TITLE PAGE - GSK Clinical Study Register · PDF fileFive Moore Drive P.O. 13398 Research Triangle Park, NC 27709-3398, USA Telephone: ... under thegiven hospital’s/clinic’s/institution’s

2013N183049_02 CONFIDENTIALThe GlaxoSmithKline group of companies 200820

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TITLE PAGE

Division: Worldwide DevelopmentInformation Type: Protocol Amendment

Title: Protocol 200820: Country-Specific Protocol Amendment for South Korea

Compound Number: GW685698+GW642444

Development Phase: III

Effective Date: 13-OCT-2014

Protocol Amendment Number: 02

Author (s):

Revision Chronology

GlaxoSmithKlineDocument Number

Date Version

2013N183049_00 2013-DEC-19 Original

2013N183049_01 2014-OCT-13 Amendment No. 01: Country-Specific Protocol Amendment for Applicable Sites in Japan

2013N183049_02 2014-OCT-13 Amendment No. 02: Country-Specific Protocol Amendment for South Korea

Amendment No. 02: Country-Specific Amendment for South Korea

Purpose of amendment: Provide additional detail regarding the a priori-defined blinded data review to assess whether the sample size re-estimation requires re-adjustment, in response to a request from the Ministry of Food and Drug Safety in South Korea

Copyright 2014 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:

Sponsor Legal Registered Address:

GlaxoSmithKline Research & Development Limited980 Great West RoadBrentfordMiddlesex, TW8 9GSUK

Sponsor Contact Address

GlaxoSmithKline Research & Development LimitedIron Bridge Road Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UKTelephone:

GlaxoSmithKline Research & Development LimitedFive Moore Drive P.O. 13398Research Triangle Park, NC 27709-3398, USATelephone:

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:

Primary Medical Monitor:

M.D.GlaxoSmithKlineFive Moore Drive P.O. 13398Research Triangle Park, NC 27709-3398, USATelephone:

Alternate Medical Monitors*:

Europe/South Africa

M.D.GlaxoSmithKlineIron Bridge RoadStockley Park West, UxbridgeMiddlesex UB11 1BT, UK

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* Dr. is the primary medical monitor; however, due to time zone differences, the alternate medical monitor may be contacted in the event that the primary medical monitor is not available.

Sponsor Serious Adverse Events (SAE) Contact Information:

Case Management Group, GCSP – Stockley Park, UKE-mail: Fax:

Regulatory Agency Identifying Number(s):

FDA IND Number: 077855 and 074696; EudraCT #: 2013-004548-44

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INVESTIGATOR PROTOCOL AGREEMENT PAGE

For protocol number 200820:

I confirm agreement to conduct the study in compliance with the protocol, as amended by this protocol amendment.

I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or supervise the described study.

I agree to ensure that all associates, colleagues and employees assisting in the conduct of the study are informed about their obligations. Mechanisms are in place to ensure that site staff receives the appropriate information throughout the study.

Investigator Name:

Investigator Address:

Investigator Phone Number:

Investigator Signature Date

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SECTION 8.2.3. SAMPLE SIZE RESTIMATION

Provide additional detail regarding the a priori-defined blinded data review to assess whether the sample size re-estimation requires re-adjustment, in response to a request from the Ministry of Food and Drug Safety in South Korea.

Original Text:

To understand the variability in the data and, therefore, whether the sample size requires re-adjustment, a blinded review of the trough FEV1 data is planned after 50% of the subjects have completed 4 weeks of double-blind treatment. This review will also evaluate the assumption on the withdrawal rate.

Revised Text:


All available data for subjects with post-baseline trough FEV1 measurements will be used in the analysis.

As the review will be blinded, treatment will not be allowed for in any calculations.

The standard deviation will be estimated in 2 ways:

a. A raw standard deviation of the data will be calculated

b. MMRM without treatment in the model to give us a residual standard deviation

Existing data will be used to allow exploration of the relationship between the SDs obtained from 1a and 1b above with the intended final model based residual SD.

If the variability is vastly different to our sample size assumptions, this would prompt investigation into whether a sample size adjustment should be implemented. If it is only slightly different, then it is unlikely this would prompt any sample sizemodification.

Although no explicit imputation for missing data will be made, the MMRM model is consistent with the primary analysis model that will be used at the end of the study and it is not expected that missing data will have a big impact on the estimate of standard deviation. As it is only a 12-week study with 2 active treatment arms, a large amount of missing data is not expected.

This review will also evaluate the assumption on the withdrawal rate. If a higher rate is observed than originally planned for, then this would be examined in conjunction with the observed blinded variability to assess whether a sample size adjustment should be implemented.

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TITLE PAGE

Division: Worldwide DevelopmentInformation Type: Protocol Amendment

Title: Protocol 200820: Country-Specific Protocol Amendment for Applicable Sites in Japan


Development Phase: III

Effective Date: 13-OCT-2014

Protocol Amendment Number: 01

Author (s):

Revision Chronology

GlaxoSmithKlineDocument Number

Date Version

2013N183049_00 2013-DEC-19 Original

2013N183049_01 2014-OCT-13 Amendment No. 01

Country-Specific Protocol Amendment for Applicable Sites in Japan

Purpose of amendment:

Applicable Sites in Japan: Addition of oxitropium bromide (an anticholinergic) as a permitted medication during the study for subjects at applicable sites in Japan whereoxitropium bromide is a covered medication instead of or in addition to ipratropium bromide (an anticholinergic) under the given hospital’s/clinic’s/institution’s formulary


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GlaxoSmithKline Research & Development LimitedIron Bridge Road Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UKTelephone:







Europe/South Africa


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For protocol number 200820:

I confirm agreement to conduct the study in compliance with the protocol, as amended by this protocol amendment.

I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or supervise the described study.


Investigator Name:

Investigator Address:

Investigator Phone Number:


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SECTION 1.3.1 RISK ASSESSMENT

Study Design and Procedures, Data /Rationale for Risk, Page 23

Original Text

“…The use of rescue medication (albuterol [salbutamol]) and/or ipratropium bromide alone must be withheld for 4 hours prior to and during each clinic visit…”

Revised Text

“…The use of rescue medication (albuterol [salbutamol]) and/or ipratropium bromide alone must be withheld for 4 hours prior to and during each clinic visit. [Applicable Sites in Japan: The use of oxitropium bromide alone must be withheld for 8 hours prior to and during each clinic visit]…”

SECTION 4.3 EXCLUSION CRITERIA

Criterion #17 (Medication prior to spirometry), Page 33

Original Text

17. Medication prior to spirometry: Subjects who are medically unable to withhold their albuterol (salbutamol) or their ipratropium bromide for the 4-hour period required prior to spirometry testing at each study visit.

Revised Text

17. Medication prior to spirometry: Subjects who are medically unable to withhold their albuterol (salbutamol) or their ipratropium bromide for the 4-hour periodrequired prior to spirometry testing at each study visit [Applicable Sites in Japan:or their oxitropium bromide alone for the 8-hour period required prior to spirometry testing at each study visit].

Criterion #18 (Additional medication), Page 34

Revised Text

Addition of the following row and footnote:

Medication No use within the following time intervalsprior to Screening (Visit 1) and thereafter at

any time during the study[Applicable Sites in Japan: oxitropium bromide/albuterol [salbutamol] combination products3

8 hours]

3. Oxitropium bromide alone is permitted, provided that the subject is on a stable dose from the Screening Visit and remains on this stable dose throughout the study; however, it must be withheld for at least 8 hours prior to and during each clinic visit. Concomitant use of both ipratropium bromide and oxitropium bromide is not permitted during the study.

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SECTION 5.6.1. PERMITTED MEDICATIONS AND NON-DRUG THERAPIES

COPD Medications, Page 44

Revised Text

Addition of the following bullet:

[Applicable Sites in Japan: Oxitropium bromide alone is permitted, provided that the subject is on a stable dose from Screening (Visit 1) and remains on this stable dose throughout the study; however, it must be withheld for 8 hours prior to and during each clinic visit

Note: Concomitant use of both ipratropium bromide and oxitropium bromide is not permitted during the study]

SECTION 6.2.5. DIARY CARD ASSESSMENTS

Page 53

Original Text

“Each morning (from the morning following the Screening Visit until completion of the Treatment Period or Early Withdrawal Visit), subjects will be instructed to complete the Daily Diary, prior to taking study medication (i.e., single-blind or double-blind) and rescue medication (albuterol [salbutamol] if applicable) and ipratropium (if applicable) and to base their assessment of symptoms experienced over the last 24 hours…”

Revised Text

“Each morning (from the morning following the Screening Visit until completion of the Treatment Period or Early Withdrawal Visit), subjects will be instructed to complete theDaily Diary, prior to taking study medication (i.e., single-blind or double-blind) andrescue medication (albuterol [salbutamol] if applicable) and ipratropium [Applicable Sites in Japan: oxitropium] (if applicable) and to base their assessment of symptoms experienced over the last 24 hours…”

SECTION 6.2.5.1. COPD SYMPTOM EVALUATIONS

Page 54

Original Text

“…Subjects will be instructed to complete the diary in the morning, prior to taking studymedication (i.e., single-blind, and double-blind), supplemental medication (albuterol[salbutamol] if applicable) and ipratropium bromide (if applicable) and to base their assessment on symptoms experienced over the last 24 hours…”

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Revised Text

“…Subjects will be instructed to complete the diary in the morning, prior to taking studymedication (i.e., single-blind, and double-blind), supplemental medication (albuterol[salbutamol] if applicable) and ipratropium bromide [Applicable Sites in Japan: oxitropium bromide] (if applicable) and to base their assessment on symptoms experienced over the last 24 hours…”

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TITLE PAGE

Division: Worldwide DevelopmentInformation Type: Clinical Protocol

Title: A 12-Week Study to Evaluate the Efficacy and Safety of Fluticasone Furoate/Vilanterol Inhalation Powder (FF/VI) 100/25 mcg Once Daily Compared with Vilanterol InhalationPowder (VI) 25 mcg Once Daily in Subjects with Chronic Obstructive Pulmonary Disease (COPD)


Development Phase III

Effective Date: 19-DEC-2013

Subject: COPD, Fluticasone Furoate (FF), Vilanterol (VI), Dry Powder Inhaler

Author(s):


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GlaxoSmithKline Research & Development LimitedIron Bridge RoadStockley Park West, Uxbridge, Middlesex, UB11 1BU, UKTelephone:







Europe/South Africa


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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.


Investigator Name: _____________________________


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TABLE OF CONTENTS

PAGE

LIST OF ABBREVIATIONS.............................................................................................9

PROTOCOL SUMMARY...............................................................................................12

1. INTRODUCTION....................................................................................................171.1. Background ................................................................................................171.2. Rationale ....................................................................................................171.3. Benefit:Risk Assessment ............................................................................18

1.3.1. Risk Assessment .........................................................................191.3.2. Benefit Assessment .....................................................................241.3.3. Overall Benefit:Risk Conclusion...................................................25

2. OBJECTIVE(S) ......................................................................................................252.1. Primary .......................................................................................................252.2. Secondary ..................................................................................................252.3. Exploratory Objective..................................................................................25

3. INVESTIGATIONAL PLAN.....................................................................................253.1. Study Design ..............................................................................................253.2. Discussion of Design ..................................................................................27

4. SUBJECT SELECTION AND WITHDRAWAL CRITERIA.......................................294.1. Number of Subjects ....................................................................................294.2. Inclusion Criteria .........................................................................................294.3. Exclusion Criteria........................................................................................314.4. Withdrawal Criteria .....................................................................................364.5. Screening/Run-in Failures ..........................................................................37

4.5.1. Re-Screening Criteria ..................................................................384.6. Early Withdrawals .......................................................................................38

5. STUDY TREATMENTS..........................................................................................405.1. Investigational Product and Other Study Treatment....................................40

5.1.1. Storage........................................................................................415.1.2. Investigational Product Return .....................................................42

5.2. Treatment Assignment................................................................................425.3. Blinding.......................................................................................................425.4. Product Accountability ................................................................................435.5. Treatment Compliance................................................................................435.6. Concomitant Medications and Non-Drug Therapies....................................44

5.6.1. Permitted Medications and Non-Drug Therapies..........................445.6.2. Prohibited Medications and Non-Drug Therapies.........................45

5.7. Treatment after the End of the Study ..........................................................455.8. Treatment of Study Treatment Overdose....................................................45

6. STUDY ASSESSMENTS AND PROCEDURES .....................................................466.1. Critical Baseline Assessments ....................................................................506.2. Efficacy.......................................................................................................51

6.2.1. Primary Endpoint .........................................................................51

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6.2.2. Secondary Endpoints...................................................................516.2.3. Other Endpoints...........................................................................516.2.4. Spirometry and Reversibility Testing............................................52

6.2.4.1. Spirometry..................................................................526.2.4.2. Reversibility ................................................................53

6.2.5. Diary Card Assessments .............................................................536.2.5.1. COPD Symptom Evaluations......................................546.2.5.2. Supplemental Albuterol (Salbutamol) Use ..................546.2.5.3. Nighttime Awakenings Requiring Albuterol

(Salbutamol) ...............................................................546.2.5.4. Medical Problems/Medications Taken ........................55

6.2.6. COPD Exacerbations and Pneumonia .........................................556.2.7. St. George’s Respiratory Questionnaire – Chronic

Obstructive Pulmonary Disorder Questionnaire (SGRQ-C)..........576.2.8. COPD Assessment Test (CAT)....................................................58

6.3. Safety .........................................................................................................586.3.1. Liver Chemistry Stopping and Follow-up Criteria .........................586.3.2. Adverse Events............................................................................61

6.3.2.1. Definition of an AE......................................................626.3.2.2. Definition of an SAE ...................................................636.3.2.3. Sentinel Events ..........................................................64

6.3.3. Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs.........................................................64

6.3.4. Cardiovascular Events .................................................................656.3.5. Death Events ...............................................................................656.3.6. Disease-Related Events and/or Disease-Related

Outcomes Not Subject to Expedited Reporting ............................656.3.7. Pregnancy ...................................................................................656.3.8. Medical Devices...........................................................................666.3.9. Time Period and Frequency of Detecting AEs and SAEs.............676.3.10. Method of Detecting AEs and SAEs.............................................686.3.11. Prompt Reporting of Serious Adverse Events and Other

Events to GSK .............................................................................686.3.11.1. Regulatory Reporting Requirements for SAEs............71

6.3.12. Vital Signs....................................................................................716.3.13. 12-lead ECG Assessments..........................................................716.3.14. Oropharyngeal Examination.........................................................726.3.15. Clinical Laboratory Assessments .................................................726.3.16. Smoking Cessation Counselling ..................................................73

6.4. Health Outcomes........................................................................................736.4.1. Health Outcome Assessments Not Included as Primary or

Key Secondary Endpoints............................................................736.5. Exploratory Endpoint ..................................................................................736.6. Pharmacogenetic Research........................................................................74

7. DATA MANAGEMENT ...........................................................................................74

8. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................748.1. Hypotheses.................................................................................................748.2. Study Design Considerations......................................................................75

8.2.1. Sample Size Assumptions ...........................................................758.2.2. Sample Size Sensitivity................................................................75

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8.2.3. Sample Size Re-estimation..........................................................778.3. Data Analysis Considerations .....................................................................77

8.3.1. Analysis Populations....................................................................778.3.2. Analysis Data Sets.......................................................................788.3.3. Treatment Comparisons ..............................................................78

8.3.3.1. Primary Comparisons of Interest ................................788.3.3.2. Other Comparisons of Interest....................................78

8.3.4. Interim Analysis ...........................................................................788.3.5. Key Elements of Analysis Plan ....................................................78

8.3.5.1. Efficacy Analyses .......................................................798.3.5.2. Safety Analyses..........................................................79

8.3.5.2.1. Extent of Exposure .................................798.3.5.2.2. Adverse Events (AEs).............................798.3.5.2.3. Deaths and SAEs ...................................808.3.5.2.4. Adverse Events of Special Interest

(AESI).....................................................808.3.5.2.5. Pneumonia .............................................80

8.3.5.3. Health Outcomes Analyses ........................................808.3.5.3.1. SCRQ-C and CAT ..................................808.3.5.3.2. Exploratory Endpoint ..............................81

8.3.5.4. Pharmacogenetic Analyses ........................................81

9. STUDY CONDUCT CONSIDERATIONS ...............................................................819.1. Posting of Information on Publicly Available Clinical Trial Registers............819.2. Regulatory and Ethical Considerations, Including the Informed

Consent Process ........................................................................................819.3. Quality Control (Study Monitoring) ..............................................................829.4. Quality Assurance.......................................................................................829.5. Study and Site Closure ...............................................................................829.6. Records Retention ......................................................................................839.7. Provision of Study Results to Investigators, Posting of Information

on Publicly Available Clinical Trials Registers and Publication ....................839.8. Independent Data Monitoring Committee (IDMC) .......................................84

