” data 
collection tool.  
“Liver Event CRF” 
and “Liver 
Imaging” and/or 
“Liver Biopsy” 
CRFs, if 
applicable3
24 hours
Updated “SAE” 
data collection 
tool/“Liver Event” 
Documents3
Remaining liver chemistry abnormalities Phase III to IV:
ALT8xULN; 
ALT3xULN with 
hepatitis or rash or 
3xULN and <5xULN 
that persists4 weeks
24 hours2
“Liver Event” 
Documents 
(defined above) 3
24 hours
Updated “Liver 
Event” Documents3
ALT5xULN plus 
bilirubin <2xULN
24 hours2
“Liver Event” 
Documents 
(defined above) 
do not need 
completing unless 
elevations persist 
for 2 weeks or 
subject cannot be 
monitored weekly 
for 2 weeks3
24 hours
Updated “Liver 
Event” Documents, 
if applicable3
ALT5xULN and 
bilirubin <2xULN that 
persists 2 weeks
24 hours2
“Liver Event” 
Documents 
(defined above) 3
24 hours
Updated “Liver 
Event” Documents3
 
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ALT3xULN and <5x 
ULN and bilirubin 
<2xULN
24 hours2
“Liver Event” 
Documents 
(defined above) 
do not need 
completing unless 
elevations persist 
for 4 weeks or 
subject cannot be 
monitored weekly 
for 4 weeks3
24 hours
Updated “Liver 
Event” Documents, 
if applicable3
1.
INR measurement is not required; if measured, the threshold value stated will not apply to patients receiving 
anticoagulants.
2.
GSK must be contacted at onset of liver chemistry elevations to discuss subject safety
3.
Liver Event Documents (i.e., “Liver Event CRF” and “Liver Imaging CRF” and/or “Liver Biopsy CRF”, as 
applicable) should be completed as soon as possible.
The method of detecting, recording, evaluating and follow-up of AEs and SAEs plus 
procedures for completing and transmitting SAE reports to GSK are provided in the 
SPM. Procedures for post-study AEs/SAEs are provided in the SPM.
6.2.14.1.
Regulatory reporting requirements for SAEs
Prompt notification of SAEs by the investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
6.2.15.
SpirometryTesting
Lung function will be measured by spirometry at Visits 1, 2, 4, 6, 8, 10, 12, and 14, or at 
Early Withdrawal using site available spirometry equipment that meets or exceeds the 
minimum performance recommendations of the ATS/ERS [Miller, 2005].  For Visits 2 
onward, FEV1 will be measured prior to administration of morning study medication.
For each observation, at least 3 valid (with no more than 8) efforts will be obtained using 
ATS/ERS guidelines.  The largest FEV1 and FVC from the 3 acceptable efforts should be 
 
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recorded, even if they do not come from the same effort. Acceptable spirometry efforts 
should have a satisfactory start of test and end of test (i.e. a plateau in the volume-time 
curve) and be free from artifacts due to cough, early termination, poor effort, obstructed 
mouthpiece, equipment malfunction, or other reasons [Miller, 2005]. The subject’s 
position during spirometry measurements (sitting or standing) should remain constant for 
the duration of the study.
A post-albuterol (salbutamol) FEV1/FVC ratio of < 0.70 and predicted normal value of 
50% ≤ FEV1 ≤ 70% is required at Screening Visit 1.  
All predicted values will be taken from Hankinson [Hankinson, 1999].
The investigator will retain a printed copy of the spirometry data in the subject’s source 
documents.
6.2.15.1.
Reversibility Testing
At Visit 1, reversibility to albuterol (salbutamol) will be assessed. To determine 
reversibility, the subject will self-administer 4 puffs (360mcg) of albuterol (salbutamol) 
without the use of a spacer or holding chamber. Triplicate spirometry efforts will be 
performed immediately pre-albuterol (salbutamol) and within 30 minutes post-albuterol 
(salbutamol). The highest FEV1 from three valid forced expiratory curves will be used to 
determine reversibility.
Reversibility is defined as an increase in FEV1 of ≥12% and ≥200mL following 
administration of albuterol (salbutamol).  Non-reversible is defined as a post-albuterol 
(salbutamol) increase in FEV1 of <200mL or a ≥200mL increase that is <12% from pre-
albuterol (salbutamol) FEV1.
6.2.16.
Laboratory Assessments
Routine, non-fasting clinical laboratory (hematology and biochemistry), will be 
performed in all subjects at the Screening Visit 1.  
For women of childbearing potential, a serum pregnancy test will be included in the 
laboratory panel collected at Visit 1 if applicable.  
At the discretion of the investigator, additional samples may be taken for safety reasons.  
If the subject has an abnormal laboratory finding for any analyte from the Screening Visit 
laboratory panel, which in the opinion of the Investigator does not preclude the subject 
from participating in the study, but for which the Investigator feels warrants 
treatment/correction with a non-excluded medication(s) (e.g., calcium supplement for 
hypocalcemia), a blood sample for repeat analysis of the analyte(s) should be collected 
pre-dose at Visit 2 (Randomization)
All protocol required laboratory assessments, as defined in Appendix 1 must be 
performed by the central laboratory. Laboratory assessments must be conducted in 
accordance with the Central Laboratory Manual and Protocol Time and Events Schedule.
Laboratory requisition forms must be completed and samples must be clearly labelled 
 
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with the subject number, protocol number, site/center number, and visit date. Details for 
the preparation and shipment of samples will be provided by the central laboratory.
Reference ranges for all safety parameters will be provided to the site by the central 
laboratory.
6.2.17.
Oropharyngeal Examination
Oropharyngeal examinations for clinical evidence of infection (i.e., Candida albicans) 
will be performed at each study visit as shown in the Time and Events Table. If there is 
evidence of infection, a culture swab may be taken and appropriate therapy should be 
instituted at the discretion of the Investigator. Subjects with culture-positive infection 
may continue in the study on appropriate anti-infective treatment at the discretion of the 
Investigator. The results of these assessments, and any relative pharmacotherapy, will be 
recorded in the subject’s clinic notes and in the eCRF. After randomization, all culture 
positive results must be reported as adverse events.
6.2.18.
Diary Card - Medical Problems/Medications Taken
Subjects will be instructed to record any medical problems they may have experienced 
and any medications used to treat those medical problems in their diaries from Screening 
(Visit 1) through the Follow-up Phone Contact.  
Subjects will be instructed on how to complete the diary and will be asked to return 
completed diaries at each clinic visit.  The study coordinator must review the diary at 
each clinic visit and will inquire about the diary data during the Follow-up Phone Contact 
as well.  If the subject does not mention an event which is recorded on the diary, he/she 
should be questioned for further information in order to determine if there was the 
occurrence of an AE.  Any confirmed AE and/or concurrent medication will be entered 
into the eCRF.
6.2.19.
12-lead ECG Assessment
A single 12-lead ECG and rhythm strip will be recorded prior to spirometry at the 
Screening Visit 1.
All ECG measurements will be performed with the subject resting in a supine position for 
approximately 5 minutes before each reading, which should be carried out after 
measurement of vital signs and before spirometry.
The investigator, a designated sub-investigator, or other appropriately trained site 
personnel, will be responsible for performing the 12-lead ECG recording on each study 
visit, if applicable.  The investigator must provide his/her dated signature on the original 
paper tracing, attesting to the authenticity of the ECG machine interpretation.
6.2.20.
Smoking Cessation Counselling
During the Screening Visit 1, 6, 10, and 14 or EW visit (if necessary), subjects will be 
given smoking cessation counselling, which includes advice regarding the following:
 
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
the health effects that smoking may cause.

the health benefits that may result if they stop smoking.

if they do not feel capable of discontinuing smoking that their primary care physician 
may be able to discuss anti-smoking strategies with them. 

that they may discontinue smoking at any time during the study and will not have to 
be withdrawn from the study if they do so.  
6.3.
Pharmacogenetic Research
Information regarding pharmacogenetic research is included in Appendix 2.  The 
IEC/IRB and, where required, the applicable regulatory agency must approve the PGx 
assessments before these can be conducted at the site.  The approval(s) must be in writing 
and will clearly specify approval of the PGx assessments.  In some cases, approval of the 
PGx assessments can occur after approval is obtained for the rest of the study.  If so, then 
the written approval will clearly indicate approval of the PGx assessments is being 
deferred and the study, except for PGx assessments, can be initiated.  When PGx 
assessments will not be approved, then the approval for the rest of the study will clearly 
indicate this and therefore, PGx assessments will not be conducted.
7.
DATA MANAGEMENT
For this study subject data will be entered into GSK defined eCRFs, transmitted 
electronically to GSK and combined with data (e.g. laboratory data, diary data) provided 
from other sources in a validated data system.
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.  Adverse events and concomitant medications 
terms will be coded using MedDRA and an internal validated medication dictionary, 
GSKDrug.  An appropriate medical dictionary that covers all approved drugs in the 
region will be referenced. eCRFs (including queries and audit trails) will be retained by 
GSK, and copies will be sent to the investigator to maintain as the investigator copy. In 
all cases, subject initials will not be collected or transmitted to GSK according to GSK 
policy.
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
8.1.
Hypotheses
The null hypothesis for the primary measure is that the change in BMD assessed at the 
total hip is worse for the FF/VI combination product arm compared with the VI arm. The 
alternative hypothesis that the change in BMD assessed at the total hip is not worse for 
the FF/VI arm compared with the VI arm.
This is also the null and alternative hypothesis for the secondary measure of BMD 
assessed at the L1-L4 lumbar spine.
 
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8.2.
Study Design Considerations
8.2.1.
Sample Size Assumptions
This study will evaluate non-inferiority in both males and females separately as key 
secondary measures.  56 subjects per gender per treatment would provide 80% power to 
demonstrate non-inferiority by comparing the lower boundary of a two-sided 95% 
confidence interval on the treatment difference to -1%/year assuming a true treatment 
difference of -0.3%/year.  In study SCO40041, approximately 20% of subjects did not 
provide post-baseline data, therefore 70 subjects per gender per treatment will be 
randomized (280 total subjects).  Randomization will be stratified by gender.
For the primary evaluation of BMD for the total hip, males and females will be 
combined, and will have >90% power to demonstrate non-inferiority by comparing the 
lower boundary of a two-sided 95% confidence interval on the treatment difference to      
-1%/year assuming a true treatment difference of -0.3%/year.
8.2.2.
Sample Size Sensitivity
The following table presents the power of the study under different circumstances in 
terms of the standard deviation and the observed treatment difference in change from 
baseline in bone mineral density for the total hip.
True Treatment Difference between FF/VI and VI
SD
-0.2%/yr
-0.3%/yr
-0.4%/yr
1.3%/yr
>99%
99%
96%
1.4%/yr
>99%
98%
94%
1.5%/yr
>99%
97%
91%
8.2.3.
Sample Size Re-estimation
No sample size re-estimation is planned for this study.
8.3.
Data Analysis Considerations
8.3.1.
Analysis Populations
All Subjects Enrolled Population: This population will consist of all subjects, for whom a 
record exists on the study database, including screen failures and any subject who was 
not screened but signed the informed consent form. This population will be used for 
reporting subject disposition, reasons for withdrawal prior to randomisation, and 
inclusion, exclusion and randomisation criteria deviations and SAEs for non-randomised 
subjects.
(Modified) Intent-to-Treat (ITT) Population: This population will consist of all subjects 
who are randomised and receive at least one dose of study drug. The ITT Population will 
be the primary population for all analyses of safety and efficacy measures.
 
