Protocol 1. This trial protocol has been provided by the authors to give readers additional information about their work.

Transcription

1 Protocol 1 This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Pavord ID, Chanez P, Criner GJ, et al. Mepolizumab for eosinophilic chronic obstructive pulmonary disease. N Engl J Med;377: DOI: /NEJMoa

2 Chronic Obstructive Pulmonary Disease, mepolizumab, SB Protocol and statistical analysis plan for NCT (GSK ID ) This supplement contains the following items: 1. Original protocol, final protocol, summary of changes 2. Original statistical analysis plan, final statistical analysis plan, summary of changes Contents Original protocol 2 Final protocol (amendment) 103 Details of protocol amendments 203 Original statistical analysis plan 225 Final statistical analysis plan 328 Details of statistical analysis plan amendments 335

3 2013N183405_00 GlaxoSmithKline group of companies TITLE PAGE Division: Worldwide Development Information Type: Clinical Protocol Title: Compound Number: Development Phase Effective Date: Study : Mepolizumab vs. Placebo as add-on treatment for frequently exacerbating COPD patients SB Phase IIIA 03-DEC-2013 Subject: Chronic Obstructive Pulmonary Disease, mepolizumab, SB240563, exacerbations, eosinophils Author(s): PPD Copyright 2013 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited. 1

4 PPD PPD

5 2013N183405_ SPONSOR INFORMATION PAGE Clinical Study Identifier: Sponsor Legal Registered Address: GlaxoSmithKline Research & Development Limited 980 Great West Road Brentford Middlesex, TW8 9GS UK Sponsor Contact Address: GlaxoSmithKline Research & Development Limited Five Moore Drive P.O Research Triangle Park, NC , USA PPD Telephone: GlaxoSmithKline Research & Development Limited Iron Bridge Road Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK PPD Telephone: In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate company (or designee). Where applicable, the details of the Sponsor and contact person will be provided to the relevant regulatory authority as part of the clinical trial submission. Sponsor Global Medical Monitor Contact Information: PPD PPD Tel: Mobile: PPD MD (Medical Monitor, Respiratory Research and Development) Sponsor Back-up Global Medical Monitor Contact Information: PPD PPD Tel: Mobile: PPD MD (Director, Respiratory Research and Development) Sponsor Serious Adverse Events (SAE) Co-ordinator: PPD MD (Director, Respiratory Research and Development) 3

6 2013N183405_00 PPD Tel: Mobile: PPD Regulatory Agency Identifying Number(s): IND No EudraCT number:

7 2013N183405_ INVESTIGATOR PROTOCOL AGREEMENT PAGE I confirm agreement to conduct the study in compliance with the protocol. I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or supervise the described clinical study. I agree to ensure that all associates, colleagues and employees assisting in the conduct of the study are informed about their obligations. Mechanisms are in place to ensure that site staff receives the appropriate information throughout the study. Investigator Name: Investigator Signature Date 5

8 2013N183405_00 TABLE OF CONTENTS PAGE 1. INTRODUCTION Background Rationale Benefit:Risk Assessment Risk Assessment Benefit Assessment Overall Benefit:Risk Conclusion OBJECTIVE(S) INVESTIGATIONAL PLAN Study Design Schema Study Design Discussion of Design Dose Rationale SUBJECT SELECTION AND WITHDRAWAL CRITERIA Number of Subjects Eligibility Criteria Inclusion Criteria Exclusion Criteria Randomization Criteria Pre-Screening/Screening/Run-in Failures Investigational Product (IP) Discontinuation Criteria Protocol defined Stopping IP Criteria Permanent Discontinuation from IP Withdrawal Criteria Withdrawal from Study Study Withdrawal assessments Lost to Follow-up Reasons for Study Withdrawal Follow up Visit STUDY TREATMENTS Investigational Product and Other Study Treatment Treatment Assignment Blinding Product Accountability Treatment Compliance Concomitant Medications and Non-Drug Therapies Permitted Medications and Non-Drug Therapies Prohibited Medications and Non-Drug Therapies Treatment after the End of the Study Treatment of Study Treatment Overdose STUDY ASSESSMENTS AND PROCEDURES Critical Baseline Assessments Pre-screening Visit Critical Procedures Performed at Visit 1 (Screening)

9 2013N183405_ Modified Medical Research Council Grading System (mmrc) Charlson Co-morbidity index (CCI) Definition of child bearing and non-child bearing potential Critical Procedures Performed at Visit 2 (Randomization) Efficacy Primary Efficacy Endpoint Secondary Efficacy Endpoints Other Efficacy Endpoints Spirometry and Bronchodilator Responsiveness Testing Spirometry Bronchodilator Responsiveness Testing Diary Assessment Moderate and Severe COPD Exacerbations Symptom Defined COPD Exacerbations Exacerbation Treatment St. George's Respiratory Questionnaire for COPD patients EQ-5D-5L COPD Assessment Test Safety Safety assessment and endpoints Hepatitis B screening and monitoring Liver chemistry stopping and follow up criteria Adverse Events Definition of an AE Definition of an SAE Sentinel Events Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs Cardiovascular Events Death Events Pregnancy Time Period and Frequency of Detecting AEs and SAEs Method of Detecting AEs and SAEs Prompt Reporting of Serious Adverse Events and Other Events to GSK Regulatory reporting requirements for SAEs Other Safety Outcomes Laboratory Assessments Physical Exam Vital Signs Medical Problems and Concomitant Medications Lead ECG Pneumonia Health Outcomes Health Outcome Assessments Not Included as Primary or Key Secondary Endpoints Healthcare Resource Utilization Additional Health Outcomes Assessments SF

10 2013N183405_ Rating of Activity Limitation and Impression of Change Clinician/Subject Rated Response to Therapy Pharmacokinetics/Pharmacodynamics/Biomarker(s) Pharmacodynamics Immunogenicity Pharmacogenetic Research Novel Biomarkers DATA MANAGEMENT DATA ANALYSIS AND STATISTICAL CONSIDERATIONS Hypotheses Study Design Considerations Sample Size Assumptions Sample Size Sensitivity Sample Size Re-estimation Data Analysis Considerations Analysis Populations Analysis Data Sets Treatment Comparisons Primary Comparisons of Interest Other Comparisons of Interest Interim Analysis Meta-analysis Key Elements of Analysis Plan Primary Analyses Efficacy Analyses Key Secondary Endpoints Other Endpoints Safety Analyses Extent of Exposure Adverse Events Clinical Laboratory Evaluations Other Safety Measures Immunogenicity Health Outcomes Analyses Pharmacokinetic Analyses Pharmacodynamic Analyses Pharmacokinetic/Pharmacodynamic Analyses Pharmacogenetic Analyses Novel Biomarker(s) Analyses STUDY CONDUCT CONSIDERATIONS Posting of Information on Publicly Available Clinical Trial Registers Regulatory and Ethical Considerations, Including the Informed Consent Process Quality Control (Study Monitoring) Quality Assurance Study and Site Closure Records Retention

11 2013N183405_ Provision of Study Results to Investigators, Posting of Information on Publicly Available Clinical Trials Registers and Publication Independent Data Monitoring Committee (IDMC) Adjudication Committee REFERENCES APPENDICES Appendix 1: Acceptable Birth Control Appendix 2: ECG Exclusion Criteria for Screening and Pre-Dose Randomization Appendix 3: Hepatitis B screening and monitoring Appendix 4: ECG Premature Discontinuation from IP Criteria Appendix 5: Pharmacogenetic Research Appendix 6: Country Specific Requirements Appendix 7: Liver Chemistry Stopping and Follow-up Criteria Appendix 8: Anaphylaxis Criteria

12 2013N183405_00 LIST OF ABBREVIATIONS ADA AE ALT ASE AST ATS BiPAP BMI CAT COPD CPK CT scan CPAP CRF CV ECG ecrf ED ediary EGPA FAAN FCBP FEV 1 FSH FVC GCP GCSP GSK HRT IB ICF ICH ICS IDMC IEC IL IM INR IP IRB ITT IV IVRS IU LABA LAMA Anti-drug antibody Adverse Event Alanine aminotransferase All subjects enrolled population Aspartate aminotransferase American Thoracic Society Bilevel positive airway pressure Body mass index COPD Assessment Test Chronic Obstructive Pulmonary Disease Creatine phosphokinase Computerized Tomography Continuous positive airway pressure Case Report Form Cardiovascular Electrocardiography Electronic case report form Emergency department Electronic diary Eosinophilic Granulomatosis with Polyangitis Food Allergy and Anaphylaxis Network Female of child bearing potential Forced expiratory volume in one second Follicle stimulating hormone Forced vital capacity Good Clinical Practice GSK's global clinical safety and pharmacovigilance group GlaxoSmithKline Hormone replacement therapy Investigator's Brochure Informed consent form International Conference on Harmonisation Inhaled corticosteroid Independent Data Monitoring Committee Independent ethics committee Interleukin Intramuscular International normalized ratio Investigational Product Institutional research board Intent to treat Intravenous Interactive Voice Response System International Units Long acting beta 2 -agonist Long acting muscarinic anatagonist 10

13 2013N183405_ LDH LFT LRTI LTOT MAOIs MDI MedRA MSDS NAB NHANES NIAID NK NYHA OCS PK PD PGx PP prn QTcF RAP SABA SAMA SC SGRQ-C SAE SoC SOC SPM ULN URTI Lactate dehydrogenase Liver function testing Lower Respiratory Tract Infection Long term oxygen therapy Monoamine oxidase inhibitors Metered dose inhaler Medical Dictionary for Regulatory Activities Materials Safety Data Sheet Neutralizing Antibody National Health and Nutrition Examination Survey National Institute of Allergy and Infectious Disease Natural Killer New York Heart Association Oral corticosteroid Pharmacokinetic Pharmacodynamic Pharmacogenetics Per protocol As needed QT interval corrected with Fridericia's formulas Reporting and analysis plan Short acting beta 2 -agonist Short acting muscarinic antagonist Subcutaneous St. George's Respiratory Questionnaire for COPD patients Serious Adverse Event Standard of Care System Organ Class Study Procedures Manual Upper limit of normal Upper respiratory tract infection Trademark Information Trademarks of the GlaxoSmithKline group of companies NONE Trademarks not owned by the GlaxoSmithKline group of companies NONMEM Xolair 11

14 2013N183405_00 PROTOCOL SUMMARY Rationale While Chronic Obstructive Pulmonary Disease (COPD) is generally viewed as a disease driven by neutrophilic inflammation up to 40% of COPD patients have an inflammatory pattern that includes elevated sputum eosinophils [Brightling, 2005; Saha, 2006]. In severe COPD patients, sputum eosinophils and interleukin 5 (IL-5) levels are elevated to similar levels as those seen in severe asthmatics [Bafadhel, 2012]. Notably, COPD patients with eosinophilic inflammation cannot be distinguished based on clinical features and lung function from those without eosinophilic inflammation [Saha, 2006]. COPD exacerbations are characterized by periods of acute worsening of symptoms, deterioration in lung function, and decreased health-related quality of life [Seemunga, 1998; Connors, 1996; Donaldson, 2002] and potentially contribute to further permanent decline in lung function. Recent studies identified that increased eosinophilic airway inflammation occurs during COPD exacerbations [Bafadhel, 2012] and that peripheral eosinophils levels were used successfully as a surrogate to predict response to corticosteroid therapy [Bafadhel, 2012]. While further research is required experience in the clinic suggests that management of exacerbations could possibly be tailored by phenotype-specific management. A study by Siva et al [Siva, 2007] showed that a treatment strategy that aimed to reduce sputum eosinophils in COPD showed a significant reduction in severe exacerbations compared to a treatment strategy towards optimizing symptoms alone. Based on the identification of a COPD subgroup of frequent exacerbators with elevated eosinophils and IL-5 levels and the finding from the severe asthma study MEA post-hoc analysis of mepolizumab in COPD-like patients (based on age, FEV1/FVC ratio, and lack of reversibility) there is reason to believe that mepolizumab will reduce IL-5 and eosinophils in a well-defined COPD population. The study target population consists of a population who despite a history of use of optimal standard of care therapy continue to be at risk for future exacerbation and is further defined by study eligibility criteria. Based on extrapolation of the efficacy findings in severe asthma and the similarities between the severe asthma and severe COPD patients in terms of eosinophils and IL-5 levels it is hypothesized that the reduction of eosinophils with mepolizumab in COPD patients would translate into a reduction of COPD exacerbations. Mepolizumab is a fully humanized IgG antibody (IgG1, kappa) which binds to and inhibits the ability of IL-5 to bind to the IL-5 receptor. IL-5 receptors are primarily expressed on eosinophils. IL-5, through binding to the IL-5 receptor is a major regulator of eosinophils resulting in accumulation in tissues and modulation of eosinophil behavior at every stage from maturation to survival. Mepolizumab reduces eosinophils in the periphery and in tissues. Data from study MEA demonstrate that responders to mepolizumab with severe asthma (i.e. subjects with a reduction in exacerbation rate despite treatment with corticosteroids) had a baseline blood eosinophil count of at least150 cells/l or a historical blood eosinophil count of at least 300 cells/μl. Accordingly, these thresholds 12

15 2013N183405_ for blood eosinophil counts will be used to operationally define a group of subjects as eosinophilic. This study will determine the reduction in exacerbations in subjects who are above and below the baseline blood eosinophil count of at least 150 cells/l ensuring that the hypothesis bridges from asthma to COPD. Objective(s) Primary Objective To evaluate the efficacy and safety of mepolizumab 100 mg subcutaneous (SC) given every 4 weeks compared to placebo on the frequency of moderate and severe exacerbations in COPD subjects at high risk of exacerbations despite the use of optimized standard of care background therapy. Secondary Objective To evaluate other efficacy assessments of mepolizumab 100 mg subcutaneous (SC) compared to placebo on changes in health care utilization, COPD symptoms, quality of life, and lung function. Study Design This is a multi-center, randomized, placebo-controlled, double-blind, parallel group trial evaluating mepolizumab 100 mg against placebo given every 4 weeks through subcutaneous (SC) injection. The target global enrolment is approximately 800 randomized subjects. The total duration of subject participation will be approximately 62 weeks, consisting of a 1 to 2 week screening period, 52-week treatment period and 8- week follow-up period. Subjects will initially participate in a pre-screening visit (Visit 0) where the details about the study and procedures will be explained through the informed consent process. Subjects who meet all inclusion criteria and none of the exclusion criteria at Visit 1 will enter a 1 to 2 week screening period during which time subjects will remain on a stable dose of their current COPD therapy. Laboratory assessments will be collected at Visit 1 and will include a hematology assessment for determination of baseline eosinophil level. The site must receive the results of the Visit 1 laboratory assessments and other assessments prior to the determination of eligibility at Visit 2. Baseline subject reported electronic diary (ediary) data will be captured during the screening period and subjects must meet the ediary compliance requirement to be eligible for randomization. Subjects must understand and agree to completion of the ediary on a daily basis in the morning to be considered for this study. Site personnel must train subjects on the proper use of the ediary at Visit 1. The ediary will capture daily COPD symptoms, rescue medication use, and activity level, as well as patient reported outcomes and this information will be transmitted daily. Sites will have real time access to subject symptom data. Study inclusion criteria require a history of regular use of at least one triple COPD standard of care (SoC) option (as defined in inclusion criteria) for at least 12 months prior 13

16 2013N183405_ to screening. In addition, for at least 3 months prior to screening, each subject must have a history of use of a specific inhaled triple SoC regimen (ICS + long acting beta 2 -agonist (LABA) + long acting muscarinic antagonist (LAMA)). Subjects are also required to have a history of at least 2 moderate or 1 severe exacerbation in the 12 months prior to Visit 1 and one of the exacerbations had to have occurred while treated with ICS + LABA + LAMA. All subjects will continue on their baseline optimized SoC COPD medications throughout the entire duration of the study regardless of treatment arm assignment. If for medical reason the subject must change their baseline SoC COPD medication the primary investigator should discuss with the GSK medical monitor. Eligible subjects will be randomized 1:1 to mepolizumab 100 mg or placebo. Stratification within treatment groups will be based on baseline eosinophil levels. Investigational Product (IP) will be administered as one SC injection given every 4 weeks. The first dose will be administered at Visit 2 (Week 0) and the last dose administered at Week 48 (Visit 14). For those subjects randomized to mepolizumab, 13 doses will provide therapeutic coverage for 52 weeks (4 weeks following the last dose). The Exit Visit (Visit 15, Week 52) will occur 4 weeks after last administration of study treatment. Study treatment will not be administered at this visit. The primary efficacy endpoint will be evaluated from Visit 2 (Week 0) to Visit 15 (Week 52). All subjects will be requested to return for a Follow-up Visit (Visit 16) approximately 12 weeks after their last dose of investigational product (and approximately 8 weeks after Visit 15) to conduct safety assessments and collect an immunogenicity sample. An adjudication committee and an independent data monitoring committee (IDMC) will be utilized in this study to ensure external objective medical and statistical review of safety issues in order to protect the ethical and safety interests of subjects and to protect the scientific validity of the study. Study Endpoints/Assessments Primary Frequency of moderate/severe exacerbations Moderate exacerbations are defined as COPD exacerbations that require either systemic corticosteroids (intramuscular (IM), intravenous, or oral) and/or antibiotics. Severe exacerbations are defined as COPD exacerbations requiring hospitalization or resulting in death. Efficacy endpoints will be measured from Visit 2 through Visit 15. Secondary Time to first moderate/severe exacerbation Frequency of COPD exacerbations requiring emergency department (ED) visits and/or hospitalizations 14

17 2013N183405_ Other Change from baseline mean total St. George s Respiratory Questionnaire-COPD (SGRQ-C) score Change from baseline COPD assessment test (CAT) score Frequency of moderate COPD exacerbations Frequency of severe COPD exacerbations Occasions of rescue medication use Proportion of SGRQ-C responders Change from baseline in trough FEV 1 and FVC Change from baseline EQ-5D-5L Frequency of COPD exacerbations requiring re-hospitalization within 30 days Safety Endpoints Incidence of adverse events including systemic and local site injection-related reactions Vital signs including blood pressure, body temperature, pulse rate, and pulse oximetry ECG measurements Mortality (all cause, respiratory, cardiovascular) Immunogenicity Hematological and clinical chemistry parameters throughout the 52-week treatment period and the 8-week follow up period. Health Outcome Endpoints Healthcare utilization including hospitalization, emergency department, and physician office/clinic visits Change from baseline in SF-36 total score and all domains Change from baseline in rating of activity limitation Change from baseline in subject's impression of change Change in Clinician rated response to therapy Change in Subject rated response to therapy 15

18 2013N183405_00 1. INTRODUCTION 1.1. Background Chronic Obstructive Pulmonary Disease (COPD is a chronic progressive disease with rising morbidity and mortality. COPD is currently the fourth leading cause of death in the world [World Health Report, 2000] and is predicted to be the third leading cause of death in the world by 2030 [Eltboli, 2013; World Health Organization, 2008]. COPD is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response, in the airways and the lung, in response to noxious particles or gases GOLD, 2013]. While the disease course is marked by progressive deterioration in airflow it is punctuated by COPD exacerbations which contribute to the overall disease severity and increase in frequency as disease worsens GOLD, 2013; Soler-Cataluña, 2005]. In addition to the increased risk of morbidity and mortality associated with COPD exacerbations, these events place a huge economic burden on healthcare systems which is predicted to increase with the increasing prevalence of the disease globally [Toy, 2010] Rationale While COPD is generally viewed as a disease driven by neutrophilic inflammation, up to 40% of COPD patients have an inflammatory pattern that includes elevated sputum eosinophils [Brightling, 2005; Saha, 2006]. In severe COPD patients, sputum eosinophils and IL-5 levels are elevated to similar levels as those seen in severe asthmatics [Bafadhel, 2012]. Notably, COPD patients with eosinophilic inflammation cannot be distinguished based on clinical features and lung function from those without eosinophilic inflammation [Saha, 2006]. COPD exacerbations are characterized by periods of acute worsening of symptoms, deterioration in lung function, and decreased health-related quality of life [Seemunga, 1998; Connors, 1996; Donaldson 2002] and potentially contribute to further permanent decrements in lung function. Recent studies identified that increased eosinophilic airway inflammation occurred during COPD exacerbations [Bafadhel, 2011] and that peripheral eosinophils levels were used successfully as a surrogate to predict response to corticosteroid therapy [Bafadhel, 2012]. While further research is required experience in the clinic suggests that management of exacerbations could possibly be tailored by phenotype-specific management. A study by Siva et al [Siva, 2007] showed that a treatment strategy that aimed to reduce sputum eosinophils in COPD showed a significant reduction in severe exacerbations compared to a treatment strategy towards optimizing symptoms alone. Based on the identification of a COPD subgroup of frequent exacerbators with elevated eosinophils and IL-5 levels and the finding from the severe asthma study MEA post-hoc analysis of mepolizumab in COPD-like patients (based on age, FEV1/FVC ratio, and lack of reversibility) there is reason to believe that mepolizumab will reduce IL-5 and eosinophils in a well-defined COPD population. The study target population consists of a population who despite a history of use of optimal standard of care therapy continue to be at risk for future exacerbation and is further defined by study eligibility criteria. Based on extrapolation of the efficacy findings in severe asthma and the 16