10. REFERENCES.......................................................................................................85

11. APPENDICES ........................................................................................................8811.1. Appendix 1: ECG Exclusion/Withdrawal Criteria .........................................8811.2. Appendix 2: Clinical Laboratory Assessments ............................................9011.3. Appendix 3: Pharmacogenetic Research ....................................................9111.4. Appendix 4: Country Specific Requirements ...............................................9711.5. Appendix 5: Liver Chemistry Stopping and Follow-up Criteria.....................98

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LIST OF ABBREVIATIONS

AE Adverse EventALAT Alanine Amino-TransferaseALT Alanine TransaminaseAM MorningANCOVA Analysis of CovarianceASAT Aspartate Amino-TransferaseATS American Thoracic SocietyAST Aspartate TransaminaseAV AtrioventricularBP Blood PressureBPM Beats Per MinuteCASA-Q Cough and Sputum Assessment QuestionnaireCAT COPD Assessment TestCI Confidence IntervalCOPD Chronic Obstructive Pulmonary DiseaseCPAP Continuous Positive Airway PressureCPK Creatine PhophokinaseCT Computerized TomographyCV CardiovascularDNA Deoxyribonucleic AcidDSUR Data Safety Update ReportECG ElectrocardiogrameCRF Electronic Case Report FormEU EuropeEW Early WithdrawalFDA Food and Drug AdministrationFEV1 Forced Expiratory Volume in One SecondFF Fluticasone FuroateFF/VI Fluticasone Furoate/Vilanterol Inhalation Powder

CombinationFP Fluticasone PropionateFVC Forced Vital CapacityGCP Good Clinical PracticeGCSP Global Clinical Safety and PharmacovigilanceGGT Gamma Glutamyl TransferaseGLI Global Lung Function InitiativeGOLD Global Initiative for Chronic Obstructive Lung DiseaseGSK GlaxoSmithKlinehCG Human Chorionic GonadotropinHPA Hypothalamic Pituitary AdrenalHPLC High-Performance Liquid ChromatographyIB Investigator’s BrochureICF Informed Consent FormICS Inhaled CorticosteroidIDMC Independent Data Monitoring Committee

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IEC Independent Ethics CommitteeIgG Immunoglobulin GIgM Immunoglobulin MIND Investigational New DrugIP Investigational ProductINR International Normalized RatioIRB Institutional Review BoardITT Intent to TreatIVD In vitro DiagnosticsIVRS Interactive Voice Response SystemLABA Long-Acting Beta-AgonistLAMA Long-Acting Muscarinic AntagonistLDH Lactate DehydrogenaseLTOT Long Term Oxygen TherapyMAOI Monoamine Oxidase Inhibitormcg MicrogramMDI Metered Dose InhalerMedDRA Medical Dictionary for Regulatory ActivitiesMI Myocardial InfarctionmL MilliliterMMRM Mixed Models Repeated MeasuresMSDS Material Safety Data SheetNIPPV Non-Invasive Positive Pressure VentilationOTC Over the CounterPCR Polymerase Chain ReactionPD PharmacodynamicPK PharmacokineticPGx PharmacogeneticsPM EveningPR Pulse RatePRN As neededQD Once DailyQTc Corrected QT intervalQTcB Corrected QT interval - Bazett’s formulaQTcF Corrected QT interval - Fridericia’s formulaRAMOS Registration and Medication Ordering SystemRAP Reporting Analysis PlanRMP Risk Management PlanRNA Ribonucleic AcidSAE Serious Adverse EventSD Standard DeviationSFC Salmeterol/Fluticasone Propionate CombinationSGOT Serum Glutamic Oxaloacetic TransaminaseSGPT Serum Glutamic Pyruvic TransaminaseSGRQ-C St. George Respiratory Questionnaire – COPD SpecificSOC System Organ ClassSPM Study Procedures ManualSRT Safety Review Team

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TORCH TOwards a Revolution in COPD HealthULN Upper Limit of NormalUS United States of AmericaVI VilanterolWBCWHO

White Blood CellWorld Health Organization

Trademark Information

Trademarks of the GlaxoSmithKline group of companies

Trademarks not owned by the GlaxoSmithKline group of companies

ACCUHALER CASA-QADOAIR InFormADVAIR SASBREO SGRQ-CCOPD Assessment Test SymbicortDISKUS TurbohalerELLIPTARELVAR

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PROTOCOL SUMMARY

Rationale

Chronic obstructive pulmonary disease (COPD) has been defined as a preventable and treatable disease with some significant extrapulmonary 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, 2013] and contributing significantly to health care costs and morbidity [Chapman, 2006; Lopez, 2006]. According to the World Health Organization (WHO), an estimated 64 million people had COPD worldwide in 2004 and more than 3 million people died of COPD in 2005, which is equal to 5% of all deaths globally that year [WHO, 2012]. The WHO predicts that COPD will become the leading cause of death worldwide by 2030 [WHO, 2012].

Current 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, 2013]. Recent clinical research has indicated that an inhaled corticosteroid (ICS) combined with a long acting beta2-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 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 (ICS) 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.

Fluticasone furoate, as the ICS component, and VI, as the LABA component, of an ICS/LABA combination had been developed for use as a once-daily treatment in asthma and COPD. FF/VI is the first, once-daily ICS/LABA. FF/VI Inhalation Powder 100/25 mcg QD (trade name BREO™ ELLIPTA™) is approved in the United States (May 2013) and Canada (July 2013) for the maintenance treatment of airflow obstruction and for reducing exacerbations in patients with COPD and in Europe (November 2013, trade name RELVAR™ ELLIPTA™) for the regular treatment of asthma (in adults and adolescents aged 12 years and older where use of a combination medicinal product [long-acting beta2-agonist and inhaled corticosteroid] is appropriate: patients not adequately controlled with inhaled corticosteroids and 'as needed' inhaled short-acting beta2-agonists) and for the symptomatic treatment of adults with COPD with a FEV1<70%

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predicted normal (post-bronchodilator) with an exacerbation history despite regular bronchodilator therapy. RELVAR ELLIPTA is approved in Japan (September 2013) for the treatment of bronchial asthma (in cases where concurrent use of inhaled corticosteroid and long-acting inhaled beta2 agonist is required); currently, RELVAR ELLIPTA is not approved for the treatment of COPD in Japan. Applications for the treatment of asthma and COPD are currently under review in other countries worldwide. Two other ICS/LABA combinations are currently available worldwide for treatment of COPD, fluticasone propionate/salmeterol (trade names ADVAIR®, DISKUS®/ACCUHALER®, ADOAIR®) and budesonide/formoterol (Symbicort, Turbohaler) approved in the majority of the European countries). These medications require twice-daily administration. A once daily ICS/LABA combination has the potential to improve patient compliance and, as a result, overall disease management.

In the Phase III clinical development program in subjects with COPD, the contribution of VI 25mcg QD to the FF/VI 100/25 mcg QD combination was demonstrated by clinically meaningful and sustained improvement in lung function [Kerwin, 2013; Martinez, 2013] and the contribution of FF 100 mcg QD to the FF/VI 100/25 mcg QD combination was demonstrated by clinically meaningful reductions in the rate of moderate or severe COPD exacerbations, risk for time to first moderate or severe COPD exacerbation and rate of exacerbations requiring treatment with oral/systemic corticosteroids [Dransfield, 2013]. However, the contribution of FF 100 mcg to the combination on lung function, as determined by the comparison of FF/VI 100/25 with VI 25 on trough FEV1 was demonstrated numerically, but not statistically in either study HZC112206 or HZC112207 [Kerwin, 2013; Martinez, 2013]. Statistical significance may not have been achieved for the comparison between FF/VI 100/25 and VI 25 because, the studies were not adequately powered to detect treatment differences of the magnitude observed for FF/VI compared with VI alone, which was due to larger than planned variability and smaller than anticipated treatment differences . Demonstration of a statistically significant contribution of FF 100 mcg to the combination on lung function is pivotal for the approval of FF/VI 100/25 mcg QD for the treatment of COPD in Japan.

The present study will evaluate the efficacy and tolerability profile of FF/VI 100/25 mcg QD compared with VI 25mcg QD in subjects with COPD who have a history of at least one COPD exacerbation in the year prior to Screening and who demonstrate current symptoms of COPD. In particular, this study will assess the contribution on lung function (trough FEV1) of FF 100 mcg in the FF/VI 100/25 mcg QD combination.

Information on the physical, chemical and pharmaceutical properties of FF and VI, and a thorough summary of available pre-clinical and clinical data may be found in the FF/VI and VI Investigator Brochures (IBs).

Objective(s)

Primary Objective

The primary objective of the study is to evaluate the contribution on lung function (as measured by trough FEV1) of FF 100 mcg to FF/VI 100/25mcg QD by the comparison of the latter with VI 25mcg QD (each administered via the ELLIPTA™ inhaler) and the safety of FF/VI 100/25 mcg QD over a 12-week treatment period in subjects with COPD.

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Secondary Objective

Secondary objectives of the study are to:

Evaluate the effect of FF/VI 100/25 mcg QD compared with VI 25 mcg QD on subject-recordings of rescue medication (albuterol [salbutamol]) use and symptoms of COPD (breathlessness, cough and sputum production)

Evaluate the effect of FF/VI 100/25 mcg QD compared with VI 25 mcg QD on health-related quality of life using the using the St. George’s Respiratory Questionnaire – Chronic Obstructive Pulmonary Disorder (SGRQ-C)

Evaluate the effect of FF/VI 100/25 mcg QD compared with VI 25 mcg QD on COPD health status using the COPD Assessment Test (CAT)

Exploratory Objective

An exploratory objective of this study is to evaluate the effect of FF/VI 100/25 mcg QD compared with VI 25 mcg QD on COPD symptoms of cough and sputum using the Cough and Sputum Assessment Questionnaire (CASA-Q).

Study Design

This will be a 12-week, Phase IIIa, multicenter, randomized (1:1), stratified (reversibilitystatus), double-blind, parallel-group study to evaluate the efficacy and safety of FF/VI 100/25mcg QD compared with VI 25mcg QD, administered via the ELLIPTA; treatments will be administered in the morning.

Subjects will visit the clinic a minimum of seven times over a 14-week period (Screening Day -14 [Visit 1], Study Days 1, 2, 14, 28, 56, and 84 [Visit 7]). Subjects will sign the informed consent form (ICF) at Visit 0 and will be assigned a subject identifier. Subjectswho meet all of the Inclusion Criteria and none of the Exclusion Criteria will enter a 2-week, single-blind, placebo, Run-In Period following the Screening Visit (Visit 1). At the end of the Run-In Period (Visit 2), eligible subjects will be randomized (1:1) to double-blind investigational study medication and will enter a 12-week treatment period. Randomization will be stratified based upon the subject’s reversibility status (reversible/non-reversible). At the end of the 12-week Treatment Period, a safety follow-up phone contact (Study Day 91) will be completed 7 days after the last dose of study medicaton. Subjects will be provided with albuterol (salbutamol) to be used, as needed, throughout the Run-In and Treatment Periods. At the end of Treatment Period (Visit 7), subjects can resume conventional COPD therapy as prescribed by the Investigator. There are no plans to provide the investigational study medicaton for compassionate use following study completion.

Assuming a 12% withdrawal rate, the target enrollment across approximately 250 study centers worldwide is approximately 1,582 randomized subjects, to achieve approximately 1,392 subjects who complete the 12-week Treatment Period. The total duration of subject participation will be approximately 15 weeks.

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Study Endpoints/Assessments

Primary

Change from baseline in Clinic Visit trough (pre-bronchodilator and pre-dose) FEV1, (to evaluate the contribution of FF) on Treatment Day 84 (Visit 7).

Trough FEV1 on Treatment Day 84 is defined as the mean of the FEV1 values obtained 23 and 24 hours after dosing on Treatment Day 83, measured at Visit 7.

Baseline FEV1 is the mean of the two assessments made 30 minutes pre-dose and immediately pre-dose on Treatment Day 1.

Secondary

Percentage of rescue-free 24-hour periods over the entire 12-week Treatment Period

Time to first moderate/severe COPD exacerbation

Other(s)

Other endpoints include:

Percentage of rescue-free 24-hour periods averaged over each week of the 12-week Treatment Period

Number of occasions rescue albuterol (salbutamol) used during a 24-hour period averaged over each week and over the entire 12-week Treatment Period

Symptom scores (breathlessness, cough and sputum production) averaged over each week and over the entire 12-week Treatment Period

Percentage of symptom-free 24-hour periods during each week of treatment and over the entire 12-week Treatment Period

Percentage of nights with no nighttime awakenings requiring albuterol (salbutamol) during each week of treatment and over the entire 12-week Treatment Period in subjects who had at least one nighttime awakening requiring albuterol (salbutamol) during baseline

Number of nighttime awakenings requiring albuterol (salbutamol) averaged over each week of treatment and over the entire 12-week Treatment Period in subjects who had at least one nighttime awakening requiring albuterol (salbutamol) during baseline

Proportion of responders on the SGRQ total score as measured by the SGRQ-C

Health status using the CAT at Visits 2 (Randomization) and 7 (Week 12) or Early Withdrawal

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Safety

Incidence of AEs

Serious adverse event reporting

Incidence of all pneumonias

Incidence of COPD exacerbations

Health-Related Quality of Life/Health Outcomes

Health-related quality of life using the SGRQ-C as noted in the ‘Other Endpoints’ section above

Health status using the CAT as noted in the ’Other Endpoints’ section above

Exploratory Endpoint(s)

The Cough and Sputum Assessment Questionnaire (CASA-Q) [Crawford, 2008] will be completed by all randomized subjects at participating sites in countries for which a validated and translated version(s) of this questionnaire is (are) available at the time of study initiation at Visits 2 (Randomization), 5 (Week 4) and 7 (Week 12) or Early Withdrawal.

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1. INTRODUCTION

1.1. Background

Chronic obstructive pulmonary disease (COPD) has been defined as a preventable and treatable disease with some significant extrapulmonary 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, 2013] and contributing significantly to health care costs and morbidity [Chapman, 2006; Lopez, 2006]. According to the World Health Organization (WHO), an estimated 64 million people had COPD worldwide in 2004 and more than 3 million people died of COPD in 2005, which is equal to 5% of all deaths globally that year [WHO, 2012]. The WHO predicts that COPD will become the leading cause of death worldwide by 2030 [WHO, 2012].

Current 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, 2013]. Recent clinical research has indicated that an inhaled corticosteroid (ICS) combined with a long acting beta2-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 (ICS) 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

Fluticasone furoate(FF), as the ICS component, and vilanterol (VI), as the LABA component, of an ICS/LABA combination had been developed for use as a once-daily treatment in asthma and COPD. FF/VI is the first, once-daily ICS/LABA. FF/VI Inhalation Powder 100/25 mcg QD (trade name BREO™ ELLIPTA™) has been approved in the United States (May 2013), Canada (July 2013) for the maintenance treatment of airflow obstruction and for reducing exacerbations in patients with COPDand in Europe (November 2013, trade name RELVAR™ ELLIPTA™) for the regular treatment of asthma (in adults and adolescents aged 12 years and older where use of a

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combination medicinal product [long-acting beta2-agonist and inhaled corticosteroid] is appropriate: patients not adequately controlled with inhaled corticosteroids and 'as needed' inhaled short-acting beta2-agonists) and for the symptomatic treatment of adults with COPD with a FEV1<70% predicted normal (post-bronchodilator) with an exacerbation history despite regular bronchodilator therapy. Applications for the treatment of asthma and COPD are currently under review in other countries worldwide. Two other ICS/LABA combinations are currently available worldwide for treatment of COPD, fluticasone propionate/salmeterol (trade names ADVAIR DISKUS®, SERETIDE ACCUHALER®, ADOAIR™ DISKUS™) and budesonide/formoterol (Symbicort Turbohaler). These medications require twice-daily administration. A once daily ICS/LABA combination has the potential to improve patient compliance and, as a result, overall disease management.

In the Phase III clinical development program in subjects with COPD, the contribution of VI 25mcg QD to the FF/VI 100/25 mcg QD combination was demonstrated by clinically meaningful and sustained improvement in lung function [Kerwin, 2013; Martinez, 2013] and the contribution of FF 100 mcg QD to the FF/VI 100/25 mcg QD combination was demonstrated by clinically meaningful reductions in the rate of moderate or severe COPD exacerbations, risk for time to first moderate or severe COPD exacerbation and rate of exacerbations requiring treatment with oral/systemic corticosteroids [Dransfield, 2013]. However, the contribution of FF 100 mcg to the combination on lung function, as determined by the comparison of FF/VI 100/25 with VI 25 on trough FEV1 was demonstrated numerically, but not statistically in either study HZC112206 or HZC112207 [Kerwin, 2013; Martinez, 2013]. Statistical significance may not have been achieved for the comparison between FF/VI 100/25 and VI 25 because, the studies were not adequately powered to detect treatment differences of the magnitude observed for FF/VI compared with VI alone, which was due to larger than planned variability and smaller than anticipated treatment differences Demonstration of a statistically significant contribution of FF 100 mcg to the combination on lung function is pivotal for the approval of FF/VI 100/25 mcg QD for the treatment of COPD in Japan.