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8.3.2.
Analysis Data Sets
The bone mineral density data will comprise the primary data set of interest.  Details of 
derived data in analysis datasets to be created will be provided in the Reporting and 
Analysis Plan (RAP).
8.3.3.
Treatment Comparisons
8.3.3.1.
Primary Comparisons of Interest
BMD measured for the total hip will be summarized by visit and as change from baseline 
at each visit for raw values, percent changes from baseline, t-scores, and z-scores.  The 
percent change from baseline in BMD for the total hip will be the primary endpoint, and 
analyzed using a repeated measures model with terms for treatment, time, time by 
treatment, baseline BMD, baseline BMI and gender.  Contrasts will be formed using the 
time by treatment variable to provide 95% confidence intervals for the treatment 
difference with the unit of percent change per year.  The 95% confidence interval will be 
compared to a lower bound of -1%/year in order to assess clinical non-inferiority.  Any 
additional covariates for the model, along with other details, including model inclusion 
and exclusion criteria for those covariates, will be determined a priori in a detailed 
Reporting and Analysis Plan (RAP) that will be completed prior to unblinding of the 
study.
The percent change from baseline in BMD at the L1-L4 region of the spine will also by 
summarized and analyzed in the same manner as the BMD data for the total hip.
8.3.4.
Interim Analysis
No interim analysis is planned for this study.
8.3.5.
Key Elements of Analysis Plan
8.3.5.1.
Efficacy Analyses
No efficacy analyses are planned for this study
8.3.5.2.
Safety Analyses
8.3.5.2.1.
Extent of Exposure
The extent of exposure to study drug will be summarized by treatment group.
8.3.5.2.2.
Adverse Events (AEs)
AEs will be coded using the standard GSK dictionary, Medical Dictionary for Regulatory 
Activities (MedDRA), and grouped by body system. AEs occurring pre-treatment, during 
active treatment and post-treatment will be summarized separately. The number and 
percentage of subjects experiencing at least one AE of any type, AEs within each body 
system and AEs within each preferred term will be presented for each treatment group. 
 
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Separate summaries will be provided for all AEs, drug related AEs, SAEs, and for AEs 
leading to withdrawal.
8.3.5.2.3.
Deaths and SAEs
All SAEs will be listed by treatment group. Deaths and SAEs will be documented in case 
narrative format.
8.3.5.2.4.
Fractures
The number and percent of patients experiencing a bone fracture during the study will be 
summarized.
8.3.5.2.5.
COPD Exacerbations and Pneumonias
The number of moderate or severe COPD exacerbations and the percent of patients 
experiencing moderate or severe COPD exacerbations will be summarized.
8.3.5.3.
Pharmacogenetic Analyses
See Appendix 2: Pharmacogenetic Research for details about the Pharmacogenetics 
Analysis Plan.
9.
STUDY CONDUCT CONSIDERATIONS
9.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins.
9.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a study site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the ethical principles that are outlined in the Declaration of Helsinki
2008, including, but not limited to:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments.

Subject informed consent.

Investigator reporting requirements.
 
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GSK will provide full details of the above procedures, either verbally, in writing, or both.
Written informed consent must be obtained from each subject prior to participation in the 
study.
No study related procedures may be performed until the informed consent form 
document has been signed by the subject.  A pre-screening visit may be required in 
order to administer the informed consent before any changes are made to the subject’s 
current medication regimen. The informed consent may be given at Screening (Visit 1) if 
the subject does not take or has not taken any protocol excluded medications.
In approving the clinical protocol the IEC/IRB and, where required, the applicable 
regulatory agency are also approving the optional assessments e.g., PGx assessments 
described in Appendix 2, unless otherwise indicated.  Where permitted by regulatory 
authorities, approval of the optional assessments can occur after approval is obtained for 
the rest of the study.  If so, then the written approval will clearly indicate approval of the 
optional assessments is being deferred and the study, except for the optional assessments, 
can be initiated.  When the optional assessments are not approved, then the approval for 
the rest of the study will clearly indicate this and therefore, the optional assessments will
not be conducted.
9.3.
Quality Control (Study Monitoring)
In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK 
requirements.  When reviewing data collection procedures, the discussion will include 
identification, agreement and documentation of data items for which the CRF will serve 
as the source document.
GSK will monitor the study to ensure that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
9.4.
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of 
the study. In the event of an assessment, audit or inspection, the investigator (and 
institution) must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to 
all relevant documents and to allocate their time and the time of their staff to discuss the 
 
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conduct of the study, any findings/relevant issues and to implement any corrective and/or 
preventative actions to address any findings/issues identified.
9.5.
Study and Site Closure
Upon completion or termination of the study, the GSK monitor will conduct site closure 
activities with the investigator or site staff (as appropriate), in accordance with applicable 
regulations, GCP, and GSK Standard Operating Procedures.
GSK reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe non-
compliance.  If GSK determines that such action is required, GSK will discuss the 
reasons for taking such action with the investigator or head of the medical institution 
(where applicable).  When feasible, GSK will provide advance notice to the investigator 
or head of the medical institution of the impending action.
If a study is suspended or terminated for safety reasons, GSK will promptly inform all 
investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study.  GSK will also promptly inform the relevant regulatory authorities 
of the suspension/termination along with the reasons for such action.  Where required by 
applicable regulations, the investigator or head of the medical institution must inform the 
IRB/IEC promptly and provide the reason(s) for the suspension/termination.
9.6.
Records Retention
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere) in a safe and secure location.  The records must 
be easily accessible when needed (e.g., for a GSK audit or regulatory inspection) and 
must be available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned,
electronic); however, caution must be exercised before such action is taken.  The 
investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original.  In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required.  The investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions.
GSK will inform the investigator of the time period for retaining the site records in order 
to comply with all applicable regulatory requirements.  The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, GSK standard operating procedures, and/or institutional requirements.
The investigator must notify GSK of any changes in the archival arrangements, including, 
but not limited to archival of records at an off-site facility or transfer of ownership of the 
records in the event that the investigator is no longer associated with the site.
 
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9.7.
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as
appropriate.
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
GSK aims to post a results summary to the GSK Clinical Study Register and other 
publicly available registers no later than 8 months after the last subject’s last visit (LSLV) 
[this applies to each data analysis phase for studies with multiple phases, e.g., primary 
analysis, follow up analysis etc]. In addition, the aim is to submit a manuscript to a peer-
reviewed journal for publication within 18 months of LSLV. GSK also aims to publish 
the full study protocol on the GSK Clinical Study Register at the time the results of the 
study are published as a manuscript in the scientific literature. 
When manuscript publication in a peer-reviewed journal is not feasible, further study 
information will be posted to the GSK Clinical Study Register to supplement the results 
summary.
9.8.
Independent Data Monitoring Committee (IDMC)
There is no IDMC in this study.
 
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10.
REFERENCES
Calverley PM, Anderson JA, Celli B. Salmeterol and fluticasone propionate and survival 
in chronic obstructive pulmonary disease. NEJM. 2007;356:775-89.
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.
Chapman KR, Mannino DM, Soriano JB, Vermeire PA, Buist AS, Thun MJ, Connell C. 
Epidemiology and costs of chronic obstructive pulmonary disease. Eur Respir J. 
2006;27:188-207.
Ferguson GT, Anzueto A, Fei R, Emmett A, Knobil K, Kalberg C.  Effect of fluticasone 
propionate/salmeterol (50/250g) or salmeterol (50 g) on COPD exacerbations. Resp 
Med. 2008;102:1099-1108.
GOLD. Global Initiative for Chronic Obstructive Lung Disease. Executive Summary: 
Global strategy for the diagnosis, management, and prevention of chronic obstructive 
pulmonary disease (Updated 2010).  http://www.gold.copd.org
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of 
the general US population.  Am J Resp Crit Care Med. 1999;159:179-187.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37: 1779-1784. 
Kardos P, Wencker M, Glaab T. Impact of Fluticasone Propionate/Salmeterol versus 
salmeterol on exacerbations in severe chronic obstructive pulmonary disease. Am J Resp 
Crit Care Med. 2007;175:144-149.
Lopez AD, Shibuya K, Rao C, Mathers CD, Hansell AL, Held LS, Schmid V, Buist S. 
Chronic obstructive pulmonary disease: current burden and future projections. Eur Respir 
J. 2006;27:397-412.
Miller MR, Hankinson J, Brusasco Vet al. Standardisation of spirometry. Eur Respir J. 
2005;26:319-338.
WHO. Chronic Obstructive Pulmonary Disease (COPD). Burden of COPD. WHO. 2010.
 
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11.
APPENDICES
11.1.
Appendix 1: Laboratory Assessments
Refer to the Time and Events Table 3 for information regarding the timing of laboratory 
tests.
CHEMISTRY
HEMATOLOGY 
OTHER
Albumin 
Hemoglobin
Hepatitis B surface antigen1
Alkaline phosphatase 
Hematocrit
Hepatitis C virus antibody1
Alanine amino-transferase (ALAT or SGPT)
Platelet count
Urine pregnancy test (in 
clinic/home test)2
Aspartate amino-transferase (ASAT or 
SGOT)
WBC count
Fungal culture of oral mucosa (if 
visual evidence of candidiasis )
Bilirubin, direct
Neutrophils, absolute
hCG qualitative (serum 
pregnancy)2 
Bilirubin, indirect
Neutrophils, segs (%)
Bilirubin, total
Neutrophils, bands 
(%)
Calcium
Basophils (%)
Chloride
Eosinophils (%)
CO2 content/Bicarbonate
Eosinophils , absolute
Creatinine
Lymphocytes (%)
Creatine phosphokinase (CPK), total
Monocytes (%)
Gamma glutamyl transferase (GGT)
Glucose
Phosphorus 
Potassium
Protein, total serum
Sodium
Urea nitrogen (BUN)
Uric Acid 
1.
Assessed at Visit 1 (Screening) only, result is not exclusionary
2.
Only females of child-bearing potential; refer to Time and Events Table for specific visit information
11.2.
Appendix 2: Pharmacogenetic Research
Pharmacogenetics – Background
Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary 
factors in populations.  There is increasing evidence that an individual's genetic 
background (i.e., genotype) may impact the pharmacokinetics (absorption, distribution, 
metabolism, elimination), pharmacodynamics (relationship between concentrations and 
pharmacologic effects or the time course of pharmacologic effects) and/or clinical 
outcome (in terms of efficacy and/or safety and tolerability).  Some reported examples of 
PGx associations with safety/adverse events include:
 
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Drug
Disease
Gene Variant
Outcome
Abacavir
HIV 
[Hetherington, 2002; 
Mallal, 2002; 
Mallal, 2008]
HLA-B* 5701
Carriage of the HLA-B*5701 variant has been shown to 
increase a patient's risk for experiencing 
hypersensitivity to abacavir.  Prospective HLA-B*5701 
screening and exclusion of HLA-B*5701 positive 
patients from abacavir treatment significantly decreased 
the incidence of abacavir hypersensitivity.  Treatment 
guidelines and abacavir product labeling in the United 
States and Europe now recommend (US) or require 
(EU) prospective HLA-B*5701 screening prior to 
initiation of abacavir to reduce the incidence of abacavir 
hypersensitivity.  HLA-B*5701 screening should 
supplement but must never replace clinical risk 
management strategies for abacavir hypersensitivity.
Carbamazepin
e
Seizure, Bipolar 
disorders & 
Analgesia Chung, 
2010; Ferrell, 2008
HLA-B*1502
Independent studies indicated that patients carrying 
HLA-B*1502 are at higher risk of Stevens-Johnson 
Syndrome and toxic epidermal necrolysis and that this 
marker is prevalent in some populations, particularly 
with Asian ancestry.  Regulators, including the US FDA 
and the Taiwanese TFDA, have updated the 
carbamazepine drug label to indicate that patients with 
ancestry in genetically at risk populations should be 
screened for the presence of HLA-B*1502 prior to 
initiating treatment with carbamazepine.
Irinotecan
Cancer [Innocenti, 
2004; Liu, 2008; 
Schulz, 2009]
UGT1A1*28
Variations in the UGT1A1 gene can influence a 
patient’s ability to break down irinotecan, which can 
lead to increased blood levels of the drug and a higher 
risk of side effects. A dose of irinotecan that is safe for 
one patient with a particular UGT1A1 gene variation 
might be too high for another patient without this 
variation, raising the risk of certain side-effects, that 
include neutropenia following initiation of Irinotecan 
treatment.  The irinotecan drug label indicates that 
individuals who have two copies of the UGT1A1*28 
variant are at increased risk of neutropenia.  A genetic 
blood test is available that can detect variations in the 
gene.    
A key component to successful PGx research is the collection of samples during the 
conduct of clinical studies.
Collection of whole blood samples, even when no a priori hypothesis has been identified, 
may enable PGx analysis to be conducted if at any time it appears that there is a potential 
unexpected or unexplained variation in response to FF/VI Inhalation Powder. 
Pharmacogenetic Research Objectives
The objective of the PGx research (if there is a potential unexpected or unexplained 
variation) is to investigate a relationship between genetic factors and response to FF/VI 
Inhalation Powder.  If at any time it appears there is potential variability in response in 
this clinical study or in a series of clinical studies with FF/VI Inhalation Powder, the 
following objectives may be investigated – the relationship between genetic variants and 
study treatment with respect to:
 
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
Relationship between genetic variants and the pharmacokinetics and/or 
pharmacodynamics of investigational product

Relationship between genetic variants and safety and/or tolerability of investigational 
product

Relationship between genetic variants and efficacy of investigational product
Study Population
Any subject who is enrolled in the clinical study, can participate in PGx research.  Any 
subject who has received an allogeneic bone marrow transplant must be excluded from 
the PGx research.
Subject participation in the PGx research is voluntary and refusal to participate will not 
indicate withdrawal from the clinical study or result in any penalty or loss of benefits to 
which the subject would otherwise be entitled.
Study Assessments and Procedures
Saliva samples can be taken for Deoxyribonucleic acid (DNA) extraction and used in 
PGx assessments.
No additional whole blood samples will be necessary for the PGx analysis. Saliva (2mL) 
is collected into the DNA self-collection kit. A single sample will be taken but can be 
duplicated if the first sample is unusable. It is recommended that the saliva sample be 
collected at Visit 2.  