19 2013N183405_ similarities between the severe asthma and severe COPD patients in terms of eosinophils and IL-5 levels it is hypothesized that the reduction of eosinophils with mepolizumab in COPD patients would translate into a reduction of COPD exacerbations. Mepolizumab is a fully humanized IgG antibody (IgG1, kappa) which binds to and inhibits the ability of IL-5 to bind to the IL-5 receptor. IL-5 receptors are primarily expressed on eosinophils. IL-5, through binding to the IL-5 receptor is a major regulator of eosinophils resulting in accumulation in tissues and modulation of eosinophil behavior at every stage from maturation to survival. Mepolizumab reduces eosinophils in the periphery and in tissues. Data from study MEA demonstrate that responders to mepolizumab (i.e. subjects with a reduction in exacerbation rate despite treatment with corticosteroids) had a baseline blood eosinophil count of at least150 cells/l or a historical blood eosinophil count of at least 300 cells/μl. Accordingly, these thresholds for blood eosinophil counts will be used to operationally define a group of subjects as eosinophilic. This study will determine the reduction in exacerbations in subjects who are above and below the baseline blood eosinophil count of at least 150 cells/l ensuring that the hypothesis bridges from asthma to COPD Benefit:Risk Assessment Summaries of findings from both clinical and non-clinical studies conducted with mepolizumab can be found in the Investigator s Brochure (IB) or IB supplement [GlaxoSmithKline Document Number CM2003/00010/08 ] Risk Assessment The following table (Table 1) outlines the risk assessment and mitigation strategy for this protocol. Table 1 Risk Assessment with Mitigation Strategy Potential Risk of Clinical Significance Data/Rationale for Risk Mitigation Strategy Investigational Product Risk of Systemic Allergic and Non-allergic Reactions, including Anaphylaxis Biopharmaceutical products may elicit anti-drug antibody (ADA) and neutralizing antibody (NAB), which have the potential to modulate pharmacokinetic (PK), pharmacodynamic (PD) or produce adverse reactions. However, humanized and Daily monitoring of serious adverse events (SAEs) by medical monitor; regular systematic review of adverse event (AE)/SAE data from ongoing studies by a GSK safety review team. Independent Data 17

20 2013N183405_ Potential Risk of Clinical Significance Data/Rationale for Risk fully human antibodies are less immunogenic than mouse or chimeric monoclonal antibodies. Reactions reported to date across the mepolizumab program are summarized in the IB; see Special Warnings and Special Precautions for Use section located in Section 6 titled Summary of Data and Guidance for the Investigator. Mitigation Strategy Monitoring Committee (IDMC) will be utilized during the study. Specific case report form (CRF) pages utilized for targeted collection of reactions data. Utilization of Joint NIAID/FAAN 2nd Symposium on Anaphylaxis to collect data on reports of anaphylaxis (see Appendix 8). Subjects are monitored in clinic for 1 hour following dosing. Risk of Immunogenicity Potential risk for adverse See previous risk for background information in literature. Immunogenicity data reported to date across the mepolizumab development program are summarized in the IB; see Section 5.4 Clinical Immunogenicity and a summary of immunogenicity findings in the Other Potentially Clinically Relevant Information for the Investigator section located in Section 6 titled Summary of Data and Guidance for the Investigator. Mepolizumab binding was restricted to human Blood samples are collected in clinical studies for detection of both ADA and NAB. See previous risk for mitigation strategy related to clinical safety risks. Daily monitoring of SAE by medical monitor; regular 18

21 2013N183405_ Potential Risk of Clinical Significance cardiovascular (CV) effects Data/Rationale for Risk lymphoid tissues in an immunohistochemistry tissue binding study suggesting a low likelihood of non-pharmacologic effects on cardiovascular (CV) function. No AEs concerning cardiac conduction or repolarization evident in cynomolgus monkeys at doses at least 10-fold in excess of humans dosed at 10 mg/kg or 750 mg. No clinically relevant trends observed in ECG data in humans. In one study in subjects with severe refractory asthma, cardiac events were reported in similar frequencies across treatment groups with a small numerical increase observed in serious ischemic cardiac events in the mepolizumabtreated groups. However, an integrated safety analysis of all placebo-controlled multiple dose asthma trials showed similar frequency of SAEs reported overall from the cardiac and vascular system organ class (SOC). Additionally, similar findings were observed in other SOCs with thrombotic events (e.g., stroke in the Nervous System SOC). Mitigation Strategy systematic review of AE/SAE data from ongoing studies by a GSK safety review team. CV monitoring for study includes: ECG monitoring during the trial; Use of standardized CRFs to collect relevant data on CV events of interest (i.e., myocardial infarction, hospitalization for unstable angina and congestive heart failure, arterial thrombosis, pulmonary embolism and deep vein thrombosis); Use of an IDMC during the study. Potential risk for increase in No evidence of increased Daily monitoring of SAE by 19

22 2013N183405_ Potential Risk of Clinical Significance infections - theoretical concern with biologics; however, the pharmacological properties of mepolizumab suggest the risk is low. Data/Rationale for Risk incidence of infections in any preclinical studies. Murine data demonstrate that IL-5 antagonism is unlikely to influence cellular or humoral immunity, particularly in response to parasitic infections. No mepolizumab-related effects on lymphocyte Immunophenotyping in monkeys or humans, including T-cell activation, distribution of CD4/CD8 subtypes or Th1/Th2 cytokine patterns, B-cells, NK cells or γδ-t-cells. An integrated safety analysis of all placebocontrolled multiple dose asthma trials showed SAEs reported in the infection and infestation SOC were 5/345 (1%) in placebo subjects and 18/754 (2%) in mepolizumab subjects. Infections reported to date across the mepolizumab development program are summarized in the IB; see Special Precautions and Warnings (for exclusion of subjects with underlying parasitic infections) and Undesirable Effects (for very common infections of nasopharyngitis, URTI, rhinitis and bronchitis reported in other patient populations) sections Mitigation Strategy medical monitor; regular systematic review of AE/SAE data from ongoing studies by a GSK safety review team An IDMC will be utilized during the study Standard safety assessments to be conducted as outlined in protocols. 20

23 2013N183405_ Potential Risk of Clinical Significance Data/Rationale for Risk Mitigation Strategy Potential risk for increase in malignancies - theoretical concern with biologics; however, blockade of IL-5 is not associated with generalized immunosuppression or impaired host resistance. Potential risk for rebound eosinophilia with associated clinical consequences located in Section 6 titled Summary of Data and Guidance for the Investigator. Role of IL-5 and eosinophils in tumour surveillance is not fully characterised in the literature. No evidence of defective tumour surveillance in IL-5 or eosinophil-deficient mice. Direct assessment of the carcinogenic potential of long-term IL-5 blockade in rodent models not technically feasible. Malignancies reported to date across the mepolizumab development program are summarized in the IB. Early published data with Schering-Plough anti- IL5 mab suggested potential for rebound eosinophilia and disease exacerbation when treatment was stopped [Kim, 2004; Gevaert, 2006]; however, no standard definition of rebound was used and criteria for reporting were variable. There have been no verbatim reports of rebound from completed clinical trials of subjects Daily monitoring of SAE by medical monitor; regular systematic review of AE/SAE data from ongoing studies by a GSK safety review team An IDMC will be utilized during the study. Standard safety assessments to be conducted as outlined in protocols Daily monitoring of SAE by medical monitor; regular systematic review of AE/SAE data from ongoing studies by a GSK safety review team IDMC will be utilized during the study. Standard safety assessments to be conducted as outlined in protocols 21

24 2013N183405_ Potential Risk of Clinical Significance Data/Rationale for Risk Mitigation Strategy Study Procedures Inclusion of a placebo arm Blinding eosinophil counts with asthma, atopic dermatitis and eosinophilic esophagitis. Furthermore, the data do not support an exaggerated return of symptoms after cessation of treatment. The objective of the study is to compare the efficacy and safety of mepolizumab versus placebo in COPD subjects receiving standardof-care therapy This study is a double-blind study which will be used to support approval for the use of mepolizumab in the reduction of moderate/severe COPD exacerbations. Unblinding eosinophil counts may compromise the integrity of the study. Because all subjects are receiving background standard-of-care therapy in this study the Sponsor considers inclusion of a placebo arm to be justified. Patients will be seen monthly by investigators specialized in COPD. IDMC will be utilized during the study. Neither the site nor GSK personnel will be sent results from the central laboratory for: i) absolute eosinophil count or ii) white blood count differentials (% neutrophil, lymphocyte, monocyte, eosinophil and basophil), for each subject s duration in the study for any visits post-randomisation. However, sites will be sent total white blood counts throughout the study Benefit Assessment Study will investigate the efficacy and safety of mepolizumab in the reduction of moderate/severe COPD exacerbations in subjects receiving standard of care COPD 22

25 2013N183405_ treatment recommended for this population (i.e. with the severity and risk level defined per the protocol). Exacerbations are a major concern to COPD patients and lead to a worsening of the quality of life for subjects. A reduction of moderate and severe exacerbations will improve a patient s quality of life and may reduce hospitalizations. A primary benefit will be the identification of a COPD subgroup of frequent exacerbators whose eosinophil level predicts a response to IL-5 inhibition. One reason to believe that COPD subjects will respond to IL-5 inhibition is derived from a clinical trial in severe asthma (MEA112997) where a post-hoc analysis of mepolizumab in COPD-like patients showed a reduction in exacerbations indicating that that mepolizumab may reduce IL-5 and eosinophils in a well-defined COPD population and have an impact on reducing the rate of exacerbations. Data obtained from study will provide a robust evaluation of the efficacy and safety of mepolizumab in the reduction of moderate/severe COPD exacerbations with a view towards supporting a regulatory approval for mepolizumab for the reduction of COPD exacerbations in patients with severe COPD. While it is believed that mepolizumab will only affect subjects with eosinophil levels of at least 150cells/µl, there is limited data to support this in COPD subjects. Therefore in this study each treatment arm will have 2 strata based on the eosinophil cell count; At least150cell/µl at Visit 1 or a historic count in the previous year of >300 cells/l < 150cells/l at Visit 1 Subjects participating in this study will be required to attend monthly visits and therefore may benefit from the additional monitoring to their current standard of care Overall Benefit:Risk Conclusion Data from mepolizumab preclinical and clinical development demonstrate the ability of mepolizumab to inhibit IL-5, and consequently treat inflammatory conditions linked to an eosinophil signal, such as COPD subjects predisposed for future exacerbations. To date, the safety profile of mepolizumab across other programs has been favorable in all patient populations studied and AEs reported commonly have been manageable with minimal medical intervention. Furthermore, preclinical data and the observed safety profile in over 1200 subjects receiving mepolizumab in clinical trials to date has not identified a safety concern that would preclude the investigation in COPD. Therefore investigation of the efficacy, safety, and tolerability of mepolizumab is thereby justified in study OBJECTIVE(S) Primary Objective To evaluate the efficacy and safety of mepolizumab 100 mg subcutaneous (SC) given every 4 weeks compared to placebo on the frequency of moderate and 23

26 2013N183405_ severe exacerbations in COPD subjects at high risk of exacerbations despite the use of optimized standard of care background therapy. Secondary Objective To evaluate other efficacy assessments of mepolizumab 100 mg subcutaneous (SC) compared to placebo on changes in health care utilization, COPD symptoms, quality of life, and lung function. 3. INVESTIGATIONAL PLAN 3.1. Study Design Schema 3.2. 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 2), are essential and required for study conduct. This is a multi-center, randomized, placebo-controlled, double-blind, parallel group trial evaluating mepolizumab 100 mg against placebo given every 4 weeks through subcutaneous (SC) injection. The target global enrolment is approximately 800 randomized subjects. The total duration of subject participation will be approximately 62 weeks, consisting of a 1 to 2 week screening period, 52-week treatment period and 8- week follow-up period. Subjects will initially participate in a pre-screening visit (Visit 0) where the details about the study and procedures will be explained through the informed 24

27 2013N183405_ consent process. Subjects who meet all inclusion criteria and none of the exclusion criteria at Visit 1 will enter a 1 to 2 week screening period during which time subjects will remain on a stable dose of their current COPD therapy. Laboratory assessments will be collected at Visit 1 and will include a hematology assessment for determination of baseline eosinophil level. The site must receive the results of the Visit 1 laboratory assessments (e.g. blood eosinophils) prior to the determining eligibility at Visit 2. Baseline patient reported electronic diary (ediary) data will be captured during the screening period and subjects must meet the ediary compliance requirement to be eligible for randomization. Subjects must understand and agree to completion of the ediary on a daily basis in the morning to be considered for this study. Site personnel must train subjects on the proper use of the ediary at Visit 1. Baseline subject reported electronic diary (ediary) data will be captured during the screening period and subjects must meet the ediary compliance requirement to be eligible for randomization. Subjects must understand and agree to completion of the ediary on a daily basis in the morning to be considered for this study. Site personnel must train subjects on the proper use of the ediary at Visit 1. The ediary will capture daily COPD symptoms, rescue medication use, and activity level, as well as patient reported outcomes and this information will be transmitted daily. Sites will have real time access to subject symptom data. Study inclusion criteria require a history of regular use of at least one triple COPD standard of care (SoC) option (as defined in inclusion criteria) for at least 12 months prior to screening. In addition, for at least 3 months prior to screening, each subject must have a history of use of a specific inhaled triple SoC regimen (ICS + long acting beta 2 -agonist (LABA) + long acting muscarinic antagonist (LAMA)). Subjects are also required to have a history of at least 2 moderate or 1 severe exacerbation in the 12 months prior to Visit 1 and one of the exacerbations had to have occurred while treated with ICS + LABA + LAMA. All subjects will continue on their baseline optimized SoC COPD medications throughout the entire duration of the study regardless of treatment arm assignment. If for medical reason the subject must change their baseline SoC COPD medication the primary investigator should discuss with the GSK medical monitor. Eligible subjects will be randomized 1:1 to mepolizumab 100 mg or placebo. Stratification within treatment groups will be based on baseline eosinophil levels. Investigational Product (IP) will be administered as one SC injection given every 4 weeks. The first dose will be administered at Visit 2 (Week 0) and the last dose administered at Week 48 (Visit 14). For those subjects randomized to mepolizumab, 13 doses will provide therapeutic coverage for 52 weeks (4 weeks following the last dose). The Exit Visit (Visit 15, Week 52) will occur 4 weeks after last administration of study treatment. Study treatment will not be administered at this visit. The primary efficacy endpoint will be evaluated from Visit 2 (Week 0) to Visit 15 (Week 52). All subjects will be requested to return for a Follow-up Visit (Visit 16) approximately 12 weeks after their last dose of investigational product (and approximately 8 weeks after Visit 15) to conduct safety assessments and collect an immunogenicity sample. Serious adverse events (SAEs) reported from ongoing clinical studies with mepolizumab are reviewed daily by the project Medical Monitor. Additionally, regular, systematic 25

28 2013N183405_ reviews of emerging safety data from all clinical studies are conducted by an in-house multi disciplinary Safety Review Team (SRT) which provides a central and dedicated forum for review of emerging data which could impact subject safety. The SRT, which includes the project Medical Monitor, other physicians assigned to the project, clinical scientists and a statistician, reviews blinded and unblinded (i.e., from open-label trials) safety data from ongoing clinical studies with mepolizumab on a regular basis and conducts a comprehensive evaluation of the safety data upon completion of each study. Moreover, an integrated analysis of safety across the program is completed annually when additional safety data are available from completed studies. A re-assessment of benefit risk and the current Developmental Core Safety Information (DCSI) is completed at each SRT meeting subsequent to review of new data. Additionally, an adjudication committee and an Independent Data Monitoring Committee (IDMC) will be utilized during the study. There is also a standard and comprehensive process for the reporting and management of Sentinel Events. A Sentinel Event is an SAE that is not necessarily drug-related, but that has been associated historically with adverse reactions for other drugs, and is therefore worthy of heightened pharmacovigilance. Sentinel Events include acquired long QT syndrome, agranulocytosis, anaphylactic and anaphylactoid reactions, hepatotoxicity, renal failure, seizures, and Stevens Johnson syndrome/toxic epidermal necrolysis. Subsequent to the reporting of a Sentinel Event, the Medical Monitor promptly notifies the SRT and the GSK Global Safety Board and leads a thorough and comprehensive follow-up of the Sentinel Event with collection of all relevant data. 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 Discussion of Design This study is designed to evaluate the efficacy and safety of mepolizumab, over 52 weeks, in subjects who exacerbate despite regular use of maximal tolerated therapy, appropriate for severe COPD patients, in the 12 months prior to study start. Optimized SoC therapy must include a history of regular use of at least one triple COPD standard of care (SoC) option (per inclusion criteria) for at least 12 months prior to screening. Subjects are also required to have a history of at least 2 moderate or 1 severe exacerbation in the 12 months prior to Visit 1 and one of the exacerbations had to have occurred while using inhaled triple therapy (i.e. while the subjects was treated with ICS + LABA+ LAMA). Prior to study medication eligibility requirements and exacerbation history requirements are more fully defined in Section 4.2. All subjects will continue on their baseline optimized SoC COPD medications throughout the entire duration of the study regardless of treatment arm assignment. If for medical reason the subject must change their baseline SoC COPD medication the primary investigator should discuss with the medical monitor. Allowing use of optimized SoC therapy supports inclusion of a placebo group contributing to a favorable benefit:risk profile for participating subjects. 26

29 2013N183405_ The 1 to 2 week run-in period allows for the assessment of subject understanding of and compliance with the daily ediary, to establish baseline diary symptoms, and to allow adequate time for receipt of results from assessments collected at Visit 1. The study will be stratified based on blood eosinophil levels with the aim of recruiting equal numbers of subjects in the two strata to each treatment group. Subjects will be assigned to strata according to the following: Eosinophils 150 cells/l at Visit 1 or a historic eosinophil level in the preceding 12 months 300 cells/l, or Eosinophils <150 cells/l at Visit 1 The eosinophil count level, although determined primarily in severe asthmatics, is thought to be appropriate also for COPD. The study duration permits the evaluation of mepolizumab across seasonal periods. The protocol objective is to collect data over the full study period, whether subjects continue on investigational product (IP) and complete the study in-full, or even in the case of premature discontinuation from IP. However, the decision to continue in the study after premature discontinuation from IP remains the prerogative of the subject. Subjects who agree to continue in the study after premature discontinuation from IP (for any reason) will continue to be contacted by the study site, either through in clinics visit or by phone as agreed with the subject, on a monthly basis (aligned to their previous study schedule) until the end of their planned 52-week participation to enable capture of post-treatment assessments Dose Rationale The rationale for the mepolizumab selected dose to be studied in this trial in COPD is based on the evidence that the levels of IL-5 and eosinophils in the sputum of severe asthma and severe COPD patients are comparable and a steroid treatment approach aimed at reducing sputum eosinophils led to a reduction in exacerbations in both asthma and COPD patients compared to optimizing symptoms alone [Bafadhel 2012, Siva 2007, Green 2002] The dose selection is based on previous experience from a phase 2b/3 placebo controlled study (MEA112997) that demonstrated the safety and efficacy of mepolizumab at doses of 75mg, 250mg and 750mg administered IV, every 4 weeks, over a 52-week treatment period in patients with severe refractory asthma. Mepolizumab reduced blood and sputum eosinophils in a dose-related manner. Mepolizumab reduced the frequency of exacerbations similarly across the 3 doses studied. The absence of dose response implies that the reduction in blood eosinophils achieved with mepolizumab 75 mg IV every four weeks was adequate to confer the desired clinical benefit in a severe asthma patient population. This study also demonstrated that mepolizumab had an acceptable safety profile in severe asthma patients across a 10-fold dose range. 27