The present study will evaluate the efficacy and tolerability profile of FF/VI 100/25 mcg QD compared with VI 25mcg QD in subjects with COPD who have a history of at least one COPD exacerbation in the year prior to Screening and who demonstrate current symptoms of COPD. In particular, this study will assess the contribution on lung function (trough FEV1) of FF 100 mcg in the FF/VI 100/25 mcg QD combination.

1.3. Benefit:Risk Assessment

Summaries of findings from both clinical and non-clinical studies conducted with FF (GW685698)/VI (GW642444) and VI can be found in the corresponding Investigator’s Brochures and in the BREO ELLIPTA (RELVAR ELLIPTA) Prescribing Information forcountries in which FF/VI is approved for marketing. The following section outlines the risk assessment and mitigation strategy for this protocol:

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1.3.1. Risk Assessment

For FF/VI the following risks and the mitigation strategy as applicable to COPD patients are taken from the summary of safety concerns in the European Union – Risk Management Plan (EU-RMP, version 6.1). The data/ rationale for the risk are derived from the latest Data Safety Update Report (DSUR; Reporting Period: July 2012-July 2013).

For the VI section, information is taken from the DSUR (Reporting Period: July 2012-July 2013).

Potential Risk of Clinical

Significance

Data/Rationale for Risk Mitigation Strategy

Investigational Product (IP): FF/VI

Pneumonia in patients with COPD

The absolute risk of pneumonia with FF appears to be very small and is consistent with other ICS. The incidence of pneumonia in FF/VI COPD studies (6-7%) was commonin subjects with a history of exacerbations in one-year studies.

Risk factors for pneumonia on FF/VI compared with VI in these studies included current smokers, patients with a history of prior pneumonia,patients with a body mass index <25 kg/m

2and patients with an

FEV1<50% predicted

This protocol includes specific exclusion criteria with respect to this risk as well as guidance to the investigator should such an event occur during the trial.

Core labelling identifies this risk in the warnings and precautions section and provides information in adverse events section.

Clinical studies are ongoing to further characterise this risk. In addition, this risk will be monitored through routine proactive pharmacovigilance

Serious cardiovascular events

This is a class effect of LABA. Preclinical data showed VI to be comparable with other LABA. An analysis was performed on the l key studies in subjects with COPD: (HZC112206, HZC112207, HZC102871, HZC102970, HZC110946, HZC111348, and B2C111045) to summarize events that could be considered cardiac in nature and found that thepercentages of subjects with fatal events that were cardiovascular in nature were similar in all treatment groups (0 to <1%).

This protocol includes specific exclusion criteria with respect to this risk as well as guidance to the investigator should such an event occur during the trial.

Core labelling raises awareness of the risk in the warnings and precautions section with caution for use in patients with severe cardiovascular disease.

Cardiovascular events are being assessed in ongoing studies with FF/VI. This risk will be monitored through routine proactive pharmacovigilance.

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Significance


Decreased bone mineral density and associated fractures

This is a class effect of corticosteroids in COPD. Preclinical data showed that high dose corticosteroid effects of FF were comparable to other corticosteroids.In an integrated analysis of 10 studies with inhaled FF (6,219 patients), the incidence of fractures with FF was <1%, and usually associated with trauma.

In two replicate 12-month studies in a total of 3,255 patients with COPD, the incidence of bone fractures overall was low in all treatment groups, with a higher incidence in all FF/VI groups (2%) compared with the vilanterol 25 mg group (<1%). Fractures typically associated with corticosteroid use (e.g. spinal compression/thoracolumbar vertebral fractures, hip and acetabular fractures) occurred in <1% of the FF/VI and vilanterol treatment arms.

Patients on depot or oral corticosteroids are excluded in this trial.

Core labelling raises awareness of the possible systemic effects.

Post approval studies will evaluate the effect of FF/VI on bone mineral density. This risk will be monitored through routine pharmacovigilance.

Hypersensitivity In the COPD placebo-controlled studies of 6 months’ duration (HZC102206/HZC102207), events related to hypersensitivity, such as pruritus and rash, occurred at similar incidences in the active treatment groups (<1% to 2%) and placebo (<1%), and there appeared to be no increased risk of drug-associatedhypersensitivity.

Adverse events in the Anaphylactic reactions Sub MedDRA Query occurred at similar incidences in all active treatment groups (3% to 4%)and placebo (4%) except for a lower incidence in the FF/VI 200/25 treatment group (<1%).

Angioedema occurred at a slightly higher incidence in the FF/VI 200/25 group (2%) and at lower incidences within each of the remaining treatment groups (<1% to 1%).

In the COPD 1-year exacerbation studies (HZC102871/HZC102970),events related to hypersensitivity, such as pruritus and rash, occurred

This protocol includes specific exclusion criteria with respect to this risk.

The core labelling contraindicates against patients with a known allergy:

Risk will be monitored through routine proactive pharmacovigilance.

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Significance


at similar incidences in the FF/VI groups (4% to 5%) and the VI 25 group (3%), and analysis indicated no increased risk of drug- associated hypersensitivity in any treatment group.

Adverse events in the Anaphylactic reactions Sub MedDRA Query occurred at similar incidences in all FF/VI treatment groups (10% to 13%) and at similar incidence to that in the VI 25 treatment group (11%). Angioedema occurred at similar incidences in the FF/VI groups (3% to 5%) and similar to the VI 25 treatment group (5%). In these studies as all patients were on VI, either as monotherapy or in combination with FF, assessment of hypersensitivity to VI is difficult.

Adrenal Suppression This is a known class effect of ICS. Preclinical studies showed that FF effects are comparable with other corticosteroids. No studies have shown a clinically relevant effect of FF/VI on the hypothalamic-pituitary-adrenal axis (HPA). This includes aformal HPA study (HZA106851), using 24-hour serum cortisol measurements, and multiple studies with COPD and asthma subjects which monitored urinary cortisol.

Patients on depot corticosteroids are excluded in this trial.

Core labelling raises awareness of the possible systemic effects.


Corticosteroid associated eye disorders

This is considered a class effect. Preclinical studies showed FF at high dose comparable to other high dose corticosteroids. In study HZA106839 (FF/VI, FF and FP in subjects with asthma), formal ophthalmic assessments were conducted (including LOCS III evaluations for ocular opacities) throughout the study. This study showed no apparent effects on lens opacification, compared to baseline.During studies in both subjects with asthma and COPD, no associated affect on ocular disorders was observed.

Patients on depot corticosteroids are excluded in this trial.

Core labelling includes warnings to raise awareness of the possible systemic effects.


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Significance


Off label use of the 200/25 mcg strengthin patients with COPD

No increased efficacy benefits were apparent for FF/VI 200/25 compared with FF/VI 100/25 in one-year studies in subjects with COPD who had a history of COPD exacerbations. At the 200/25 mcg strength, a higher incidence of pneumonia cases was recorded (7% at 200/25 mcg vs 6% at 100/25 mcg). The totality of data in subjects with asthma and COPD from both direct and indirect comparisons suggests that the incidence of pneumonia and serious pneumonia (see Section 6.3.2.2) for FF/VI is similar to the incidence observed following treatment with a marketed ICS/LABA FP/salmeterol.The company therefore believes the risk of pneumonia with FF/VI is not different other from marketed ICS/LABA products.

This protocol specifies the dose to be investigated in this clinical trial.

Core labelling includes the recommended dose for patients with COPD. Post authorization drug utilization studies will explore the extent of off-label use of 200/25 mcg in patients with COPD. This will inform further risk mitigation strategies if required.

Investigational Product (IP): VISerious cardiovascular events:

- Acquired Long QT- Cardiac- Arrhythmia- Cardiac Failure- Cardiac Ischaemia - Hypertension- Sudden Death

This is a class effect of LABA. Preclinical data showed VI to be comparable with other LABA. An analysis was performed on the key studies (HZC112206,HZC112207, HZC102871, HZC102970, HZC110946,HZC111348, and B2C111045) to summarize events that could be considered cardiac in nature found that the percentages of subjects with fatal events that were cardiovascularin nature were similar in all treatment groups (0 to <1%).

This protocol includes specific exclusion criteria with respect to this risk as well as guidance to the investigator should such an event occur during the trial

Core labelling raises awareness of the risk in the warnings and precautions section with caution for use in patients with severe cardiovascular disease.

Cardiovascular events are being assessed in ongoing studies with VI and this risk will be monitored through routine proactive pharmacovigilance.

Study Design and Procedures

Unknown risks to an embryo, fetus (unborn baby) or nursing infant

There are no studies with FF/VI or the individual components (FF and VI) in pregnant women

As specified in the protocol:

Women who are pregnant, lactating or are planning on becoming pregnant during the study are not eligible to participate in this study

Female subjects must be post-menopausal or using a highly effective method for avoidance of pregnancy while in this study

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Significance


If a female subject becomes pregnant during the study, she should let the study doctor know immediately. The study medication will be stopped and the subject will not be allowed to continue in the study

For women of child-bearing potential, a serum pregnancy test will be included in the laboratory panel collected at Screening (Visit 1). For these subjects, a urine pregnancy test will be performed at home during the Follow-Up period and the result reported to the site study staff during the Follow-Up Phone Contact

COPD symptoms may worsen during the study


The use of certain medications is excluded prior to and during the study

The use of rescue medication (albuterol [salbutamol]) and/or ipratropium bromide alone must bewithheld for 4 hours prior to and during each clinic visit

Uncontrolled COPD can be life threatening

The informed consent advises the subject to:

Talk to the study doctor about the excluded medications before deciding and consenting to participate in the study

Use the rescue medication (albuterol [salbutamol]) if COPD symptoms worsen

Notify the study doctor or staff if his/her COPD symptoms worsen do not get better after using the rescue medication

Go immediately to the emergency department/seek medical attention if the symptoms are severe

Shortness of breath, coughing, light-headedness or fainting, and/or chest tightness during the spirometry measurements

. As specified in the informed consent form for this study, if any of these symptoms should happen to the subject, he/she will receive medical treatment

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Significance


Feeling faint, or experiencing mild pain, bruising, irritation or redness at the site

In rare cases, an infection where the needle entered the skin

The medically qualified site staff conducting the phlebotomy will follow standard medical practice to minimize these risks

Skin irritation from the ECG electrodes placed on the subject’s chest

The medically qualified site staff conducting the ECG measurement will follow standard medical practice for performing the ECG

Risk of radiation from a chest X-ray


A chest X-ray, for purposes of determining subject eligibility, will only be performed if a subject has not had a chest X-ray or CT scan within 1 year prior to Screening (Visit 1)

A chest X-ray, for confirmation of a suspected case of pneumonia, is encouraged rather than required

There is limited information on the safety of FF/VI in pregnancy and lactation, on the long term use > 1 year in both asthma and COPD and the safety in adolescent asthmatic patients treated with the 200/25 microgram strength.

1.3.2. Benefit Assessment

Combined treatment with ICS and LABA has been shown to be more effective than the individual components in both asthma and COPD, leading to the development of fixed dose combination inhalers. The use of ICS/LABA combinations is now well established in international treatment guidelines for COPD patients with an exacerbation history or severe airflow limitation and in moderate to severe persistent asthma patients for whom treatment with ICS alone is not sufficient. Currently available ICS/LABA combinations need to be administered twice daily. Data with marketed products suggests that compliance improves with less frequent administration and therefore it is expected that a once-daily treatment will improve compliance, which may lead to improvements in disease control and reductions in healthcare resource utilization costs. FF/VI is a once-daily ICS/LABA combination that has demonstrated clinically relevant efficacy in clinical trials in asthma and COPD.

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1.3.3. Overall Benefit:Risk Conclusion

Taking into account the measures taken to minimize risk to subjects participating in this study, the potential risks identified in association with FF/VI are justified by the anticipated benefits that may be afforded to patients with COPD.

2. OBJECTIVE(S)

2.1. Primary

The primary objective of the study is to evaluate the contribution on lung function (as measured by trough FEV1) of FF 100 mcg to FF/VI 100/25mcg QD by the comparison of the latter with VI 25mcg QD (each administered via the ELLIPTA™ inhaler) and the safety of FF/VI 100/25 mcg QD over a 12-week treatment period in subjects with COPD.

2.2. Secondary

Secondary objectives of the study are to:

Evaluate the effect of FF/VI 100/25 mcg QD compared with VI 25 mcg QD on subject-recordings of rescue medication (albuterol [salbutamol]) use and symptoms of COPD (breathlessness, cough and sputum)

Evaluate the effect of FF/VI 100/25 mcg QD compared with VI 25 mcg QD on health-related quality of life using the using the St. George’s Respiratory Questionnaire – Chronic Obstructive Pulmonary Disorder (SGRQ-C)

Evaluate the effect of FF/VI 100/25 mcg QD compared with VI 25 mcg QD on COPD health status using the COPD Assessment Test (CAT)

2.3. Exploratory Objective

An exploratory objective of this study it to evaluate the effect of FF/VI 100/25 mcg QD compared with VI 25 mcg QD on COPD symptoms of cough and sputum using the Cough and Sputum Assessment Questionnaire (CASA-Q).

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 (Table 4), are essential and required for study conduct.

This will be a 12-week, Phase IIIa, multicenter, randomized (1:1), stratified (reversibilitystatus), double-blind, parallel-group study to evaluate the efficacy and safety of FF/VI 100/25mcg QD compared with VI 25mcg QD, administered via the ELLIPTA; treatments will be administered in the morning.

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The target enrolment across approximately 250 study centers worldwide is as follows:

approximately 2,260 subjects screened (assuming a 30% screen failure rate) to achieve

approximately 1,582 randomized subjects in order to achieve

approximately 1,392 subjects who complete the 12-week Treatment Period(assuming a 12% withdrawal rate)

Subjects will visit the clinic a minimum of seven times over a 14-week period (Screening Day -14 [Visit 1], Study Days 1, 2, 14, 28, 56, and 84 [Visit 7]) as shown in Figure 1. The total duration of subject participation will be approximately 15 weeks.

Figure 1 Study Schematic Diagram:

Subjects will sign the informed consent form (ICF) at Visit 0/Visit 1 (see Section 6.1) and will be assigned a subject identifier. At Visit 1 (Screening Visit, start of Run-In Period), subjects who meet all of the Inclusion Criteria and none of the Exclusion Criteria will enter a 2-week, single-blind (placebo), Run-In Period. The purpose of the Run-In Period is to obtain subject-obtained baseline assessments of albuterol (salbutamol) use and symptom scores. Additional objectives of the Run-In period are to evaluate the subject’s adherence with study treatment and procedures, diary card completion and assessment of disease stability. 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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At the end of the Run-In Period (Visit 2), subjects will return to the clinic for Visit 2 (Randomization Visit). At this visit, eligible subjects will be randomized (1:1) to double-blind investigational study medicaton and will enter a 12-week Treatment Period. Randomization will be stratified based upon the subject’s reversibility status (reversible/non-reversible). A subject is classified as reversible if he/she has a post-albuterol (salbutmaol) increase in FEV1 that is ≥200 mL and ≥12% above the pre-albuterol (salbutamol) FEV1 measurement. Otherwise, the subject is classified as non-reversible.

At the end of Treatment Period (Visit 7 or Early Withdrawal), subjects can resume conventional COPD therapy as prescribed by the Investigator. There are no plans to provide the investigational study medicaton for compassionate use following study completion.

A follow-up phone contact will be performed approximately 7 days after the last clinic visit (Visit 7 or Early Withdrawal).

The overall study duration (Screening to Follow-up) for each subject is approximately 15 weeks (see study design schematic above).

Randomized subjects will be considered to have completed the study upon completion of all the assessments and procedures up to and including the Follow-Up phone contact, for subjects who complete the study up through Visit 7 as well as subjects who are prematurely withdrawn. Subjects will be considered to have completed the Treatment Period if they have participated in Clinic Visits 1 through 7.

The Intent-to Treat (ITT) population will be the primary population of interest and is defined as all randomized subjects who have received at least one dose of study medication during the treatment period.

Supplementary study conduct information not mandated to be present in this protocol is provided in the accompanying Study Procedures Manual (SPM). The SPM will provide the site personnel with administrative and detailed technical information that does not impact subject safety.

3.2. Discussion of Design

The design of this study (i.e., randomized, double-blind, parallel-group) is well-established to evaluate the efficacy, safety and tolerability of an investigational drug.

The 12-week duration is considered adequate for assessment of lung function and symptoms in response to treatment intervention and is consistent with regulatory guidance on clinical studies in COPD. The choice of a lung function endpoint, change from baseline in trough FEV1, as the primary efficacy endpoint, is a robust, well-established, and objective means of demonstrating efficacy. Trough (pre-dose) FEV1

assessments of lung function will provide for an evaluation of the contribution on lung function of FF 100mcg QD in the FF/VI 100/25mcg combination.