The PGx sample is labelled (or “coded”) with a study specific number that can be 
traced or linked back to the subject by the investigator or site staff.  Coded samples 
do not carry personal identifiers (such as name or social security number).  The 
saliva sample is taken on a single occasion unless a duplicate sample is required due 
to inability to utilize the original sample.  
The DNA extracted from the saliva sample may be subjected to sample quality control 
analysis.  This analysis will involve the genotyping of several genetic markers to confirm 
the integrity of individual samples.  If inconsistencies are noted in the analysis, then those 
samples may be destroyed.
The need to conduct PGx analysis may be identified after a study (or a set of studies) of 
FF/VI Inhalation Powder has been completed and the clinical study data reviewed.  In 
some cases, the samples may not be studied. e.g., no questions are raised about how 
people respond to FF/VI Inhalation Powder.
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will use samples collected from the study for 
the purpose stated in this protocol and in the informed consent form.  
Subjects can request their sample to be destroyed at any time.
 
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Subject Withdrawal from Study
If a subject who has consented to participate in PGx research and has had a sample taken 
for PGx research withdraws from the clinical study for any reason other than lost to 
follow-up, the subject will be given the following options:

Retain the sample for PGx research 

Destroy the PGx sample 
If a subject withdraws consent for PGx research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Screen and Baseline Failures
If a blood sample for PGx research has been collected and it is determined that the 
subject does not meet the entry criteria for participation in the clinical study, then the 
investigator should instruct the participant that their PGx sample will be destroyed. No 
forms are required to complete this process as it will be completed as part of the consent
and sample reconciliation process.  In this instance a sample destruction form will not be 
available to include in the site files.
Pharmacogenetics Analyses
Pharmacogenetics Analyses
1.
Specific genes may be studied that encode the drug targets, or drug mechanism of 
action pathways, drug metabolizing enzymes, drug transporters or which may
underpin adverse events, disease risk or drug response. These candidate genes may 
include a common set of ADME (Absorption, Distribution, Metabolism and 
Excretion) genes that are studied to determine the relationship between gene variants 
or treatment response and/or tolerance. 
In addition, continuing research may identify other enzymes, transporters, proteins or 
receptors that may be involved in response to FF/VI Inhalation Powder.  The genes that 
may code for these proteins may also be studied.
2.
Genome-wide scans involving a large number of polymorphic markers (e.g., single 
nucleotide polymorphisms) at defined locations in the genome, often correlated with 
a candidate gene, may be studied to determine the relationship between genetic 
variants and treatment response or tolerance. This approach is often employed when 
a definitive candidate gene(s) does not exist and/or the potential genetic effects are 
not well understood. 
If applicable and PGx research is conducted, appropriate statistical analysis methods will 
be used to evaluate pharmacogenetic data in the context of the other clinical data. Results 
of PGx investigations will be reported either as part of the main clinical study report or as 
a separate report. Endpoints of interest from all comparisons will be descriptively and/or 
graphically summarized as appropriate to the data.  A detailed description of the analysis 
 
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to be performed will be documented in the study reporting and analysis plan (RAP) or in 
a separate pharmacogenetics RAP, as appropriate.  
Informed Consent
Subjects who do not wish to participate in the PGx research may still participate in the 
clinical study.  PGx informed consent must be obtained prior to any saliva being taken for 
PGx research.
Provision of Study Results and Confidentiality of Subject’s PGx Data
GSK may summarize the PGx research results in the clinical study report, or separately, 
or may publish the results in scientific journals. 
GSK does not inform the investigator, subject, or anyone else (e.g., family members, 
study investigators, primary care physicians, insurers, or employers) of individual 
genotyping results that are not known to be relevant to the subject’s medical care at the 
time of the study, unless required by law. This is due to the fact that the information 
generated from PGx studies is generally preliminary in nature, and therefore the 
significance and scientific validity of the results are undetermined.
 
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References
Chung WH, Hung SL, Chen YT. Genetic predisposition of life-threatening antiepileptic-
induced skin reactions.  Expert Opin. Drug Saf. 2010; 9: 15-21.
Ferrell PB, McLeod HL.  Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson 
syndrome and toxic epidermal necrolysis: US FDA recommendations.  
Pharmacogenomics. 2008; 9: 1543-46.
Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, 
Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses 
AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. 
Lancet. 2002; 359:1121-2.
Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch 
L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ.  Genetic variants in the UDP-
glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J 
Clin Oncol 2004; 22: 1382-1388.
Liu CY, Chen PM, Chiou TJ, Liu JH, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, 
Wang WS.  UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities 
without affecting treatment outcome and survival in patients with metastatic colorectal 
carcinoma.  Cancer. 2008; 112: 1932-40.
Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte 
C, Maxwell D, James I.  Association between presence of HLA-B*5701, HLA-DR7, and 
HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir.  
Lancet. 2002; 359:727-32.
Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, Jägel-Guedes E, 
Rugina S, Kozyrev O, Cid JF, Hay P, Nolan D, Hughes S, Hughes A, Ryan S, Fitch N, 
Thorborn D, Benbow A; PREDICT-1 Study Team.  HLA-B*5701 screening for 
hypersensitivity to abacavir. N Engl J Med. 2008; 358; 568-78
Schulz C, Heinemann V, Schalhorn A, Moosmann N, Zwingers T, Boeck S, Giessen C, 
Stemmler HJ. UGT1A1 gene polymorphism: Impact on toxicity and efficacy of 
irinotecan-based regimens in metastatic colorectal cancer.  World J. Gastroenterol. 2009; 
15: 5058-66.
 
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11.3.
Appendix 3: Country Specific Requirements
 
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11.4.
Appendix 4: Liver Chemistry Stopping and Followup Criteria
Phase III-IV Liver Safety Algorithms
ALT>3xULN
plus 
bilirubin >2x 
ULN (>35%
direct) (or plus
INR >1.5, if   
measured)*
No
Yes
Yes
•Instruct subject to stop investigational product (IP)
•Notify GSK within 24h and arrange clinical followup 
within 24-72h
•Perform liver chemistries and liver event follow up 
assessments (serology, PK sample etc as in protocol) 
•Complete liver event CRF, SAE data collection tool if 
appropriate, and liver imaging and/or biopsy CRFs if  
tests performed.
•Obtain weekly liver chemistries [**as far as possible in 
these subjects] until resolved, stabilised or returned to 
baseline 
•Withdraw subject from study after monitoring 
complete unless protocol has option to restart drug
•Instruct subject to stop investigational product (IP)
•Notify GSK and arrange clinical followup within 24h
•Perform liver chemistries and liver event follow up 
assessments (serology, PK sample etc as in protocol) 
•Report as SAE (excl. hepatic impairment or cirrhosis 
studies) and complete liver event CRF, SAE data 
collection tool, and liver imaging and/or biopsy CRFs if 
tests performed.
•Obtain twice weekly liver chemistries until resolved, 
stabilised or returned to baseline values
•Consultation with hepatologist/specialist recommended
•Withdraw subject from study after monitoring 
complete unless protocol has option to restart drug
Hepatitis 
symptoms
or rash?
No
Able to 
monitor 
weekly for 
4 weeks?
Yes
No**
Yes
Continue IP
Obtain twice 
monthly liver 
chemistries until 
normalised or 
back to baseline 
values
Yes
Yes
ALT<3xULN 
+ bilirubin 
<2xULN 
after ≤ 4 
wks?
Yes
ALT 
>5xULN 
but 
<8xULN
No
ALT  
>8xULN
Yes
ALT >5 
and 
<8xULN 
for > 2 
wks
Yes
No
ALT>3xULN 
but <5xULN + 
bilirubin 
<2xULN+no 
symptoms
No
Able to 
monitor 
weekly for 
> 2 wks?
No
No
Notify GSK within 24h 
to discuss subject 
safety; continue IP;
check liver chemistry 
weekly for 4 weeks
Yes
No
*INR value not applicable to subjects on anticoagulants
 
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SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
HZC102972
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for HZC102972, a multi-centre, 
randomised, double-blind, parallel-group study evaluating the 
effect of Fluticasone Furoate/ Vilanterol (FF/VI) Inhalation 
Powder once daily compared with Vilanterol (VI) Inhalation 
Powder Once Daily on Bone Mineral Density (BMD) in 
subjects with Chronic Obstructive Pulmonary Disease 
(COPD)
Compound Number 
:
GW685698+GW642444
Effective Date 
:
17-MAY-2018
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol HZC102972 (2012N150072_01).

This RAP is intended to describe the final analyses required for the study. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
Approver
Date
Approval Method
N/A
N/A
Statistician (Respiratory, Clinical Statistics)
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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The GlaxoSmithKline group of companies
HZC102972
2
RAP Team Approvals:
Approver
Date
Approval 
Method
15-MAY-2018
eSignature
Programmer (Respiratory, Clinical Programming)
15-MAY-2018
eSignature
Clinical Development Director (Respiratory, HUP 
Clinical Development)
10-MAY-2018
Email
Clinical Development Manager (Respiratory, RD 
PCPS Therapy Area Delivery)
17-MAY-2018
eSignature
Principal Data Manager (Respiratory, Clinical Data 
Management)
11-MAY-2018
Email
Medical Writing Manager (Respiratory, Clinical 
Development Medical Writing)
17-MAY-2018
eSignature
Director of Clinical Development (Respiratory, 
MDC Global Clinical)
15-MAY-2018
Email
Manager (Respiratory, Regulatory)
11-MAY-2018
Email
Associate Medical Director (Respiratory, GCSP)
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval 
Method
15-MAY-2018
eSignature
Statistics Director (Respiratory, Clinical Statistics)
(On behalf of 
 Senior Statistics 
Director)
16-MAY-2018
eSignature
Manager Clinical Programming (Respiratory, 
Clinical Programming)
 
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CONFIDENTIAL
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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................7
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................7
2.2.
Study Objective(s) and Endpoint(s)...............................................................8
2.3.
Study Design ................................................................................................9
2.4.
Statistical Hypotheses / Statistical Analyses .................................................9
2.5.
Sample Size Sensitivity...............................................................................10
3.
PLANNED ANALYSES ..........................................................................................11
3.1.
Final Analyses ............................................................................................11
4.
ANALYSIS POPULATIONS ...................................................................................12
4.1.
Protocol Deviations.....................................................................................12
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................13
5.1.
Study Treatment & Sub-group Display Descriptors.....................................13
5.2.
Baseline Definitions ....................................................................................13
5.3.
Multicentre Studies .....................................................................................13
5.4.
Examination of Covariates, Other Strata and Subgroups............................14
5.4.1.
Covariates and Other Strata ........................................................14
5.4.2.
Examination of Subgroups...........................................................14
5.5.
Multiple Comparisons and Multiplicity .........................................................14
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................15
6.
STUDY POPULATION ANALYSES .......................................................................16
6.1.
Overview of Planned Study Population Analyses........................................16
6.1.1.
Study Populations........................................................................16
6.2.
Medical Conditions .....................................................................................16
6.3.
Concomitant Medications............................................................................17
6.4.
Screening Results.......................................................................................17
7.
SAFETY ANALYSES .............................................................................................18
7.1.
Primary Safety Analyses.............................................................................18
7.1.1.
Endpoint / Variables.....................................................................18
7.1.2.
Summary Measure ......................................................................18
7.1.3.
Population of Interest...................................................................18
7.1.4.
Strategy for Intercurrent (Post-Randomisation) Events ................18
7.1.5.
Statistical Analyses / Methods .....................................................19
7.1.5.1.
Statistical Methodology Specification..........................19
7.2.
Secondary Safety Analyses ........................................................................21
7.2.1.
Endpoint / Variables.....................................................................21
7.2.2.
Summary Measure ......................................................................21
7.2.3.
Population of Interest...................................................................21
7.2.4.
Strategy for Intercurrent (Post-Randomisation) Events ................21
7.2.5.
Statistical Analyses / Methods .....................................................21
 