30 2013N183405_ MEA114092, a dose ranging PK/PD study, studied 4 doses of mepolizumab administered by IV and SC injection, every 4 weeks, in adult patients with asthma and elevated blood eosinophils. The study included a low dose of 12.5 mg SC along with 125 mg SC, 250 mg SC, and 75 mg IV. The absolute bioavailability of mepolizumab administered SC into the upper arm is approximately 75% [GlaxoSmithKline Document Number CM2003/00010/08 ]. Similarly to MEA112997, this study demonstrated a dose related decrease in the blood and sputum eosinophil ratio to baseline with increasing dose of mepolizumab. The 12.5 mg SC dose showed a notably lower degree of eosinophil reduction and clearly differentiated from the other SC doses, and from the 75 mg IV dose. A non-linear inhibition dose-response model based on blood eosinophil counts at Week 12, identified 99 mg SC (approximately 75 mg IV) every 4 weeks as the ID90 (i.e., dose providing 90% of the maximum blood eosinophil reduction achievable by the drug) for blood eosinophil reduction. The data from MEA and MEA demonstrate concordance in the blood eosinophil reduction at 75 mg IV dose. Mean MEA data super-imposed on the mepolizumab - blood eosinophil dose response curve developed from MEA data were reasonably captured by the model. Together the results from these studies demonstrated that 75 mg IV (100 mg SC) is the minimum appropriate dose based on blood eosinophils and it is therefore not considered necessary to assess a dose lower than 75 mg IV/100 mg SC in further Phase 3 studies. Based on the absolute bioavailability of SC mepolizumab, combined with the dose response established on blood eosinophil count, a 100 mg SC regimen as the targeted effective dose is included in this trial. A SC route of administration is more convenient to administer compared to IV and is generally preferred by patients. An additional higher dose of mepolizumab (300 mg) is included in Study , to include an assessment of dose-ranging of mepolizumab in a COPD population at high risk for exacerbations and to collect additional safety data over the one-year study period. The 300 mg SC dose corresponds approximately to a 250 mg IV dose that was used in previous studies demonstrating favorable safety margin and tolerability. 4. SUBJECT SELECTION AND WITHDRAWAL CRITERIA 4.1. Number of Subjects Number of Randomised Subjects: Eligibility Criteria 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 or IB supplement [GlaxoSmithKline Document Number CM2003/00010/08 ]. 28

31 2013N183405_ 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. COPD diagnosis: Subjects with a clinically documented history of COPD for at least 1 year in accordance with the following definition by the American Thoracic Society/European Respiratory Society [Celli, 2004] 2. Severity of COPD: Subjects must present with the following: A measured pre and post-salbutamol FEV 1 /FVC ratio of <0.70 at Visit 1 to confirm the diagnosis of COPD A measured post-salbutamol FEV 1 > 20% and 80% of predicted normal values calculated using NHANES III reference equations [Hankinson 1999, Hankinson, 2010] at Visit 1 3. History of exacerbations: A well documented history (e.g., medical record verification) in the 12 months prior to Visit 1 of: OR at least two moderate COPD exacerbations. Moderate is defined as the use of systemic corticosteroids (intramuscular (IM), intravenous, or oral) and/or treatment with antibiotics. at least one severe COPD exacerbation. Severe is defined as having required hospitalization Note: At least one exacerbation must have occurred while the subject was taking ICS plus LABA plus LAMA. Note: Prior use of antibiotics alone does not qualify as a moderate exacerbation unless the use was specifically for the treatment of worsening symptoms of COPD. 4. Concomitant COPD therapy: A well documented requirement for optimized standard of care (SoC) background therapy that includes ICS plus 2 additional COPD medications (i.e., triple therapy) for the 12 months prior to Visit 1 and meets the following criteria: Immediately prior to Visit 1, minimum of 3 months of use of an a) inhaled corticosteroid at a dose 500 mcg/day fluticasone propionate dose equivalent plus b) LABA and c) LAMA. For subjects who are not continually maintained on ICS plus LABA plus LAMA for the entire 12 months prior to Visit 1 use of following is allowed (but not in the 3 months immediately prior to Visit 1): a. inhaled corticosteroid at a dose 500 mcg/day fluticasone propionate dose equivalent plus b. a LABA or a LAMA and 29

32 2013N183405_ c. use of at least one other class of COPD medication suggested by the 2013 GOLD guidelines for patients who are prone to exacerbation (i.e., phosphodiesterase-4-inhibitors, methylxanthines, or a combination of short acting beta 2 -agonist and short acting muscarinic antagonist). Note: Subjects must be willing to stay on their SoC COPD medication for the duration of the study. 5. Informed Consent: Able to give written informed consent prior to participation in the study, which will include the ability to comply with the requirements and restrictions listed in the consent form. Subjects must be able to read, comprehend, and write at a level sufficient to complete study related materials. 6. Gender: Male or Eligible Female To be eligible for entry into the study females of child bearing potential (FCBP; see Appendix 1 for definition) must commit to consistent and correct use of an acceptable method of birth control from the time of consent, for the duration of the trial, and for 4 months after last study drug administration. See Appendix 1 for a listing of acceptable methods of birth control. 7. Age: At least 40 years of age at Visit 1 8. Smoking status: Subject with confirmed COPD are eligible to participate independent of their smoking status and smoking history, i.e. current smokers, never smokers or ex-smokers can be enrolled into the study. Note: Pipe and/or cigar use cannot be used to calculate pack-year history. Current smokers are defined as those with a history of cigarette smoking of 10 pack-years [number of pack years = (number of cigarettes per day / 20) x number of years smoked (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years)]. Former smokers are defined as those who meet the definition of a current smoker but have stopped smoking for at least 6 months prior to Visit 1. Never smokers are those that do not meet the definition of a current or former smoker. French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category 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. 30

33 2013N183405_ Subjects meeting any of the following criteria must not be enrolled in the study: 1. Asthma: Current and Former Smokers: Subjects with a current diagnosis of asthma (those with a prior history are eligible if they meet inclusion criteria for a current diagnosis of COPD) Never-Smokers: Subjects with any history of asthma 2. Other respiratory disorders: The investigator must judge that COPD is the primary diagnosis accounting for the clinical manifestations of the lung disease. Subjects with α1-antitrypsin deficiency as the underlying cause of COPD are excluded. Also, excluded are subjects with active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, primary pulmonary hypertension, interstitial lung diseases or other active pulmonary diseases. Subjects are also excluded if maintenance use of bi-level positive airway pressure is required for the treatment of respiratory disorder. 3. COPD stability: Subjects with pneumonia, exacerbation, lower respiratory infection within the 4 weeks prior to Visit Lung resection: Subjects with lung volume reduction surgery within the 12 months prior to Visit Pulmonary rehabilitation program: Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1. Subjects who are in the maintenance phase of a pulmonary rehabilitation program are not excluded. 6. Oxygen: Subjects receiving treatment with oxygen more than 4.0L/min. While breathing supplemental oxygen, subjects should demonstrate an oxyhemoglobin saturation greater than or equal to 89% lead ECG finding: An abnormal and significant ECG finding from the 12-lead ECG conducted at Visit 1 if considered to be clinically significant by the Investigator. Specific ECG findings that preclude subject enrolment are found in Appendix lead ECGs will be over-read by a centralized independent cardiologist to assist in consistent evaluation of subject eligibility. Results from the 12-lead ECG over-read must be received prior to assessing eligibility at Visit Unstable or life threatening cardiac disease: Subjects with any of the following would be excluded: Myocardial infarction or unstable angina in the last 6 months Unstable or life threatening cardiac arrhythmia requiring intervention in the last 3 months New York Heart Association (NYHA) Class IV Heart failure 9. Other diseases/abnormalities: Subjects with (historical or) current evidence of clinically significant, neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or haematological abnormalities that are uncontrolled. Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through 31

34 2013N183405_ participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study. 10. Eosinophilic disease: Subjects with other conditions that could lead to elevated eosinophils such as Hypereosinophilic syndromes including Eosinophilic Granulomatosis with Polyangiitis (EGPA, also known as Churg-Strauss Syndrome), or Eosinophilic Esophagitis. 11. Parasitic infection: Subjects with a known, pre-existing parasitic infestation within 6 months prior to Visit 1 are also excluded. 12. Malignancy: A current malignancy or previous history of cancer in remission for less than 12 months prior to Visit 1 (Subjects that had localized carcinoma of the skin or cervix which was resected for cure will not be excluded). Note for South Korea: Korean subjects with a diagnosis of malignancy within 5 years of Visit 1 are excluded 13. Immunodeficiency: A known immunodeficiency (e.g human immunodeficiency virus HIV), other than that explained by the use of corticosteroids taken for COPD. 14. Liver disease: Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices, or persistent jaundice), cirrhosis, and known bilary abnormalities (with the exception of Gilbert s syndrome or asymptomatic gallstones). Chronic stable hepatitis B and C are acceptable if subject otherwise meets entry criteria (e.g., presence of hepatitis B surface antigen or positive hepatitis C test result within 3 months of screening) 15. Monoclonal antibodies: Subjects who have received any monoclonal antibody within 5 half-lives of Visit Investigational medications: Subjects who have received an investigational drug within 30 days of Visit 1, or within 5 drug half-lives of the investigational drug, whichever is longer (this also includes investigational formulations of a marketed product). 17. Hypersensitivity: Subjects with a known allergy or intolerance to another monoclonal antibody or biologic including history of anaphylaxis to another biologic 18. Inability to read: In the opinion of the investigator, any subject who is unable to read and/or would not be able to complete study related materials. 19. 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. 20. 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. 21. Drug or alcohol abuse: A known or suspected history of alcohol or drug abuse within 2 years prior to Visit Previous participation: Subjects who have previously participated in any study of mepolizumab. 32

35 2013N183405_ Affiliation with Investigator Site: Is an investigator, sub-investigator, study coordinator, employee of a participating investigator or study site, or immediate family member of the aforementioned that is involved in this study Randomization Criteria 1. Blood eosinophils: While there is no threshold for enrolment, information on eosinophil level should be obtained prior to randomization. 2. Electronic Diary Compliance: Compliance with completion of the ediary defined as completion of all questions on 5 or more days out of the 7 days immediately preceding Visit lead ECG: No evidence of an abnormal and significant ECG finding from the 12- lead ECG conducted at Visit 1 as indicated on the over-read provided by the centralized independent cardiologist. Subjects with a QTcF 450 msec are not eligible. For subjects with a QRS interval 120msec, those with QTcF 480 msec are not eligible. Specific ECG findings that preclude subject eligibility are listed in the Appendix Abnormal 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. If a chest X-ray or CT scan is not available within 6 months prior to Visit 1, then a chest X-ray must be taken at Visit 1 and the results reviewed prior to randomization. For sites in Germany: If a chest X-ray (or CT scan) within 6 months prior to Screening (Visit 1) is not available, approval to conduct a diagnostic chest X-ray will need to be obtained from the Federal Office for Radiation Protection (BfS). 5. Laboratory abnormality: No evidence of clinically significant abnormality in the haematological, biochemical, or urinalysis screen at Visit 1, as judged by the investigator. 6. Hepatitis B: Subjects who are HBsAg positive or HBcAb positive must not have a HBV DNA level 2000 IU/ml. 7. Liver function test: Subjects must meet the following based on results from sample taken at Visit 1: Alanine aminotransferase (ALT) <2x ULN (upper limit of normal) Alkaline Phosphatase (Alk Phos) 2x ULN Bilirubin 1.5x ULN (isolated bilirubin>1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) 8. Pregnancy: Subjects who are pregnant or breastfeeding. Subjects should not be enrolled if they plan to become pregnant during the time of study participation 4.3. Pre-Screening/Screening/Run-in Failures A subject will be assigned a subject number at the time the informed consent is signed. 33

36 2013N183405_ A subject who is assigned a subject number but does not have a Visit 1 procedure will be considered a pre-screen failure. The study interactive voice response system (IVRS) will be contacted to report pre-screen failures. The following information will be collected for subjects who are pre-screen failures: Date of ICF signature Demographic information including race, age, and gender Child bearing status assessment for all potential female subjects Subject number Details of COPD medications within 3 months of Visit 0 Details of COPD exacerbations during pre-screening period (yes/no status) Serious Adverse Events information only for any SAE considered as related to study participation (e.g., study treatment, protocol mandated procedures, invasive tests, or change in existing therapy) Investigator signature page Any subject who performs a Visit 1 procedure but no Visit 2 procedures will be designated as a screen failure. RAMOS will be contacted to report screen failures. In addition to the information above, the following information will be collected for screen failures: Date of screening visit Reason for screen failure Any subject who completes Visit 1 and enters the screening period, and completes at least one Visit 2 procedure but is not randomized is classified as a run-in failure. IVRS will be contacted to report run-in failures. In addition to the information above, the following information will be collected for run-in failures: Date of randomization visit Reason for run-in failure Additional information related to data collection for pre-screen failures, screen failures, and run-in failures can be found in the ecrf completion guidelines. 34

37 2013N183405_ Re-screening of subjects will be allowed only upon approval by the GSK medical monitor Investigational Product (IP) Discontinuation Criteria Subjects that permanently stop IP are not required to withdraw from the study. If for any reason a subject must permanently stop IP every effort should be made by the PI/staff to keep the subject in the study to collect important efficacy and safety data. A subject will be considered to have completed study treatment if he/she continues to take study treatment until Visit 14 (Week 48) and completes Visit 15 (Week 52). A subject will be considered to have completed the study if they continue to participate in the study until Visit 15 (Week 52) regardless of whether they continue to take IP Protocol defined Stopping IP Criteria A subject must be permanently discontinued from IP if any of the following stopping criteria are met: Liver Chemistry: Meets any of the protocol-defined liver chemistry stopping criteria as defined in Section Hepatitis B Positive Subjects: If HBV DNA increases from baseline by 1 log and levels are 2000 IU/ml. Subjects who are discontinued from IP should be evaluated by the primary Investigator to determine if treatment with nucleoside analogues should be initiated (See Appendix 3). Pregnancy: Positive pregnancy test ECG: ECGs are required at specified study visits (see Table 2). Subjects should discontinue study treatment if any of the following QTcF or QT findings, as outlined in Appendix 4, are observed. Results from ECG central over-read will indicate if a subject meets protocol defined discontinuation from IP criteria. If additional ECGs are performed at the discretion of the investigator during the study these criteria also apply. QTcF >500 msec Uncorrected QT >600 msec Change from baseline: QTcF > 60 msec These criteria should be based on the average QTcF 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 QTcF values of the three ECGs to determine whether the subject should be discontinued from IP. Additional ECG criteria that would result in premature discontinuation from IP are presented in Appendix 4. 35

38 2013N183405_ For subjects with underlying prolonged QRS interval ( 120 msec) discontinuation from IP due to QTc is based on the QTcF value at baseline (Visit 2; see table below): Baseline (Visit 2) QTcF Inclusion Criteria During Study Premature IP Discontinuation Criteria <450 msec with QRS <120 msec 500 msec with QRS <120 msec msec with QRS 120 msec 530 msec with QRS 120 msec Non-Compliance with daily diary: Subjects must be compliant in completing their daily diary between each pair of on-treatment visits. Subjects who are non-compliant should be re-educated on the requirement for daily diary entry compliance. Subjects who continue to be non-compliant after multiple visit assessments may be permanently discontinued from IP after consultation with the GSK clinical team Permanent Discontinuation from IP Subjects have the right to stop taking IP before the end of the study. A subject may also be asked to stop IP at the investigator s discretion. Subjects who have permanently discontinued IP are not required to withdraw from the study. Subjects who have permanently discontinued IP and have not withdrawn consent may continue in the study and will complete all remaining protocol specified visits by continued in-clinic visits or by phone contact. In the event that a subject permanently discontinues IP before the end of the randomized treatment period (i.e. Visit 15), every effort will be made by the investigator to encourage the subject to remain in the study and to complete all remaining study visits. Subjects will be provided with the option to continue to have regularly scheduled in-clinic visits or to have regularly scheduled phone visits. The Investigator must document the reason for discontinuation of IP in the ecrf. The PI/site staff should continue contact with the subject at the protocol designated visit time intervals to complete study assessments. If a subject discontinues from IP while attending a scheduled visit the Discontinuation from IP Visit assessments should be completed. Otherwise, the investigator should make every effort to have the subject return to the clinic as soon as possible after the subject permanently discontinues IP in order to complete the Discontinuation from IP Visit. The subject will then be followed up monthly, at regularly scheduled intervals, either by inclinic visit or scheduled phone contact. The required study assessments at the off-ip visits will depend on whether the subject is attending an in-clinic visit or a scheduled phone visit. At a minimum an assessment of exacerbations, SAEs, and concomitant medications will be completed. In addition to the monthly follow-up in-clinic visit or monthly phone contact a safety Follow-up Visit should be completed as described in Section 4.6. The primary reason for discontinuation from IP will be recorded in the ecrf. 36

39 2013N183405_ Withdrawal Criteria For this study there are no pre-determined protocol specific study withdrawal criteria (see Section for protocol defined stopping IP criteria). Every effort should be made by the investigator to keep the subject in the study. However a subject may voluntarily withdraw from participation in this study at any time. The investigator may also, at his or her discretion, withdraw a subject from further study participation. Subjects who are withdrawn from the study will not be replaced Withdrawal from Study Subjects have the right to withdraw from the study and to withdraw their consent for further participation in the study (i.e. this precludes continued data collection). The Investigator must document the reason (if specified by the subject) for withdrawal of consent in the ecrf. Subjects who wish to withdraw from further participation in the study should be encouraged to return to the clinic as soon as possible to complete the Withdrawal from Study Visit and also to complete the safety follow-up visit in order to collect important safety information. No further study visits or study-related telephone contacts can be conducted unless the subject s consent allows for contact after withdrawing from the study then every effort should be made by the Investigator and site to determine the subject s survival status at the end of the study Study Withdrawal assessments Subjects who are on IP and wish to withdraw from further participation in the study should be encouraged to return to the clinic as soon as possible to complete the Withdrawal from Study Visit assessments (see Table 2) and to complete the safety follow-up Visit as described in Section 4.6. Subjects who have previously discontinued IP (and have already completed their Discontinuation from IP Visit) but then decide that they no longer wish to participate in the study, may withdraw from the study by contacting the site by telephone to notify the site of their intention to withdraw; no additional safety follow-up visit is required Lost to Follow-up 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 (e.g., 3 telephone calls and if 37

40 2013N183405_ 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. Every effort should be made to collect survival status (whether the subject is still alive). Note: If contact is lost with the subject, only the specific additional actions as clearly outlined in each subjects Informed Consent form (e.g. attempt contact with subject s listed contact and/or a primary care physician; request access to the subject s medical record) should be attempted to collect survival status Reasons for Study Withdrawal The primary reason for study withdrawal will be recorded in the ecrf. When a subject withdraws consent, the Investigator must document the reason (if specified by the subject) in the ecrf Follow up Visit A Follow-up Visit will be conducted 12 weeks following last dose of IP. The follow-up contact must be done by an in clinic visit. The procedures to be conducted at the Followup Visit are listed in the T&E table (Table 2). 5. STUDY TREATMENTS 5.1. Investigational Product and Other Study Treatment Mepolizumab (SB ) is a fully humanized IgG antibody (IgG1, kappa) with human heavy and light chain frameworks. Mepolizumab will be provided as a lyophilised cake in sterile vials for individual use. The vial will be reconstituted with Sterile Water for Injection, just prior to use. Further details of dose preparation and administration can be found in the Investigator s Brochure (IB), the Study Procedures Manual (SPM), and in the unblinded reference manual. The contents of the label will be in accordance with all applicable regulatory requirements. Under normal conditions of handling and administration, investigational product is not expected to pose significant safety risks to site staff. Take adequate precautions to avoid direct eye or skin contact and the generation of aerosols or mists. Notify the monitor of any unintentional occupational exposure. A Material Safety Data Sheet (MSDS) describing the occupational hazards and recommended handling precautions will be provided to site staff if required by local laws or will otherwise be available from GSK upon request. Mepolizumab will be provided by GSK as open-label product to the unblinded site staff. Unblinded site staff are required for this study. Unblinded site staff will be responsible 38

41 2013N183405_ for receipt, storage, reconstitution, and labelling, and accountability of investigational product. Mepolizumab must be stored in a secure area. Access to mepolizumab will be limited to the investigator s authorized unblinded site staff. Mepolizumab must be stored under the appropriate physical conditions which includes storage in a refrigerator or at a temperature of 2-8C and protected from light. Maintenance of a temperature log (manual or automated) is required. The placebo in this study will be 0.9% sodium chloride solution and will be provided by the study site. Mepolizumab will be reconstituted using sterile water for injection and swirled gently to enable complete dissolution of the product. Detailed instructions for product preparation can be found within the unblinded reference manual. Once prepared by unblinded site staff the active treatment will be indistinguishable from the placebo. Further details on preparation of investigational product are provided in the unblinded reference manual. Investigational product must be dispensed or administered only to subjects enrolled in the study and in accordance with the protocol. Blinded site staff will administer investigational product as three SC injections.. Additional instruction on product administration can be found in the SPM. Investigational Product should be administered after other Visit assessments have been completed. Refer to Table 2 for the list of assessments that must be completed at each Visit (Table 2). Procedures must be in place to ensure the blind is maintained by any site staff involved in administration of the drug or clinical care or assessment of the subject, and by the subject themselves. Safety monitoring of subjects will occur during SC administration and for one hour after the end of injection. Such monitoring will include general safety monitoring including monitoring for both systemic hypersensitivity (i.e., allergic/ige-mediated and nonallergic) and local site reactions. Trained rescue personnel and rescue medications/equipment must be available for use at all times. See Appendix 8 for additional information. Salbutamol metered dose inhaler (MDI) for use as rescue medication throughout the study will be sourced by GSK for centers in the United States of America. For all other centers it will be sourced locally where possible Treatment Assignment At Visit 2 (Week 0) those subjects who meet the randomization eligibility criteria will be randomized in a 1:1 ratio to receive one of the following treatments every 4 weeks for a total of 13 doses: Mepolizumab 100 mg SC 39