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The FF/VI strength (100/25mcg) chosen for this study is the approved strength for treatment of COPD in the United States, Canada and Europe and the strength proposed for registration in the COPD application currently under review in other countries worldwide. This strength showed no clinically relevant systemic safety effects in previous studies.

The VI 25mcg QD monotherapy arm is included in this study to allow for a quantitative assessment of the contribution of FF 100mcg QD (in the FF/VI 100/25 mcg combination) on lung function (trough FEV1).

Morning dosing will be used in the present study, consistent with the time of dosing in other studies in the Phase III clinical development program for FF/VI in subjects with COPD, and consistent with the approved Prescribing Information in the United States, Canada and Europe.

FF/VI (ICS/LABA) Dose Selection

FF/VI 100/25 QD has been selected for evaluation in this study and other Phase III studies of the FF/VI combination in subjects with COPD, based upon the results of the global, Phase IIIa program and as this is the dose approved for treatment of COPD in the United States, Canada and Europe.

The FF dose of 100mcg QD in the morning is the dose of FF in the FF/VI 100/25mcg QD combination. This dose was selected as the effective dose in COPD, based upon the results from the global Phase IIIa program in COPD, which evaluated three strengths of FF/VI (50/25, 100/25 and 200/25). Optimal efficacy, as defined by the reduction in the annual rate of moderate and severe exacerbations was demonstrated with FF/VI 100/25mcg QD. FF/VI 50/25 mcg QD was less efficacious than the 100/25 strength and no incremental efficacy was afforded with the higher 200/25 mcg QD strength.

VI (LABA) Dose Selection

The VI dose of 25mcg QD in the morning is the dose of VI in the FF/VI 100/25mcg QD combination (approved for treatment of COPD in the United States, Canada and Europe) and for the monotherapy arm. The 25mcg dose of VI was selected as the effective dose in COPD, based upon the results from a Phase IIb, dose-ranging study in subjects with COPD (B2C111045) and confirmed in the global, Phase IIIa program in COPD.

Pharmacodynamic (PD) Profile

The PD profiles of FF and VI indicate that steady state is likely to be reached after 6 and 2 days, respectively. A 12-week duration was chosen to allow additional evaluation of the efficacy and tolerability beyond steady states.

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4. SUBJECT SELECTION AND WITHDRAWAL CRITERIA

4.1. Number of Subjects

Approximately 2,260 male and female subjects will be screened to randomize approximately 1,582 subjects, to obtain approximately 1,392 who complete 12 weeks of treatment. Approximately 250 centers in multiple countries will be required to recruit 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/IB supplement(s) andin the BREO ELLIPTA (RELVAR ELLIPTA) Prescribing Information for countries in which FF/VI is approved for marketing.

Deviations from inclusion criteria are not allowed because they can potentially jeopardise the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.

Subjects eligible for enrolment in the study must meet all of the following criteria:

1. Type of subject: Outpatient

2. Informed consent: Subjects must give their signed and dated written informed consent to participate.

3. Gender: Male subjects 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.

4. Age: 40 years of age at Screening (Visit 1)

5. 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 is also associated with significant systemic consequences.

6. Severity of disease:

Subjects with a measured post-albuterol (salbutamol) FEV1/FVC ratio of 0.70 at Screening (Visit 1) [Pelligrino, 2005]

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Subjects with a measured post- albuterol (salbutamol) FEV1 ≥30 to 70% of predicted normal values calculated (via standardized spirometry equipment provided by a centralized vendor) using Global Lung Function Initiative (GLI) 2012 reference equations [Quanjer, 2012] at Screening (Visit 1)

Note: For reporting purposes, in addition to the Quanjer values, the NHANES III predicted values [Hankinson, 1999; Hankinson, 2010] at Screening (Visit 1) will be presented for consistency with previous Phase IIIa-b studies with FF/VI in subjects with COPD.

Post-bronchodilator spirometry will be performed approximately 10-15 minutes after the subject has self-administered 4 inhalations (i.e., total of 400mcg) of albuterol (salbutamol) via an MDI with a valved-holding chamber. The study-provided standardized spirometry equipment will calculate the FEV1/FVC ratio and FEV1

percent predicted values.

7. 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.

Note: Pipe and/or cigar use cannot be used to calculate pack-year history.

Number of pack years = (number of cigarette per day/20)) x number of years smoked

8. History of COPD exacerbation: A documented history (e.g., medical record verification) of at least one COPD exacerbation in the 12 months prior to Screening (Visit 1) that required either systemic/oral corticosteroids, antibiotics and/or hospitalization

Note: Prior use of antibiotics alone does not qualify as an exacerbation history, unless the use was associated with treatment of worsening symptoms of COPD, such as increased dyspnea, cough or sputum volume, or sputum purulence (color),onset or worsening of chest tightness. Subject verbal reports are not acceptable.

9. Current symptoms of COPD: A Subject Diary combined symptom score (combination of breathlessness, cough, sputum, and nighttime awakenings requiring treatment with albuterol [salbutamol]) of ≥4 on at least 5 of the 7 days immediately preceding Visit 2 (Randomization)

10. QTc Criteria: QTc <450msec or QTc <480msec for patients with bundle branch block.

The QTc is the QT interval corrected for heart rate according to either Bazett’s formula (QTcB), Fridericia’s formula (QTcF), or another method, machine or manual overread.

For eligibility and withdrawal, ideally the same QT correction formula will be used for all subjects. However, because this is not always possible, the same QT correction formula must be used for each individual subject to determine eligibility for and withdrawal from the study.

The specific formula that will be used to determine eligibility and withdrawal for an individual subject should be determined prior to initiation of the study. Note that the QT correction formula used is

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usually site-dependent since not all ECG machines are programmed by the manufacturer with the same formula.

The QTc should be based on single or averaged QTc values of triplicate electrocardiograms (ECGs) obtained over a brief recording period.

4.3. Exclusion Criteria

Deviations from exclusion criteria are not allowed because they can potentially jeopardise 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. Other respiratory disorders: Subjects with 1-antitrypsin deficiency as the underlying cause of COPD as the underlying cause of COPD, active tuberculosis, lung cancer, bronchiectasis (Note: focal bronchiectasis is not exclusionary), sarcoidosis, pulmonary fibrosis (Note: focal fibrotic pulmonary lesions are not exclusionary), primary pulmonary hypertension, interstitial lung diseases, or other active pulmonary diseases.

4. Lung resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening (Visit 1).

5. Chest X-ray (or CT scan): Subjects with a chest X-ray (or CT scan) that reveals evidence of clinically significant abnormalities not believed to be due to the presence of COPD. A chest X-ray must be taken at Screening (Visit 1) if a chest X-ray or CT scan is not available within 1 year prior to Screening (Visit 1). For sites in Germany: if a chest X-ray (or CT scan) within 1 year of Screening (Visit 1) is not available, approval to conduct a diagnostic chest X-ray (CT scan) will need to be obtained from the Federal Office for Radiation Protection (BfS).

6. Hospitalization: Subjects who are hospitalized due to poorly controlled COPD that has not resolved at least 4 weeks prior to Screening (Visit 1) and at least 6 weeks following the last dose of systemic corticosteroids.

7. Poorly controlled COPD: Subjects with poorly controlled COPD, defined as the occurrence of any of the following in the 6 weeks prior to Screening (Visit 1):

Acute worsening of COPD that is managed by subject with systemic corticosteroids or antibiotics or that requires treatment prescribed by a physician.

8. Lower respiratory tract infection: Subjects with lower respiratory tract infection that required the use of antibiotics within 6 weeks prior to Screening (Visit 1).

9. COPD exacerbation/lower respiratory tract infection during Run-In Period: Subjects who experience a moderate/severe COPD exacerbation (See definition in

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“COPD Exacerbations and Pneumonia” Section 6.2.6) and/or a lower respiratory tract infection (including pneumonia) during the Run-In Period.Note: Subjects who experience a moderate/severe exacerbation and/or pneumonia during the Run-In period must not be randomized at the randomization visit (Visit 2), but may be re-screened at a later time provided that the COPD exacerbation and/or pneumonia has resolved prior to the re-screening visit. At the re-screening visit, chest x-ray should confirm resolution of pneumonia. The re-screening visit must be conducted at least 6 weeks following the resolution date of the exacerbation and/or pneumonia and at least 6 weeks following the last dose of systemic corticosteroids (if applicable).

10. Abnormal clinically significant laboratory finding: Subjects who have an abnormal clinical significant finding in any liver chemistry test at Screening (Visit 1) or upon repeat prior to randomization.

11. Abnormal clinically significant 12-Lead ECG at Screening (Visit 1): Subjects who have an abnormal, clinically significant ECG finding at Screening (Visit 1) or upon repeat prior to randomization.

Note: Investigators will be responsible for using their own ECG equipment and for reviewing and interpreting the Screening ECGs, or contracting with a medically qualified provider to provide these services if they are unable to perform these services (i.e., no standardized equipment or centralized review by an independent cardiologist will be provided for this study) to evaluate subject eligibility. For this study, an abnormal and clinically significant finding that would preclude a subject from entering the trial is defined as a 12-lead tracing that is interpreted as, but not limited to, the findings listed inAppendix 1. The study investigator will determine the medical significance of any ECG abnormalities not listed in Appendix 1 and determine if the subject is precluded from entering the study (ECG[s] collected prior to randomization).

12. Other diseases/abnormalities: Subjects with historical or current evidence of clinically significant and unstable disease such as cardiovascular (e.g., patients requiring ICD, pacemaker requiring a rate set >60bpm, uncontrolled hypertension, New Your Heart Association Class IV [New York Heart Association, 1994], known left ventricular ejection fraction <30%) neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease), peptic ulcer disease, or hematological abnormalities. Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study.

13. Liver Disease: Subjects who have unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones)

Note: Subjects with chronic stable hepatitis B and C are eligible if the subject otherwise meets entry criteria (e.g., presence of hepatitis B surface antigen or positive hepatitis C test result within 3 months of screening). However, subjects with chronic stable hepatitis B are excluded if significant immunosuppressive or

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cytotoxic agents are administered, due to risk of hepatitis B reactivation, unless the hepatitis B antivirals are administered as outlined in the Chronic Hepatitis B AASLD Practice Guidelines.

14. 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.

15. Contraindications: Subjects with a history of allergy or hypersensitivity to any of the study medications (e.g. beta-agonists, corticosteroids) or components of the inhalation powder (e.g., lactose, magnesium stearate). In addition, subjects with a history of severe milk protein allergy that, in the opinion of the investigator, contraindicates the subject’s participation will also be excluded.

16. Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years

17. Medication prior to spirometry: Subjects who are medically unable to withhold their albuterol (salbutamol) or their ipratropium bromide for the 4-hour period required prior to spirometry testing at each study visit.

18. Additional medication: Use of the following medications within the following time intervals prior to Screening (Visit 1) or during the study:

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Medication No use within the following time intervals prior to Screening (Visit 1) and thereafter at any time during the

studyDepot corticosteroids 12 weeks Systemic, oral, parenteral (intra-atrtricular) corticosteroids 6 weeks

(systemic corticosteroids may be used to treat a COPD exacerbation during the study)

Antibiotics 6 weeks(except for the short-term [14 days]

treatment of a COPD exacerbation during the study or for short-term [14 days] treatment of

other acute infections during the study)Cytochrome P450 3A4 strong inhibitors including but not limited to antiretrovirals (protease inhibitors) (e.g., indinavir, nelfinavir, ritonavir, saquinavir, atazanavir); imidazole and triazole anti-fungals (e.g. ketaconazole, itraconazole, voriconazole); clarithromycin, telithromycin, troleandomycin, mibefradil, cyclosporin nefazodone

6 weeksGrapefruit is allowed up to Visit 1, then limited to no more than one glass of grapefruit juice (250 mL/8 ounces) or one grapefruit per day

Inhaled corticosteroids 1 weekInhaled ICS/LABA combination products 1 weekInhaled LAMA/LABA combination products 1 weekLong-acting anticholinergics (e.g., tiotropium) 1 weekTheophylline preparations 48 hoursOral leukotriene inhibitors (zafirlukast, montelukast, zileuton) 48 hoursInhaled long-acting beta2-agonists (e.g., salmeterol) 48 hoursOral beta2-agonists Long-acting Short-acting

48 hours12 hours

Inhaled sodium cromoglycate or nedocromil sodium 24 hoursShort-acting anticholinergics (e.g., ipratropium bromide) 4hoursInhaled short-acting beta-agonists1 4 hours

(albuterol [salbutamol] will be supplied for rescue during the study)

Ipratropium bromide2 4 hoursIpratropium/albuterol(salbutamol) combination products 4 hoursAny other investigational medication 30 days or 5 half-lives, whichever is longer

1. Use of study-provided albuterol (salbutamol) is permitted throughout the study; however, it must be withheld for 4 hours prior to and during each clinic visit

2. Ipratropium bromide alone is permitted, provided that the subject is on a stable dose from the Screening Visit and remains on this stable dose throughout the study; however, it must be withheld for 4 hours prior to and during each clinic visit

19. 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.

20. Sleep apnea: Subjects with clinically significant sleep apnea who require use of continuous positive airway pressure (CPAP) device or non-invasive positive pressure ventilation (NIPPV).

21. 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.

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Subjects who are in the maintenance phase of a Pulmonary Rehabilitation Program are not excluded.

22. Non-Compliance during Run-In Period: Failure to demonstrate adequate compliance defined as completion of Diary Card (completed all diary entries on at least 5 of the last 7 consecutive days), the ability to withhold anti-COPD medications and to keep clinic visit appointments. In addition, subjects must have recorded the Run-In study medication use on at least 5 of the last 7, consecutive days of the Run-In period to continue in the study.

23. Potential of 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. Prior use of study medication/other investigational drugs: Subjects who have received an investigational drug within 30 days of entry into this study (Screening), or within 5 drug half-lives of the investigational drug, whichever is longer.

Note: Subjects who participated in a previously completed study and/or were excluded/withdrawn from an ongoing study that included/includes FF/VI and/or VI are eligible to participate in the current study, if they have not received investigational study medication within 30 days of Screening (Visit 1) as shown below:

Examples of completed studies:

Phase IIb dose-ranging study with VI (B2C111045)

Phase IIa, study with FF/VI (HZC111348)

Phase III studies with FF/VI (some of which also included a VI arm (e.g., HZC112206, HZC112207, HZC102970, HZC102871, HZC110946, HZC113107, HZC113109, HZC112352, HZC115805, etc.)

Phase III studies with umeclidinium (UMEC)/VI (some of which also included a VI arm) (e.g., DB2113360, DB2113361, DB2113373, DB2114417, DB2114418, DB2116132, DB2116133, etc.)

Examples of ongoing studies:

Phase III study with FF/VI (some of which also include a VI arm) (e.g., HZC113782 [SUMMIT], HZC115151 [Salford], HZC113108, etc.)

Studies with FF/VI/UMEC (which also includes an FF/VI and/or UMEC/VI arm) (e.g., CTT116855)

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.

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4.4. Withdrawal Criteria

A subject may voluntarily discontinue participation in this study at any time. The Investigator may also at his/her discretion discontinue a subject from this study at any time. Every effort should be made by the Investigator to keep the subject in the study.

Subjects who are withdrawn from the study will not be replaced and cannot be re-screened.

Should a subject fail to attend the clinic for a required study visit, the site should attempt to contact the subject and re-schedule the missed visit as soon as possible. The site should also counsel the subject on the importance of maintaining the assigned visit schedule and ascertain whether or not the subject wishes to and/or should continue in the study based on previous non-compliance. In cases where the subject does not return for the rescheduled visit or cannot be reached to reschedule the missed visit, the site should make every effort to regain contact with the subject (3 telephone calls and if necessary a certified letter to the subject’s last known mailing address), so that they can appropriately be withdrawn from the study. These contact attempts should be documented in the subject’s medical record. Should the subject continue to be unreachable, then and only then will he/she be considered to have withdrawn from the study with a primary reason of “Lost to Follow-up”. For all other subjects withdrawing from the study, an alternative reason for discontinuation should be recorded in the eCRF.

The primary reason for subject withdrawal will be recorded in the electronic Case Report Form (eCRF). Primary reasons for withdrawal will be categorized as:

adverse event

withdrew consent

lost to follow-up

protocol deviation

lack of efficacy

subject reached protocol-defined stopping criteria

study closed/terminated

investigator discretion

Specific regard should be given to distinguishing withdrawals due to an adverse event, lack of efficacy and protocol deviation. Subject compliance with double-blind study medication will be assessed at Visits 2 through 7, by reviewing the dose counter on the ELLIPTA. Subjects must be ≥80% to ≤120% compliant on taking study medication between-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

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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 medicalmonitor and principal investigator, if any of the following stopping criteria are met:

1. Laboratory measurements: Demonstrate a clinically important change(s) in a laboratory parameter(s), if a laboratory test is conducted during the Treatment Period

2. Pneumonia: Presumptive diagnosis or radiographically confirmed (See definition in “COPD Exacerbations and Pneumonia” Section 6.2.6)

Note: If a subject is withdrawn due to pneumonia, the AE/SAE section and the pneumonia/chest X-ray section, if applicable, of the eCRF should be completed and the subject should be followed until clinical resolution of the pneumonia.