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7.2.5.1.
Statistical Methodology Specification..........................22
7.3.
Adverse Events Analyses ...........................................................................22
7.4.
Adverse Events of Special Interest Analyses..............................................22
7.5.
On-treatment Fractures...............................................................................22
7.6.
On-treatment Pneumonia............................................................................23
7.7.
On-treatment Moderate/Severe COPD Exacerbations................................23
7.8.
Clinical Laboratory Analyses.......................................................................23
7.9.
Vital Signs and Non-Laboratory Analyses...................................................23
8.
REFERENCES.......................................................................................................24
9.
APPENDICES........................................................................................................25
9.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................25
9.1.1.
Exclusions from Per Protocol Population .....................................25
9.2.
Appendix 2: Schedule of Activities ..............................................................26
9.3.
Appendix 3: Assessment Windows .............................................................29
9.3.1.
Definitions of Assessment Windows for Analyses: BMD 
Data.............................................................................................29
9.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................30
9.4.1.
Study Phases for Measurements Taken at Visits (FEV1
and Vital Signs Only) ...................................................................30
9.4.2.
Study Phases for Bone Mineral Density Measurements 
Taken at Visits (Bone Mineral Density Data Only)........................30
9.4.3.
Study Phases for Adverse Events and All Other Data 
Recorded in Logs (excluding Concomitant Medications)..............30
9.4.4.
Study Phases for Concomitant Medications.................................31
9.4.5.
Treatment Emergent Flag for Adverse Events, Pneumonia 
and Exacerbations.......................................................................32
9.5.
Appendix 5: Data Display Standards & Handling Conventions....................33
9.5.1.
Reporting Process .......................................................................33
9.5.2.
Reporting Standards....................................................................33
9.6.
Appendix 6: Derived and Transformed Data ...............................................35
9.6.1.
General........................................................................................35
9.6.2.
Study Population..........................................................................35
9.6.3.
Safety ..........................................................................................36
9.7.
Appendix 7: Reporting Standards for Missing Data.....................................38
9.7.1.
Premature Withdrawals................................................................38
9.7.2.
Handling of Missing Data.............................................................38
9.7.2.1.
Handling of Missing and Partial Dates ........................38
9.8.
Appendix 11: Abbreviations & Trade Marks ................................................39
9.8.1.
Abbreviations...............................................................................39
9.8.2.
Trademarks .................................................................................40
9.9.
Appendix 12: List of Data Displays..............................................................41
9.9.1.
Data Display Numbering..............................................................41
9.9.2.
Mock Example Shell Referencing ................................................41
9.9.3.
Deliverable [Priority].....................................................................41
9.9.4.
Study Population Tables..............................................................42
9.9.5.
Study Population Figures.............................................................45
9.9.6.
Safety Tables...............................................................................46
9.9.7.
Safety Figures .............................................................................51
 
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9.9.8.
ICH Listings .................................................................................53
9.9.9.
Non-ICH Listings..........................................................................55
9.10.
Appendix 13: Example Mock Shells for Data Displays ................................58
 
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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol HZC102972:
Revision Chronology:
2012N150072_00
07-JAN-2013
Original
2012N150072_01
14-AUG-2013
Amendment No.: 01 This protocol amendment is being 
implemented to revise and clarify exclusion criteria concerning 
participation in pulmonary rehabilitation programs; clarify the 
description of DEXA procedures and clinical labs; correction of
typographical errors.
 
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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1.
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes

The percent change from 
baseline in BMD for the total 
hip will be the primary 
endpoint, and analysed using 
a repeated measures model 
with terms for treatment, time, 
time by treatment, baseline 
BMD, baseline BMI and 
gender.

The primary endpoint will 
be analysed using a 
repeated measures 
model with terms for 
treatment, visit, visit by 
treatment, baseline BMD, 
baseline BMI, age and 
gender. Weighted 
contrasts will be formed 
between all visits to 
calculate the average 
change per year over the 
3 year study treatment 
period.  

The wording in protocol 
used time and not visit,
which may imply time as 
a continuous variable, 
rather than categorical. 
The analysis was clarified 
in the RAP text.
Additional text added 
around contrast 
statement as use of SAS 
code in RAPs is now 
discouraged. In addition,
age was missed from the 
model

Only included analysis of the ITT 
population

Safety and ITT population 
will be defined.

As this is a safety and not 
an efficacy study it is more 
appropriate to use the 
Safety population.

Section 8.2.2 of the Protocol 
Sample Size Sensitivity – the 
power calculations are 
inconsistent

Section 2.5 of this RAP 
provides the amended 
power calculations

Previous power calculations 
for sample size sensitivity 
were inconsistent, and have 
been corrected. 
 
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2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

Evaluate the effect of FF/VI on BMD at 
the total hip

BMD measured at the total hip
Secondary Objectives
Secondary Endpoints

Evaluate the effect of FF/VI on BMD 
by gender

BMD measurements by gender 

Evaluate the effect of FF/VI on BMD 
as assessed at the lumbar spine L1-L4

BMD measured at the lumbar spine (L1-L4)
Other Objectives
Other Endpoints

Evaluate safety of FF/VI

Adverse Event reporting

Serious Adverse Event reporting

Incidence of Fractures

Incidence of Pneumonias

COPD exacerbations
 
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2.3.
Study Design
Overview of Study Design and Key Features
Design 
Features

Multi-center, randomised, double-blind, parallel-group study
Dosing

FF/VI 100/25 mcg once daily via ELLIPTA inhaler

VI 25 mcg once daily via ELLIPTA inhaler

Note: ELLIPTA was previously referred to as NDPI
Treatment 
Assignment

Following a 14-21 day run-in period, eligible subjects will be randomised 
(1:1) to either Fluticasone Furoate /Vilanterol 100/25 mcg once daily or 
Vilanterol 25 mcg once daily, administered as one inhalation each morning.

Approximately 400 male and female subjects will be screened to randomise 
approximately 280 subjects, to obtain at least 224 who complete 156 weeks 
of treatment.

The randomisation will be stratified by gender.
Interim 
Analysis

No interim analysis is planned for this study
2.4.
Statistical Hypotheses / Statistical Analyses
The null hypothesis for the primary measure is that the decrease in BMD assessed at the 
total hip is larger for the FF/VI combination product arm compared with the VI arm. The 
alternative hypothesis that the change in BMD assessed at the total hip is not worse for 
the FF/VI arm compared with the VI arm. The 95% confidence interval will be compared 
to a lower bound of -1%/year in order to assess clinical non-inferiority such that:
H0: μ FF/VI ≤ μ VI – 1%
H1: μ FF/VI > μ VI – 1%
This is also the null and alternative hypothesis for the secondary measure of BMD 
assessed at the L1-L4 lumbar spine.
 
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2.5.
Sample Size Sensitivity
For the primary endpoint of BMD at the total hip, males and females will be combined in 
order to have >90% power to demonstrate non-inferiority. This will be done by 
comparing the lower boundary of a two-sided 95% confidence interval of the treatment 
difference to -1 % year, assuming a true treatment difference of -0.3 %/year with a 
standard deviation of 1.3 %/year.
As detailed in Section 2.1, the power calculations for sample size sensitivity given in the 
protocol were inconsistent, and hence have been corrected as shown in Table 2. These 
demonstrate that across a true treatment difference of -0.2 to -0.4 %/year and a true 
standard deviation of 1.3 to 1.5 %/year, the primary endpoint of BMD at the total hip for 
males and females combined will have at least 85% power.
Table 2
Sample Size Sensitivity
True Treatment Difference between FF/VI and VI
SD
-0.2%/yr
-0.3%/yr
-0.4%/yr
1.3%/yr
>99%
98%
93%
1.4%/yr
99%
96%
89%
1.5%/yr
98%
94%
85%
 
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3.
PLANNED ANALYSES
3.1.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All subjects have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database has 
been released (DBR).
3.
All criteria for unblinding the randomisation codes have been met. 
4.
Randomisation codes have been unblinded and distributed according to the 
unblinding procedures.
5.
Database freeze (DBF) has been declared by Data Management.
 
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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All subjects 
enrolled (ASE)

All subjects for whom a record exists on the study 
database, including screen failures and any subjects
who were not screened but signed the informed consent 
form.

Study Population
Pre-screen, 
Screen and Run-
in Failures (SRIF)

All subjects who were enrolled but were either pre-
screen failures, screen failures, run-in failures or 
subjects randomised in error.

Study Population
Randomised

All subjects who were given a randomisation number, 
including subjects who were randomised in error.

Study Population
(Modified) Intent 
to treat (ITT)

All randomised subjects who received at least one dose 
of study treatment.

This population will be based on the treatment the 
subject was randomised to.

Study Population
Safety (SAF)

All randomised subjects who received at least one dose 
of study treatment.

This population will be based on the treatment the 
subject took for the majority of the treatment period 
(>50%).

Study Population

Safety
Safety excluding 
closed sites

This population would be the same as the safety 
population but excluding any sites that were closed due 
to audit findings, failures to adhere to GCP or any other 
findings.

This population will not be used unless there is a need 
to exclude sites.

Study Population

Safety
Refer to Appendix 12: List of Data Displays which details the population used for each display.
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan Version 2 (26-Sep-2016) or 
higher.
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations are captured and categorised on the protocol deviations 
dataset. 
o This dataset will be the basis for the summaries and listings of protocol 
deviations.
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF.
 
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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment comparisons will be displayed as follows using the descriptors as specified:
1.
FF/VI vs VI
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order [1]
3
FF/VI 100/25mcg QD
FF/VI 100/25
2
4
VI  25mcg QD
VI 25
1
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.
QD = Once Daily
5.2.
Baseline Definitions
For all endpoints, the baseline value will be the latest pre-dose assessment with a non-
missing value, including those from unscheduled visits. If time is not collected, Day 1 
assessments are assumed to be taken prior to first dose and used as baseline.
Parameter
Study Assessments Considered As Baseline
Baseline Used in 
Data Display [1]
Screening
Day -1
Day 1 (Pre-Dose)
Primary/Secondary Endpoint
BMD
X
Screening
Other Endpoints
FEV1
X
Day 1 (Pre-Dose)
Vital Signs
X
Day 1 (Pre-Dose)
NOTES :

Unless otherwise stated, the mean of replicate assessments at any given time point will be used as the value for 
that time point.

[1] = If any additional assessments closer to Day 1 (Dose) are taken then these will be used instead.
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing.
5.3.
Multicentre Studies
In this multicentre global study, enrolment will be presented by investigative site and
country.
 
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Central randomisation was used for this study. It is likely that many centres will enrol a 
very small number of subjects and hence data from all participating centres will be 
pooled prior to analysis.
5.4.
Examination of Covariates, Other Strata and Subgroups
5.4.1.
Covariates and Other Strata
The list of covariates and other strata may be used in descriptive summaries and 
statistical analyses, some of which may also be used for subgroup analyses. Additional 
covariates and other strata of clinical interest may also be considered.
Category
Details
Covariates:
All models
Age, Gender, Baseline BMD, Visit, Baseline BMI
Covariates:
To be investigated
Treatment*covariate interactions will be included in the model, and if these are 
significant (10% level) then a split model will be investigated.
5.4.2.
Examination of Subgroups
The analysis of bone mineral density will be presented overall and by gender (males and 
females). For the gender analysis, each individual gender will have its own separate 
model fitted excluding any data from the opposite gender (split model).
There are no other planned subgroup analyses unless the treatment*covariate interaction 
is shown to be significant at the 10% level, in which case subgroups will be calculated 
and presented in the same way as gender. For example, if smoking status was shown to 
be significant it would be categorised as demonstrated below and then presented by these 
categories.
Table 3 shows all potential subgroups that will be investigated.
Table 3
Potential Subgroups
Covariate
Categorical or Continuous
Age
Continuous
Baseline BMI
BMI will be modelled as continuous but if it needs to be categorised for the 
purposes of producing summaries by subgroups the following categories 
will be used; < 25, 25 <= to < 30 and >= 30. This is based on the WHO 
definition for categorising BMI but combining the < 18.5 and 18.5 <= to <25 
categories due to low number of subjects in the HZC102972 study having a 
BMI < 18.5.
Smoking Status 
Categorical: Current or Former. 
5.5.
Multiple Comparisons and Multiplicity
No multiple comparison adjustments will be made.
 