42 2013N183405_ Placebo SC The study will be stratified based on blood eosinophil levels with the aim of recruiting equal numbers of subjects in the two strata to each treatment group. Subjects will be assigned to strata according to the following: Eosinophils 150 cells/l at Visit 1 or a historic eosinophil level in the preceding 12 months 300 cells/l, or Eosinophils <150 cells/l at Visit 1 Subjects will be assigned to study treatment in accordance with the randomization schedule. Subcutaneous preparations of mepolizumab will be administered by a designated blinded member of the site staff. To ensure the blind of those involved in the evaluation of the study is maintained at all times, mepolizumab must be prepared by a designated unblinded member of staff who remain independent of the study assessments. A unique Subject Number will be assigned to subjects who have consented. This unique subject number will be used to identify the individual subject throughout the study and will not be re-assigned to any other subject. Subjects will be assigned to study treatment in accordance with the randomization schedule. Once a randomization number has been assigned to a subject, it cannot be reassigned to any other subject in the study. The randomization schedule will be generated using the GSK validated randomisation software RandAll NG. Subjects will be randomized using an IVRS. The study will be randomized separately for each country and the randomisation will be stratified according to whether or not the subject has elevated eosinophils (defined as either a blood eosinophil count of 150 cells/l at baseline or a count of 300 cells/l within the past 12 months). Equal numbers of subjects will be allocated to each treatment and equal numbers of subjects will be assigned to the two eosinophil strata. Details of how to use the IVRS to register and randomize subjects will be provided in the SPM Blinding 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 40

43 2013N183405_ soon as possible, but without revealing the treatment assignment of the unblinded subject, unless that information is important for the safety of subjects currently in the study. The date and reason for the unblinding must be 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 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 Treatment Compliance All doses of study treatment will be administered at the study site by designated site staff. Drug dispensing/accountability logs will be maintained by a designated unblinded member of the site staff Concomitant Medications and Non-Drug Therapies Permitted Medications and Non-Drug Therapies All concomitant medications taken during the treatment phase of the study will be recorded in the electronic case report form (ecrf). The minimum requirement is that the drug name and the dates of administration (start and stop dates) must be recorded. The following COPD medications are permitted during the treatment period while the subject is on IP: Salbutamol MDI (study supplied), or nebules, for prn rescue use (must be withheld for at least 4 hours prior to spirometry testing) Ipratropium bromide MDI, or nebules, for prn rescue use (must be withheld for at least 4 hours prior to spirometry testing) If taken as standard of care therapy prior to Visit 1 the following are permitted and should be maintained at a stable dose for the duration of the treatment period: o inhaled corticosteroids (ICS) o inhaled long-acting muscarinic antagonists (LAMA) o inhaled long-acting beta 2 -agonists (LABA) o methylxanthines o phosphodiesterase-4 (PDE-4) inhibitor o oral corticosteroids (chronic use) 41

44 2013N183405_ Oral or injectable corticosteroids (short course <14 days) only for the short term treatment of COPD exacerbations and/or pneumonia Antibiotics (short course <14 days) for the short term treatment of COPD exacerbations and/or pneumonia Mucolytics such as acetylcysteine Long term oxygen therapy (LTOT). To be eligible to enter the study subjects who are on LTOT must be using at a flow rate of 4 liters/minute over 24 hours. However, oxygen therapy may be adjusted as deemed medically necessary at any time during the study. Oxygen therapy must be captured on the concomitant medication page of the ecrf. Supplemental oxygen is recommended for patients who exhibit oxyhemoglobin desaturation with rest or exertion (e.g. SaO2 88%) Maintenance phase of pulmonary rehabilitation treatment (subjects are not allowed to initiate treatment during the study). The following non-copd medications are permitted during the study (for example): Medications for rhinitis (e.g. intranasal corticosteroids, antihistamines, cromolyn, nedocromil, nasal decongestants) Topical and ophthalmic corticosteroids Unplanned localized corticosteroid injections (e.g. intra-articular and epidural) Vaccinations (Influenza vaccine, Pneumonia vaccine, Shingles vaccine, etc). Administration of influenza and pneumonia vaccines should be considered based on clinical discretion of the investigator and local/national guidelines. Influenza vaccines and pneumonia vaccines will be captured on the concomitant medication pages of the ecrf) Allergy immunotherapy Antibiotics for short-term treatment (14 days) of acute infections. Long term treatment with antibiotics is not allowed Systemic and ophthalmic beta-blockers Smoking cessation treatments Cough suppressants Anti-depressants and anxiolytics Continuous Positive Airway Pressure (CPAP) Prohibited Medications and Non-Drug Therapies Medications noted as part of exclusion criteria are prohibited for the duration of the treatment period. Eligible subjects are expected to continue their baseline COPD medications during the run-in period. On the morning of the screening visit (Visit 1) subjects will refrain from taking their morning dose of their usual COPD medications until instructed to do so by clinic personnel. Rescue medication (i.e. salbutamol or ipratropium) must be withheld for at least 4 hours before visits when spirometry is required (see Table 2) and prior to reversibility testing at Visit 1. 42

45 2013N183405_ COPD medications and non-drug therapies that are prohibited during the randomized portion of the study: Acute phase of pulmonary rehabilitation (at any time during the study including run-in) Long term systemic antibiotic therapy (antibiotics used for <14 days for acute infections or for exacerbations or pneumonia are allowed) Omalizumab [Xolair] Other monoclonal antibodies Experimental anti-inflammatory drugs (non biologicals) Immunosuppressive medications including but not limited to o Corticosteroids intramuscular, long-acting depot if used to treat a condition other than COPD o Methotrexate, troleandomycin, cyclosporine, azathioprine o Oral gold o Chemotherapy used for conditions other than COPD o Regular systemic (oral or parenteral) corticosteroids for the treatment of conditions other than COPD Other investigational products (subjects must have not received investigational products for 1 months or 5 half-lives prior to Visit 1, whichever is longer) Bilevel positive airway pressure (BiPAP) is not permitted Radiation therapy is excluded for 12 months prior to visit one and throughout the study Acetaminophen should not be used in patients with acute viral hepatitis Treatment after the End of the Study The investigator is responsible for ensuring that consideration has been given to the poststudy care of the patient s medical condition whether or not GSK is providing specific post study treatment Treatment of Study Treatment Overdose The dose of mepolizumab considered to be an overdose has not been defined. There are no known antidotes and GSK does not recommend a specific treatment in the event of a suspected overdose. The investigator should use clinical judgement in treating the symptoms of a suspected overdose. 43

46 2013N183405_ STUDY ASSESSMENTS AND PROCEDURES Table 2 Time and Events Protocol Activity Screen/Run-in Pre-screening V1(S) Week 0 Study Day 1 Randomized Treatment (visit window is ± 7 days) V0 a V1 V2 b V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 Week 28 Week 32 Week 36 Week 40 Week 44 Week 48 Exit Visit Week 52 Withdrawal Discontinue from IP Visit c Withdraw from study Visit c Procedures Written Informed Consent/PGx consent X d Demography/child bearing status X assessment Medical history including cardiovascular, COPD, X and exacerbation Concomitant Medication Assessment X X X X X X X X X X X X X X X X X X X Inclusion/Exclusion Criteria e X X CCI X mmrc X Smoking Status X X X X X Smoking Cessation Counseling X X Parasite Screening f X Register Visit in RAMOS/IVRS X X X X X X X X X X X X X X X X X X X Follow Up V16 Week 60 44

47 2013N183405_ Screen/Run-in Randomized Treatment (visit window is ± 7 days) Exit Visit Withdrawal Protocol Activity V0 a V1 V2 b V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 Withdraw Discontinue from from IP study Visit c Visit c V16 Pre-screening V1(S) Week Week Week Week Week Week Week Week Week Week Week Week Week Week Week Study Day 1 Efficacy Assessements Spirometry X X X X X X X X X X Reversibility Testing X ediary data review X X X X X X X X X X X X X X X X Exacerbation and Healthcare Utilization X X X X X X X X X X X X X X X Assessment SGRQ-C X X X X X X X EQ-5D-5L X X X X X CAT X X X X X X X X X X X X X X X X SF-36 X X X X X Subject global rating of activity level X X X X X X X X X X X X X X X X Subject global rating of activity change X X X X X X X X X X X X X X X Clinician rated response to therapy X X X X X X X Subject rated response to therapy X X X X X X X Safety Assessments Adverse Events/Serious Adverse Event X X X X X X X X X X X X X X X X X X Assessment Medical Problems Diary Review X X X X X X X X X X X X X X X Follow Up 45

48 2013N183405_ Screen/Run-in Randomized Treatment (visit window is ± 7 days) Exit Visit Withdrawal Protocol Activity V0 a V1 V2 b V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 Withdraw Discontinue from from IP study Visit c Visit c V16 Pre-screening V1(S) Week Week Week Week Week Week Week Week Week Week Week Week Week Week Week Study Day 1 COPD symptoms summary report review X X X X X X X X X X X X X X X X Physical Examination X g X h X h X g X h X g Xg X g Vital Signs (including pulse oximetry) X X X X X X X X X X X X X X X X X X ECG X X X X X X X X X Chest x-ray X i Laboratory Assessments Hematology with differential j X X X X X X X X X X X X X X X X X X Clinical Chemistry X X X k X k X X X X X X X Clinical chemistry with lipoproteins (fasting) l X X X X X Urine Pregnancy Test m X X X X X X X X X X X X X X X X X PGx Sampling (blood) X n Hepatitis B and C testing o X LFT testing (only in hepatitis B positive X X X X X X X X X X X X X X X X subjects) p Pharmacokinetic Sample q X X X X X X X Immunogenicity sample X X X X X X Exploratory Lab Assessments Total IgE X Blood Biomarker X X X X X Serum IL-5 X X X Follow Up 46

49 2013N183405_ Protocol Activity Screen/Run-in Randomized Treatment (visit window is ± 7 days) V0 a V1 V2 b V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 Exit Visit Withdrawal Discontinue from IP Visit c Withdraw from study Visit c Pre-screening V1(S) Week Week Week Week Week Week Week Week Week Week Week Week Week Week Week Study Day 1 Study Supplies and Investigational Product Electronic Diary registration and training X r Electronic Diary close out X X Administer Investigational Product X X X X X X X X X X X X X Dispense Rescue Salbutamol X X X X X X X X X X X X X X Collect Used Rescue Salbutamol X X X X X X X X X X X X X X X Complete electronic Case Report Form (ecrf) X X X X X X X X X X X X X X X X X X a. The pre-screening visit (Visit 0) can occur on the same day as the screening visit (Visit 1) but must be completed prior to initiating any Visit 1 procedures. b. Visit 2 can occur 1 to 2 weeks after Visit 1. Results from Visit 1 procedures must be available for review of randomization criteria. c. See definition in Section 4.4 and Section 4.5 for additional information. d. Informed consent for optional PGx (pharmacogenetics) research must be obtained before collecting a sample. e. Inclusion and Exclusion criteria should be assessed at Visit 1 and Randomization Criteria assessed at Visit 2. f. Parasitic screening is only required in countries with high-risk or for subjects who have visited high-risk countries in the past 6 months. Sites should use local laboratories. g. A comprehensive physical exam should be conducted. See Section for specific details of the comprehensive physical exam. h. A brief physical exam should be conducted. See Section for specific details of the brief exam. i. Only required if results from a chest x-ray or CT-scan, taken within the past 6 months, is not available. j. Differential results will be blinded from Visit 3 onwards. k. Liver panel only l. Subject must be in fasting state. If subject has not fasted they may return to the clinic to provide this sample. Follow Up V16 47

50 2013N183405_ m. Pregnancy testing is only required for females of child bearing potential. An assessment must be made at baseline to determine child bearing potential of each female study participant (see Section ). n. PGx consent must be obtained prior to collecting the PGx blood sample. The PGx sample can be collected at any visit post-randomization (i.e. at Visit 3 or any visit after Visit 3). o. If hepatitis C positive confirmation by testing the same sample is required. See Quest manual for details. For subjects who are HBsAg positive or HBcAb positive reflexive testing must be conducted to assess HBV DNA p. If ALT 3X ULN, reflexive testing should be conducted for HBV-DNA q. PK samples must be taken pre-dose r. Thorough ediary training should be conducted at Visit 1 and throughout the study on an as-needed basis 48

51 2013N183405_ Critical Baseline Assessments Subjects should conduct the pre-screening visit (Visit 0) up to 30 days prior to the screening visit (Visit 1). A subject number will be assigned at this time of signing informed consent. During the pre-screening Visit, study designated personnel should provide informed consent, and pharmacogenetics (PGx) informed consent, to potential study participants. Site staff will review with the subject any study related procedures that must be taken prior to the next visit (i.e., fasting for lab assessments, withholding of SABA or SAMA for 4 hours and withholding of COPD medication on the morning of Visit 1, etc) Pre-screening Visit Subjects can complete pre-screening and screening visits on the same day. Once the informed consent process is complete, and the subject has agreed to participate by signing the informed consent documents, additional pre-screening assessments can be conducted. The pre-screening assessment will include the collection of demographic information (including race, age, and gender), an assessment of child bearing status for all potential female study participants, and an assessment of COPD medication use in the 3 months prior to study Critical Procedures Performed at Visit 1 (Screening) The required order of completion of these assessments can be found in the SPM. Medical history including but not limited to COPD history (comprised of date of diagnosis and COPD type [emphysema and/or chronic bronchitis]), smoking status, history of diabetes, history of hypertension, history of osteoporosis, and history of cataracts. See ecrf completion guidelines for additional information of the data that will be captured. Cardiovascular (CV) medical history/risk factors and CV medication history will be assessed at screening. This assessment must include a review of the subject s blood pressure, smoking history, cardiovascular medical conditions, and family history of premature cardiovascular disease. Current and prior COPD medication history used in the 12 months prior to Visit 1 COPD exacerbation history in the 12 months prior to Visit 1 including the recording of COPD maintenance medications taken at the time of exacerbation and details of exacerbation treatment A comprehensive physical exam (see Section for details) Vital sign measurement including measurement of pulse rate, blood pressure, body temperature, and pulse oximetry. Comprehensive training on the electronic diary including subject in office completion of the training diary and a practice data transmission. 49

52 2013N183405_ Completion of questionnaires outlined in Table 2, including baseline assessment with modified Medical Research Council grading system (mmrc; see Section ) and the Charlson co-morbidity index (CCI; see Section ), prior to spirometry. Pulmonary function tests including bronchodilator responsiveness testing Chest X-ray or if available review of chest x-ray conducted in the prior 6 months Resting 12 lead ECG Inclusion/exclusion criteria assessment Determination and documentation in source of child bearing potential for female subjects (see definition in Section ). If child bearing potential is questionable an assessment of follicle stimulating hormone (FSH) and estradiol should be obtained and analyzed to confirm childbearing potential. A pregnancy test is required for females of child bearing potential (FCBP) at screening and prior to randomization and at each scheduled study visit prior to the administration of investigational product Laboratory testing as indicated in Section which includes but not limited to the following: Clinical Chemistry including glucose and potassium Hematology with differential Hepatitis B and Hepatitis C screening. For those who are Hepatitis B positive (surface antigen or core antibody) reflexive testing will be performed to assess Hepatitis B virus (HBV-DNA) load to determine eligibility and/or required on treatment monitoring. Parasitic screening (only in countries with a high risk or in subjects who have visited a high risk country) Modified Medical Research Council Grading System (mmrc) The subject s degree of dyspnea to different levels of activity will be rated on the five point mmrc scale. The mmrc, administered by an interviewer, asks subjects to rate how breathless they are on a 5-point Guttman scale Charlson Co-morbidity index (CCI) The Charlson Co-morbidity Index contains 19 categories of co-morbidity and predicts the ten-year mortality for a patient who may have a range of co-morbid conditions. Each condition is assigned with a score of 1, 2, 3, or 6 depending on the risk of dying associated with this condition Definition of child bearing and non-child bearing potential Females of childbearing potential are defined as females with functioning ovaries (i.e., post-menarche, premenopausal women with no documented impairment of oviductal or 50

53 2013N183405_ uterine function that would cause sterility). This category includes females with oligomenorrhea, females who are peri-menopausal, and young females who have begun to menstruate (adolescents). The information on the lack of impairment of oviductal or uterine function that would cause sterility can come from the site personnel s: Review of subject s medical records Medical examination of the subject Interview with the subject on her medical history. Females of non-childbearing potential are defined as females with functioning ovaries and with a documented tubal ligation or hysterectomy; or females who are postmenopausal defined as 12 months of spontaneous amenorrhea with an appropriate clinical profile, e.g., age appropriate, >45 years, in the absence of hormone replacement therapy (HRT). In questionable cases a blood sample for follicle stimulating hormone (FSH) and estradiol will be obtained and analyzed to confirm childbearing potential. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods listed above for females of childbearing potential if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks should elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method Critical Procedures Performed at Visit 2 (Randomization) Review the results of assessments collected at Visit 1, including laboratory and safety assessments and re-assess subject eligibility. Review of electronic diary (ediary) data and compliance. Address any concerns the subject may have with the completion of the daily ediary. Conduct additional training if deemed necessary. Complete Questionnaires as indicated in Table 2. Questionnaires must be completed prior to the administration of Investigational Product. Conduct spirometry. Spirometry must be completed prior to the administration of Investigational Product. Conduct laboratory assessments as listed in Table 2. Laboratory assessments must be collected prior to administration of Investigational Product. This visit includes chemistry plus lipoprotein panel. The subject must have fasted. Administer Investigational Product 51

54 2013N183405_ Train subjects on the completion of the medical problems and healthcare utilization worksheets. Provide worksheets and instruct subject to return worksheets at the next visit. Safety monitor subjects for the protocol specified time following administration of Investigational Product. See Section Efficacy Primary Efficacy Endpoint Frequency of moderate/severe exacerbations. Moderate exacerbations are defined as COPD exacerbations that require either systemic corticosteroids (intramuscular (IM), intravenous, or oral) and/or antibiotics. Severe exacerbations are defined as COPD exacerbations requiring hospitalization or result in death Secondary Efficacy Endpoints Time to first moderate/severe exacerbation Frequency of COPD exacerbations requiring emergency department (ED) visits and/or hospitalizations Change from baseline mean total St. George s Respiratory Questionnaire-COPD (SGRQ-C) score Change from baseline COPD assessment test (CAT) score Other Efficacy Endpoints Frequency of moderate COPD exacerbation Frequency of severe COPD exacerbations Occasions of rescue medication use Proportion of SGRQ-C responders Change from baseline in FEV 1 and FVC Change from baseline EQ-5D-5L Frequency of COPD exacerbations requiring re-hospitalization within 30 days Spirometry and Bronchodilator Responsiveness Testing Spirometry Spirometry measurements will be obtained using spirometry equipment that meets or exceeds the minimal performance recommendations of the ATS [Miller, 2005]. All 52

55 2013N183405_ subjects will have spirometry performed at Screening and scheduled clinic visits during the treatment period as indicated in Table 2. For FEV 1 and FVC determinations, at least 3 acceptable spirometry efforts (with no more than 8) should be obtained. Acceptable spirometry efforts should have a satisfactory start of test and end of test (i.e. a plateau in the volume-time curve) and be free from artifacts due to cough, early termination, poor effort, obstructed mouthpiece, equipment malfunction, or other reasons [Miller, 2005]. The largest FEV 1 and FVC from the 3 acceptable efforts should be recorded, even if they do not come from the same effort. Additional details about acceptable, quality, spirometry testing are provided in the SPM. Spirometry must be performed as follows: Started approximately between 6:00AM and 11:00 AM After completing questionnaires at Visits where these assessments are captured (as specified in Table 2) After withholding salbutamol for 4 hours After withholding ipratropium for 4 hours After withholding the morning dose of usual COPD medications Prior to IP dosing Subjects should refrain from smoking for 1 hour prior to each pulmonary function test Subjects should abstain from drinking beverages with high levels of caffeine such as tea and coffee for 2 hours prior to each pulmonary function test A full description of the timing and conduct of spirometry procedures is provided in the SPM Bronchodilator Responsiveness Testing At the screening visit (Visit 1), both pre- and post-salbutamol spirometry will be obtained to determine subject eligibility. Bronchodilator responsiveness testing will be completed as follows: Following pre-salbutamol spirometry (three acceptable spirometry efforts), the subject will self-administer 4 puffs of salbutamol MDI. Three acceptable spirometry efforts will be obtained approximately 10 to 30 minutes after salbutamol administration Diary Assessment Subjects will be trained at Screening (Visit 1) on the completion of daily questions through an electronic diary (edairy). The ediary should be completed each morning during the study starting the morning after Visit 1. 53