3. ECG: An abnormal clinically significant ECG finding, if an ECG is conducted during the Treatment Period. In addition, subjects who meet any of the following criteria:

QTc >500 msec

Uncorrected QT >600 msec

Change from baseline: QTc > 60 msec

These criteria should be based on the average QTc value of triplicate ECGs. For example, if an ECG demonstrates a prolonged QT interval, obtain two more ECGs over a brief period, and then use the averaged QTc values of the three ECGs to determine whether the subject should be discontinued from the study.

The same QT correction formula (Fridericia’s or Bazetts’s) to be used depends upon the ECG equipment to be utilized for a given site (see Section 6.3.13). The same formula should be used throughout the study for all subjects at the given site.

For subjects with underlying Bundle Branch Block:

Baseline QTc withBundle Branch Block

Discontinuation QTc withBundle Branch Block

<450 msec >500 msec450-480 msec ≥530 msec

4. Liver Chemistry: Meets any of the liver chemistry stopping criteria as defined in Section 6.3.1.

5. Pregnancy: Positive pregnancy test

4.5. Screening/Run-in Failures

Subjects will be assigned a subject number after completing written informed consent.

A screen failure is defined as any subject who has been assigned a subject identifier, has completed at least one Visit 1 procedure, but does not continue in the study beyond Visit

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1 (Screening) 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 (Visit 2).

The Registration and Medication Ordering System (RAMOS), the interactive voice response system (IVRS) will be contacted to report screen failures. Additionally, the following information will be collected in the eCRF for screen failures:

Date of screening visit

Subject number

Demographic information, including race, age and gender

Inclusion/exclusion criteria

Reason subject failed to be randomized

Serious Adverse Events information, if applicable, only for any SAE considered as related to study participation (e.g. study treatment, protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant medication

4.5.1. Re-Screening Criteria

A subject who fails Inclusion Criterion 6 (Severity of disease) at Screening (Visit 1), irrespective of any other Inclusion or Exclusion criteria met or failed, cannot be re-screened.

Any subject who experiences a moderate/severe COPD exacerbation and/or pneumonia on the day of Screening (Visit 1) or during the Run-In period will be excluded from participating. However, the subject may be re-screened in accordance with the Note in Exclusion Criterion 9. In rare instances, subjects failing for other reasons may be eligible for re-screening. Please refer to the SPM for details. Re-screening of subjects must be approved by the central GSK team prior to re-screening. Only one re-screening is allowed per subject.

Any re-screened subject must meet all of the protocol-specified inclusion/exclusionrequirements at the re-screen visit. In particular, any subject who is re-screened due to amoderate/severe COPD exacerbation and/or pneumonia on the day of Screening (Visit 1) or during the Run-In period must repeat all Screening (Visit 1) procedures.

4.6. Early Withdrawals

Subjects will be considered to have completed the study upon completion of assessments and procedures up to and including a successful Follow-up Phone Contact (7 ± 2 days post Visit 7). The definition of subject withdrawal from the study will be any subject who is randomized to double-blind medication and, for any reason, does not complete Visit 7 procedures and the Follow-up Phone Contact.

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The investigator must make every effort to have the subject return to the clinic as soon as possible for an Early Withdrawal Visit. The following evaluations and procedures should be completed and recorded in the eCRF, as required, prior to discharging the subject from the study:

Concomitant medication assessment

Smoking status/smoking cessation counselling

Diary review

Exacerbation assessment

AE/SAE assessment

Spirometry Testing

Physical examination (including vital signs)

Oropharyngeal exam

Dispense urine pregnancy test to be completed at home prior to the Follow-Up Phone Contact, if applicable

Investigational Product collection/compliance assessment

Rescue albuterol (salbutamol) collection

Register visit in IVRS

The Follow-up Phone Call should be performed 7(2) days after the Early Withdrawal Visit, at which time the following will be completed and collected:

Urine pregnancy test results, if applicable

AE/SAE assessment

Exacerbation Assessment

Concomitant medications including anything issued during discharge from the study

Register visit in IVRS

Any clinically significant adverse event or physical examination finding observed during final assessments will be followed as medically appropriate until resolved or explained. Each subject should be prescribed appropriate COPD therapy by the investigator as needed.

A subject who is withdrawn early from the study after being randomized to treatment cannot be re-screened.

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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 ELLIPTA. The ELLIPTA 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 contents of each strip are described in Table 1- Table 2.

The ELLIPTA inhalers containing randomized treatment and single-blind, Run-In medication (placebo) will appear identical on the outside to the subject (and his/her caregiver) and the investigator.

Subjects will receive single-blind placebo during the Run-In period. Subjects will be instructed to take one inhalation each morning. In addition, 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 2-week, Run-In Period, eligible subjects will be randomized (1:1) to one of the following two possible treatments, administered as one inhalation each morning for 12 weeks:

FF/VI 100/25 mcg QD

VI 25 mcg QD

Randomization will be stratified based upon the subject’s reversibility to albuterol (salbutamol) (i.e., reversible or non-reversible). A subject is classified as reversible if he/she has a post-albuterol (salbutamol) increase in FEV1 that is ≥200 mL and ≥12% above the pre-albuterol (salbutamol) FEV1 measurement. Otherwise, the subject is classified as non-reversible.

A description of the single-blind, placebo (to be used only during the Run-In Period) is provided in Table 1:

Table 1 Description of Placebo (Run-In Period Only)

Formulation First strip: Lactose Second strip: Lactose blended with magnesium stearate1

Dosage Form ELLIPTA with 30 doses (2 strips with 30 blisters per strip)Unit Dose Strengths N/A N/APhysical description Dry white powder Dry white powderRoute of Administration Inhaled1. Magnesium stearate 1% w/w of total drug product

A description of the investigational treatments is provided in Table 2 and Table 3:

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Table 2 Description of FF/VI ELLIPTA

Formulation First strip: FF micronized drug blended with lactose

Second strip: VI micronized drug (as the ‘M’ salt triphenylacetate) blended with lactose and magnesium stearate1

Dosage Form ELLIPTA with 30 doses (2 strips with 30 blisters per strip)Unit Dose Strengths 100mcg per blister 25mcg per blisterPhysical description Dry white powder Dry white powderRoute of Administration Inhaled1. Magnesium stearate 1% w/w of total drug product

Table 3 Description of VI ELLIPTA

Formulation First strip: Lactose Second strip: VI micronized drug (as the ‘M’ salt triphenylacetate) blended with lactose and magnesium stearate1

Dosage Form ELLIPTA with 30 doses (2 strips with 30 blisters per strip)Unit Dose Strengths N/A 25mcgPhysical description Dry white powder Dry white powderRoute of Administration Inhaled1. Magnesium stearate 1% w/w of total drug product

The contents of the label will be in accordance with all applicable regulatoryrequirements.

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.

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 authorised site staff. Investigational product must be dispensed or administered only to subjects enrolled in the study and in accordance with the protocol.

Investigational product must be stored at up to 25° C (77°F). The ELLIPTAs 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 ELLIPTA has a 30-day in-use shelf life.

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5.1.2. Investigational Product 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 ELLIPTA device or ELLIPTA device packaging is defective. The device and packaging should be returned to GSK.

Details for both destruction and return of study medication are provided 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 device to the clinic as soon as possible and avoid missing any doses if possible. The site should then call RAMOS, an Interactive Voice Response System (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.

5.2. Treatment Assignment

Subjects will be assigned to study treatment in accordance with the randomization schedule.

Randomization will be centralized by country.

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 reversibility status (reversible/non-reversible).

Subjects will be centrally randomized using RAMOS, an IVRS. This is a telephone-based system that will be used by the investigator or designee to register the subject, randomize the subject and provide medication assignment information. Details on how to use RAMOS to register and randomize subjects are provided in the SPM.

Following the 2-week, 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 12 weeks:

Fluticasone Furoate /Vilanterol Inhalation Powder 100/25 mcg once daily

Vilanterol Inhalation Powder 25 mcg once daily

5.3. Blinding

The study medication taken during the 12-week Treatment Period will be double-blind. Neither the subject nor the study physician will know which study medication the subject is receiving.

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The investigator or treating physician may unblind a subject’s treatment assignment only in the case of an emergency or in the event of a serious medical condition, when knowledge of the study treatment is essential for the appropriate clinical management or welfare of the subject, as judged by the investigator. Investigators have direct access to the subject’s individual study treatment. It is preferred (but not required) that the investigator first contacts the GSK Medical Monitor or appropriate GSK study personnel to discuss options before unblinding the subject’s treatment assignment. If GSK study personnel are not contacted before the unblinding, the investigator must notify GSK as soon as possible after unblinding, 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 fully documented 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 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 thesubject as needed.

Subject compliance with double-blind study medication will be assessed at Visits 3through 7, by reviewing the dose counter on the ELLIPTA and by counting the number of capsules used. Subjects must be ≥80% to ≤120% compliant in taking study medicationbetween-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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5.6. Concomitant Medications and Non-Drug Therapies

All COPD medications taken within 3 months prior to Visit 1 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.

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 Treatment Periods

Ipratropium bromide alone is permitted, provided that the subject is on a stable dose from Screening (Visit 1) and remains on this stable dose throughout the study; however, it must be withheld for 4 hours prior to and during each clinic visit

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.)

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).

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 week prior to Visit 1 and remains on this dose throughout the study

Topical (1 % hydrocortisone in strength) or ophthalmic corticosteroids

Antibiotics that are not strong inhibitors of cytochrome P450 3A4 (e.g., erythromycin) for short-term treatment (14 days) of acute non-respiratory tract infections (e.g., urinary tract infection), acute upper respiratory tract infections (e.g., sinusitis) and for the treatment of pneumonia and COPD exacerbations.

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.

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Diuretics. Caution is advised in the co-administration of beta-agonists with non-potassium –sparing diuretics.

Treatment(s) for smoking cessation

All medications for other disorders as long as the dose remains constant wherever possible and their use would not be expected to affect lung function

5.6.2. Prohibited Medications and Non-Drug Therapies

Acetaminophen is not used in patients with acute viral hepatitis.

Medications prohibited at specific time intervals prior to Visit 1 and at any time during the study are identified in Section 4.3, Exclusion Criteria.

As discussed in Section 6.1, 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.

5.7. Treatment after the End of the Study

The investigator is responsible for ensuring that consideration has been given to the post-study care of the patient’s medical condition whether or not GSK is providing specific post study treatment.

Subjects will be prescribed appropriate COPD therapy at Visit 7 or the Early Withdrawal Visit if required. There are no plans to provide the study medication for compassionate use following study completion.

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 medicaton(s) being used in this study. Such documents may include, but not be limited to, the approved product labeling for albuterol (salbutamol), and the approved product labelling for FF/VI (applicable countries) and the FF/VI and VI IBs or equivalent document provided by GSK for double-blind medications.

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6. STUDY ASSESSMENTS AND PROCEDURES

The Time and Events Table is provided in Table 4. All study assessments should be conducted by the Investigator or his/her qualified designee. All clinic visits should start early enough to complete the pre-dose spirometry between 6 AM and 10 AM. Please refer to the SPM for a suggested order of assessments.

Subjects should be reminded to do the following prior to the start of clinic visit days:

Withhold rescue albuterol (salbutamol) for 4 hours

Withhold morning dose of scheduled COPD medications (permitted and/or blinded study medication)

Refrain from smoking at least 1 hour prior to spirometry assessments

Subjects will self-administer their first dose of double-blind study medication in the clinic at Visit 2.

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Table 4 Time and Events Table

Pre-Screening

Single-Blind Treatment Period

Double-Blind Treatment Period

Visit 0 1(Screen-

ing)

Run-In Period

2(Random-

ization)

3 4 5 6 7 EarlyWithdrawal

Follow-Up(Phone Contact)

Day -14 -141 to -1

1 2 142 282 562 842 Visit 7/Early Withdrawal+ 72 days

Week -2 1 2 4 8 12

Informed Consent X2 X2

PGx Informed Consent X2 X2

Demography X2 X2

Medical History XPhysical Examination X X XReversibility Test with Albuterol (Salbutamol)

X

Review Smoking Status X X X X X X XSmoking Cessation Counselling X X XRegister Visit in IVRS3 X X X X X X X X X XPGx Sampling X4

Safety AssessmentsChest X-ray5 XVital Signs6,7 XLiver Function Tests X7,8 X7,8

Serum Pregnancy Test9 XUrine Pregnancy Test Dispensed9,10 X XUrine Pregnancy Test Results10 X12-lead ECG & Rhythm Strip7 XExacerbation Assessment X11 X11 X X X X X X XAdverse Event Assessment12 X X X X X X X XEfficacy AssessmentsSpirometry Testing X13 X13 X13

Spirometry Testing – Trough X14 X14 X14 X14 X14

Subject Daily Diary Assessments15 X X X X X X X X

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Pre-Screening

Single-Blind Treatment Period

Double-Blind Treatment Period

Visit 0 1(Screen-

ing)

Run-In Period

2(Random-

ization)

3 4 5 6 7 EarlyWithdrawal

Follow-Up(Phone Contact)

Day -14 -141 to -1

1 2 142 282 562 842 Visit 7/Early Withdrawal+ 72 days

Week -2 1 2 4 8 12

Health Outcomes AssessmentsSGRQ-C X16 X16 X16

CAT X16 X16 X16

CASA-Q (Applicable Sites) X16 X16 X16 X16

Medication AssessmentsConcurrent Medication Assessment X17 X17 X X X X X X X XDispense Albuterol (Salbutamol)18 X X X X X XDispense Single-Blind Study medication XCollect Single-Blind Study medication XDispense Double-Blind Study medication X X X19

Collect Double-Blind Study medication X X X XDiaryDispense Subject Diary X X X20 X20 X X20

Collect and Review Diary X X X X X X XOtherDischarge from Study21 X X1. A +3 day window is allowed during the Run-In Period (i.e., the Run-in period can last up to 17 days)2. Written informed consent (ICF) must be obtained prior to initiation of study procedures or initiating any changes in medications. ICF will be signed only once, either at the Pre-

Screening Visit (Visit 0) or the Screening Visit (Visit 1). Demography data will be collected at the time the ICF is obtained.3. A telephone-based Interactive Voice Response System (IVRS) (Randomization And Medication Ordering System [RAMOS]) that will be used by the Investigator or designee to

register the subject, randomize the subject and provide medication assignment information4. Saliva (2mL) is spit into 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 obtained prior to PGx sampling.5. Chest X-ray must be taken if a Chest X-ray or CT scan is not available within 1 year preceding Visit 16. Blood pressure and pulse7. Conducted at Screening Visit (Visit 1) only, for purposes of determining subject eligibility8. Visit 1: Non-fasting, liver function tests only;: Visit 2: Pre-dose lab only completed if any part of the Screening liver function tests needs to be repeated9. Females of child-bearing potential only

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10. Urine pregnancy test dispensed during Visit 7/Early Withdrawal and performed by the subject at home prior to the Follow-Up Phone Contact11. All COPD exacerbations will be recorded from the time the subject signs the ICF at Visit 0 or Visit 1 as applicable12. Serious adverse events related to study procedures/drug will be recorded from the time of consent. All other serious and non-serious adverse events will be recorded following

randomization until the Follow-Up Contact13. Visit 1: Pre- and post-albuterol (salbutamol) spirometric measurements performed; Visit 2: Spirometric assessments performed at 30 minutes pre-dose and immediately pre-dose

(Baseline is the mean of these two assessments); Early Withdrawal: A single spirometric measurement performed14. Trough testing: Performed at 23 and 24 hours after the previous morning’s dosing15. Subject Daily Diary assessments over the previous 24 hours (symptoms of breathlessness, cough, and sputum production, number of occasions supplemental albuterol

(salbutamol) MDI and/or nebules used, number of nighttime awakenings requiring albuterol (salbutamol), and any medical problems and any medications used to treat those medical problems)

16. Completed prior to performing any other study procedures (including Diary Card review, concurrent medication assessment, adverse event assessment, clinic spirometry, etc.), with the CAT completed first then the SGRQ-C and then the CASA-Q; at Visit 5, only the CASA-Q will be completed

17. All COPD medications taken within 30 days prior to Visit 0/Visit 1 will be collected.18. Collect and re-dispense as needed after Visit 119. The last dose of double-blind study medication during the Treatment Period will be taken the morning prior to Visit 7 using the device dispensed at Visit 620. The Subject Diary Book dispensed at Visit 2 will be reviewed and re-dispensed to the subject at Visits 3 and 4; the Subject Diary Book dispensed at Visit 5 will be reviewed and re-

dispensed to the subject at Visit 6 and reviewed and collected from the subject at Visit 7 21. 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, height, and weight)

During the Screening Visit (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

Exacerbation assessment (documented history of ≥1 COPD exacerbation that required treatment with systemic/oral corticosteroids, antibiotics and/or hospitalization in the year prior to Screening [Visit 1] is required)

COPD symptom assessment (A Subject Diary mean symptom score [combination of breathlessness, cough, sputum, and nighttime awakenings requiring treatment with albuterol (salbutamol) of ≥4 on at least 5 of the 7 days immediately preceding Visit 2 [Randomization] is required)

Concomitant medication review

ECG and rhythm strip

Spirometry with reversibility testing

Physical exam (including vital signs)

Chest X-ray (posterioranterior and lateral), if no chest X-ray or CT scan available within 1 year of Screening (Visit 1)

Laboratory assessments (liver function panel and pregnancy test [females of child-bearing potential])

See Section 4.5 for information regarding Screening/Run-In Failures.