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5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
9.3
Appendix 3: Assessment Windows
9.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
9.5
Appendix 5: Data Display Standards & Handling Conventions
9.6
Appendix 6: Derived and Transformed Data
9.7
Appendix 7: Reporting Standards for Missing Data
 
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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the Safety population unless otherwise 
stated.
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
exposure and treatment compliance will be based on GSK Core Data Standards.  Details 
of the planned displays are presented in Appendix 12: List of Data Displays.
6.1.1.
Study Populations
The number of subjects randomised and the number of subjects who were in the mITT 
and Safety population will be presented by treatment group and overall.
The number of subjects in the ASE population, the number and percentage of subjects 
who were screening and run-in failures, and who had exacerbations during the run-in 
period will be presented. In addition, the reasons for screening failures will also be 
provided. 
The number and percentage of subjects who completed the study, who withdrew 
prematurely from the study and who reported each primary and sub-reason for 
withdrawal will be presented for each treatment group and overall. Similarly, tables of 
demography and baseline characteristics will be produced by treatment group and overall.  
If any sites were closed due to audit findings, failures to adhere to GCP or any other 
findings, an additional ‘Safety excluding closed sites’ population will be added to all 
study population tables, or in the case of demography and baseline characteristic tables a 
repeat table for this population will be produced. If no sites were closed, this information 
will be included in the footnote and no additional tables will be provided. 
6.2.
Medical Conditions
The number and percentage of subjects reporting each current medical condition 
specified in the eCRF will be presented by randomised treatment group and overall. All 
medical conditions must be summarised on this table regardless of frequency, and will be
repeated for current and past medical conditions.
A separate table of ‘Cardiovascular Risk Factors’ will also be produced. This will 
summarise the number and percentages of subjects with the following current or past 
medical conditions:   Arrhythmia, Cerebrovascular Accident, Congestive Heart Failure, 
Coronary Artery Disease, Diabetes Mellitus, Hypertension, Hypercholesterolemia, 
Myocardial Infarction.
 
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6.3.
Concomitant Medications
Medications categorised as ‘Other medications’ will include medications not used to treat
COPD or low bone mineral density [BMD] and will be summarised by Anatomical-
Therapeutic-Chemical (ATC) level 1 and ingredient. COPD medications not given for an 
exacerbation will be summarised by Respiratory Medication Class (RMC). COPD 
medications given for exacerbations whilst on treatment will also be summarised by 
RMC. Multi-ingredient medications will be presented according to their combination 
ATC classification rather than the classifications of the individual ingredients.
BMD medications, taken to improve bone mineral density, will be summarised by 
treatment group and overall. Bone mineral density medications will be identified using 
ATC codes along with reviewing all concomitant medications prior to database freeze to 
ensure all relevant medications are included.
COPD, BMD and Other medications will be listed separately. The COPD medications 
listing will indicate whether each medication was taken for an exacerbation. Listings will 
indicate in which study phases each medication was taken (pre-treatment and/or on-
treatment and/or post-treatment).
A listing of the relationship between ATC Level 1, ingredient and verbatim text will be 
produced for ‘Other medications’ only.
6.4.
Screening Results
Screening (which will be baseline) bone mineral density results at both total hip and 
lumbar spine (L1-L4) will be summarised overall and by gender according to treatment.
Pre- and post-bronchodilator FEV1, FVC, FEV1/FVC ratio, post-bronchodilator FEV1
percentage of predicted normal and FEV1 reversibility to bronchodilator (expressed in 
mL and as a percentage of post-bronchodilator and grouped into the following categories: 
“<12% or <200mL” “≥12% and ≥200mL”; reversibility will also be expressed also as a 
percentage of predicted) at screening (see Section 5.2) will be summarised by treatment 
group and overall. At randomisation FEV1, FVC and FEV1/FVC will be summarised by 
treatment group and overall.
 
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7.
SAFETY ANALYSES
7.1.
Primary Safety Analyses
Due to the known variability between sites and scanners, prior to the end of the study 
each machine has a phantom scanned. This phantom is a standardised bone image with a 
set density. As the true density of the phantom is known, it means that the difference 
between the true value and the machine value can be calculated, this is known as the 
correction factor.
Throughout the reporting of this study, all summaries and analysis of bone mineral 
density will use the corrected bone mineral density values only as these can be considered 
as standardised values where machine variability had been accounted for. 
It is also important to highlight that if a subject was affected by a hip fracture during the 
study then the other native hip was used for all subsequent BMD assessments.
7.1.1.
Endpoint / Variables
Bone mineral density measured at the Total Hip
7.1.2.
Summary Measure
Percentage change from baseline per annum
7.1.3.
Population of Interest 
The primary safety analyses will be based on the Safety populations, unless otherwise 
specified. In the instance that all subjects are assigned their randomised treatment for at 
least 50% of the treatment period, the Safety population will be identical to the mITT.
7.1.4.
Strategy for Intercurrent (Post-Randomisation) Events
The four key intercurrent events in this study are;

Use of concomitant medication taken to increase a subject’s bone mineral density 
(which we will term “BMD medication”)

Use of systemic corticosteroids (SCS) which may decrease a subject’s BMD

Temporary discontinuation of investigational product 

Permanent discontinuation of IP. 
The primary aim of this study is to generate the ‘while on treatment’ estimand of the 
difference in percentage change from baseline per annum between FF/VI ± BMD 
medication/SCS and VI ± BMD medication/SCS.
Therefore, after a subject takes BMD medication or SCS, or temporarily discontinues IP, 
BMD will continue to be collected, and this data will be used in the analysis. 
However, once a subject has permanently discontinued IP their inhaled therapy may be 
switched, and so data after this event will no longer reflect the treatment comparison of 
 
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interest. As this is a non-inferiority study, focusing on safety not efficacy, BMD data 
collected after this event will not be used in the analysis. 
Intermittent missing data not due to an intercurrent event, e.g. sporadic missing of a visit, 
will not be explicitly imputed and will be treated as missing at random. Subsequent data 
collected will be included in the analysis.
7.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and
listed.
7.1.5.1.
Statistical Methodology Specification
Endpoint(s)

Bone mineral density measured at the total hip
Model Specification
Model:

The ratio of post-baseline BMD values to baseline BMD values will be log transformed prior to 
analysis. Note: Log(post baseline BMD/baseline BMD) is equivalent to log(post baseline BMD) 
– log(baseline BMD).

A repeated measures model with terms for treatment, visit, visit by treatment, the logarithm of 
baseline BMD, the logarithm of baseline BMD by visit, baseline BMI (continuous), age
(continuous) and gender will be fitted.

This will make the analysis model: log(post baseline BMD/baseline BMD)= treatment + visit + 
visit*treatment + log(baseline BMD) + log(baseline BMD)*visit + BMI + age + gender

The difference between FF/VI and VI will be calculated using the log estimate for FF/VI – the 
log estimate for VI.
Estimates:

The estimates of the mean and difference for each treatment group from the model will be 
exponentiated to produce ratios. This will then be presented as a percentage change in BMD 
per year with 95% confidence intervals.
I.e. percentage change = (exp(estimate)-1)*100. 

In addition, these percent changes will be converted to annual percent changes by dividing by 
the year. E.g. the 1.5 year visit annual percent change will be calculated as (exp(estimate/1.5)-
1)*100

For the treatment difference, this will be presented as a percent difference in change in BMD 
per year with 95% confidence interval. I.e. difference = [exp(log_estimate for FF/VI –
log_estimate for VI)-1]*100. In addition, the difference will be converted to annual percent 
difference as explained above.
 
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
The estimates of the percent change in BMD and the percent change per year by treatment 
arm and the treatment difference will be presented at each 6 monthly analysis visit to check for 
consistency.

These 6 monthly estimates will be averaged (see diagram below) to calculate the overall 
treatment estimates and the treatment difference, which will be used for the primary test of 
non-inferiority.  

The calculation would be: Overall estimate of percentage change in BMD per year = (a/0.5 + 
b/1 + c/1.5 + d/2 +e/2.5 + f/3) / 6, where a to f are the estimates at each 6 monthly post-
baseline analysis visit.
0.5 years ÷ 0.5                       1.5 years ÷ 1.5            2.5 years ÷ 2.5
1 year                        2 years ÷ 2                         3 years ÷ 3
Model Structure:

The variance-covariance matrix will be assumed unstructured.

Kenward Roger (KR) method will be used for calculating degrees of freedom. If the analysis 
does not run using the KR method then the residual method will be used instead. 

An observed margins (OM) dataset will be used to derive the LS means using coefficients 
which are based on the subjects used in the analysis. This is a dataset with a row for every 
subject-visit combination that contains all of the covariates. The OM will be at the average 
logarithm of baseline BMD, the average baseline age and the average baseline BMI.
Covariates to be investigated:

Treatment*Covariate interactions will be included in the model individually. If these are 
significant at the 10% level then a model split by the covariate of interest will be investigated.
Model Checking & Diagnostics

Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the fitted 
values (i.e. checking the normality assumption and constant variance assumption of the model 
respectively) to gain confidence that the model assumptions are reasonable.
Model Results Presentation
Overall Estimate of % Change in BMD:

The overall raw percentage change in BMD per year along with the LS means ratio and % 
change from baseline will be presented by treatment.

In addition, the LS means ratio and % change from baseline for the treatment comparison will 
also be produced.
Estimates of % Change in BMD by visit:
Study Treatment Period
(3 Years)
 
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
For each visit the raw baseline, raw mean and raw % change from baseline will be presented 
by treatment.

The adjusted mean and adjusted ratio to baseline will be produced along with the % change 
from baseline by treatment. 

In addition, the LS means treatment difference for the ratio and % change at visit along with 
the % change per annum will be produced. 
All LS means will be presented with their associated 95% confidence intervals.
Plots of BMD:

Plots of raw mean, raw % change from baseline and LS mean percentage change from 
baseline by visit will be generated for each treatment.
7.2.
Secondary Safety Analyses
7.2.1.
Endpoint / Variables

Bone mineral density measured at the Total Hip by Gender

Bone mineral density measured at the Lumbar Spine L1-L4

Bone mineral density measured at the Lumbar Spine L1-L4 by Gender
7.2.2.
Summary Measure

Percentage change from baseline
7.2.3.
Population of Interest 
The secondary analyses will be based on the Safety populations, unless otherwise 
specified.
7.2.4.
Strategy for Intercurrent (Post-Randomisation) Events
See Section 7.1.4.
7.2.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
 
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7.2.5.1.
Statistical Methodology Specification
Endpoint(s)

Bone mineral density measurements by Gender

Bone mineral density measured at the Lumbar Spine (L1-L4)

Bone mineral density measured at the Lumbar Spine (L1-L4) by Gender
Model Specification

See Section 7.1.5.1.

For the models of bone mineral density measurements by Gender, each gender will have their 
own model fitted excluding any data from the opposite gender (split model).
Model Checking & Diagnostics

See Section 7.1.5.1.
Model Results Presentation

See Section 7.1.5.1.
7.3.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs) 
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 12: List of Data Displays.
7.4.
Adverse Events of Special Interest Analyses
A comprehensive list of MedDRA terms based on clinical review will be used to identify 
each type of event. Changes to the MedDRA dictionary may occur between the start of 
the study and the time of reporting and/or emerging data from on-going studies may 
highlight additional adverse events of special interest, therefore the list of terms to be 
used for each event of interest and the specific events of interest will be based on the 
safety review team (SRT) agreements in place at the time of reporting. These will be 
produced for both LABA and ICS AESIs. The details of the planned displays are 
provided in Appendix 12: List of Data Displays.
7.5.
On-treatment Fractures 
Fracture events including the number and percentage of subjects recorded as having at 
least one bone fracture, location of fractures and whether they were traumatic or not 
traumatic (severity) will be summarised. If a subject suffers fractures in multiple 
locations with the same date of fracture, this is considered to be one fracture incident.
The frequency and percentage of subjects with 0, 1, 2 and more than 2 fracture incidents 
will also be summarised.
In addition, the rates of fractures will be summarised as described in Section 9.6.3. The 
details of the planned displays are in Appendix 12: List of Data Displays.
 