56 2013N183405_ Each day the subject will be asked to respond to questions about the following: Number of nighttime awakenings due COPD symptoms Use of supplemental rescue medication Major symptoms of COPD exacerbations concerning the subject s dyspnea, sputum volume, sputum purulence (color) Minor symptoms of COPD exacerbations: cough, wheezing, sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause Daily activity Site staff will have access to the subject COPD symptom summary report through a webbased portal. When symptoms meet a pre-defined threshold, the subject will be notified, through the ediary, to consult their study site. The primary Investigator should review the COPD symptom summary report at least monthly prior to the subject's scheduled in clinic visit. The COPD symptom summary report should be reviewed at any time the primary Investigator has concerns about worsening of the subject's condition. Investigator judgment should be used in deciding whether to report the signs and symptoms (and/or determined diagnosis) recorded in the daily diary as an AE/SAE in the ecrf. Refer to Section and Section for definitions of AE and SAE, respectively. Subjects compliance with completion of the daily diary should be reviewed at each clinic visit subject who are non-compliant should be re-educated on the importance for compliance. Every effort will be made to re-educate those subjects who continue to be non-compliant. The ediary will also be used to administer patient reported outcomes during clinic visits. Details regarding completion of the ediary are located in the SPM Moderate and Severe COPD Exacerbations Moderate exacerbations are defined per protocol as clinically significant exacerbations that require treatment with oral/systemic corticosteroids and/or antibiotics. Severe exacerbations are defined per protocol as clinically significant exacerbations that require in-patient hospitalization (i.e., 24 hours). The decision to treat moderate exacerbations should be corroborated by review of data from the daily symptoms ediary to confirm that the exacerbation was associated with deterioration of symptoms. 54

57 2013N183405_ For safety reasons alerts will be programmed into the ediary to encourage the subject to contact the investigator if their COPD symptoms worsen. The site will also receive notification of the alert. An alert itself will not be classified as a moderate exacerbation unless it resulted in subsequent treatment for the worsening of symptoms meeting the definition above Symptom Defined COPD Exacerbations Symptom-defined exacerbation will be identified using the following criteria. Worsening of two or more of the following major symptoms for at least two consecutive days: OR Dyspnea Sputum volume Sputum purulence (color) Worsening of any one major symptom together with any one of the following minor symptoms for at least two consecutive days: Sore throat Colds (nasal discharge and/or nasal congestion) Fever (oral temperature > 37.5 C) without other cause Increased cough Increased wheeze Site staff will have access to a symptom summary report through a web-based portal. The symptoms summary report will indicate when symptoms meet the above criteria. If a subject is determined to have an exacerbation it should be treated per protocol as described in Section Exacerbation Treatment If in the opinion of the investigator/treating physician the exacerbation is severe enough to warrant the need for oral corticosteroids (with or without antibiotics) the following guidelines should be used. The duration of treatment with oral corticosteroids should be 14 days (dose and type according to local practice) The duration of treatment with oral corticosteroids should not exceed 14 days unless given approval by the sponsor or representative Any course of oral corticosteroids started within 7 days of finishing a previous course will be considered as treatment for a single exacerbation 55

58 2013N183405_ If, in the opinion of the investigator/treating physician there is evidence of respiratory bacterial infection that warrants treatment with antibiotics the following guidelines should be followed: The duration of treatment with antibiotics should be 7 to 14 days (dose and type according to local practice). If first line antibiotic treatment fails and additional antibiotics are used, the total duration of antibiotic treatment should not exceed 30 days unless given approval by the sponsor or representative. Any course of antibiotics started within 7 days of finishing a previous course will be considered as treatment for a single exacerbation. Use of antibiotics for the treatment of upper or lower respiratory tract infections is not considered a COPD exacerbation unless worsening of COPD symptoms meets the criteria noted in Section All medications used for the treatment of exacerbations must be recorded in the source documents and the exacerbation page of the ecrf. Exacerbations should not be recorded in the AE section of the ecrf unless they meet the definition of an SAE St. George's Respiratory Questionnaire for COPD patients The SGRQ-C is a 40-item patient questionnaire, designed to measure health impairment by addressing the frequency of respiratory symptoms (questions 1-7) and the patient's current state (questions 8-14). The SGRQ-C is derived from the original SGRQ, and produces scores equivalent to the SGRQ instrument [Meguro, 2007]. The questionnaire (and all other visit questionnaires, as noted in the T&E table) should be completed before any other visit procedures. The questionnaire should be completed in a quiet area free from distraction while sitting at a table or a desk. Site staff should explain to the subject the importance of completing of the questionnaire for clinicians and researchers to understand how COPD affect their daily lives. The subject should be asked to complete the questionnaire as honestly as they can and stress that there are no right or wrong answers. Explain that they must answer every question. The SGRQ-C is designed for supervised self-administration which means that the subject should answer the questionnaire by themselves but that site staff can provide advice if required. It is appropriate to help clarify a question but do not provide an answer. If patients have difficulty reading questions may be read out loud. However, you may not challenge the subject's response. Subjects must complete the questionnaire while in the clinic for their scheduled study visit. The SGRQ-C should be administered at Randomization (Visit 2) and at additional visits indicated in the Time and Events table (Table 2) EQ-5D-5L The EQ-5D-5L questionnaire will be completed by subjects at randomization and at additional visits as indicated Table 2. 56

59 2013N183405_ The EQ-5D-5L is a standardized instrument for use as a measure of health utility. It is designed for self-completion and is cognitively simple, taking only a few minutes to complete. The EQ-5D-5L is a two-part self-assessment questionnaire. The first part consists of five items covering five dimensions (mobility, self care, usual activities, pain/discomfort, and anxiety/depression). Each dimension is measured by a five-point Likert scale (no problems, slight problems, moderate problems, severe problems, and extreme problems). Respondents are asked to choose one level that reflects their "own health state today" for each of the five dimensions. Respondents can be then classified into one of 243 distinct health states. The second part is a 20-cm visual analogue scale (EQ-VAS) that has endpoints labelled "best imaginable health state" and "worst imaginable health state "anchored at 100 and 0, respectively. Respondents are asked to indicate how they rate their own health by drawing a line from an anchor box to that point on the EQ-VAS which best represents their own health on that day. EQ-5D-5L health states are converted to a single summary index by applying a formula that essentially attaches weights to each of the levels in each dimension. The formula is based on the valuation of EQ-5D health states from general population samples COPD Assessment Test The COPD Assessment Test (Jones, 2009; Jones, 2012) 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 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 (maximum impairment) to 5 (no impairment) with a scoring range of Higher scores indicate greater disease impact. The CAT should be completed at each scheduled in clinic visit as indicated in Table Safety Safety assessment and endpoints Incidence of adverse events including systemic (i.e., allergic/ige mediated and non-allergic) and local site injection-related reactions reported throughout the 52- week treatment period. o Systemic reactions can be allergic or non-allergic in nature and are typically mild to moderate in intensity, generally develop within several hours of the injection, and are most commonly associated with a complex of symptoms including chills, fever, nausea, vomiting, asthenia, headache, skin rash, pruritus, urticaria, arthralgia/myalgia, hypotension/hypertension, dizziness, bronchospasm, dyspnea or cough. Subjects must be monitored during IP administration and for 1 hour post-administration. o Anaphylaxis, the most severe form of hypersensitivity reactions will be assessed using the diagnostic criteria outlined by the 2006 Joint NIAID/FAAN Second Symposium on Anaphylaxis [Sampson, 2006; See Appendix 8]. 57

60 2013N183405_ Vital signs including blood pressure, body temperature, pulse rate, and pulse oximetry ECG measurements Mortality (all cause, respiratory, cardiovascular) Immunogenicity Hematological and clinical chemistry parameters throughout the 52-week treatment period and the 8-week follow up period Hepatitis B screening and monitoring Chronic stable hepatitis B is acceptable if the subject otherwise meets entry criteria (see Section 4). For subjects who are Hepatitis B surface antigen positive or hepatitis B core antibody positive with HBV DNA levels of < 2000 IU/ml at baseline, monthly liver monitoring will be required and must continue for 12 weeks after last dose of study treatment. Additional information required liver function testing is provided in Section Liver chemistry stopping and follow up criteria Phase III-IV liver chemistry stopping and follow up criteria have been designed to assure subject safety and evaluate liver event etiology (in alignment with the FDA premarketing clinical liver safety guidance). Phase III-IV liver chemistry stopping criteria 1-5 are defined below and are presented in a figure in Appendix 7: 1. ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) (or ALT 3xULN and INR>1.5, if INR measured) NOTE: if serum bilirubin fractionation is not immediately available, discontinue IP for that subject if ALT 3xULN and bilirubin 2xULN. Serum bilirubin fractionation should be performed if testing is available. If testing is unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 2. ALT 8xULN. 3. ALT 5xULN but <8 xuln persists for 2 weeks 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 discontinue IP for that subject Report the event to GSK within 24 hours of learning its occurrence 58

61 2013N183405_ Complete the liver event CRF and SAE data collection tool if the event also meets the criteria for an SAE. All events of ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 3xULN and INR>1.5, if INR measured); INR measurement is not required and the threshold value stated will not apply to patients receiving anticoagulants), termed Hy s Law, must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis). NOTE: if serum bilirubin fractionation is not immediately available, discontinue IP for that subject if ALT 3xULN and bilirubin 2xULN. Serum bilirubin fractionation should be performed if testing is available. If testing is unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. Complete the liver imaging and/or liver biopsy CRFs if these tests are performed Perform liver event follow up assessments, and monitor the subject until liver chemistries resolve, stabilise, or return to baseline values as described below. Discontinue IP (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 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 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 59

62 2013N183405_ 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 assessments described below: Viral hepatitis serology including: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); For subjects who were hepatitis B surface antigen positive or hepatitis B core antibody positive at baseline HBV DNA testing is also required; 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 one week of the liver event. Record the date/time of the PK blood sample draw and the date/time of the last dose of investigational product prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected within a week of the liver event, 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: 60

63 2013N183405_ 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]). 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) [LeGal, 2005]. Liver imaging (ultrasound, magnetic resonance, or computerised tomography) to evaluate liver disease 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 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/selfharming 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. 61

64 2013N183405_ 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 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 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 jeopardise the subject or may require medical or 62

65 2013N183405_ 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 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 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 judgment of the investigator are to be recorded as AEs or SAEs. 63

66 2013N183405_ 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 Cardiovascular Events Investigators will 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 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 Pregnancy Any pregnancy that occurs during study participation must be reported using a clinical trial pregnancy form. To ensure subject safety, each pregnancy must be reported to GSK within 2 weeks of learning of its occurrence. The pregnancy must be followed up to determine outcome (including premature termination) and status of mother and child. Pregnancy complications and elective terminations for medical reasons must be reported as an AE or SAE. Spontaneous abortions must be reported as an SAE. Any SAE occurring in association with a pregnancy, brought to the investigator s attention after the subject has completed the study and considered by the investigator as possibly related to the study treatment, must be promptly reported to GSK. 64

67 2013N183405_ Time Period and Frequency of Detecting AEs and SAEs The investigator or site staff is responsible for detecting, documenting and reporting events that meet the definition of an AE or SAE. AEs will be collected from the start of study treatment and until the follow up contact. SAEs will be collected over the same time period as stated above for AEs. However, any SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant medication, will be recorded from the time a subject consents to participate in the study up to and including any follow up contact. All SAEs will be reported to GSK within 24 hours, as indicated in Section 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? Have you had any (other) medical problems since your last visit/contact? Have you taken any new medicines, other than those provided in this study, since your last visit/contact? Prompt Reporting of Serious Adverse Events and Other Events to GSK SAEs, pregnancies and liver function abnormalities meeting pre-defined criteria will be reported promptly by the investigator to GSK as described in the following table once the investigator determines that the event meets the protocol definition for that event. Initial Reports Follow-up Information on a Previous Report Type of Event Time Frame Documents Time Frame Documents All SAEs 24 hours SAE data collection tool 24 hours Updated SAE data collection tool 65

68 2013N183405_ Initial Reports Follow-up Information on a Previous Report Type of Event Time Frame Documents Time Frame Documents 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 Pregnancy 2 weeks Pregnancy Notification Form Initial and follow up 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 2 weeks Pregnancy Follow-up Form Liver chemistry abnormalities for Phase I to IV: ALT3xULN and Bilirubin2xULN (>35% direct) (or ALT3xULN and INR>1.5, if INR measured) 1 24 hours 2 SAE data collection tool. Liver Event CRF and Liver Imaging and/or Liver Biopsy CRFs, if applicable 3 24 hours Updated SAE data collection tool/ Liver Event Documents 3 Remaining liver chemistry abnormalities Phase III to IV: ALT8xULN; ALT3xULN with hepatitis or rash or 3xULN and <5xULN that persists4 weeks 24 hours 2 Liver Event Documents (defined above) 3 24 hours Updated Liver Event Documents 3 66

69 2013N183405_ Initial Reports Follow-up Information on a Previous Report Type of Event Time Frame Documents Time Frame Documents ALT5xULN plus bilirubin <2xULN ALT5xULN and bilirubin <2xULN that persists 2 weeks ALT3xULN and <5x ULN and bilirubin <2xULN 24 hours 2 Liver Event Documents (defined above) do not need completing unless elevations persist for 2 weeks or subject cannot be monitored weekly for 2 weeks 3 24 hours 2 Liver Event Documents (defined above) 3 24 hours 2 Liver Event Documents (defined above) do not need completing unless elevations persist for 4 weeks or subject cannot be monitored weekly for 4 weeks 3 24 hours Updated Liver Event Documents, if applicable 3 24 hours Updated Liver Event Documents 3 24 hours Updated Liver Event Documents, if applicable 3 1. INR measurement is not required; if measured, the threshold value stated will not apply to patients receiving anticoagulants. 2. GSK must be contacted at onset of liver chemistry elevations to discuss subject safety 3. Liver Event Documents (i.e., Liver Event CRF and Liver Imaging CRF and/or Liver Biopsy CRF, as applicable) should be completed as soon as possible. The method of 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. 67

70 2013N183405_ 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 Other Safety Outcomes Laboratory Assessments All protocol required laboratory assessments, as defined in Table 2, must be performed by the central laboratory, Quest Diagnostics. All lab assessments must be completed prior to injection of investigational product. Laboratory assessments must be conducted in accordance with the Central Laboratory Manual and Protocol Time and Events Schedule. Laboratory requisition forms must be completed and samples must be clearly labelled with the subject number, protocol number, site/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. All study-required laboratory assessments will be performed by a central laboratory. Routine non-fasting clinical chemistry including serum glucose and serum potassium levels will be performed at screening (Visit 1), at randomization (Visit 2) and at clinic treatment visits indicated in the Time and Events table (Table 2). In the event of premature discontinuation from the study a sample should be collected at the premature discontinuation visit. Samples should also be collected at follow-up visit as specified in Table 2 68

71 2013N183405_ In addition to routine clinical chemistry subjects must provide a fasted blood sample on Visit 1, Visits 2, Visit 8, and Visit15 or premature discontinuation for an assessment of lipoproteins. A blood sample for Hematology with differential will be collected at every study visit, including premature discontinuation (if required) and at the follow-up visit. The results of the differential will be blinded to the study site staff and Sponsor after Visit Physical Exam A comprehensive physical exam will be performed at Visit 1, Visit 8, Visit 15 or Withdrawal. The physical exam will be conducted by the primary investigator or a qualified designee at the visits specified in Table 2 The comprehensive physical exam will include an assessment of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and extremities and will include a comprehensive medical history, and COPD history. A brief physical exam will be conducted at visits specified in Table 2 and will include an assessment of the skin, lungs, cardiovascular system and abdomen (liver and spleen) Vital Signs Vital signs including pulse oximetry will be performed at all study visits. At Screening (Visit 1) vital signs must be taken prior to spirometry. At randomization (Visit 2) and on subsequent Visits as indicated in Table 2, vital signs must be performed prior to administration of study medication and prior to spirometry. Blood pressure (systolic and diastolic) and pulse rate will be measured in the sitting position after approximately 5 minutes rest. A single set of values will be collected and recorded in the source documentation and ecrf. Oxygen saturation should be measured by pulse oximetry as part of the vital signs assessment at each visit. A single value will be collected and recorded in the source documentation and ecrf. Body temperature should also be measured Medical Problems and Concomitant Medications Subjects will be instructed to record any medical problems and the medications used to treat them over each day. These entries will be reviewed by the study coordinator at each study visit and recorded in the ecrf as adverse events as appropriate. 69

72 2013N183405_ Lead ECG All sites will use standardized ECG equipment provided by a centralized external vendor. A single 12-lead ECG and rhythm strip will be recorded after measurement of vital signs and prior to spirometry. Recordings will be made at time points outlined in Table 2. All ECG measurements will be made with the subject in a supine position having rested in this position for approximately 5 minutes before each reading. The investigator, a designated sub-investigator or other appropriately trained site personnel will be responsible for performing each 12-lead ECG. The investigator must provide his/her dated signature on the original paper tracing, attesting to the authenticity of the ECG machine interpretation. All ECGs will be electronically transmitted to an independent cardiologist (contracted by GSK) and evaluated. The independent cardiologist, blinded to treatment assignment, will be responsible for providing measurements of heart rate, QT intervals and an interpretation of all ECGs collected in this study. A hard copy of these results will be sent to the investigator. The investigator must provide his/her dated signature on the confirmed report, attesting to his/her review of the independent cardiologist s assessment. Details of the cardiac monitoring procedures will be provided by the centralized cardiology service provider Pneumonia All pneumonias should be confirmed by the presence of new infiltrate on chest x-ray and captured on the AE/SAE page and on the pneumonia page of the ecrf. Investigators and site staff should remain vigilant for the possible development and diagnosis of pneumonia as the clinical features of such infections overlap with the symptoms of COPD exacerbations. For all suspected cases of pneumonia, Investigators must confirm the diagnosis by obtaining a chest x-ray or documentation of the result of a chest x-ray performed outside of the clinic site. Appropriate therapy should be initiated for confirmed pneumonia. Confirmation by chest x-ray should occur within 48 hours of suspected pneumonia Health Outcomes All patient reported outcomes should be administered at the beginning of a study visit before spirometry and before administration of IP. SGRQ-C should be administered first followed by EQ-5D-5L, CAT, and Patient Global Rating of activity limitation and impression of change and Subject rated response to therapy, according to the scheduled outlined in Table 2. 70

73 2013N183405_ Health Outcome Assessments Not Included as Primary or Key Secondary Endpoints Healthcare Resource Utilization All unscheduled COPD-related health care utilization will be recorded including telephone contacts, specialist nurse visits, visits to a physician s office, home visits (day and night time), outpatient visits, visits to urgent care, visits to the emergency department, and hospitalizations associated with the subject s exacerbations will be recorded in the ecrf. Hospitalization data should be stratified by ward type (e.g; ICU, high dependency and usual care). Hospital length of stay in each type of ward will also be recorded. The resource utilization worksheet used by the patient to record all health care contacts experienced since the last visit will be presented to the investigator (or designated coordinator) at the visits indicated in Table 2 The investigator (or designated coordinator) should ask the subject if any of the health care contacts that are recorded on the worksheet were due to a COPD exacerbation. The investigator can refer to his/her records to verify or supplement information given by the subject, if necessary. If any unscheduled healthcare contact is due to a COPD exacerbation, then the COPD Exacerbation section of the ecrf must be completed. Details regarding completion of the Healthcare Utilization worksheet are located in the SPM Additional Health Outcomes Assessments Change from baseline in SF-36 total score and all domains Change from baseline in rating of activity limitation Change from baseline in subject's impression of change Change in clinician and subject response to therapy SF-36 The SF-36 is a multi-purpose, short-form health survey with only 36 questions. It yields an 8-scale profile of functional health and well-being scores as well as psychometricallybased physical and mental health summary measures and a preference-based health utility index. It is a generic measure, as opposed to one that targets a specific age, disease, or treatment group. Accordingly, the SF-36 has proven useful in surveys of general and specific populations, comparing the relative burden of diseases, and in differentiating the health benefits produced by a wide range of different treatments Rating of Activity Limitation and Impression of Change Subjects will complete the Global Rating of Activity limitation as outlined in Table 2. This single global question will ask subjects to rate their activity limitation on a fourpoint scale (not limited, slightly limited, limited, very limited). 71