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6.2. Efficacy

6.2.1. Primary Endpoint

The primary endpoint is change from baseline in Clinic Visit trough (pre-bronchodilator and pre-dose) FEV1, (to evaluate the contribution of FF) on Treatment Day 84 (Visit 7)

Trough FEV1 on Treatment Day 84 is defined as the mean of the FEV1 values obtained 23 and 24 hours after dosing on Treatment Day 83, measured at Visit 7.

Baseline FEV1 is the mean of the two assessments made 30 minutes pre-dose and immediately pre-dose on Treatment Day 1.

6.2.2. Secondary Endpoints

The secondary endpoints are:

Percentage of rescue-free 24-hour periods over the entire 12-week Treatment Period

Time to first moderate/severe COPD exacerbation

6.2.3. Other Endpoints

Other endpoints include:

Percentage of rescue-free 24-hour periods averaged over each week of the 12-week Treatment Period

Number of occasions rescue albuterol (salbutamol) used during a 24-hour period averaged over each week and over the entire 12-week Treatment Period

Symptom scores (breathlessness, cough and sputum production) averaged over each week and over the entire 12-week Treatment Period

Percentage of symptom-free 24-hour periods during each week of treatment and over the entire 12-week Treatment Period

Percentage of nights with no nighttime awakenings requiring albuterol (salbutamol) during each week of treatment and over the entire 12-week Treatment Period in subjects who had at least one nighttime awakening requiring albuterol (salbutamol) during baseline

Number of nighttime awakenings requiring albuterol (salbutamol) averaged over each week of treatment and over the entire 12-week Treatment Period in subjects who had at least one nighttime awakening requiring albuterol (salbutamol) during baseline

Proportion of responders on the SGRQ total score as measured by the SGRQ-C

Health status using the CAT at Visits 2 (Randomization) and 7 (Week 12) or Early Withdrawal

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6.2.4. Spirometry and Reversibility Testing

6.2.4.1. Spirometry

Spirometry measurements will be obtained using spirometry equipment that meets or exceeds the minimal performance recommendations of the ATS [Miller, 2005]. All sites will use standardized spirometry equipment provided by an external vendor. All subjects will have lung function performed at each visit to assess FEV1, and FVC. At least 3 valid spirometry efforts should be attempted (with no more than 8) using the ATS guidelines [Miller, 2005]. Spirometry will be performed as shown in Table 4.

A post-albuterol (salbutamol) FEV1 30 to 70% of predicted normal and an FEV1/FVC ratio of 0.70 are required at Screening (Visit 1).

Spirometry must be performed:

Initiated between 6:00AM and 10:00AM at visits when clinic FEV1 is performed

At Visit 1, after withholding COPD medications as indicated in the Exclusion Criteria (Section 4.3)

After withholding single-blind (Visit 2) or double-blind (Visits 3-7) study medication on the morning of the clinic visits

At Visit 2: prior to administration of double-blind study medication

At all clinic visits: after withholding albuterol (salbutamol) rescue medication for ≥4 hours prior to the clinic spirometry assessments

At all clinic visits: after refraining from exercise for 2 or more hours, smoking for 1 hour, and exposure to cold air for 15 minutes

At all clinic visits: after refraining from drinks with high levels of caffeine such as tea and coffee on the morning of clinic visits

A subject who fails to meet Inclusion Criteria 6 (Severity of Disease) at Screening (Visit 1), irrespective of any other Inclusion or Exclusion criteria met or failed, respectively, cannot be re-screened.

Measurements should be made as close to the scheduled time points as possible. Where multiple assessments are scheduled at the same time point the sequence of assessments should be:

1. Vital signs

2. 12-lead ECG

3. Blood sampling

4. Spirometry assessment

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6.2.4.2. Reversibility

Subjects’ reversibility will be assessed at Visit 1 (Screening). To determine reversibility, the subject will self-administer 4 inhalations of albuterol (salbutamol) via metered dose inhaler (MDI) with a spacer/valved-holding chamber following pre-dose spirometry. At least 3 valid spirometry efforts should be attempted (with no more than 8) using the ATS guidelines [Miller, 2005] after approximately 10-15 minutes, and the highest FEV1 from 3 valid forced expiratory curves will be used to determine reversibility. Reversibility is defined as an increase in FEV1 of ≥12% and ≥200 mL following administration of albuterol (salbutamol). Non-reversible is defined as a post-albuterol (salbutamol) increase in FEV1 of <200 mL or a ≥200 mL increase that is <12% from pre-albuterol (salbutamol) baseline. Randomization will be stratified based upon reversibility status (reversible/non-reversible).

Spirometry equipment, provided through a centralized vendor, will calculate the percentreversibility for each subject.

Details regarding the spirometric procedures are provided in the SPM.

6.2.5. Diary Card Assessments

Each morning (from the morning following the Screening Visit until completion of the Treatment Period or Early Withdrawal Visit), subjects will be instructed to complete the Daily Diary, prior to taking study medication (i.e., single-blind or double-blind) and rescue medication (albuterol [salbutamol] if applicable) and ipratropium (if applicable) and to base their assessment of symptoms experienced over the last 24 hours. Subjects will be instructed to record the following information on the Daily Diary:

Symptoms of breathlessness, cough, and sputum production over the previous 24 hours

Number of occasions supplemental albuterol (salbutamol) (MDI and/or nebules) used over the previous 24 hours. Study-provided albuterol (salbutamol) use will only be recorded in the Daily Diary and will not be collected in the eCRF.

Number of nighttime awakenings requiring albuterol (salbutamol) over the previous 24 hours

Any medical problems the subject may have experienced and any medications used to treat those medical problems over the previous 24 hours

Subjects will be instructed on how to complete their diary cards and will be asked to return completed diary cards at each clinic visit. The study coordinator must review thediary cards at each clinic visit for completeness, legibility, and consistency with subject-reported AEs. Signs and symptoms of COPD should be evaluated according to Section6.2.6.

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6.2.5.1. COPD Symptom Evaluations

Breathlessness, cough and sputum production, and scores will be recorded on a daily basis in subject Daily Diary.

Subjects will be instructed to complete the diary in the morning, prior to taking study medication (i.e., single-blind, and double-blind), supplemental medication (albuterol [salbutamol] if applicable) and ipratropium bromide (if applicable) and to base their assessment on symptoms experienced over the last 24 hours. Subjects will assess their symptoms using the following scales:

Symptom ScoreVariable 0 1 2 3 4

Breathlessness Not breathless at rest or on exertion

Not breathless at rest, but breathless on moderate exertion (e.g., walking quickly, climbing stairs)

Not breathless at rest, but breathless on mild exertion (e.g., walking on the level)

Not breathless at rest, but breathless on minimal exertion (e.g., getting washed or dressed)

Breathless at rest (e.g., sitting down reading or watchingTV)

Cough No cough Mild cough (e.g., some coughing mostly in the morning)

Moderate cough (e.g., coughing in the morning and sometimes during the day)

Severe cough (e.g., coughing in the morning and throughout the day)

Sputum production

None Mild sputum production (e.g., only in the morning)

Moderate sputum production (e.g., in the morning and sometimes during the day)

Severe sputum production (e.g., throughout the whole day)

At each clinic visit following Visit 1, symptom scores will be reviewed by study site personnel for determination of worsening symptoms.

Any exacerbation identified based on diary card review and/or investigator judgment must be documented in the study source documents and eCRF and the severity of each exacerbation must be determined.

6.2.5.2. Supplemental Albuterol (Salbutamol) Use

Subjects will be instructed to record the number of occasions on which supplemental (rescue) albuterol (salbutamol) (MDI and/or nebules) was used in the past 24 hours for relief of COPD symptoms. Study-provided albuterol (salbutamol) use will only be recorded in the Daily Diary and will not be collected in the eCRF.

6.2.5.3. Nighttime Awakenings Requiring Albuterol (Salbutamol)

Subjects will be instructed to record on their Daily Diary the number of nighttime awakenings requiring the use of albuterol (salbutamol) experienced during the previous night.

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6.2.5.4. Medical Problems/Medications Taken

Subjects will be instructed to record daily any medical problems (besides COPD symptoms) they may have experienced and any medications used to treat those medical problems on a “Medical Problems/Medications Diary.”

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.

6.2.6. COPD Exacerbations and Pneumonia

For the purpose of this study, exacerbation of COPD is defined by a worsening of symptoms requiring additional treatment as follows:

Mild COPD exacerbation: Worsening symptoms of COPD that are self-managed by the subject. Mild exacerbations are not associated with the use of systemic corticosteroids or antibiotics.

Moderate COPD exacerbation: worsening symptoms of COPD that requiretreatment with antibiotics and/or systemic corticosteroids

Severe COPD exacerbation: worsening symptoms of COPD that requiretreatment with in-patient hospitalization

Use of antibiotics for the treatment of upper or lower respiratory tract infections will notbe considered a COPD exacerbation unless the subject experiences worsening symptoms of COPD which match the definition of an exacerbation as given above.

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

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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 0 (Pre-Screening) or Visit 1 (Screening) 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.

As noted in the Exclusion Criteria section, subjects are excluded from participating if any of the following apply:

They are hospitalized due to poorly controlled COPD that has not resolved at least 4 weeks prior to Screening (Visit 1) and at least 6 weeks following the last dose of systemic corticosteroids.

They have poorly controlled COPD, defined as acute worsening of COPD that is managed by the subject with corticosteroids or antibiotics or that requires treatment prescribed by a physician in the 6 weeks prior to Screening (Visit 1)

They have a lower respiratory tract infection that required the use of antibiotics within 6 weeks prior to Screening (Visit 1)

They experience a moderate/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.

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 FF/VI 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 the purpose of this study, pneumonia is defined as new auscultatory findings compatible with parenchymal lung infection and/or radiographic evidence of

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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.

All medications used to treat a COPD exacerbation and/or pneumonia are to be recorded in the source documentation and on the Exacerbation form in the eCRF.

6.2.7. St. George’s Respiratory Questionnaire – Chronic Obstructive Pulmonary Disorder Questionnaire (SGRQ-C)

Health-related quality of life will be assessed using the SGRQ-C at the visits noted in the Time and Events Table (Table 4). The SGRQ-C will be administered as a paper questionnaire. Subjects should be instructed to complete the SGRQ-C prior to performing any other study procedures (including Diary Card review, concurrent medication assessment, adverse event assessment, clinic spirometry, etc.), but after completion of the CAT and before completion of the CASA-Q.

The SGRQ-C is a newly developed version of the well-established SGRQ instrument. It is a COPD specific questionnaire designed to measure the impact of COPD and its treatment on the subject’s health-related quality of life [Meguro, 2007]. This version was developed to reduce the patient burden, reduce missing data and improve the psychometric properties, while retaining the established properties of the instrument. In contrast to the original, SGRQ-C has been reduced from the original 50 to 40 items.

As well as producing an overall summary score, it is also possible to calculate scores for the individual domains of symptoms, activity and impacts [Jones, 1992]. It has been widely used in studies of COPD subjects and has been translated and validated for use in most major languages. Research has demonstrated that it is sensitive to change and interpretation of the results has been enhanced by determination of the score change necessary to achieve a clinically meaningful improvement in quality of life [Jones, 2005]. The SGRQ-C is self-completed by subjects, taking on average 20 minutes.

It is recommended that the SGRQ-C should be administered at the same time during each applicable visit (see the Time and Events Table [Table 4]). Adequate time (at least 20 minutes) should be allowed, although the subject will not be given any stated or implied time limit for completing the questionnaires. The investigator will ask the subject to

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complete the questionnaires as accurately as possible. If the subject requests help or clarification of any question in the questionnaires, the investigator is to instruct the subject to re-read the instructions to give the best answer possible. The investigator will not supply the subject with an answer to any question.

6.2.8. COPD Assessment Test (CAT)

COPD-related health status will be assessed using the CAT at the visits noted in the Time and Events Table (Table 4). The CAT will be administered as a paper questionnaire. Subjects should be instructed to complete the CAT prior to performing any other study procedures (including Diary Card review, concurrent medication assessment, adverse event assessment, clinic spirometry, etc.), but prior to completion of the SGRQ-C and CASA-Q.

The CAT (www.CATestonline.org) is a validated, short and simple patient completed questionnaire which has been developed for use in routine clinical practice to measure the health status of patients with COPD. The CAT is designed to measure overall COPD-related health status for the assessment and long-term follow-up of individual patients. The CAT is an 8-item questionnaire suitable for completion by all patients diagnosed with COPD. When completing the questionnaire, subjects rate their experience on a 6-point scale, ranging from 0 (no impairment) to 5 (maximum impairment) with a scoring range of 0-40 [Jones, 2009].

6.3. Safety

Incidence of AEs

Serious adverse event reporting

Incidence of all pneumonias

Incidence of COPD exacerbations

6.3.1. Liver Chemistry Stopping and Follow-up Criteria

NOTE: if serum bilirubin fractionation is not immediately available, withdraw study medication 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.

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 are presented in a figure in Appendix 3:

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1. ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) (or ALT 3xULN and INR>1.5, if INR measured)


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).


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, stabilise, or return to baseline values as described below

Withdraw the subject from the study (unless further safety follow-up is required) after completion of the liver chemistry monitoring as described below

Do not restart 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

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A specialist or hepatology consultation is recommended

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilise 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, stabilise 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 x3xULN, 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, stabilise 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 normalise or return to within baseline values.

For criteria 1-5, make every attempt to carry out the liver event follow up assessmentsdescribed 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

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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.

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 and quantitative total immunoglobulin G (IgG or gamma globulins).

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) [Le Gal, 2005].

Liver imaging (ultrasound, magnetic resonance, or computerised tomography) to evaluate liver disease.

6.3.2. 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.

Signs and symptoms of COPD included on the diary will not be considered AEs and will not be recorded in the eCRF, unless they meet the definition of an SAE.

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. The time period for collection of COPD exacerbations will begin form the time of Visit 2 (Randomization) and will end when the 7-day Follow-up period has been completed.

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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 FF/VI 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, 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.

6.3.2.1. 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.

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The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will be reported if they fulfill the definition of an AE or SAE. Also, “lack of efficacy” or “failure of expected pharmacological action” also constitutes an AE or SAE.

Events that do not meet the definition of an AE include:

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to the procedure is an AE

Situations where an untoward medical occurrence did not occur (social and/or convenience admission to a hospital)

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen

The disease/disorder being studied, or expected progression, signs, or symptoms of the disease/disorder being studied, unless more severe than expected for the subject’s condition

6.3.2.2. Definition of an 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 hospitalisation or prolongation of existing hospitalisation

NOTE: In general, hospitalisation 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 hospitalisation are AEs. If a complication prolongs hospitalisation or fulfills any other serious criteria, the event is serious. When in doubt as to whether “hospitalisation” occurred or was necessary, the AE should be considered serious.

Hospitalisation 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

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f. Medical or scientific judgment 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 hospitalisation but may jeopardisethe 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 hospitalisation, 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).

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.

6.3.2.3. Sentinel Events

A Sentinel Event is a GSK-defined SAE that is not necessarily drug-related but has been associated historically with adverse reactions for other drugs and is therefore worthy of heightened pharmacovigilance. Medical monitor review of all SAEs for possible Sentinel Events is mandated at GSK. The GSK medical monitor may request additional clinical information on an urgent basis if a possible Sentinel Event is identified on SAE review. The current GSK-defined Sentinel Events are listed below:

Acquired Long QT Syndrome

Agranulocytosis/Severe Neutropenia

Anaphylaxis & Anaphylactoid Reactions

Hepatotoxicity

Acute Renal Failure

Seizure

Stevens Johnson syndrome/Toxic epidermal necrosis

6.3.3. 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.

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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.

6.3.4. 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 thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularisation

This information should be recorded in the specific cardiovascular eCRF within one week of when the AE/SAE(s) are first reported.

6.3.5. Death Events

In addition, all deaths 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 in the specific death eCRF within one week of when the death is first reported.