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7.6.
On-treatment Pneumonia 
Pneumonia events including severity, outcomes, those supported by x-rays, those within 
14 days of moderate/severe exacerbations and number of events per subject will be 
summarised. 
A chest x-ray/CT scan is associated with pneumonia if it is performed within the duration 
of the pneumonia or between -7 to +10 days (inclusive) of the date of onset.
In addition, the rates of events will be summarised as described in Section 9.6.3. The 
details of the planned displays are in Appendix 12: List of Data Displays.
7.7.
On-treatment Moderate/Severe COPD Exacerbations
The number and percentage of subjects reporting an on-treatment moderate/severe 
exacerbation along with the outcome category (fatal, resolved or not resolved), result 
(withdrawal, treatment by corticosteroids, antibiotics, emergency room visits or
hospitalisations) will be presented along with the primary cause.
A moderate COPD exacerbation is defined as requires treatment with antibiotics and/or
systemic corticosteroids. A severe COPD exacerbation is defined as requires 
hospitalization.
The details of the planned displays are in Appendix 12: List of Data Displays.
7.8.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, and liver function tests will be based on GSK Core Data Standards. The 
details of the planned displays are in Appendix 12: List of Data Displays.
7.9.
Vital Signs and Non-Laboratory Analyses
The analyses of non-laboratory safety test results including vital signs will be based on
GSK Core Data Standards, unless otherwise specified. 
 
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8.
REFERENCES
GSK Document 2012N150072_01, Multi-centre, randomized, double-blind, parallel-
group study evaluating the effect of Fluticasone Furoate/ Vilanterol (FF/VI) Inhalation 
Powder once daily compared with Vilanterol (VI) Inhalation Powder Once Daily on Bone 
Mineral Density (BMD) in subjects with Chronic Obstructive Pulmonary Disease 
(COPD), 14-AUG-2013
 
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9.
APPENDICES
9.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
9.1.1.
Exclusions from Per Protocol Population
There will be no per protocol population analysed in this study.
 
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9.2.
Appendix 2: Schedule of Activities
Protocol Defined Schedule of Events
 
 
 
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9.3.
Appendix 3: Assessment Windows
9.3.1.
Definitions of Assessment Windows for Analyses: BMD Data
Analysis Set 
/ Domain
Target 
Analysis Window
Analysis 
Timepoint
Beginning 
Timepoint
Ending 
Timepoint
ITT”, “Safety”
Week 26
Day 2
Day 272
VISIT 4
ITT”, “Safety”
Week 52
Day 273
Day 454
VISIT 6
ITT”, “Safety”
Week 78
Day 455
Day 636
VISIT 8
ITT”, “Safety”
Week 104
Day 637
Day 818
VISIT 10
ITT”, “Safety”
Week 130
Day 819
Day 1000
VISIT 12
ITT”, “Safety”
Week 156
Day 1001
Day 1182
VISIT 14
In order to include all bone mineral density assessments, the analysis window has been 
increased to ± 3 months. A schematic of the above windowing is given below.
273            454
637            818
1001        1182
Week 26
Visit 4
Week 52
Visit 6
Week 78
Visit 8
Week 104
Visit 10
Week 130
Visit 12
Week 156
Visit 14
2                272
455            636
819          1000
If there are multiple assessments within a window these will be averaged on the raw scale 
(i.e. before log transformation).
 
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9.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
Subjects who do not take study treatment who have will have events, log recordings and 
measurements assigned to pre-treatment.
Events, log recordings and measurements with missing dates will be assigned to on-
treatment for subjects who have taken study treatment, unless there is evidence it was not 
on-treatment.
9.4.1.
Study Phases for Measurements Taken at Visits (FEV1 and Vital 
Signs Only)
Study Phase
Definition
Pre-Treatment 
Date ≤Study Treatment Start Date
On-Treatment
Study Treatment Start Date < Date ≤ Study Treatment Stop Date + 1
Post-Treatment
Date > Study Treatment Stop Date + 1
These definitions would only apply to vital signs and FEV1 data, in which baseline 
measurements are taken on Day 1 pre-dose (as define in the Schedule of Activities). If the 
standard definition (Section 9.4.3) were used then the baseline data would be considered 
on-treatment as it occurs on Day 1 even though it occurs prior to first dose. As a result, a 
separate definition of study phase has been used to ensure this data to captured 
appropriately.
9.4.2.
Study Phases for Bone Mineral Density Measurements Taken at 
Visits (Bone Mineral Density Data Only)
Study Phase
Definition
Pre-Treatment 
Date ≤Study Treatment Start Date 
On-Treatment
Study Treatment Start Date < Date ≤ Study Treatment Stop Date + 30 days (1 month)
Post-Treatment
Date > Study Treatment Stop Date + 30 days
9.4.3.
Study Phases for Adverse Events and All Other Data Recorded in 
Logs (excluding Concomitant Medications)
Study Phase
Definition
Pre-Treatment 
Event Onset Date < Study Treatment Start Date 
On-Treatment
Study Treatment Start Date ≤ Event Onset Date ≤ Study Treatment Stop Date + 1
Post-Treatment
Event Onset Date > Study Treatment Stop Date + 1
 
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9.4.4.
Study Phases for Concomitant Medications
Treatment phases for summaries of COPD and non-COPD concomitant medications will 
be defined as follows: 
Definition
Treatment Phase
Pre-
Treatment
On-
Treatment
Post-
Treatment
Subject did not take study treatment (e.g, 
screening failures) and conmed stop date > 
date of Screening or variable that asks if 
conmed is on-going (refer hereafter as 
goingmed) is “yes”
Y
(Conmed start date<treatment start date or 
variable that asks if medication taken prior to 
study is ”yes”(refer hereafter as priormed)) and 
date of Screening < conmed stop date 
<treatment start date
Y
(Conmed start date<treatment start date or 
priormed is yes) and  treatment start 
dateconmed stop datetreatment stop date 
Y
Y
(Conmed start date<treatment start date or 
priormed is yes) and 
(conmed stop date>treatment stop date or 
goingmed is “yes”)
Y
Y
Y
(Treatment start dateconmed start 
date<treatment stop date and treatment start 
dateconmed stop datetreatment stop date) 
or (Treatment start date=conmed start 
date=conmed stop date=treatment stop date)
Y
([Treatment start dateconmed start 
date<treatment stop date] or [Treatment start 
date=conmed start date=treatment stop date]) 
and(conmed stop date>treatment stop date or 
goingmed is Yes)
Y
Y
Conmed start≥ treatment stop date and 
treatment start date ≠ treatment stop date
Y
NOTES: 

A concomitant medication will be classed in every period of the study in which it was taken (e.g., run-in, on-
treatment or post-treatment).  

See Section 9.7.2.1 for handling of partial dates.

If the study treatment stop date is missing, it will be imputed as described in Section 9.6.2.

Medications that stopped prior to Screening will not be assigned a treatment phase and will not be 
summarized.
 
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9.4.5.
Treatment Emergent Flag for Adverse Events, Pneumonia and 
Exacerbations
Flag
Definition
Treatment 
Emergent

If AE onset date is on or after treatment start date & on or before treatment stop 
date plus one day. 

Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date + 1.
NOTES: 

If the study treatment stop date is missing, then the AE will be considered to be On-Treatment.

Time of study treatment dosing and start/stop time of AEs should be considered, if collected.
 
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9.5.
Appendix 5: Data Display Standards & Handling 
Conventions
9.5.1.
Reporting Process
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
UK1SALX00175
HARP Area
gw685698_gw642444\hzc102972\final_02
QC Spreadsheet
gw685698_gw642444\hzc102972\final_02\documents
Analysis Datasets 

Analysis datasets will be created according to CDISC standards 
Generation of RTF Files

RTF files will be generated for all reporting efforts 
9.5.2.
Reporting Standards
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated:

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 
Formats

All data will be reported according to the actual treatment the subject received unless 
otherwise stated.

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of DP’s. 
 
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Reporting Standards
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 

Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will 
be included in listings but omitted from figures, summaries and statistical analyses.
Unscheduled Visits

Unscheduled visits will not be included in summary tables.

Unscheduled visits will not be included in figures.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Reporting of Pharmacokinetic Concentration Data
Descriptive 
Summary Statistics
Refer to IDSL Statistical Principle 6.06.1
Assign zero to NQ values (Refer to GUI_51487 for further details)
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
 
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9.6.
Appendix 6: Derived and Transformed Data
9.6.1.
General
Multiple Measurements at One Analysis Time Point
Bone Mineral Density Data:

If there are two values within a time window (as per Section 9.3.1) the mean of the measurements will 
be calculated and used in any derivation of summary statistics and for any analysis.

If the data is listed however all data will be presented.
Study Day

Calculated as the number of days from First Dose Date:

Ref Date = Missing              → Study Day = Missing 

Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date

Ref Date ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1    
9.6.2.
Study Population
Age

Date of birth will be set as 30-JUN-YYYY where YYYY is the year of birth taken from the 
CRF. For subjects who attended a screening visit, age will be calculated at the screening 
visit date. For pre-screen failures, age will be calculated at the pre-screening visit date.
Body Mass Index (BMI)

BMI = Weight (kg) / Height(m)2
Study Treatment Stop Date
If the treatment stop date is missing, it will be imputed as the minimum of:

Date of death

Study conclusion date

Last dispensed date + number of doses dispensed and not returned
Treatment Compliance

Treatment compliance will be calculated based on the formula:  
Treatment Compliance = Number of Actual Doses / (Treatment Duration in Days * Frequency)

Frequency is once daily. Treatment compliance could be greater than 100% if there are events of 
overdose. Cumulative compliance (since Day 1) at each visit will be calculated.

Compliance is based on number of doses taken across all containers dispensed and returned 
during the study – ie, it is calculated regardless of incorrect containers being dispensed. Any 
containers that are dispensed and not returned during the study are not included in the 
calculation. If any dose counter stop is missing, then the number of doses taken will be set to 
missing for that inhaler.

Compliance will be summarized by the following categories:
<80%,
≥ 80% to < 95%, 
≥95% to <105%,
≥ 105% to <120% and
≥120%
 
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Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Years = (Treatment Stop Date – (Treatment Start Date) + 1) / 365.25

This will also be the exposure used to calculate rate of events

Duration of exposure will be summarised by the following categories:
≤3months, 
> 3 months < to ≤6 months,
> 6 months to ≤12 months,
>12 months to ≤ 24 months,
>24 months to ≤ 36 months and 
>36 months
where 1 month is equal to (365.25 days/12).
9.6.3.
Safety
Adverse Events
AE’S OF Special Interest
The following AESI have been selected using the reference dataset 
(arenv/arprod/respiratory/res_safety/aesi/refdata) and sub setting on the relevant study medications (VI or 
FF) with an indication of COPD along with review by Global Clinical Safety Pharmacovigilance (GCSP):
Adrenal Suppression (Selected PTs)
Asthma/Bronchospasm (SMQ)
Cardiovascular effects including the following subgroups: 

Cardiac Arrhythmia (Selected SMQs)

Cardiac failure (SMQ)

Stroke (CNS system haemorrhages and cerebrovascular conditions SMQ)

Hypertension (SMQ)

Cardiac Ischaemia (Ischaemic heart disease SMQ)
Decreased Bone Mineral Density and associated Fractures (Selected PTs + Osteoporosis/Osteopenia SMQ)
Effects on potassium (Selected PTs)
Effects on glucose (Hyperglycaemia/New onset Diabetes Mellitus SMQ)
Hypersensitivity (Selected PTs)
LRTI Excluding Pneumonia (Selected PTs)
Local Steroid Effects (Selected PTs)
Ocular effects including the following subgroups: 

Glaucoma (SMQ)

Lens Disorders (SMQ)
Pneumonia (Selected PTs)
Tremor (Selected PTs)
If this reference data is updated between the RAP being approved and the reporting of the study, then this list 
will be updated and re-reviewed. A listing of all preferred terms used to identify AESIs will be produced.
Rate of Adverse Events per 100 Treatment Years
Rate of on-treatment adverse events per 100 treatment years will be calculated using:
Rate = number of events * 100 / total treatment exposure in years
 
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Rate of Adverse Events per 100 Treatment Years
where subjects can contribute more than one event.  
This is equivalent to: 
Rate = number of events * 100 / (number of subjects in treatment group * mean treatment exposure in 
years).
Note: The rate must be produced to sufficient decimal places to allow the conversion to rate of adverse 
events per 1000 treatment years if required. Exposure will be calculated as defined in Section 9.6.2.
Kaplan-Meier Plot of Time to Premature Discontinuation from Investigational Product
Within the Kaplan Meier plot subjects will either be counted as an event or they will be censored.
Events:

Subjects who discontinue investigational product before the end of the study will be counted as an 
event, with the date of IP discontinuation being used as the treatment end date.