74 2013N183405_ Subjects will complete an activity specific Global Impression of Change question as outlined in Table 2. Response options will be on a 7 point Likert scale ranging from much better to much worse Clinician/Subject Rated Response to Therapy The clinician and the subject will be asked to rate the response to therapy at the visits specified in the Time and Events schedule (Table 2). This is an overall evaluation of response to treatment, conducted separately by the investigator and the subject using a rating scale. In this rating scale, a seven-point scale score is used with the following definitions: 1 = significantly improved 2 = moderately improved 3 = mildly improved 4 = no change 5 = mildly worse 6 = moderately worse 7 = significantly worse. The subject will indicate their response on a paper questionnaire which will be transcribed into the ecrf by study designated site staff Pharmacokinetics/Pharmacodynamics/Biomarker(s) Blood samples for analysis of mepolizumab plasma concentration will be obtained as per the Time and Events table (Table 2). Samples should be obtained prior to dosing on dosing days. The date and exact time of collection for each sample will be documented in the ecrf. Details for collection and processing of samples may be found in the SPM. Plasma analysis will be performed under the control of GSK PTS-DMPK/Scinovo, the details of which will be included in the Study Procedures Manual. Concentrations of mepolizumab will be determined in plasma samples using the currently approved bioanalytical methodology. Raw data will be archived at the bioanalytical site (detailed in the SPM) Pharmacodynamics Blood eosinophil counts will be recorded as part of standard haematological assessments performed at visits specified in the Time and Events Table (Table 2). After Visit 2 blood eosinophil counts will be blinded to the Sponsor and site staff. 72

75 2013N183405_ Immunogenicity Blood samples will be collected prior to dosing at visits specified in the Time and Events Table (Table 2). Samples will be analysed for the presence of anti-mepolizumab antibodies and neutralizing antibodies. Further details regarding sample collection and processing may be found in the lab manual and the SPM Pharmacogenetic Research Information regarding pharmacogenetic (PGx) research is included in Appendix Novel Biomarkers After completion of the clinical trial, investigations will be performed on samples collected during the course of the trial to detect factors or profiles that correlate with other measures of response to treatment with mepolizumab or with COPD status. The results gained may also be of application for medically related conditions. Performance of these investigations may be conditional on the results of the clinical trial and samples may be selected for analysis on the basis of the clinical outcome. Unless stated otherwise, these investigations may be performed irrespective of whether a response to mepolizumab is observed. Comparative examination of pre-dosing profiles of participants may uncover known or novel candidate biomarkers/profiles which could be used to predict response to treatment with mepolizumab or provide new insights into COPD and medically related conditions. Comparative examination of post-dosing profiles in conjunction with pre-dosing profiles may yield known and novel candidate biomarkers/profiles and new insights which relate to the action of mepolizumab. All samples will be retained for a maximum of 15 years after the last subject completes the trial. Novel candidate biomarkers and subsequently discovered biomarkers of the biological response associated with COPD or medically related conditions and/or the action of mepolizumab may be identified by application of: Proteome analysis of plasma serum samples. 7. DATA MANAGEMENT For this study subject data will be entered into GSK defined electronic case report forms (ecrfs), transmitted electronically to GSK or designee and combined with data provided from other sources in a validated data system. Management of clinical data will be performed in accordance with applicable GSK standards and data cleaning procedures to ensure the integrity of the data, e.g., removing errors and inconsistencies in the data. Adverse events and concomitant medications terms will be coded using MedDRA and an internal validated medication dictionary, 73

76 2013N183405_ GSKDrug. An appropriate medical dictionary that covers all approved drugs in studies where Japan is participating will be referenced. Electronic CRFs (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 This study is designed to test the superiority of mepolizumab 100mg SC vs placebo for the group of subjects with elevated eosinophils and for all subjects in the study. The study will be stratified at randomisation according to whether or not the subject has elevated eosinophils (defined as either a blood eosinophil count of 300 cells/μl within the past 12 months or 150 cells/l at baseline). To control the experiment-wise Type 1 error rate of α=0.05, the α will be split such that 0.04 is assigned to treatment comparisons within the group with elevated eosinophils and the remaining 0.01 to treatment comparisons involving all subjects in the study. The multiple treatment comparisons planned between the primary and secondary endpoints within the group with elevated eosinophils and for all subjects in the study will be controlled using a hierarchical testing procedure; further details are given in Section Study Design Considerations Sample Size Assumptions The primary analysis in the group of subjects with elevated eosinophils is a comparison of the rate of moderate/severe exacerbations in those treated with mepolizumab 100mg SC vs placebo, this same analysis is also of interest using data from all subjects in the study. Within the group with elevated eosinophils, the null hypotheses used to test the superiority of the mepolizumab 100mg SC dose against placebo will be: H 0 : μ i = μ p where μ i is the exacerbation rate on the mepolizumab 100mg SC arm and μ p is the exacerbation rate on the placebo arm. The (one-sided) alternative hypothesis is that the exacerbation rate is lower on the mepolizumab arm: H a : μ i < μ p The estimated rate of moderate/severe exacerbations in the placebo arm is 2 exacerbations per annum (p.a.). 74

77 2013N183405_ With a two-sided 4% level of significance and a sample size of 200 randomized subjects per arm, it is estimated that within this group the smallest observed treatment effect which will result in a rejection of the null hypothesis of no difference is a reduction in exacerbation rate of 23%. Based on a true population reduction of 35%, there is a 90% chance that the reduction will be greater than 23% and hence 90% power for demonstrating a statistically significant result for this assumed true population effect. To account for the loss of patient years data from subjects who withdraw early from the trial and for whom no follow-up data off-treatment is available, this sample size includes an additional 28 subjects per arm; this approximates to an additional 12.5% of patients years of data being collected. In total 400 subjects will be randomized to the group of subjects with elevated eosinophils, 200 to each treatment arm with a randomisation ratio of 1:1 placebo : mepolizumab 100mg SC. To allow for a comparison of treatments in the group of all subjects, an additional 400 subjects will be randomised into a group who do not fulfill the criteria of having elevated eosinophils (i.e. no evidence of a blood eosinophil count of 300cells/μL within the past 12 months and baseline eosinophil levels <150cells/μL), 200 to each treatment arm with a randomisation ratio of 1:1 placebo : mepolizumab 100mg SC. For the group of all subjects, with a two-sided 1% level of significance and a sample size of 400 subjects per treatment arm, it is estimated that the smallest observed treatment effect which will result in a rejection of the null hypothesis of no difference is a reduction in exacerbation rate of 20%. Based on a true population reduction of 30%, there is a 90% chance that the reduction will be greater than 20% and hence 90% power for demonstrating a statistically significant result for this assumed true population effect. Overall in this study, a total of 800 subjects will be randomised with a randomisation ratio of 1:1 placebo : mepolizumab 100mg SC. Randomisation will be stratified based on historical and baseline levels of eosinophils (see Section 5.2) with 400 subjects in the strata with elevated eosinophils and 400 in the strata with no evidence of elevated eosinophils. The above sample size calculation assumes the number of exacerbations p.a. follow a negative binomial distribution [Keene, 2007] with a dispersion parameter k=0.8. The estimated value for the dispersion parameter is based on data observed in a previous study (MEA112997). For patients who complete the study, exacerbations occurring on-treatment and within 4 weeks of the last dose will be included in the primary analysis. For subjects who withdraw early from the study, the intent is to continue collecting data on exacerbations for up to 52 weeks following randomization and include this in the primary analysis Sample Size Sensitivity The sample size in Section is based on assumed exacerbation rates in the placebo group and an expected reduction in this rate for subjects treated with mepolizumab. If the assumed placebo exacerbation rate or the expected reduction with mepolizumab differ then, at the given sample size there will be an effect on the power of the study.table 3 illustrates this effect on power in the group of subjects with elevated eosinophils (based 75

78 2013N183405_ on 172 subjects per arm, excluding the additional 28 subjects to account for early withdrawals, and a dispersion parameter k=0.8). Table 3 Effect on power of varying placebo rates and reductions in rates with mepolizumab Placebo: Exacerbations rate p.a. % reduction in exacerbation rate p.a with mepolizumab 30% % % Sample Size Re-estimation No sample size re-estimation is planned for this study Data Analysis Considerations Analysis Populations All Subjects Enrolled Population (ASE) The All Subjects Enrolled Population will comprise all subjects enrolled and for whom a record exists on the study database. This population will be used for summarising reasons for screen and run-in failures. Intent-to-Treat Population (ITT) This population will consist of all randomised subjects who receive at least one dose of trial medication, and will be the primary population for all analyses of efficacy and safety data. In cases where there is a discrepancy between the treatment to which a subject was randomised and the treatment they actually received a profile of the subjects data will be produced. Intent-to-Treat Population with elevated eosinophils (ITT-EE) A subset of the ITT population, consisting of subjects with elevated eosinophils (ITT-EE) will be the primary population for the analyses of efficacy and safety data for subjects with elevated eosinophils. Intent-to-Treat Population without elevated eosinophils (ITT-nonEE) A subset of the ITT population, consisting of subjects without elevated eosinophils (ITTnonEE) will be used for descriptive analyses of efficacy and safety data for subjects without elevated eosinophils. Per Protocol Population (PP) The Per Protocol (PP) population will consist of all subjects in the Intent-to-Treat population who have not been identified as full protocol deviators with respect to criteria that are considered to impact the primary efficacy analysis. The decision to exclude a subject from the PP Population or exclude part of 76

79 2013N183405_ their data from the PP Population analyses will be made prior to breaking the blind. A subset of this population, consisting of subjects with elevated eosinophils (PP-EE) will be used for a supplementary analysis of the primary endpoint in these subjects Analysis Data Sets All analyses will be carried out using all available data and will be detailed in the RAP Treatment Comparisons Primary Comparisons of Interest The primary treatment comparison of interest in this study is mepolizumab 100mg SC vs placebo. This treatment comparison will be made for the primary and key secondary endpoints in the group of subjects with elevated eosinophils and for all subjects in the study. To control for the multiplicity due to the two primary treatment comparisons of interest the overall of 0.05 will be split such that 0.04 is allocated to treatment comparisons for the group of subjects with elevated eosinophils and the remaining 0.01 is allocated to the treatment comparisons pertaining to all subjects in the study. Within the group of subjects with elevated eosinophils, a hierarchical testing procedure will be used to control for the multiple comparisons between the primary and key secondary endpoints. This will be carried out using a step-down closed testing procedure where inference for an endpoint in the predefined hierarchy will be dependent on statistical significance having been achieved for the previous endpoints in the hierarchy. For example, for the primary endpoint mepolizumab will be compared to placebo at a one-sided α=0.02 (two-sided α=0.04). Significance will be declared if this test demonstrates statistical significance at the one-sided 2.0% level. The next endpoint in the hierarchy (i.e. the first key secondary endpoint) will be tested only if this test is significant at the one-sided 2.0% level. This will ensure the error rate for comparisons within this group is no greater than 2.0% (one-sided). This same step-down procedure will be applied to the treatment comparisons involving all subjects in the study with significance being declared if a test demonstrates statistical significance at the one-sided α=0.005 level (two-sided α=0.01), this will ensure the error rate for comparisons involving all subjects in the study is controlled at 0.5% (one-sided). Further details are given in Section The hierarchy of endpoints to be tested is as follows: 6. Frequency of moderate/severe exacerbations (primary endpoint) 7. Time to first moderate/severe exacerbation 8. Frequency of COPD exacerbations requiring emergency department (ED) visit and/or hospitalization. 9. Change from baseline mean total St. George s Respiratory Questionnaire-COPD (SGRQ-C) score 10. Change from baseline COPD assessment test (CAT) score 77

80 2013N183405_ Other Comparisons of Interest There are no other treatment comparisons of interest within this study Interim Analysis No formal interim analyses of efficacy data are planned for this study. The schedule of any planned interim safety analyses and the analysis plan for the IDMC review are described in the charter which is available upon request. Only members of the IDMC and the independent statistical centre responsible for preparing results for the IDMC will have access to unblinded randomisation codes and any interim safety results. The study statistician, investigators, and GSK personnel involved in monitoring of the study will not be unblinded until the study completes as planned or is terminated Meta-analysis Exacerbations requiring emergency department visits and/or hospitalization occur infrequently and therefore it is likely that there will be insufficient patients recruited within this study to appropriately assess whether there is a reduction in these events with mepolizumab. Therefore a pre-specified meta-analysis of subject level data from this study and from Study will be carried out once both studies have completed. Only data from the group of subjects with elevated eosinophils in this study will be included (study is being conducted in parallel to this study and only recruits subjects with elevated eosinophils). The primary endpoint for this meta-analysis will be the frequency of COPD exacerbations requiring an emergency department visit and/or hospitalisation, with the frequency of COPD exacerbations requiring hospitalisation as a secondary endpoint. Analysis of these endpoints will follow the methods described below for the primary endpoint, with an additional covariate of study. The primary comparison of this fixed effects meta-analysis will be of mepolizumab 100mg SC vs. placebo. Further details with regard to this pre-specified meta-analysis will be documented in a RAP which will be finalised prior to the unblinding of treatment codes in either study Key Elements of Analysis Plan The primary analyses of efficacy will be performed on the ITT-EE population. The primary endpoint will also be analysed for the PP-EE population. Additional efficacy analyses will be carried out for all subjects in the study and for subjects with no evidence of elevated eosinophils. Full details of all analysis methods to be used will be provided in the RAP. 78

81 2013N183405_ Primary Analyses The primary endpoint for the group of subjects with elevated eosinophils and for all subjects in this study is the frequency of moderate or severe exacerbations expressed as an exacerbation rate p.a. All exacerbations from the start of treatment until 4 weeks after the last dose of study medication will be included in the primary analysis. In addition the study is designed to continue collecting exacerbation data for up to 52 weeks after randomization for subjects who have withdrawn early from the study, all exacerbation data collected for these subjects will also be included in the primary analysis. Exacerbations which are separated by less than 7 days will be treated as a continuation of the same exacerbation. The numbers of moderate/severe exacerbations are assumed to follow a negative binomial distribution. The primary analysis of the rate of moderate/severe exacerbations will use a generalised linear model with a log-link function. This model will include covariates of smoking status (current vs never/ex-smoker), number of exacerbations in previous year (as an ordinal variable), baseline disease severity (as % predicted FEV 1 ) and geographic region with log e (time in study) as an offset variable. The primary analyses will be performed on the ITT-EE population with supporting analyses in the PP-EE population. Additional analyses will be carried out for all subjects in the study and for subjects with no evidence of elevated eosinophils. Full details of the analysis methods to be used will be provided in the RAP Efficacy Analyses Key Secondary Endpoints The time to the first moderate/severe exacerbation will be analysed using a Cox s proportional hazards model allowing for covariates of smoking status (current vs never/ex-smoker), number of exacerbations in previous year (as an ordinal variable), baseline disease severity (as % predicted FEV 1 ) and geographic region. Summaries and graphs of the Kaplan-Meier estimates of the proportion of subjects with a moderate/severe exacerbation over time will be produced. Exacerbations that resulted in an ED visit or hospitalization will be analysed using the same methods as for the primary endpoint. Change from baseline in the St. George s Respiratory Questionnaire-COPD (SGRQ-C) total score will be analysed using mixed model repeated measures adjusting for baseline SGRQ-C, smoking status, geographic region, visit by baseline SGRQ-C interaction and visit by treatment group interaction. Change from baseline in the COPD assessment test (CAT) score will be analysed using mixed model repeated measures adjusting for baseline CAT score, smoking status, geographic region, visit by baseline CAT score interaction and visit by treatment group interaction. 79

82 2013N183405_ Other Endpoints See Section for a list of all other endpoints. Full details of any analyses to be performed on these endpoints will be provided in the RAP Safety Analyses The ITT-EE and the ITT-nonEE population will be used for the analysis of safety data. Summaries of data will include data from scheduled assessments only, all data will be reported according to the nominal visit for which it was recorded (i.e. no visit windows will be applied). Data from unscheduled visits will be included in overall and any post-baseline summaries. Further details will be provided in the RAP Extent of Exposure The number of subjects administered investigational product, the number of treatments administered and the number of days over which treatment was administered will be summarised Adverse Events Adverse Events (AEs) will be coded using the standard GlaxoSmithKline Medical Dictionary for Regulatory Activities (MedDRA) and will be grouped by system organ class. AEs will be summarised by frequency and percentage of subjects, by system organ class and preferred term within each treatment group. Separate summaries will be presented for all AEs, drug-related AEs, serious AEs (SAEs), AE s leading to permanent discontinuation of IP or withdrawal from study and for any AEs of special interest Clinical Laboratory Evaluations Haematology (including blood eosinophils) and clinical chemistry data will be summarized at each scheduled assessment. The proportion of values outside of the normal reference range and those meeting the criteria for potential clinical significance will also be summarised. Further details will be provided in the RAP Other Safety Measures Actual values and change from baseline for other scheduled safety assessments such as vital signs (pulse rate, systolic and diastolic blood pressure), 12-lead ECG parameters (QTcF, QTcB and heart rate) will be summarized at each scheduled visit. Further details will be provided in the RAP Immunogenicity Immunogenicity data will be summarised using appropriate descriptive statistics. 80

83 2013N183405_ Health Outcomes Analyses Full details of the analyses to be performed on all health outcomes endpoints will be given in the RAP Pharmacokinetic Analyses Blood samples will be collected to determine mepolizumab plasma concentrations as Visits specified in the Time and Events Table (Table 2). Sparse blood sampling is being implemented in this study. The mepolizumab plasma concentrations from this study will be evaluated using the population PK model developed based on previous mepolizumab data collected during mepolizumab clinical development. The analysis will be conducted using for example NONMEM 7 and will allow the determination for example of the population and/or individual systemic exposure, volume of distribution and clearance as well as characterise the between- and within subject variability. The effect of subjects characteristics such as, for example, body weight, age, sex, serum creatinine on mepolizumab systemic exposure will also be explored in order to explain the inter-subject variability in drug exposure. Pharmacokinetic data will be presented in graphical and/or tabular form and will be summarized descriptively. No statistical analysis of PK data will be carried out Pharmacodynamic Analyses Blood eosinophils ratio to baseline will be analysed using mixed model repeated measures adjusting for baseline, smoking status, geographic region, visit by baseline interaction and visit by treatment group interaction Values below the lower limit of quantification will be imputed as half the lower limit of quantification prior to analysis. Data will be log-transformed prior to analysis Pharmacokinetic/Pharmacodynamic Analyses If deemed appropriate, details of any PK/PD analyses to be performed will be given in the RAP Pharmacogenetic Analyses See Appendix 5 for details of Pharmacogenetics Analyses Novel Biomarker(s) Analyses The results of these biomarker investigations will be reported separately from the main clinical study report. All endpoints of interest from all comparisons will be descriptively and/or graphically summarised as appropriate to the data. 81

84 2013N183405_ 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 Regulatory and Ethical Considerations, Including the Informed Consent Process Prior to initiation of a study site, GSK will obtain favourable opinion/approval from the appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical Practice (GCP) and applicable country-specific regulatory requirements. The study will be conducted in accordance with all applicable regulatory requirements. The study will be conducted in accordance with ICH GCP, all applicable subject privacy requirements, and the ethical principles that are outlined in the Declaration of Helsinki 2008, including, but not limited to: Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and favourable opinion/approval of study protocol and any subsequent amendments. Subject informed consent. Investigator reporting requirements. GSK will provide full details of the above procedures, either verbally, in writing, or both. Written informed consent must be obtained from each subject prior to participation in the study. 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 5 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 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 82

85 2013N183405_ 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 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 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 noncompliance. 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. 83

86 2013N183405_ 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 Provision of Study Results to Investigators, Posting of Information on Publicly Available Clinical Trials Registers and Publication Where required by applicable regulatory requirements, an investigator signatory will be identified for the approval of the clinical study report. The investigator will be provided reasonable access to statistical tables, figures, and relevant reports and will have the opportunity to review the complete study results at a GSK site or other mutuallyagreeable location. GSK will also provide the investigator with the full summary of the study results. The investigator is encouraged to share the summary results with the study subjects, as appropriate. GSK will provide the investigator with the randomization codes for their site only after completion of the full statistical analysis. 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 84

87 2013N183405_ 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 Independent Data Monitoring Committee (IDMC) An IDMC will be utilised in this study to ensure external objective medical and/or statistical review of safety and/or efficacy issues in order to protect the ethical and safety interests of subjects and to protect the scientific validity of the study. The schedule of any planned interim analysis and the analysis plan for IDMC review is described in the charter, which is available upon request Adjudication Committee An adjudication committee will be established to independently review safety outcomes as further defined in the charter which is available upon request. The committee members will remain blinded to treatment. 85