6.3.6. Disease-Related Events and/or Disease-Related Outcomes Not Subject to Expedited Reporting

COPD exacerbation is expected in subjects with COPD and can be serious/life threatening. COPD exacerbations will be recorded on the COPD Exacerbation Form in the eCRF and will be reported as an SAE as applicable (see Section 6.2.6 and Section 6.3.2.2), but will not be subject to expedited regulatory reporting, regardless of the “expectedness” or “relatedness” of the event.

6.3.7. 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

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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.

6.3.8. Medical Devices

The valved-holding chamber that is being provided for use in this study is the only device considered a GSK medical device. Instructions for proper use of the valved-holding chamber are provided in the SPM.

GSK medical device incidents, including those resulting from malfunctions of the device, must be detected, documented, and reported by the investigator throughout the study.

Medical Device – this is any instrument, apparatus, appliance, material or other article, whether used alone or in combination, including the software necessary for its proper application intended by the manufacturer to be used for human beings for the purpose of:

diagnosis, prevention, monitoring, treatment or alleviation of disease;

diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap;

investigation, replacement or modification of the anatomy or of a physiological process;

control of conception

and which does not achieve its principle action in or on the human body by pharmacological, immunological or metabolic means, but may be assisted in its function by such means.

Note: if these means fulfill the main purpose of the product, it is a Medicinal Product. The term medical device includes in vitro diagnostic (IVD) devices.

The detection and documentation procedures described in this protocol apply to all GSK medical devices provided for use in the study.

Incident – Any malfunction or deterioration in the characteristics and/or performance of a device, as well as any inadequacy in the labeling or the instructions for use which, directly or indirectly might lead to or might have led to the death of a patient, or user or of other persons or to a serious deterioration in their state of health.

Not all incidents lead to death or serious deterioration in health. The non-occurrence of such a result might have been due to other fortunate circumstances or to the intervention of health care personnel.

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It is sufficient that

An incident associated with a device happened and

The incident was such that, if it occurred again, it might lead to death or serious deterioration in health

A serious deterioration in state of health can include:

A life-threatening illness (a)

Permanent impairment of body function or permanent damage to a body structure (b)

A condition necessitating medical or surgical intervention to prevent (a) or (b)

Any indirect harm as a consequence of an incorrect diagnostic or IVD test results when used within the manufacturer’s instructions for use

Fetal distress, fetal death or any congenital abnormality or birth defects

Incidents include, for example:

inhalation of an object that has accidentally entered a spacer device and resulted in tracheal obstruction.

Incidents do not include for example:

medical occurrences associated with metered-dose inhalers that do not fulfill the definition of a medical device (such events will be reported as medicinal product AEs)

non-serious medical occurrences which have no further safety implications for the subject or the device

Malfunction – A failure of a device to perform in accordance with its intended purpose when used in accordance with the manufacturer’s instructions.

Remedial Action – Any action other than routine maintenance or servicing of a device where such action is necessary to prevent recurrence of a reportable incident [this includes any amendment to the design to prevent recurrence].

6.3.9. 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 double-blind Investigational Product and until thefollow 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

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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 6.3.10.

6.3.10. Method of Detecting AEs and SAEs

Care must be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-leading verbal questioning of the subject is the preferred method to inquire about AE occurrence. Appropriate questions include:

“How are you feeling?” or for paediatric studies, “How does your child seem to feel?”

“Have you had any (other) medical problems since your last visit/contact?” or for paediatric studies, “Has your child had any (other) medical problems or seem to act differently in any way since his/her last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since your last visit/contact?” or for paediatric studies, ”Has your child needed to take any medicines, other than those provided in this study, since his/her last visit/contact?”

In addition, subjects will be provided with a “Medical Problems/Medications Taken Diary” on which they can record any medical problems they may have experienced and any medications used to treat those medical problems. 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. 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.

6.3.11. Prompt Reporting of Serious Adverse Events and Other Events to GSK

SAEs, pregnancies, medical device incidents, and liver function abnormalities meeting pre-defined criteria will be reported promptly by the investigator to GSK as described in the following table once the investigator determines that the event meets the protocol definition for that event.

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Initial Reports Follow-up Information on a Previous Report

Type of Event Time Frame Documents Time Frame DocumentsAll SAEs 24 hours “SAE” data

collection tool24 hours Updated “SAE”

data collection tool

Cardiovascular or death event

Initial and follow up

reports to be completed within one

week of when the

cardiovascular event or death

is reported

“CV events” and/or “death” data collection

tool(s) if applicable

Initial and followup reports to be completed within

one week of when the cardiovascular event or death is

reported

Updated “CV events” and/or “death” data

collection tool(s) if applicable

Device Incident 24 hours “Medical Device Incident Report

Form”

24 hours Updated “Medical Device Incident Report Form”

Pregnancy 2 weeks “Pregnancy Notification Form”

2 weeks “Pregnancy Follow-up Form”

Liver chemistry abnormalities for Phase I to IV:

ALT3xULN andBilirubin2xULN (>35% direct) (or ALT3xULN andINR>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

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Initial Reports Follow-up Information on a Previous Report

Type of Event Time Frame Documents Time Frame DocumentsRemaining liver chemistry abnormalities Phase III to IV:

ALT8xULN; ALT3xULN with

hepatitis or rash or 3xULN and <5xULN

that persists4 weeks

24 hours2 “Liver Event” Documents

(defined above) 3

24 hours Updated “Liver Event” Documents3

ALT5xULN plus bilirubin <2xULN


(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

ALT5xULN and bilirubin <2xULN that

persists 2 weeks


(defined above) 3

24 hours Updated “Liver Event” Documents3

ALT3xULN and <5x ULN and bilirubin

<2xULN


(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 safety3. 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 recording, evaluating and follow-up of AEs and SAEs plus procedures for completing and transmitting SAE reports to GSK are provided in the SPM. Procedures for post-study AEs/SAEs are provided in the SPM.

Procedures for documenting, transmitting and follow-up of medical device incidents along with the regulatory reporting requirements for medical devices are provided in the SPM.

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6.3.11.1. 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.

6.3.12. Vital Signs

Vital signs (pulse rate and blood pressure [systolic and diastolic]) will be performed as part of the Physical Exam (See the Time and Events Table in Table 4), prior to the spirometry maneuvers and with the subject in the sitting position. The subject must be seated at least 5 minutes before these measurements are performed and a single set of values will be collected. Immediately following completion of these measurements, spirometry will be completed as scheduled. The vital sign results will be captured in the subject’s clinic notes but not in the eCRF.

6.3.13. 12-lead ECG Assessments

Investigators will be responsible for using their own ECG equipment and for reviewing and interpreting the Screening ECGs, or contracting with a medically qualified provider to provide these services if they are unable to perform these services (i.e., no standardized equipment or centralized review by an independent cardiologist will be provided for this study) to evaluate subject eligibility. The Investigator, a designated sub-investigator, or other appropriately trained site personnel, will be responsible for performing the 12-lead ECG recording.

A single, 12-lead ECG with a 15-second rhythm strip will be recorded for each subject at Screening (Visit 1) only (as shown in the Time and Events Table [Table 4]) for purposes of determining the subject’s eligibility to participate in the study. The ECG machine should be calibrated according to the manufacturer’s instructions and schedule, prior to performing readings for the study.

The 12-lead ECG report must include the following at a minimum: subject number, date and time that the ECG was performed, heart rate, interval data (including RR, PR, QRS, QT, and QTc[F]), and an overall interpretation of the ECG. The Investigator must provide his/her dated signature on the ECG report, attesting to his/her review of the report.

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The ECG measurement will be performed with the subject resting in a supine position for at least 10 minutes before the reading, which should be carried out after measurement of vital signs and before spirometry.

For purposes of this study, an abnormal and clinically significant 12-lead ECG finding that would preclude a subject from being randomized or require withdrawal from the study (if a non-protocol-specified ECG is performed during the Treatment Period) is defined as a 12-lead tracing that is interpreted as, but not limited to, any of the findings noted in Appendix 1.

6.3.14. Oropharyngeal Examination

Oropharyngeal examinations for clinical evidence of infection (i.e., Candidaalbicans) are not a protocol-required procedure for this study. If during routine clinical examination of the subject there is evidence of infection, a culture can 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 the pharmacotherapy will be recorded in the eCRF.

After randomization, all culture positive results must be reported as adverse events.

6.3.15. Clinical Laboratory Assessments

All protocol required laboratory assessments, as defined in Appendix 2, must be performed by the central laboratory, Quest Diagnostics. Laboratory assessments must be conducted in accordance with the Central Laboratory Manual and Protocol Time and Events Schedule (Table 4). Laboratory requisition forms must be completed and samples must be clearly labelled with the subject number, protocol number, site/centre number, and visit date. Details for the preparation and shipment of samples will be provided by Quest Diagnostics. Reference ranges for all safety parameters will be provided to the site by Quest Diagnostics.

If additional non-protocol specified laboratory assessments are performed at the institution’s local laboratory and result in a change in patient management or are considered clinically significant by the investigator (e.g., SAE or AE or dose modification), the results must be recorded in the subject’s CRF. Refer to the SPM for appropriate processing and handling of samples to avoid duplicate and/or additional blood draws.

A routine, non-fasting clinical laboratory (liver function panel) will be performed in all subjects at Visit 1 (Screening) (See the Time and Events Table in Table 4).

For women of childbearing potential, a serum pregnancy test will be included in the laboratory panel collected at Visit 1. For these subjects, a urine pregnancy test will be provided at Visit 7 or Early Withdrawal. The test will be performed at home during the

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Follow-Up Period and the result reported to study staff during the Follow-Up Phone Contact.

At the discretion of the investigator, additional clinical laboratory samples may be taken for safety reasons. If the subject has an abnormal laboratory finding for any analyte from the Screening Visit liver function 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), a blood sample for repeat analysis of the analyte(s) should be collected pre-dose at Visit 2 (Randomization).

The specific list of laboratory analytes to be evaluated is shown in Appendix 2.

6.3.16. Smoking Cessation Counselling

During Visits 1 and 7 or Early Withdrawal, 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.

The specific information to be discussed with each subject is provided in the SPM.

6.4. Health Outcomes

6.4.1. Health Outcome Assessments Not Included as Primary or Key Secondary Endpoints

See Section 6.2.7 and Section 6.2.8 regarding the assessments of health-related quality of life using the SGRQ-C and health status using the CAT, respectively.

6.5. Exploratory Endpoint

As an exploratory endpoint, COPD symptoms of cough and sputum will be assessed using the CASA-Q at participating sites in countries for which a validated and translated version(s) of this questionnaire is (are) available at the time of study initiation at the visits noted in the Time and Events Table (Table 4). The CASA-Q targets cough and sputum by assessing these symptoms from two different approaches: descriptively (e.g., frequency of the symptom, severity of the symptom) and evaluating the impact of these two symptoms on daily activities. The CASA-Q was derived directly from patients of various diverse cultures and focused on not only the symptoms of cough and sputum production, but also their impact on the patient’s life [Crawford, 2008].

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The CASA-Q is a 20-item questionnaire that has four domains relating to the frequency and severity of cough and sputum symptoms and their impact on patients’ daily lives. The cough and sputum domains have three items each, whereas the cough impact domain consists of eight items, and the sputum impact domain of six items. Each item is answered on a scale from ‘never’ to ‘always’ (for frequency) or from ‘not at all’ to ‘a lot/extremely’ (for intensity), each type using five categories. Scores range from 0-100, with lower scores indicating higher symptom/impact levels. No overall score is calculated.

The CASA-Q is paper-administered and has a 7-day recall period. This recall period was selected because of the chronic nature of chronic bronchitis and COPD and the fact that important impacts in patients in the intended setting (i.e., maintenance treatment of cough and sputum symptoms) do not happen on a daily basis but will likely be covered within one week.

6.6. Pharmacogenetic Research

Information regarding pharmacogenetic (PGx) research is included in Appendix 3.

7. DATA MANAGEMENT

For this study subject and diary data will be entered into GSK defined electronic case report forms (eCRFs), transmitted electronically to GSK or designee and combined with data (e.g., laboratory and spirometry) provided from other sources in a validated data system.

Or

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 studies where Japan is participating 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 primary purpose of this superiority study is to demonstrate the contribution on lung function (trough FEV1) of FF 100mcg QD (in the FF/VI 100/25 mcg QD combination) over a 12-week Treatment Period.

For each test on each efficacy endpoint, the null hypothesis is there is no difference between the FF/VI 100/25 and VI 25 treatment groups.

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H0: T1 – T2 = 0

The alternative hypothesis is there is a difference between treatment groups (two-sided).

H1: T1 – T2 0

8.2. Study Design Considerations

8.2.1. Sample Size Assumptions

Sample size calculations are based on the primary endpoint of trough FEV1 at Week 12.

The sample size calculation uses an estimate of residual standard deviation of 230 mLbased upon the integrated results of the two, Phase III, 6-month, efficacy and safety studies of FF/VI (including the 100/25 mcg strength) in subjects with COPD (HZC112206 and HZC112207) in the subset population included in the current study i.e., subjects with at least one moderate or severe exacerbation in the year prior to screening and with a total symptom score 4 on 5 of the last 7 days pre randomization.

A study with 696 evaluable subjects in each of the active treatment groups will have 90% power to detect a 40 mL difference between FF/VI 100/25 QD and VI 25 QD in trough FEV1 at Week 12, assuming a standard error of 230 mL. A two sample t-test and two-sided 5% significance level has been used for these calculations.

Trough FEV1 will be analyzed using Mixed Models Repeated Measures (MMRM) analysis. Although, in MMRM, all available post-baseline assessments up to endpoint for subjects in the ITT Population are utilized in the analysis, data for subjects who withdraw prematurely from the study is not explicitly imputed. It is therefore important to make some adjustment for missing data. In studies HZC112206 and HZC112207, the withdrawal rate at 12 weeks of treatment for subjects with a history of at least one COPD exacerbation in the year prior to Screening was 17.5% overall, 15% in the FF/VI 100/25 QD group and 12% in the VI 25 QD group. Since the current study includes only active treatment arms, whereas the HZC112206 and HZC112207 studies included active treatment arms and a placebo arm, and given that subjects who experience a COPD exacerbation during the study are not required to be withdrawn from study treatment and/or the study in the current study compared with the HZC112206 and HZC112207 studies, a smaller withdrawal rate (12%) is estimated for the current study.

To allow for this 12% withdrawal rate post-randomization, 791 subjects will be randomized per treatment arm, for a total of 1,582 randomized subjects, to achieve 696 evaluable subjects per treatment arm, for a total of 1,392 evaluable subjects.

8.2.2. Sample Size Sensitivity

If the standard deviation observed in the study is different from the 230 mL used in the sample size calculation, the power to detect the planned difference in trough FEV1 on day 84 will be affected. Table 5 illustrates the power which would be obtained to detect a 40mL difference with various standard deviations, assuming the number of evaluable

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subjects remains constant at 696 per treatment arm. Table 5 and Figure 2 illustrate the impact on power and treatment differences of different estimates of standard deviation

Table 5 Impact on Power and Treatment Differences of Different Estimates of Standard Deviation

SD (mL) Treatment Difference (mL)

Power for 40 mL effect Treatment Difference for 90% power (mL)

190 40 98% 33210 40 94% 36230 40 90% 40250 40 85% 43270 40 79% 47

Figure 2 Impact on Power and Treatment Differences of Different Estimates of Standard Deviation

It should be noted that a trial can run to its conclusion and deliver a significant p-value for an effect smaller than the one we nominally powered for (assuming the assumptions underlying the sample size calculation are correct). In this case, based on a nominal true difference of 40 mL, SD of 230 mL and a sample size of 696 evaluable subjects per arm, we would see a p=0.05 with an effect size of 25 mL [detectable effect] and p0.05 for effect sizes >25 mL. Figure 3 shows the p-values (vertical axis) that would be seen for different effect sizes (horizontal axis) under our assumptions regarding effect size and SD:

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Figure 3 Effect Size and P-values Assuming 696 Evaluable Subjects Per Arm

Note: Number of evaluable subjects are determined by 90% power, 5% significance level, standard deviation of 230 mL and a true effect size of 40 mL

Even if we believe the nominal true difference is 40 mL we may not see 40 mL in our trial. This “detectable effect” gives us confidence that should the true difference be 40mL we could see a significant effect if the difference in our trial were as low as 25 mL.

8.2.3. Sample Size Re-estimation


8.3. Data Analysis Considerations

8.3.1. Analysis Populations

The analysis population will be the Intent-to-Treat (ITT) population, defined as all subjects who have been randomized to study medication and received at least one dose of randomized treatment. All available data collected until the time of study discontinuation will be included in the ITT analysis for subjects who withdraw from the study.

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8.3.2. Analysis Data Sets

The trough FEV1 data will comprise the primary data set of interest, with the Week 12 trough FEV1 data the primary time point of interest.