Subjects who die will be considered as having withdrawn from the IP at the date of death, unless 
they discontinued IP prior to death in which case the IP discontinuation date will be used as 
treatment end date.
Censoring:

Subjects who continue study treatment until the end of the study will be censored at their treatment 
end date. A subject takes IP for more than 156 weeks will be censored at 156 weeks (1092 days).
Time on investigational product = Treatment end date – Treatment start date + 1 
Maximum/Minimum On-Treatment Definitions for Vital Signs Data
Maximum and Minimum on-treatment: Maximum and Minimum on-treatment value over all time-points 
(including scheduled and unscheduled assessments) will be presented.
FEV1
Absolute Reversibility
Absolute reversibility (mL) = (post-bronchodilator FEV1 – pre-bronchodilator FEV1)
Percent Reversibility
Definition of Percentage Reversibility as a percentage of predicted FEV1 = ((post-bronchodilator FEV1– pre-
bronchodilator FEV1) / predicted FEV1) x 100%
Definition of Percentage Reversibility as a percentage of pre-bronchodilator FEV1 = ((post-bronchodilator 
FEV1– pre-bronchodilator FEV1) / pre-bronchodilator FEV1) x 100%
 
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9.7.
Appendix 7: Reporting Standards for Missing Data
9.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as attendance at 13 
post-randomisation visits over the schedule.

Withdrawn subjects were not replaced in the study

Withdrawal visits will be slotted as per Appendix 3: Assessment Windows or will be summarised 
as withdrawal visits.
9.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on the 
collection instrument:
o
These data will be indicated by the use of a “blank” in subject listing displays. Unless all 
data for a specific visit are missing in which case the data is excluded from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be missing 
data and should be displayed as such.
9.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to be recorded for 
AE start and end dates; that is, the day of the month may be missing. 

Any partial dates for adverse events will be raised to data management.

In such a case, the following conventions will be applied for calculating the time to onset and the 
duration of the event:
o
Missing Start Day: First of the month will be used
o
Missing Stop Day: Last day of the month will be used, unless the subject died and this date is 
after the subject’s death date in which case the stop date will be set to the death date

Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing.
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the CRF will be imputed using the 
following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will be used for the 
month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent on the 
month and year) and 'Dec' will be used for the month. If this imputed stop date is after the 
subject death date then the stop date will be set to the death date.

The recorded partial date will be displayed in listings.

Completely missing start or end dates will remain missing, with no imputation applied.
Protocol 
Devaiations

The eCRF allows for the possibility of partial dates (i.e., only month and year) to be recorded for 
protocol deviation dates; that is, the day of the month may be missing.

In this case the first day of the month will be used. This is to allow the protocol deviation to have 
occurred at the earliest possible date. 
 
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9.8.
Appendix 11: Abbreviations & Trade Marks
9.8.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CS
Clinical Statistics
CSR
Clinical Study Report
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
FF/VI
Fluticasone Furoate/ Vilanterol Inhalation Powder Combination
GCSP
Global Clinical Safety Pharmacovigilance
GSK
GlaxoSmithKline
ICH
International Conference on Harmonisation
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
GUI
Guidance
LRTI
Lower Respiratory Tract Infection
MMRM
Mixed Model Repeated Measures
PCI
Potential Clinical Importance 
PDMP
Protocol Deviation Management Plan
PP
Per Protocol
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomisation & Medication Ordering System 
SAC
Statistical Analysis Complete
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
VI
Vilanterol Inhalation Powder 
 
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9.8.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
ELLIPTA
HARP
SAS
 
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9.9.
Appendix 12: List of Data Displays
9.9.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.001 to 1.XXX
1.001 to 1.XXX
Safety 
2.001 to 2.XXX
2.001 to 2.XXX
Section
Listings
ICH Listings
1 to XX
Other Listings
XX to YY
9.9.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required an example 
mock-up displays provided in Appendix 13 15: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_F
POP_T
POP_L
Safety
SAFE_F
SAFE_T
SAFE_L
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / TST ID / Example Shell’ or ‘Programming Notes’ column as 
‘[Non-Standard] + Reference.’
9.9.3.
Deliverable [Priority]
Delivery [Priority] [1]
Description
SAC [1]
Final Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort.
 
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9.9.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
Enrolled
SP1
Summary of Study Populations 
IDSL
SAC [1]
1.2.
SAF
ES1
Summary of Subjects Disposition for the Subjects Conclusion 
Record
ICH E3, FDAAA, EudraCT
SAC [1]
1.3.
SRIF
ES6
Summary of Pre-screening, Screening and Run-in Status and 
Reasons for Screen and Run-in Failure
Journal Requirements, Page by 
Screening and Run-in
SAC [1]
1.4.
Enrolled
NS1
Summary of Number of Subjects Enrolled by Country and Site 
ID
EudraCT/Clinical Operations
SAC [1]
1.5.
SAF
SP2
Summary of Attendance at Each Clinic Visit
SAC [1]
Protocol Deviation
1.6.
SAF
DV1
Summary of Important Protocol Deviations
ICH E3
SAC [1]
1.7.
SAF
IE1
Summary of Inclusion/ Exclusion Deviations 
SAC [1]
1.8.
Screened 
IE2
Summary of Failed Inclusion/ Exclusion Criteria 
Include ‘Number of Screen or Run-in 
Failures’ row at the top of the table.  
This is to be used as the denominator 
for the % calculations.
SAC [1]
Demographic and Baseline Characteristics
1.9.
SAF
DM1 
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
SAC [1]
1.10.
SAF
DM1 
Summary of Demographic Characteristics by Country
SAC [1]
1.11.
Enrolled
DM11
Summary of Age Ranges
EudraCT
SAC [1]
1.12.
SAF
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, EudraCT
SAC [1]
1.13.
SAF
DM6
Summary of Race and Racial Combination Details
SAC [1]
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Prior and Concomitant Medications
1.14.
SAF
MH4
Summary of Current Medical Conditions
ICH E3
SAC [1]
1.15.
SAF
MH4
Summary of Past Medical Conditions
ICH E3
SAC [1]
1.16.
SAF
POP_T01
Summary of Cardiovascular History/Risk Factors
SAC [1]
1.17.
SAF
SP07
Summary of Family History of Cardiovascular Risk Factors at 
Screening
SAC [1]
1.18.
SAF
POP_T02
Summary of Disease Duration
ICH E3
SAC [1]
1.19.
SAF
CM1
Summary of Pre-treatment COPD Medications
ICH E3
SAC [1]
1.20.
SAF
CM1
Summary of On-treatment COPD Concomitant Medications
ICH E3
SAC [1]
1.21.
SAF
SP11
Summary of On-treatment Concomitant Medications Not Given 
for a COPD Exacerbation 
ICH E3
SAC [1]
1.22.
SAF
SP11
Summary of On-treatment Concomitant Medications Given for a 
COPD Exacerbation 
ICH E3
SAC [1]
1.23.
SAF
CM1
Summary of Post-treatment COPD Medications
ICH E3
SAC [1]
1.24.
SAF
CM1
Summary of On-treatment BMD Concomitant Medications
ICH E3
SAC [1]
1.25.
SAF
CM1
Summary of Post-treatment BMD Medications
ICH E3
SAC [1]
1.26.
SAF
CM1
Summary of On-treatment Other Concomitant Medications
ICH E3. Other concomitant 
mediations are all non-BMD and 
non-COPD medications.
SAC [1]
1.27.
SAF
CM1
Summary of Post-treatment Other Medications
ICH E3
SAC [1]
1.28.
SAF
SU1
Summary of Smoking History at Screening
SAC [1]
1.29.
SAF
Summary of Baseline Bone Mineral Density Test Results
SAC [1]
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Baseline Spirometry
1.30.
SAF
SP12
Summary of Lung Function Test Results at Screening and 
Randomisation 
Include Pre- and Post- albuterol 
(salbutamol) FEV1, FVC, FEV1/FVC 
and % Predicted Normal and post-
BD at screening %predicted. Page 
by visit. Include overall and by 
treatment group.
SAC [1]
Treatment Compliance
1.31.
SAF
SP6
Summary of Treatment Compliance
ICH E3
SAC [1]
 
 
 
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9.9.5.
Study Population Figures
Study Population Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Time to Withdrawal
2.1.
SAF
POP_F01
Kaplan-Meier Plot of Time to Premature Discontinuation from 
Investigational Product
SAC [1]
 
 
 
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9.9.6.
Safety Tables
Safety: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Exposure
2.1.
SAF
EX1 
Summary of Exposure to Study Treatment
ICH E3
SAC [1]
BMD at Total Hip
2.2.
SAF
SAFE_T01
Summary of On-treatment Bone Mineral Density (g/cm^2) at the 
Total Hip
SAC [1]
2.3.
SAF
SAFE_T01
Summary of On-treatment Bone Mineral Density (g/cm^2) at the 
Total Hip by Gender
SAC [1]
2.4.
SAF
SAFE_T02
Summary of On-treatment Percentage Change in Bone Mineral 
Density (g/cm^2) at the Total Hip
Page by Gender
SAC [1]
2.5.
SAF
SAFE_T02
Summary of On-treatment Percentage Change in Bone Mineral 
Density (g/cm^2) at the Total Hip by Gender
SAC [1]
2.6.
SAF
SAFE_T03
Summary of On-treatment T and Z Scores for Bone Mineral 
Density at the Total Hip
Page by Gender
SAC [1]
2.7.
SAF
SAFE_T03
Summary of On-treatment T and Z Scores for Bone Mineral 
Density at the Total Hip by Gender
SAC [1]
2.8.
SAF
SAFE_T04
Analysis of On-treatment Percentage Change from Baseline in 
Bone Mineral Density (g/cm^2)  at the Total Hip 
SAC [1]
2.9.
SAF
SAFE_T04
Analysis of On-treatment Percentage Change from Baseline in 
Bone Mineral Density (g/cm^2) at the Total Hip by Gender
SAC [1]
2.10.
SAF
SAFE_T05
On-treatment Bone Mineral Density (g/cm^2) at the Total Hip 
Mixed Model Repeated Measures Analysis Interaction Test
SAC [1]
 
 
 
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Safety: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
BMD at Lumbar Spine (L1-L4)
2.11.
SAF
SAFE_T01
Summary of On-treatment Bone Mineral Density (g/cm^2) at the 
Lumbar Spine 
SAC [1]
2.12.
SAF
SAFE_T01
Summary of On-treatment Bone Mineral Density (g/cm^2) at the 
Lumbar Spine by Gender
SAC [1]
2.13.
SAF
SAFE_T02
Summary of On-treatment Percentage Change in Bone Mineral 
Density (g/cm^2) at the Lumbar Spine
SAC [1]
2.14.
SAF
SAFE_T02
Summary of On-treatment Percentage Change in Bone Mineral 
Density (g/cm^2) at the Lumbar Spine by Gender
SAC [1]
2.15.
SAF
SAFE_T03
Summary of On-treatment T and Z Scores for Bone Mineral 
Density at the Lumbar Spine 
SAC [1]
2.16.
SAF
SAFE_T03
Summary of On-treatment T and Z Scores for Bone Mineral 
Density at the Lumbar Spine by Gender
SAC [1]
2.17.
SAF
SAFE_T04
Analysis of On-treatment Percentage Change from Baseline in 
Bone Mineral Density (g/cm^2) at the Lumbar Spine
SAC [1]
2.18.
SAF
SAFE_T04
Analysis of On-treatment Percentage Change from Baseline in 
Bone Mineral Density (g/cm^2) at the Lumbar Spine by Gender
SAC [1]
2.19.
SAF
SAFE_T05
On-treatment Bone Mineral Density (g/cm^2) at the Lumbar 
Spine Mixed Model Repeated Measures Analysis Interaction 
Test
Only include the interaction for 
gender
SAC [1]
 
 
 