88 2013N183405_ REFERENCES Bafadhel M,McKenna S, Terry S,Mistry V, Reid C, Haldar P, McCormick, M, Haldar K, Kebadze T, Duvoix A, et al. Acute exacerbations of COPD: identification of biological clusters and their biomarkers. Am J Respir Crit Care Med 2011;184: Bafadhel M., McCormick M., et al. Profiling of sputum inflammatory mediators in asthma and chronic obstructive pulmonary disease. Respiration (1): Bafadhel M., McKenna S., Terry S., Mistry V., Pancholi M., Venge P., Lomas D.A., Barer M.R., Johnston S.L., Pavord I.D., Brightling C.E. Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: A randomized placebo-controlled trial. Am J Resp Crit Care Med :1 (48-55) Brightling C.E., McKenna S., Hargadon B., Birring S., Green R., Siva R., Berry M., Parker D., Monteiro W., Pavord I., Bradding P. Sputum eosinophilia and the short term response to inhaled mometasone in chronic obstructive pulmonary disease. Thorax 2005; 60: Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004;23: Connors, A. F., Dawson, N. V., et al. Outcomes following acute exacerbation of severe chronic obstructive lung disease. The SUPPORT investigators (Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments). Am J Respir Crit Care Med (4 Pt 1): Dmitrienko A., Tamhane AC., Wiens BL., General Multistage Gatekeeping Procedures. Biom 2008: 50 (5): Donaldson G. C., Seemungal T.A., Bhowmik A., Wedzicha J.A et al. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax (10): Eltboli, O., Brightling, C.E., Eosinophils as diagnostic tools in chronic lung disease. Expert Rev Respir Med (1): Gevaert P, Lang-Loidolt D, Lackner A, et al. Nasal IL-5 levels determine the response to anti-il-5 treatment in patients with nasal polyps. J Allergy Clin Immunol. 2006; 118: GlaxoSmithKline Document Number CM2003/00010/08 Compound ID SB Investigator s Brochure for Mepolizumab. Report Date 08-APR GOLD. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease.Revised 2013:

89 2013N183405_ Green, R. H., C. E. Brightling, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet (9347): Hankinson JL, Kawut SM, Shahar E, Smith LJ, MD, Hinckley Stukovsky K, and Barr RG. Performance of American Thoracic Society-Recommended Spirometry Reference Values in a Multiethnic Sample of Adults: The Multi-ethnic Study of Antherosclerosis (MESA) Lung Study. Chest, 2010;137: 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: James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. Pharmacokinetics of Acetaminophen-Protein Adducts in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37(8): Jones, P., Harding, G., Berry, P., Wiklund, I., Chen, W-H., Leidy, N. Development and first validation of the COPD Assessment Test (CAT) Eur Respir J : Jones, P., Harding, G., Wiklund, I., Berry, P., Tabberer, M., Yu, R., Leidy, N. Tests of the Responsiveness of the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) Following Acute Exacerbation and Pulmonary Rehabilitation. Chest Keene ON, Jones MRK, Lane PW, Anderson J. Analysis of exacerbation rates in asthma and chronic obstructive pulmonary disease: example from the Tristan study. Pharmaceut. Statist. 2007; 6:89-87 Kim YJ, Prussin C, Martin B, et al. Rebound eosinophilia after treatment of hypereosinophilic syndrome and eosinophilic gastroenteritis with monoclonal anti IL-5 antibody SCH J Allergy Clin Immunol (6): LeGal 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): Meguro M, Barley EA, Spencer S et al. Development and validation of an improved COPD-Specific Version of the St. George Respiratory Questionnaire. Chest : Miller MR, Hankinson J, Odencrantz J, Standardisation of spirometry. Eur Respir J. 2005; 26: Saha S., Brightling CE. Eosinophilic airway inflammation in COPD. Int J Chron Obstruct Pulmon Dis 2006;1: Sampson HA., Munoz-Furlong A., Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: summary-report Second National Institute of 87

90 2013N183405_ Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy and Clin. Immunol 2006; 117: Seemunga, T. A., Donaldson G.C., et al. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med (5 Pt 1): Siva, R., R. H. Green, et al. Eosinophilic airway inflammation and exacerbations of COPD: a randomised controlled trial. Eur Respir J (5): Soler-Cataluña J.J., Martínez-García M.Á., Román Sánchez P., Salcedo E., Navarro M., Ochando R. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax :11 ( ) Toy, E. L., K. F. Gallagher, et al. The economic impact of exacerbations of chronic obstructive pulmonary disease and exacerbation definition: a review. COPD (3): World Health Organization, (2008). "Global burden of disease." World Health Report

91 2013N183405_ APPENDICES Appendix 1: Acceptable Birth Control To be eligible for entry into the study, females of childbearing potential (FCBP) must commit to consistent and correct use of an acceptable method of birth control from the time of consent, for the duration of the trial, and for 4 months after the last study drug administration. Male partner who is sterile prior to the female subject s entry into the study and is the sole sexual partner for that female subject Abstinence from penile-vaginal intercourse Implants of levonorgestrel or etonogestrel Injectable progestogen Oral contraceptive (either combined or progestogen alone) Estrogenic vaginal ring Percutaneous contraceptive patches Any intrauterine device (IUD) with a documented failure rate of less than 1% per year. Male condom combined with a vaginal spermicide (foam, gel, film, cream, or suppository) Male condom combined with a female diaphragm, either with or without a vaginal spermicide (foam, gel, film, cream, or suppository) Females of childbearing potential are defined as females with functioning ovaries (i.e., post-menarche, premenopausal women with no documented impairment of oviductal or uterine function that would cause sterility). This category includes females with oligomenorrhea, females who are peri-menopausal, and young females who have begun to menstruate (adolescents). The information on the lack of impairment of oviductal or uterine function that would cause sterility can come from the site personnel s: Review of subject s medical records Medical examination of the subject Interview with the subject on her medical history. Females of non-childbearing potential are defined as females with functioning ovaries and with a documented tubal ligation or hysterectomy; or females who are postmenopausal defined as 12 months of spontaneous amenorrhea with an appropriate clinical profile, e.g. age appropriate, >45 years, in the absence of hormone replacement therapy (HRT). In questionable cases a blood sample for follicle stimulating hormone (FSH) and estradiol will be obtained and analyzed to confirm childbearing potential. 89

92 2013N183405_ Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods listed above for females of childbearing potential if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks should elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method. Based on the absence of an identified reproductive hazard from preclinical studies, absence of a genotoxic potential, and very low levels of mepolizumab that might be present in semen, there is no recognized risk for mepolizumab to affect human sperm or the fetus if transferred to a female partner via semen. Therefore, the use of condoms or other methods of contraception in the male study subject is not required. 90

93 2013N183405_ Appendix 2: ECG Exclusion Criteria for Screening and Pre- Dose Randomization An abnormal and clinically significant finding that would preclude a subject from entering the trial is defined as a 12-lead tracing that is interpreted as, but not limited to, any of the following: Sinus tachycardia 120bpm *Note: sinus tachycardia 110bpm should be confirmed by two additional readings at least 5 minutes apart Multifocal atrial tachycardia (wandering atrial pacemaker with rate >120bpm) Junctional tachycardia (heart rate >100bpm) Sustained supraventricular tachycardia (>100bpm) Ventricular tachycardias (sustained, non-sustained (>3 up to 30 sec), polymorphic, or monomorphic) Atrial fibrillation with rapid ventricular response (rate >120bpm) Atrial flutter with rapid ventricular response (rate >120bpm) Ventricular flutter Ventricular fibrillation Torsades de Pointes Wide QRS tachycardia (diagnosis unknown) Evidence of Mobitz type II second degree or third degree atrioventricular (AV) block AV dissociation Trifascicular block QT >600msec For subjects with a QRS interval <120msec: QTc(F) 450msec or an ECG that is unsuitable for QT measurements (e.g., poor defined termination of the T wave). For subjects with a QRS interval 120msec: QTc(F) 480msec or an ECG that is unsuitable for QT measurements (e.g., poor defined termination of the T wave). *Note: All potentially exclusionary QTC prolongations should be confirmed by two additional readings at least 5 minutes apart. Myocardial infarction (acute or recent) *Note: Evidence of an old (resolved) myocardial infarction is not exclusionary. 91

94 2013N183405_ Appendix 3: Hepatitis B screening and monitoring Guidance on Hepatitis B Screening & Monitoring (Mepolizumab COPD program) Screen (all subjects) HBsAg HBsAg (negative) HBsAg (positive) HBcAb (-) HBcAb(+) HBV-DNA HBcAb(-) or (+) HBV-DNA Enroll with normal monitoring per protocol* > 2,000 IU/mL Do NOT enroll < 2,000 IU/mL < 2,000 IU/mL Enroll with Monitoring: Liver function testing*: Monthly Continue for at least 12 weeks after end of treatment > 2,000 IU/mL Do NOT enroll Discontinue from IP & evaluate need for nucleoside analogues DNA > 1 log increase and > 2,000 IU/mL * If ALT > 3X ULN, test HBV-DNA, then follow algorithm above 92

95 2013N183405_ Appendix 4: ECG Premature Discontinuation from IP Criteria An ECG finding that would result in subject premature discontinuation from IP postrandomization is defined as a 12-lead tracing that is interpreted as, but not limited to, any of the following: Increase in QTc (F) >60msec from baseline ECG Ventricular tachycardias (sustained, polymorphic, or monomorphic) Ventricular flutter Ventricular fibrillation Torsades de Pointes Wide QRS tachycardia (diagnosis unknown) Uncorrected QT >600msec For subjects with a QRS interval <120msec: QTc(F) 500msec or an ECG that is unsuitable for QT measurements (e.g., poor defined termination of the T wave). For subjects with QRS interval 120msec: QTc(F) 530msec or an ECG that is unsuitable for QT measurements (e.g., poor defined termination of the T wave). *Note: All potentially exclusionary QTC prolongations should be confirmed by two additional readings at least 5 minutes apart. Myocardial infarction (acute or recent) *Note: Evidence of an old (resolved) myocardial infarction is not exclusionary. 93

96 2013N183405_ Appendix 5: 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 Abacavir HIV HLA-B* [Hetherington, 2002; 57:01 Mallal, 2002; (Human Mallal, 2008] Leukocyte Antigen B) Carbama zepine Seizure, Bipolar disorders & Analgesia Chung, 2010; Ferrell, 2008 HLA- B*15:02 Outcome 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*57:01 screening should supplement but must never replace clinical risk management strategies for abacavir hypersensitivity. Independent studies indicated that patients of East Asian ancestry who carry HLA-B*57:02 are 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*57:02 prior to initiating treatment with carbamazepine. 94

97 2013N183405_ Drug Disease Gene Variant Irinotecan Cancer [Innocenti, UGT1A1* ; Liu, 2008; Schulz, 2009] Outcome Variations in the UGT1A1 gene can influence a patient s ability to break down irinotecan, which can lead to increased blood levels of the drug and a higher risk of side effects. A dose of irinotecan that is safe for one patient with a particular UGT1A1 gene variation might be too high for another patient without this variation, raising the risk of certain side-effects, that include neutropenia following initiation of Irinotecan treatment. The irinotecan drug label indicates that individuals who have two copies of the UGT1A1*28 variant are at increased risk of neutropenia. A genetic blood test is available that can detect variations in the gene. A key component to successful PGx research is the collection of samples during the conduct of clinical studies. Collection of whole blood samples, even when no a priori hypothesis has been identified, may enable PGx analysis to be conducted if at any time it appears that there is a potential unexpected or unexplained variation in response to mepolizumab. 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 mepolizumab. If at any time it appears there is potential variability in response in this clinical study or in a series of clinical studies with mepolizumab, the following objectives may be investigated the relationship between genetic variants and study treatment with respect to: 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. 95

98 2013N183405_ 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 Blood samples can be taken for Deoxyribonucleic acid (DNA) extraction and used in PGx assessments. In addition to any blood samples taken for the clinical study, a whole blood sample (~6 ml) will be collected for the PGx research using a tube containing EDTA. It is recommended that the blood sample be taken at the first opportunity after a subject has been randomized (Visit 2) and provided informed consent for PGx research, but may be taken at any time while the subject is participating in the clinical study. 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 blood sample is taken on a single occasion unless a duplicate sample is required due to inability to utilize the original sample. The DNA extracted from the blood 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 mepolizumab 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 mepolizumab. Samples will be stored securely and may be kept for up to 15 years after the last subject completes the study or GSK may destroy the samples sooner. GSK or those working with GSK (for example, other researchers) will use samples collected from the study for the purpose stated in this protocol and in the informed consent form. Subjects can request their sample to be destroyed at any time. Subject Withdrawal from Study If a subject who has consented to participate in PGx research 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, 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 96

99 2013N183405_ 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 blood sample for PGx research has been collected and it is determined that the subject does not meet the entry criteria for participation in the clinical study, then the investigator should instruct the participant that their PGx sample will be destroyed. No forms are required to complete this process as it will be completed as part of the consent and sample reconciliation process. In this instance a sample destruction form will not be available to include in the site files. Pharmacogenetics Analyses Specific genes may be studied that encode the drug targets, or drug mechanism of action pathways, drug metabolizing enzymes, drug transporters or which may underpin adverse events, disease risk or drug response. These candidate genes may include a common set of ADME (Absorption, Distribution, Metabolism and Excretion) genes that are studied to determine the relationship between gene variants or treatment response and/or tolerance. In addition, continuing research may identify other enzymes, transporters, proteins or receptors that may be involved in response to mepolizumab treatment. The genes that may code for these proteins may also be studied. Genome-wide scans involving a large number of polymorphic markers (e.g., single nucleotide polymorphisms) at defined locations in the genome, often correlated with a candidate gene, may be studied to determine the relationship between genetic variants and treatment response or tolerance. This approach is often employed when a definitive candidate gene(s) does not exist and/or the potential genetic effects are not well understood. If applicable and PGx research is conducted, appropriate statistical analysis methods will be used to evaluate pharmacogenetic data in the context of the other clinical data. Results of PGx investigations will be reported either as part of the main clinical study report or as a separate report. Endpoints of interest from all comparisons will be descriptively and/or graphically 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 blood being taken for PGx research. Provision of Study Results and Confidentiality of Subject s PGx Data 97

100 2013N183405_ 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 antiepilepticinduced skin reactions. Expert Opin. Drug Saf. 2010; 9: Ferrell PB, McLeod HL. Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations. Pharmacogenomics. 2008; 9: 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: 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 UDPglucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 2004; 22: 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: 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: 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; 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:

101 2013N183405_ Appendix 6: Country Specific Requirements 99

102 2013N183405_ Appendix 7: Liver Chemistry Stopping and Follow-up Criteria Phase III-IV Liver Safety Algorithms Continue IP No Obtain twice Yes ALT<3xULN Notify GSK within 24h monthly liver Able to + bilirubin to discuss subject chemistries until monitor ALT>3xULN <2xULN safety; continue IP; Yes No normalised or weekly for after 4 check liver chemistry back to baseline 4 weeks? wks? weekly for 4 weeks Yes values Yes plus No ALT>3xULN bilirubin >2x ALT >5 ULN (>35% Able to but <5xULN + ALT and direct) (or plus No Hepatitis monitor bilirubin No ALT No >5xULN Yes <8xULN No INR >1.5, if symptoms Yes weekly for <2xULN+no >8xULN but for > 2 symptoms measured)* or rash? > 2 wks? <8xULN wks No** Yes No Yes Instruct subject to stop investigational product (IP) Yes Yes Notify GSK within 24h and arrange clinical followup Instruct subject to stop investigational product (IP) within 24-72h Notify GSK and arrange clinical followup within 24h Perform liver chemistries and liver event follow up Perform liver chemistries and liver event follow up assessments (serology, PK sample etc as in protocol) assessments (serology, PK sample etc as in protocol) Complete liver event CRF, SAE data collection tool if Report as SAE (excl. hepatic impairment or cirrhosis appropriate, and liver imaging and/or biopsy CRFs if studies) and complete liver event CRF, SAE data collection tool, and liver imaging and/or biopsy CRFs if tests performed. tests performed. Obtain weekly liver chemistries [**as far as possible in Obtain twice weekly liver chemistries until resolved, these subjects] until resolved, stabilised or returned to stabilised or returned to baseline values baseline Consultation with hepatologist/specialist recommended Withdraw subject from study after monitoring Withdraw subject from study after monitoring complete unless protocol has option to restart drug complete unless protocol has option to restart drug *INR value not applicable to subjects on anticoagulants 100

103 2013N183405_ Appendix 8: Anaphylaxis Criteria Hypersensitivity reactions will be monitored using the diagnostic criteria for anaphylaxis as outlined by the Joint NIAID/FAAN Second Symposium on Anaphylaxis [Sampson, 2006]. The criteria do not make a distinction based on underlying mechanism. These criteria are summarized as follows: 1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lipstongue-uvula), and at least one of the following: a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia) b. Reduced BP or associated symptoms of end-organ dysfunction (e.g., hypotonia [collapse], syncope, incontinence) 2. Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours): a. Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen lips-tongue-uvula) b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia) c. Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, incontinence) d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 3. Reduced BP after exposure to known allergen for that patient (minutes to several hours): a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in systolic BP b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that person s baseline 101

104 2013N183405_02 The GlaxoSmithKline group of companies TITLE PAGE Division: Worldwide Development Information Type: Protocol Amendment Title: Study : Mepolizumab vs. Placebo as add-on treatment for frequently exacerbating COPD patients Compound Number: SB Effective Date: 05-MAR-2014 Protocol Amendment Number: 02 Subject: Infection, Quality of Life Author: PPD Revision Chronology: 2013N183405_ DEC-03 Original 2013N183405_ DEC-20 Amendment No 01: Section 5.1 updated to reflect that Investigational Product will be administered by a single subcutaneous injection. 2013N183405_ MAR-05 Amendment No.: 02 Removal of SF-36 health outcomes endpoint; removal of ECG at Visit 2; update of ECG exclusion and discontinuation criteria; addition of adverse event causality assessment guidance language; update of chest x-ray randomization criterion for Germany; wording edited for consistency and clarification of statements in multiple sections Copyright 2014 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited. 1

105 PPD

106 2013N183405_02 SPONSOR INFORMATION PAGE Clinical Study Identifier: Sponsor Legal Registered Address: GlaxoSmithKline Research & Development Limited 980 Great West Road Brentford Middlesex, TW8 9GS UK Sponsor Contact Address: GlaxoSmithKline Research & Development Limited Five Moore Drive P.O Research Triangle Park, NC , USA PPD Telephone: GlaxoSmithKline Research & Development Limited Iron Bridge Road Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK PPD Telephone: In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate company (or designee). Where applicable, the details of the Sponsor and contact person will be provided to the relevant regulatory authority as part of the clinical trial submission. Sponsor Global Medical Monitor Contact Information: PPD MD (Medical Monitor, Respiratory Research and Development) PPD Tel: PPD Mobile: Sponsor Back-up Global Medical Monitor Contact Information: PPD MD (Director, Respiratory Research and Development) PPD Tel: PPD Mobile: Sponsor Serious Adverse Events (SAE) Co-ordinator: PPD MD (Director, Respiratory Research and Development) PPD Tel: PPD Mobile: Regulatory Agency Identifying Number(s): IND No EudraCT number:

107 2013N183405_02 INVESTIGATOR PROTOCOL AGREEMENT PAGE For protocol number I confirm agreement to conduct the study in compliance with the protocol, as amended by this protocol amendment. I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or supervise the described clinical study. I agree to ensure that all associates, colleagues and employees assisting in the conduct of the study are informed about their obligations. Mechanisms are in place to ensure that site staff receives the appropriate information throughout the study. Investigator Name: Investigator Signature Date 4

108 2013N183405_02 TABLE OF CONTENTS PAGE LIST OF ABBREVIATIONS INTRODUCTION Background Rationale Benefit:Risk Assessment Risk Assessment Benefit Assessment Overall Benefit:Risk Conclusion OBJECTIVE(S) INVESTIGATIONAL PLAN Study Design Schema Study Design Discussion of Design Dose Rationale SUBJECT SELECTION AND WITHDRAWAL CRITERIA Number of Subjects Eligibility Criteria Inclusion Criteria Exclusion Criteria Randomization Criteria Pre-Screening/Screening/Run-in Failures Investigational Product (IP) Discontinuation Criteria Protocol defined Stopping IP Criteria Permanent Discontinuation from IP Withdrawal Criteria Withdrawal from Study Study Withdrawal assessments Lost to Follow-up Reasons for Study Withdrawal Follow up Visit STUDY TREATMENTS Investigational Product and Other Study Treatment Treatment Assignment Blinding Product Accountability Treatment Compliance Concomitant Medications and Non-Drug Therapies Permitted Medications and Non-Drug Therapies Prohibited Medications and Non-Drug Therapies Treatment after the End of the Study Treatment of Study Treatment Overdose STUDY ASSESSMENTS AND PROCEDURES