Details of derived data in analysis datasets to be created will be given in the Reporting and Analysis Plan (RAP).

8.3.3. Treatment Comparisons

8.3.3.1. Primary Comparisons of Interest

There is a single primary treatment comparison (FF/VI 100/25 versus VI 25) for the primary efficacy endpoint; so, no multiplicity adjustment is required. There are twosecondary endpoints (percentage of rescue-free 24-hour periods over the entire 12-week Treatment Period and time to first moderate/severe COPD exacerbation). These will be nested under the primary endpoint in the following order: If the comparison of FF/VI 100/25 versus VI 25 demonstrates statistical significance at the 5% level on the primary efficacy endpoint, then inferences relating to the secondary endpoint of percentage of rescue-free 24-hour periods will be made. If the comparison of FF/VI 100/25 versus VI 25 demonstrates statistical significance at the 5% level for this endpoint then inferences relating to the secondary endpoint of time to first moderate/severe COPD exacerbation will be made.

8.3.3.2. Other Comparisons of Interest

There are no other comparisons of interest.

8.3.4. Interim Analysis

No interim analyses are planned. No unblinding of the data for the purpose of sample re-estimation will take place (see Section 8.2.3).

8.3.5. Key Elements of Analysis Plan

Where possible, data from subjects who withdraw prematurely from the study will be included in any analyses. Specific details for inclusion will be detailed in the RAP; but, in general, the minimum data required will be a baseline evaluation and at least one post-baseline evaluation. For purposes of analysis, a completed subject is defined as anyone completing the last treatment visit (Visit 7).

Data collected during a clinic visit will be reported by the visit at which the data was collected and will not be excluded from any analysis for being collected outside of an assessment window.

Trough FEV1 will be analyzed using Mixed Models Repeated Measures (MMRM) analysis. Although, in MMRM, all available post-baseline assessments up to endpoint for subjects in the ITT Population are utilized in the analysis, data for subjects who withdraw prematurely from the study is not explicitly imputed. Sensitivity analyses will

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also be performed using single imputation LOCF and the multiple imputation method of Copy Increment from Reference.

8.3.5.1. Efficacy Analyses

All efficacy data will be summarized using means, standard deviations or standard errors, medians and ranges for continuous variables and frequencies and percentages for categorical variables.

The primary efficacy endpoint is change from baseline in Clinic Visit trough (pre-bronchodilator and pre-dose) FEV1on Treatment Day 84 (Visit 7). This endpoint will be analysed using MMRM. Treatment group will be fitted as the explanatory variable, with appropriate, pre-defined variables to include reversibility status, baseline FEV1 and region fitted as covariates. Visit will be fitted as a categorical variable and visit by baseline and treatment by visit interaction term will be fitted to allow treatment effects to be estimated at each visit separately. The variance-covariance matrix will be assumed to be unstructured.

The estimated treatment difference for the comparison of FF/VI 100/25 with VI 25, 95% confidence interval and associated p-value will be displayed.

The secondary endpoint of percentage of rescue-free 24-hour periods over the entire 12-week treatment period will be compared between treatment groups using an analysis of covariance (ANCOVA) model with effects due to baseline, reversibility status at screening, region and treatment.

The secondary endpoint of time to first moderate or severe exacerbation will be compared between treatment groups using Cox’s proportional hazards model allowing for treatment group, reversibility status and baseline disease severity (as % predicted FEV1).

Full details of the analyses to be performed for all primary, secondary and other efficacy endpoints will be provided in the RAP.

8.3.5.2. Safety Analyses

8.3.5.2.1. Extent of Exposure

The extent of exposure to study medication will be summarized by treatment group.

8.3.5.2.2. Adverse Events (AEs)

AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), and grouped by System Organ Class (SOC). 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 SOC 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 study withdrawal.

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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. Adverse Events of Special Interest (AESI)

AE groups of special interest have been defined as AEs which have specified areas of interest for one or more of the treatment groups (FF/VI and/or VI). Some AE groups may have subgroups defined.

The number and percentage of subjects experiencing at least one on-treatment AE in any group, AEs within each subgroup (if applicable) and AEs within each preferred term will be presented for each treatment group.

The following table presents the current special interest AE groups and subgroups. These may be updated prior to conclusion of the study reporting. The final list, including the preferred terms which contribute to each of the groups will be documented prior to unblinding the study.

Special Interest AE Group Special Interest AE subgroupCardiovascular Cardiac Arrhythmia

Cardiac FailureCardiac IschaemiaHypertensionStroke

Pneumonia PneumoniaLower Respiratory Tract Infection (excl. Pneumonia)

Adrenal SuppressionCorticosteroid Associated Eye DisordersEffects on glucoseEffects on potassiumTremorLocal steroid effectsDecreased bone mineral density and associated fracturesHypersensitivity

8.3.5.2.5. Pneumonia

The frequency of reported pneumonias will be summarized by treatment group.

8.3.5.3. Health Outcomes Analyses

8.3.5.3.1. SCRQ-C and CAT

Scoring of the SGRQ-C and CAT will follow the developers’ guidelines. SGRQ Total score and CAT score will be compared between treatment groups using ANCOVA. Further details of the scoring algorithms and questionnaire analyses will be provided in the RAP.

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8.3.5.3.2. Exploratory Endpoint

Scoring of the CASA-Q will follow the developers’ guidelines. The CASA-Q score will be compared between treatment groups using ANCOVA. Further details of the scoring algorithms and questionnaire analyses will be provided in the RAP.

8.3.5.4. Pharmacogenetic Analyses

See Appendix 3 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 Helsinki2008, 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.

As discussed in Section 6.1, 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.

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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 3, 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 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-

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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.

9.7. Provision of Study Results to Investigators, Posting of Information on Publicly Available Clinical Trials Registersand 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.

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GSK will also provide the investigator with the full summary of the study results. The investigator is encouraged to share the summary results with the study subjects, as appropriate.

GSK will provide the investigator with the randomisation codes for their site only after completion of the full statistical analysis.

The results summary will be posted to the Clinical Study Register no later than eight months after the final primary completion date, the date that the final subject was examined or received an intervention for the purposes of final collection of data for the primary outcome. In addition, a manuscript will be submitted to a peer reviewed journal for publication no later than 18 months after the last subject’s last visit (LSLV). When manuscript publication in a peer reviewed journal is not feasible, a statement will be added to the register to explain the reason for not publishing.

A manuscript will be progressed for publication in the scientific literature if the results provide important scientific or medical knowledge.

9.8. Independent Data Monitoring Committee (IDMC)

No IDMC will be utilized for this study.

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10. REFERENCES

American Thoracic Society and European Respiratory Society. Standards for the Diagnosis and Management of Patients with COPD Nontuberculous Respiratory Diseases. American Thoracic Society and European Respiratory Society. 2004. http://www.thoracic.org/clinical/copd-guidelines/resources/copddoc.pdf

Calverley PM, Anderson JA, Celli B. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. NEJM. 2007;356:776-89.

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.

Crawford B, Monz B, Hohlfeld J, Roche N, Rubin B, Magnussen H, Nivens C, Ghafouri M, McDonald J, Tetzlaff K. Development and validation of a cough and sputum assessment questionnaire. Respir Med. 2008 Nov;102(11):1545-55.

Dransfield MT, Bourbeau J, Jones PW, Hanania NA, Mahler DA, Vestbo J, Wachtel A, Martinez FJ, Barnhart F, Sanford L, Lettis S, Crim C, Calverley PMA. Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials. Lancet Respir Med. 2013;1:210–23.

Ferguson GT, Anzueto A, Fei R, Emmett A, Knobil K, Kalberg C. Effect of fluticasone propionate/salmeterol (250/50g) 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 2013). http://www.gold.copd.org

Hankinson JL, Kawut SM, Shahar E, Smith LJ, Stukovsky KH, Barr RG. Performance of American Thoracic Society-recommended spirometry reference values in multiethnic sample of adults - the multi-ethnic study of atherosclerosis (MESA) lung study. Chest.2010;137:138-45

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, LeeWM. Pharmacokinetics of Acetaminophen-Protein Adducts in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37(8): 1779-1784.

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Jones PW, Harding G, Berry P, Wiklund I, Chen W-H, Leidy NK. Development and first validation of the COPD Assessment Test (CAT). Eur Respir J 2009; 34: 648-54.

Jones PW. St. George's Respiratory Questionnaire: MCID. COPD. 2005;2(1):75-9.

Jones PW, Quirk FH, Baveystock CM, Littlejohn P. A self-complete measure of health status for chronic airflow limitation: The St. George’s Respiratory Questionnaire. Am Rev Respir Dis. 1992;145:1321-7.

Kardos P, Wencker M, Glaab T. Impact of salmeterol/fluticasone propionate versus salmeterol on exacerbations in severe chronic obstructive pulmonary disease. Am J Resp Crit Care Med. 2007;175:144-49.

Kerwin EM, Scott-Wilson C, Sanford L, Rennard S, Agusti A, Barnes N, Crim C. A randomised trial of fluticasone furoate/vilanterol (50/25 µg; 100/25 µg) on lungfunction in COPD. Respir Med. 2013;107, 560-569.

Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E. Quantification of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates Different Patterns of Virological Response to Interferon Therapy in Chronically Infected Patients. J Clin Microbiol. 2005;43(5):2363–2369.

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

Martinez FJ, Boscia J, Feldman G, Scott-Wilson C, Kilbride S, Fabbri L, Crim C, Calverley P. Fluticasone furoate/vilanterol (100/25; 200/25 µg) improves lung function in COPD: A randomised trial. Respir Med. 2013; 107, 550-559.

Meguro M, Barley EA, Spencer S, Jones PW. Development and validation of an improved, COPD-specific version of the St. George Respiratory Questionnaire. Chest 2007; Aug 132(2):456–63.

Miller MR, Hankinson J, Odencrantz J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright R, van der Grinten CPM, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J. Standarisation of spirometry. Eur Respir J. 2005;26:319-38.

Pelligrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, Coates A, van der Grinten CPM, Gustafsson P, Hankinson J, Jensen R, Johnson DC, MacIntyre N, McKay R, Miller MR, Navajas D, Pedersen OF, Wanger J. Interpretative strategies for lung function tests. Eur Respir J. 2005;26:948-68.

Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, Enright PL, Hankinson JL, Ip MSM, Zheng J, Stocks J, and the ERS Global Lung Function Initiative. ERS Task Force: Multi-ethnic reference values for spirometry for the 3–95-yr age range: the global lung function 2012 equations. Eur Respir J. 2012; 40: 1324–1343.

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The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256.

WHO. Chronic Obstructive Pulmonary Disease (COPD). Burden of COPD. WHO. 2012.

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11. APPENDICES

11.1. Appendix 1: ECG Exclusion/Withdrawal Criteria

For purposes of this study, an abnormal and clinically significant 12-lead ECG finding that would preclude a subject from being randomized or require withdrawal from the study (if a non-protocol-specified ECG is performed during the Treatment Period) is defined as a 12-lead tracing that is interpreted as, but not limited to, any of the following findings:

Sinus bradycardia <45bpm

Note: Sinus bradycardia <45bpm/<35bpm should be confirmed by two additional readings at least 5 minutes apart.

Sinus tachycardia >120bpm

Note: Sinus tachycardia >120bpm should be confirmed by two additionalreadings at least 5 minutes apart.

Multifocal atrial tachycardia (wandering pacemaker with rate >100bpm)

Junctional tachycardia (heart rate >100bpm)

Supraventricular tachycardia (>120bpm)

Ventricular tachycardias (sustained, polymorphic, or monomorphic)

Atrial fibrillation with rapid ventricular response (rate >100bpm)

Atrial flutter

Evidence of bigeminy, trigeminy, ventricular couplets or multifocal premature ventricular complexes (Investigator discretion as to whether or not exclusionary for a given subject)

Ventricular flutter

Ventricular fibrillation

Torsades de Pointes

R on T phenomenon

Multifocal atrial tachycardia

Wide QRS tachycardia (diagnosis unknown)

ST-T wave abnormalities (with the exception of non-specific changes)

Pacemaker (pacemaker requiring a ventricular pace rate set at >60bpm)

Note: Atrial pacing with intrinsic conduction to the ventricle is not exclusionary

Idioventricular rhythm – heart rate <100bpm

Evidence of atrioventricular (AV) block:

2nd degree block (Mobitz type II)

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3rd degree block

Evidence of atrioventricular (AV) block:

AV dissociation

Bifascicular block

Trifascicular block

Complete left bundle branch block

QT/QTc(F): See Inclusion Criterion #10 and Withdrawal Criterion #3

Accessory pathway (Wolff-Parkinson-White, Lown-Ganong-Levine)

Acute or recent (i.e. within 6 months) myocardial infarction (anterior, inferior, posterior, lateral, septal, non-Q wave)

Note: historical (i.e., >6 months prior to Screening) MI is not exclusionary; however, documentation will need to be provided to confirm that the MI occurred >6 months and that an MI has not occurred within 6 months prior to Screening

Pathological Q waves (defined as wide [>0.04 seconds] and deep [>0.4mV (4mmwith 10mm/mV setting)] or >25% of the height of the corresponding R wave,providing the R wave was >0.5mV [5mm with 10mm/mV setting], appearing in atleast two contiguous leads.

Note: prior evidence (i.e., ECG obtained at least 12 months prior) of pathological Q waves that are unchanged are not exclusionary.

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11.2. Appendix 2: Clinical Laboratory Assessments

Refer to the Time and Events Table (Table 4) for information regarding the timing of laboratory tests.

Clinical Laboratory Analytes

LIVER FUNCTION PANEL OTHERAlbumin Hepatitis B surface antigen1,2

Alkaline phosphatase Hepatitis C virus antibody1,2

Alanine amino-transferase (ALAT or SGPT) Urine pregnancy test (in home test)3

Aspartate amino-transferase (ASAT or SGOT) Fungal culture of oral mucosa (if visual evidence of candidiasis)

Bilirubin, direct hCG qualitative (serum pregnancy)3

Bilirubin, indirectBilirubin, totalGamma glutamyl transferase (GGT)Protein, total serum1. Assessed at Visit 1 (Screening) only2. Result is not exclusionary3. Only females of child-bearing potential; refer to Time and Events Table (Table 4) for specific visit

information

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11.3. Appendix 3: 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 OutcomeAbacavir HIV

[Hetherington, 2002; Mallal, 2002; Mallal, 2008]

HLA-B* 57:01(Human Leukocyte Antigen B)

Carriage of the HLA-B*57:01 variant has been shown to increase a patient's risk for experiencing hypersensitivity to abacavir. Prospective HLA-B*57:01 screening and exclusion of HLA-B*57:01 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*57:01 screening prior to initiation of abacavir to reduce the incidence of abacavir hypersensitivity. HLA-B*57:01screening should supplement but must never replace clinical risk management strategies for abacavir hypersensitivity.

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Drug Disease Gene Variant OutcomeCarbamazepine

Seizure, Bipolar disorders & Analgesia [Chung, 2010; Ferrell, 2008]

HLA-B*15:02 Independent studies indicated that patients of East Asian ancestry who carry HLA-B*15:02are at higher risk of Stevens-Johnson Syndrome and toxic epidermal necrolysis. 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*15:02 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 doseof 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 saliva 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.

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. 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, the following objectives may be investigated – the relationship between genetic variants and study treatment with respect to:

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Pharmacokinetics and/or pharmacodynamics of study treatment

Safety and/or tolerability

Efficacy

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 (2 mL) 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 as soon as practical after randomization at Visit 2, although it can be collected at any time during study participation (Table 4).

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 utilise 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 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.

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 withdraws from the clinical study for any reason other than being lost to follow-up, the subject will be given a choice of one of the following options concerning the PGx sample, if already collected:

Continue to participate in the PGx research with the PGx sample retained for analysis

Withdraw from the PGx research and 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. The investigator should forward the Pharmacogenetic Sample Destruction Request Form to GSK as directed on the form. This can be done at any time when a subject wishes to withdraw from the PGx research or have their sample destroyed whether during the study or during the retention period following close of the main study.

Screen and Baseline Failures

If a saliva 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 consentand sample reconciliation process. In this instance a sample destruction form will not be available to include in the site files.

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 mayunderpin 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. 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

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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 summarised 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 summarise 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.

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: 1543-1546.

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; 359:1121-1122.

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: 1932-1940.

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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; 359:727-732.

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; 568-579

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: 5058-5066.

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11.4. Appendix 4: Country Specific Requirements

No country-specific requirements exist.

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11.5. Appendix 5: Liver Chemistry Stopping and Follow-up Criteria

Phase III-IV Liver Safety Algorithms

ALT>3xULN

plus bilirubin >2x ULN (>35%

direct) (or plusINR >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 symptomsor rash?

No

Able to monitor

weekly for 4 weeks?

Yes

No**

Yes

Continue IPObtain 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

NoALT >8xULN

Yes

ALT >5 and

<8xULN for > 2

wksYes 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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