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Safety: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Vital Signs, Incidence of Fracture, Pneumonia, X-rays and COPD Exacerbations
2.20.
SAF
VS1
Summary of Vital Signs
All variables to have a row for 
minimum and maximum on-
treatment values along with having 
a row for early withdrawal.
SAC [1]
2.21.
SAF
VS1
Summary of Change from Baseline in Vital Signs
All variables to have a row for 
minimum and maximum on-
treatment values along with having 
a row for early withdrawal.
SAC [1]
2.22.
SAF
SAFE_T07
Summary of On-treatment Pneumonia
SAC [1]
2.23.
SAF
SAFE_T08
Summary of On-treatment Fractures
SAC [1]
2.24.
SAF
SAFE_T09
Summary of On-treatment Moderate/Severe COPD 
Exacerbations 
SAC [1]
2.25.
SAF
SAFE_T09
Summary of On-treatment Severe COPD Exacerbations 
SAC [1]
Spirometry 
2.26.
SAF
SAFE_T10
Summary of On-treatment FEV1 (L) at Clinic Visits
SAC [1]
2.27.
SAF
SAFE_T10
Summary of On-treatment FVC (L) at Clinic Visits
SAC [1]
Adverse Events
2.28.
SAF
Overview of On-treatment Adverse Events During the Study
SAC [1]
2.29.
SAF
AE1
Summary of On-treatment Adverse Events Leading to 
Permanent Discontinuation of Study Treatment or 
Withdrawal from the Study by System Organ Class and 
Preferred Term 
IDSL - Include rates.
SAC [1]
 
 
 
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Safety: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.30.
SAF
AE1 
Summary of On-treatment Adverse Events by System Organ 
Class and Preferred Term
ICH E3. Include rates.
SAC [1]
2.31.
SAF
AE1 
Summary of On-treatment Adverse Events by Age
IDSL. Use age ranges: 40 to ≤65, 
>65 to ≤ 74, and ≥75
SAC [1]
2.32.
SAF
AE1 
Summary of On-treatment Adverse Events by Region
IDSL, North America vs Europe
SAC [1]
2.33.
SAF
AE1 
Summary of On-treatment Adverse Events by Gender
IDSL
SAC [1]
2.34.
SAF
AE1 
Summary of On-treatment Adverse Events by Smoking Status
IDSL
SAC [1]
2.35.
SAF
AE1 
Summary of Post-treatment Adverse Events by System Organ 
Class and Preferred Term
ICH E3. Include rates.
SAC [1]
2.36.
SAF
AE1 
Summary of On-treatment Drug-related Adverse Events by 
System Organ Class and Preferred Term
Include rates.
SAC [1]
2.37.
SAF
AE1
Summary of On-treatment Drug Related Adverse Events
Number and % of subjects
SAC [1]
2.38.
SAF
AE1
Summary of On-treatment Drug Related Serious Adverse 
Events
Number and % of subjects
SAC [1]
2.39.
SAF
AE3
Summary of Common (>=3%) On-treatment Adverse Events by 
Overall Frequency
ICH E3
SAC [1]
2.40.
SAF
AE15
Summary of Common (>=3%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences)
FDAAA, EudraCT
SAC [1]
Serious Adverse Events
2.41.
SAF
AE1 
Summary of On-treatment Serious Adverse Events by System 
Organ Class and Preferred Term
SAC [1]
2.42.
SAF
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences)
FDAAA, EudraCT. Include rates.
SAC [1]
 
 
 
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Safety: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.43.
SAF
AE1
Summary of On-treatment Serious Adverse Events Leading to 
Permanent Discontinuation of Study Treatment by System 
Organ Class and Preferred Term
IDSL
SAC [1]
2.44.
SAF
AE16
Summary of On-treatment Fatal Serious Adverse Events by 
System Organ Class and Preferred Term
SAC [1]
2.45.
SAF
AE16
Summary of On-treatment Non-fatal Serious Adverse Events by 
System Organ Class and Preferred Term
SAC [1]
2.46.
SAF
AE16
Summary of On-treatment Drug-related Serious Adverse Events 
by System Organ Class and Preferred Term
SAC [1]
Adverse Events of Special Interest
2.47.
SAF
AE1
Summary of On-treatment Adverse Events of Special Interest
Include rates.
SAC [1]
2.48.
SAF
AE1
Summary of On-treatment Serious Adverse Events of Special 
Interest
Include rates.
SAC [1]
 
 
 
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9.9.7.
Safety Figures
Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
BMD
2.1.
SAF
SAFE_F01
Raw Geometric Percentage Change from Baseline in On-
treatment Bone Mineral Density (g/cm^2) at the Total Hip Over 
Time 
SAC [1]
2.2.
SAF
SAFE_F01
Raw Geometric Percentage Change from Baseline in On-
treatment Bone Mineral Density (g/cm^2) at the Total Hip Over 
Time By Gender
SAC [1]
2.3.
SAF
SAFE_F01
Adjusted Mean Percentage Change from Baseline in On-
treatment Bone Mineral Density (g/cm^2) at the Total Hip
Add -1% per year clinical non-inferiority 
boundary with footnote.
SAC [1]
2.4.
SAF
SAFE_F01
Adjusted Percentage Change from Baseline in On-treatment 
Bone Mineral Density (g/cm^2) at the Total Hip Over Time
SAC [1]
2.5.
SAF
SAFE_F01
Adjusted Percentage Change from Baseline in On-treatment 
Bone Mineral Density (g/cm^2) at the Total Hip Over Time by 
Gender
SAC [1]
2.6.
SAF
SAFE_F01
Raw Geometric Percentage Change from Baseline in On-
treatment Bone Mineral Density (g/cm^2) at the Lumbar Spine 
Over Time
SAC [1]
2.7.
SAF
SAFE_F01
Raw Geometric Percentage Change from Baseline in On-
treatment Bone Mineral Density (g/cm^2) at the Lumbar Spine 
Over Time by Gender
SAC [1]
2.8.
SAF
SAFE_F01
Adjusted Percentage Change per Year from Baseline in On-
treatment Bone Mineral Density (g/cm^2) at the Lumbar Spine 
Add -1% per year clinical non-inferiority 
boundary with footnote.
SAC [1]
 
 
 
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2.9.
SAF
SAFE_F01
Adjusted Mean Percentage Change from Baseline in On-
treatment Bone Mineral Density (g/cm^2) at the Lumbar Spine 
Over Time
SAC [1]
2.10.
SAF
SAFE_F01
Adjusted Mean Percentage Change from Baseline in On-
treatment Bone Mineral Density (g/cm^2) at the Lumbar Spine 
Over Time by Gender 
SAC [1]
Adverse Events
2.11.
SAF
AE10
Plot of Common (>=3%) On-treatment Adverse Events and 
Relative Risk
IDSL
SAC [1]
 
 
 
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9.9.8.
ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
Screened
ES7
Listing of Reasons for Screen and Run-in Failure
Journal Guidelines
SAC [1]
2.
SAF
ES2 
Listing of Reasons for Study Withdrawal
ICH E3
SAC [1]
3.
SAF
BL1
Listing of Subjects for Whom the Treatment Blind was Broken
ICH E3
SAC [1]
4.
SAF
TA1
Listing of Planned and Actual Treatments
IDSL
SAC [1]
Protocol Deviations
5.
SAF
DV2
Listing of Important Protocol Deviations 
ICH E3
SAC [1]
6.
SAF
IE3
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
ICH E3
SAC [1]
Populations Analysed
7.
SAF
SP3
Listing of Subjects Excluded from the Safety Population
ICH E3. Note: Only create if this 
population is used.
SAC [1]
Demographic and Baseline Characteristics
8.
SAF
DM2 / DM4
Listing of Demographic Characteristics
ICH E3
SAC [1]
9.
SAF
DM9 / DM10
Listing of Race
ICH E3
SAC [1]
Exposure and Treatment Compliance
10.
SAF
EX3 
Listing of Exposure Data
ICH E3
SAC [1]
Adverse Events
11.
SAF
AE8 
Listing of All Adverse Events
ICH E3
SAC [1]
12.
SAF
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
SAC [1]
13.
SAF
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
IDSL
SAC [1]
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Serious and Other Significant Adverse Events
14.
SAF
AE8
Listing of All Serious Adverse Events
ICH E3
SAC [1]
15.
SAF
AE8
Listing of Fatal Serious Adverse Events
ICH E3
SAC [1]
16.
SAF
AE8
Listing of Non-Fatal Serious Adverse Events
ICH E3
SAC [1]
17.
SAF
AE14
Listing of Reasons for Considering as a Serious Adverse Event
ICH E3
SAC [1]
18.
SAF
AE8
Listing of Non-Serious Adverse Events Leading to Withdrawal 
from Study / Permanent Discontinuation of Study Treatment
ICH E3
SAC [1]
19.
SAF
AE8
Listing of Serious Adverse Events Leading to Withdrawal from 
Study / Permanent Discontinuation of Study Treatment
ICH E3
SAC [1]
Hepatobiliary (Liver)
20.
SAF
MH2
Listing of Medical Conditions for Subjects with Liver Stopping 
Events
IDSL
SAC [1]
21.
SAF
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events
IDSL
SAC [1]
All Laboratory
22.
SAF
LB14
Listing of Laboratory Data 
ICH E3
SAC [1]
Bone Mineral Density
23.
SAF
SAFE_L01
Listing of Bone Mineral Density, T and Z Scores at the Total Hip
SAC [1]
24.
SAF
SAFE_L01
Listing of Bone Mineral Density, T and Z Scores at the Lumbar 
Spine
SAC [1]
 
 
 
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9.9.9.
Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Study Population
25.
SAF
SP2
Listing of the Follow-up Contact
SAC [1]
26.
SAF
TA1
Listing of Treatment Misallocations
Change Centre ID to Investigator 
ID: xxxxxx and also Investigator at 
Centre: xxxxxx 
SAC [1]
27.
SAF
SP4
Listing of Overall Percentage Treatment Compliance
SAC [1]
Adverse Events
28.
SAF
S3
Listing of COPD Exacerbation 
Include a column for severity 
SAC [1]
29.
SAF
S3
Listing of Pneumonia Data, Including Chest X-Ray Finding
Include a column for severity and 
total events per subject
SAC [1]
30.
SAF
S3
Listing of Bone Fractures
Include a column for pre- treatment 
/on- treatments / Follow-up
SAC [1]
31.
SAF
ESI8
Listing of AE Terms of Special Interest 
IDSL
SAC [1]
 
 
 
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Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Medical History and Concomitant Medications
32.
SAF
MH2
Listing of Medical Conditions at Screening
SAC [1]
33.
SAF
SP5
Listing of Family History of Cardiovascular Risk Factors
SAC [1]
34.
SAF
SP6
Listing of COPD History
SAC [1]
35.
SAF
SP7
Listing of Smoking History and Smoking Status
SAC [1]
36.
SAF
CM2
Listing of COPD Concomitant Medications
Include COPD history and 
Exacerbation history for pre-, on-
and post- treatment
SAC [1]
37.
SAF
CM2
Listing of Bone Mineral Density Medications
Include pre-, on- and post-
treatments
SAC [1]
38.
SAF
CM2
Listing of Other Concomitant Medications
Include pre-, on- and post-
treatments. Other concomitant 
mediations are all non-BMD and 
non-COPD medications.
SAC[1]
39.
SAF
CM6
Relationship between ATC Level 1, Ingredient and Verbatim 
Text for Bone Mineral Density and Other Medications
SAC [1]
Other Safety Data
40.
SAF
VS4 
Listing of All Vital Signs Data 
IDSL
SAC [1]
Lung Function
41.
SAF
SP10
Listing of Lung Function Results
SAC [1]
Liver Events: Note only produced if there is a Liver Event
42.
SAF
VS4
Listing of Liver Events
SAC [1]
43.
SAF
VS4
Listing of Liver Event Information for RUCAM Score
SAC [1]
44.
SAF
VS4
Listing of Liver Biopsy
SAC [1]
 
 
 
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Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
45.
SAF
VS4
Listing of Liver Imaging Details
SAC [1]
Cardiovascular Events: Note only produced if there is a Cardiovascular Event
46.
SAF
VS4
Listing of Myocardial infarction/unstable angina
SAC [1]
47.
SAF
VS4
Listing of Congestive heart failure
SAC [1]
48.
SAF
VS4
Listing of Arrhythmias
SAC [1]
49.
SAF
VS4
Listing of Valvulopathy
SAC [1]
50.
SAF
VS4
Listing of Pulmonary hypertension
SAC [1]
51.
SAF
VS4
Listing of Cerebrovascular events/stroke and transient ischemic 
attack
SAC [1]
52.
SAF
VS4
Listing of Peripheral arterial thromboembolism
SAC [1]
53.
SAF
VS4
Listing of Deep venous thrombosis/pulmonary embolism
SAC [1]
54.
SAF
VS4
Listing of Revascularisation
SAC [1]
55.
SAF
VS4
Listing of Deaths
SAC [1]
 
 
 
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9.10.
Appendix 13: Example Mock Shells for Data Displays
Data Display Specification will be made available on Request.
 
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