109 2013N183405_ Critical Baseline Assessments Pre-screening Visit Critical Procedures Performed at Visit 1 (Screening) Modified Medical Research Council Grading System (mmrc) Charlson Co-morbidity index (CCI) Definition of child bearing and non-child bearing potential Critical Procedures Performed at Visit 2 (Randomization) Efficacy Primary Efficacy Endpoint Secondary Efficacy Endpoints Other Efficacy Endpoints Spirometry and Bronchodilator Responsiveness Testing Spirometry Bronchodilator Responsiveness Testing Diary Assessment Moderate and Severe COPD Exacerbations Symptom Defined COPD Exacerbations Exacerbation Treatment St. George's Respiratory Questionnaire for COPD patients EQ-5D-5L COPD Assessment Test Safety Safety assessment and endpoints Hepatitis B screening and monitoring Liver chemistry stopping and follow up criteria Adverse Events Definition of an AE Definition of an SAE Sentinel Events Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs Cardiovascular Events Death Events Pregnancy Time Period and Frequency of Detecting AEs and SAEs Method of Detecting AEs and SAEs Prompt Reporting of Serious Adverse Events and Other Events to GSK Regulatory reporting requirements for SAEs Other Safety Outcomes Laboratory Assessments Physical Exam Vital Signs Medical Problems and Concomitant Medications Lead ECG Pneumonia Health Outcomes Health Outcome Assessments Not Included as Primary or Key Secondary Endpoints

110 2013N183405_ Healthcare Resource Utilization Additional Health Outcomes Assessments Rating of Activity Limitation and Impression of Change Clinician/Subject Rated Response to Therapy Pharmacokinetics/Pharmacodynamics/Biomarker(s) Pharmacodynamics Immunogenicity Pharmacogenetic Research Novel Biomarkers DATA MANAGEMENT DATA ANALYSIS AND STATISTICAL CONSIDERATIONS Hypotheses Study Design Considerations Sample Size Assumptions Sample Size Sensitivity Sample Size Re-estimation Data Analysis Considerations Analysis Populations Analysis Data Sets Treatment Comparisons Primary Comparisons of Interest Other Comparisons of Interest Interim Analysis Meta-analysis Key Elements of Analysis Plan Primary Analyses Efficacy Analyses Key Secondary Endpoints Other Endpoints Safety Analyses Extent of Exposure Adverse Events Clinical Laboratory Evaluations Other Safety Measures Immunogenicity Health Outcomes Analyses Pharmacokinetic Analyses Pharmacodynamic Analyses Pharmacokinetic/Pharmacodynamic Analyses Pharmacogenetic Analyses Novel Biomarker(s) Analyses STUDY CONDUCT CONSIDERATIONS Posting of Information on Publicly Available Clinical Trial Registers Regulatory and Ethical Considerations, Including the Informed Consent Process Quality Control (Study Monitoring) Quality Assurance Study and Site Closure

111 2013N183405_ Records Retention Provision of Study Results to Investigators, Posting of Information on Publicly Available Clinical Trials Registers and Publication Independent Data Monitoring Committee (IDMC) Adjudication Committee REFERENCES APPENDICES Appendix 1: Acceptable Birth Control Appendix 2: ECG Exclusion Criteria for Screening and Pre-Dose Randomization Appendix 3: Hepatitis B screening and monitoring Appendix 4: ECG Premature Discontinuation from IP Criteria Appendix 5: Pharmacogenetic Research Appendix 6: Country Specific Requirements Appendix 7: Liver Chemistry Stopping and Follow-up Criteria Appendix 8: Anaphylaxis Criteria Appendix 9: Protocol Changes

112 2013N183405_02 LIST OF ABBREVIATIONS ADA AE ALT ASE AST ATS BiPAP BMI CAT COPD CPK CT scan CPAP CRF CV ECG ecrf ED ediary EGPA FAAN FCBP FEV 1 FSH FVC GCP GCSP GSK HRT IB ICF ICH ICS IDMC IEC IL IM INR IP IRB ITT IV IVRS IU LABA LAMA Anti-drug antibody Adverse Event Alanine aminotransferase All subjects enrolled population Aspartate aminotransferase American Thoracic Society Bilevel positive airway pressure Body mass index COPD Assessment Test Chronic Obstructive Pulmonary Disease Creatine phosphokinase Computerized Tomography Continuous positive airway pressure Case Report Form Cardiovascular Electrocardiography Electronic case report form Emergency department Electronic diary Eosinophilic Granulomatosis with Polyangitis Food Allergy and Anaphylaxis Network Female of child bearing potential Forced expiratory volume in one second Follicle stimulating hormone Forced vital capacity Good Clinical Practice GSK's global clinical safety and pharmacovigilance group GlaxoSmithKline Hormone replacement therapy Investigator's Brochure Informed consent form International Conference on Harmonisation Inhaled corticosteroid Independent Data Monitoring Committee Independent ethics committee Interleukin Intramuscular International normalized ratio Investigational Product Institutional research board Intent to treat Intravenous Interactive Voice Response System International Units Long acting beta 2 -agonist Long acting muscarinic anatagonist 9

113 2013N183405_02 LDH LFT LRTI LTOT MAOIs MDI MedRA MSDS NAB NHANES NIAID NK NYHA OCS PK PD PGx PP prn QTcF RAP SABA SAMA SC SGRQ-C SAE SoC SOC SPM ULN URTI Lactate dehydrogenase Liver function testing Lower Respiratory Tract Infection Long term oxygen therapy Monoamine oxidase inhibitors Metered dose inhaler Medical Dictionary for Regulatory Activities Materials Safety Data Sheet Neutralizing Antibody National Health and Nutrition Examination Survey National Institute of Allergy and Infectious Disease Natural Killer New York Heart Association Oral corticosteroid Pharmacokinetic Pharmacodynamic Pharmacogenetics Per protocol As needed QT interval corrected with Fridericia's formulas Reporting and analysis plan Short acting beta 2 -agonist Short acting muscarinic antagonist Subcutaneous St. George's Respiratory Questionnaire for COPD patients Serious Adverse Event Standard of Care System Organ Class Study Procedures Manual Upper limit of normal Upper respiratory tract infection Trademark Information Trademarks of the GlaxoSmithKline group of companies NONE Trademarks not owned by the GlaxoSmithKline group of companies NONMEM Xolair 10

114 2013N183405_02 PROTOCOL SUMMARY Rationale While Chronic Obstructive Pulmonary Disease (COPD) is generally viewed as a disease driven by neutrophilic inflammation up to 40% of COPD patients have an inflammatory pattern that includes elevated sputum eosinophils [Brightling, 2005; Saha, 2006]. In severe COPD patients, sputum eosinophils and interleukin 5 (IL-5) levels are elevated to similar levels as those seen in severe asthmatics [Bafadhel, 2012]. Notably, COPD patients with eosinophilic inflammation cannot be distinguished based on clinical features and lung function from those without eosinophilic inflammation [Saha, 2006]. COPD exacerbations are characterized by periods of acute worsening of symptoms, deterioration in lung function, and decreased health-related quality of life [Seemunga, 1998; Connors, 1996; Donaldson, 2002] and potentially contribute to further permanent decline in lung function. Recent studies identified that increased eosinophilic airway inflammation occurs during COPD exacerbations [Bafadhel, 2012] and that peripheral eosinophils levels were used successfully as a surrogate to predict response to corticosteroid therapy [Bafadhel, 2012]. While further research is required experience in the clinic suggests that management of exacerbations could possibly be tailored by phenotype-specific management. A study by Siva et al [Siva, 2007] showed that a treatment strategy that aimed to reduce sputum eosinophils in COPD showed a significant reduction in severe exacerbations compared to a treatment strategy towards optimizing symptoms alone. Based on the identification of a COPD subgroup of frequent exacerbators with elevated eosinophils and IL-5 levels and the finding from the severe asthma study MEA post-hoc analysis of mepolizumab in COPD-like patients (based on age, FEV1/FVC ratio, and lack of reversibility) there is reason to believe that mepolizumab will reduce IL-5 and eosinophils in a well-defined COPD population. The study target population consists of a population who despite a history of use of optimal standard of care therapy continue to be at risk for future exacerbation and is further defined by study eligibility criteria. Based on extrapolation of the efficacy findings in severe asthma and the similarities between the severe asthma and severe COPD patients in terms of eosinophils and IL-5 levels it is hypothesized that the reduction of eosinophils with mepolizumab in COPD patients would translate into a reduction of COPD exacerbations. Mepolizumab is a fully humanized IgG antibody (IgG1, kappa) which binds to and inhibits the ability of IL-5 to bind to the IL-5 receptor. IL-5 receptors are primarily expressed on eosinophils. IL-5, through binding to the IL-5 receptor is a major regulator of eosinophils resulting in accumulation in tissues and modulation of eosinophil behavior at every stage from maturation to survival. Mepolizumab reduces eosinophils in the periphery and in tissues. Data from study MEA demonstrate that responders to mepolizumab with severe asthma (i.e. subjects with a reduction in exacerbation rate despite treatment with corticosteroids) had a baseline blood eosinophil count of at least150 cells/l or a historical blood eosinophil count of at least 300 cells/μl. Accordingly, these thresholds 11

115 2013N183405_02 for blood eosinophil counts will be used to operationally define a group of subjects as eosinophilic. This study will determine the reduction in exacerbations in subjects who are above and below the baseline blood eosinophil count of at least 150 cells/l ensuring that the hypothesis bridges from asthma to COPD. Objective(s) Primary Objective To evaluate the efficacy and safety of mepolizumab 100 mg subcutaneous (SC) given every 4 weeks compared to placebo on the frequency of moderate and severe exacerbations in COPD subjects at high risk of exacerbations despite the use of optimized standard of care background therapy. Secondary Objective To evaluate other efficacy assessments of mepolizumab 100 mg subcutaneous (SC) compared to placebo on changes in health care utilization, COPD symptoms, quality of life, and lung function. Study Design This is a multi-center, randomized, placebo-controlled, double-blind, parallel group trial evaluating mepolizumab 100 mg against placebo given every 4 weeks through subcutaneous (SC) injection. The target global enrolment is approximately 800 randomized subjects. The total duration of subject participation will be approximately 62 weeks, consisting of a 1 to 2 week screening period, 52-week treatment period and 8- week follow-up period. Subjects will initially participate in a pre-screening visit (Visit 0) where the details about the study and procedures will be explained through the informed consent process. Subjects who meet all inclusion criteria and none of the exclusion criteria at Visit 1 will enter a 1 to 2 week screening period during which time subjects will remain on a stable dose of their current COPD therapy. Laboratory assessments will be collected at Visit 1 and will include a hematology assessment for determination of baseline eosinophil level. The site must receive the results of the Visit 1 laboratory assessments and other assessments prior to the determination of eligibility at Visit 2. Baseline subject reported electronic diary (ediary) data will be captured during the screening period and subjects must meet the ediary compliance requirement to be eligible for randomization. Subjects must understand and agree to completion of the ediary on a daily basis in the morning to be considered for this study. Site personnel must train subjects on the proper use of the ediary at Visit 1. The ediary will capture daily COPD symptoms, rescue medication use, and activity level, as well as patient reported outcomes and this information will be transmitted daily. Sites will have real time access to subject symptom data. 12

116 2013N183405_02 Study inclusion criteria require a history of regular use of at least one triple COPD standard of care (SoC) option (as defined in inclusion criteria) for at least 12 months prior to screening. In addition, for at least 3 months prior to screening, each subject must have a history of use of a specific inhaled triple SoC regimen (ICS + long acting beta 2 -agonist (LABA) + long acting muscarinic antagonist (LAMA)). Subjects are also required to have a history of at least 2 moderate or 1 severe exacerbation in the 12 months prior to Visit 1 and one of the exacerbations had to have occurred while treated with ICS + LABA + LAMA. All subjects will continue on their baseline optimized SoC COPD medications throughout the entire duration of the study regardless of treatment arm assignment. If for medical reason the subject must change their baseline SoC COPD medication the primary investigator should discuss with the GSK medical monitor. Eligible subjects will be randomized 1:1 to mepolizumab 100 mg or placebo. Randomization will be stratified based on baseline eosinophil levels. Investigational Product (IP) will be administered as one SC injection given every 4 weeks. The first dose will be administered at Visit 2 (Week 0) and the last dose administered at Week 48 (Visit 14). For those subjects randomized to mepolizumab, 13 doses will provide therapeutic coverage for 52 weeks (4 weeks following the last dose). The Exit Visit (Visit 15, Week 52) will occur 4 weeks after last administration of study treatment. Study treatment will not be administered at this visit. The primary efficacy endpoint will be evaluated from Visit 2 (Week 0) to Visit 15 (Week 52). All subjects will be requested to return for a Follow-up Visit (Visit 16) approximately 12 weeks after their last dose of investigational product (and approximately 8 weeks after Visit 15) to conduct safety assessments and collect an immunogenicity sample. An adjudication committee and an independent data monitoring committee (IDMC) will be utilized in this study to ensure external objective medical and statistical review of safety issues in order to protect the ethical and safety interests of subjects and to protect the scientific validity of the study. Study Endpoints/Assessments Primary Frequency of moderate/severe exacerbations Moderate exacerbations are defined as COPD exacerbations that require either systemic corticosteroids (intramuscular (IM), intravenous, or oral) and/or antibiotics. Severe exacerbations are defined as COPD exacerbations requiring hospitalization or resulting in death. Efficacy endpoints will be measured from Visit 2 through Visit 15. Secondary Time to first moderate/severe exacerbation 13

117 2013N183405_02 Frequency of COPD exacerbations requiring emergency department (ED) visits and/or hospitalizations Change from baseline mean total St. George s Respiratory Questionnaire-COPD (SGRQ-C) score Change from baseline COPD assessment test (CAT) score Other Frequency of moderate COPD exacerbations Frequency of severe COPD exacerbations Occasions of rescue medication use Proportion of SGRQ-C responders Change from baseline in trough FEV 1 and FVC Change from baseline EQ-5D-5L Frequency of COPD exacerbations requiring re-hospitalization within 30 days Safety Endpoints Incidence of adverse events including systemic and local site injection-related reactions Vital signs including blood pressure, body temperature, pulse rate, and pulse oximetry ECG measurements Mortality (all cause, respiratory, cardiovascular) Immunogenicity Hematological and clinical chemistry parameters throughout the 52-week treatment period and the 8-week follow up period. Health Outcome Endpoints Healthcare utilization including hospitalization, emergency department, and physician office/clinic visits Change from baseline in rating of activity limitation Change from baseline in subject's impression of change Change in Clinician rated response to therapy Change in Subject rated response to therapy 14

118 2013N183405_02 1. INTRODUCTION 1.1. Background Chronic Obstructive Pulmonary Disease (COPD is a chronic progressive disease with rising morbidity and mortality. COPD is currently the fourth leading cause of death in the world [World Health Report, 2000] and is predicted to be the third leading cause of death in the world by 2030 [Eltboli, 2013; World Health Organization, 2008]. COPD is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response, in the airways and the lung, in response to noxious particles or gases GOLD, 2013]. While the disease course is marked by progressive deterioration in airflow it is punctuated by COPD exacerbations which contribute to the overall disease severity and increase in frequency as disease worsens GOLD, 2013; Soler-Cataluña, 2005]. In addition to the increased risk of morbidity and mortality associated with COPD exacerbations, these events place a huge economic burden on healthcare systems which is predicted to increase with the increasing prevalence of the disease globally [Toy, 2010] Rationale While COPD is generally viewed as a disease driven by neutrophilic inflammation, up to 40% of COPD patients have an inflammatory pattern that includes elevated sputum eosinophils [Brightling, 2005; Saha, 2006]. In severe COPD patients, sputum eosinophils and IL-5 levels are elevated to similar levels as those seen in severe asthmatics [Bafadhel, 2012]. Notably, COPD patients with eosinophilic inflammation cannot be distinguished based on clinical features and lung function from those without eosinophilic inflammation [Saha, 2006]. COPD exacerbations are characterized by periods of acute worsening of symptoms, deterioration in lung function, and decreased health-related quality of life [Seemunga, 1998; Connors, 1996; Donaldson 2002] and potentially contribute to further permanent decrements in lung function. Recent studies identified that increased eosinophilic airway inflammation occurred during COPD exacerbations [Bafadhel, 2011] and that peripheral eosinophils levels were used successfully as a surrogate to predict response to corticosteroid therapy [Bafadhel, 2012]. While further research is required experience in the clinic suggests that management of exacerbations could possibly be tailored by phenotype-specific management. A study by Siva et al [Siva, 2007] showed that a treatment strategy that aimed to reduce sputum eosinophils in COPD showed a significant reduction in severe exacerbations compared to a treatment strategy towards optimizing symptoms alone. Based on the identification of a COPD subgroup of frequent exacerbators with elevated eosinophils and IL-5 levels and the finding from the severe asthma study MEA post-hoc analysis of mepolizumab in COPD-like patients (based on age, FEV1/FVC ratio, and lack of reversibility) there is reason to believe that mepolizumab will reduce IL-5 and eosinophils in a well-defined COPD population. The study target population consists of a population who despite a history of use of optimal standard of care therapy continue to be at risk for future exacerbation and is further defined by study eligibility 15

119 2013N183405_02 criteria. Based on extrapolation of the efficacy findings in severe asthma and the similarities between the severe asthma and severe COPD patients in terms of eosinophils and IL-5 levels it is hypothesized that the reduction of eosinophils with mepolizumab in COPD patients would translate into a reduction of COPD exacerbations. Mepolizumab is a fully humanized IgG antibody (IgG1, kappa) which binds to and inhibits the ability of IL-5 to bind to the IL-5 receptor. IL-5 receptors are primarily expressed on eosinophils. IL-5, through binding to the IL-5 receptor is a major regulator of eosinophils resulting in accumulation in tissues and modulation of eosinophil behavior at every stage from maturation to survival. Mepolizumab reduces eosinophils in the periphery and in tissues. Data from study MEA demonstrate that responders to mepolizumab (i.e. subjects with a reduction in exacerbation rate despite treatment with corticosteroids) had a baseline blood eosinophil count of at least150 cells/l or a historical blood eosinophil count of at least 300 cells/μl. Accordingly, these thresholds for blood eosinophil counts will be used to operationally define a group of subjects as eosinophilic. This study will determine the reduction in exacerbations in subjects who are above and below the baseline blood eosinophil count of at least 150 cells/l ensuring that the hypothesis bridges from asthma to COPD Benefit:Risk Assessment Summaries of findings from both clinical and non-clinical studies conducted with mepolizumab can be found in the Investigator s Brochure (IB) or IB supplement [GlaxoSmithKline Document Number CM2003/00010/08] Risk Assessment The following table (Table 1) outlines the risk assessment and mitigation strategy for this protocol. Table 1 Risk Assessment with Mitigation Strategy Potential Risk of Clinical Significance Data/Rationale for Risk Mitigation Strategy Investigational Product Risk of Systemic Allergic and Non-allergic Reactions, including Anaphylaxis Biopharmaceutical products may elicit anti-drug antibody (ADA) and neutralizing antibody (NAB), which have the potential to modulate pharmacokinetic (PK), pharmacodynamic (PD) or Daily monitoring of serious adverse events (SAEs) by medical monitor; regular systematic review of adverse event (AE)/SAE data from ongoing studies by a GSK safety review 16

120 2013N183405_02 Potential Risk of Clinical Significance Data/Rationale for Risk produce adverse reactions. However, humanized and fully human antibodies are less immunogenic than mouse or chimeric monoclonal antibodies. Reactions reported to date across the mepolizumab program are summarized in the IB; see Special Warnings and Special Precautions for Use section located in Section 6 titled Summary of Data and Guidance for the Investigator. Mitigation Strategy team. Independent Data Monitoring Committee (IDMC) will be utilized during the study. Specific case report form (CRF) pages utilized for targeted collection of reactions data. Utilization of Joint NIAID/FAAN 2nd Symposium on Anaphylaxis to collect data on reports of anaphylaxis (see Appendix 8). Subjects are monitored in clinic for 1 hour following dosing. Risk of Immunogenicity See previous risk for background information in literature. Immunogenicity data reported to date across the mepolizumab development program are summarized in the IB; see Section 5.4 Clinical Immunogenicity and a summary of immunogenicity findings in the Other Potentially Clinically Relevant Information for the Investigator section located in Section 6 titled Summary of Data and Guidance for the Investigator. Blood samples are collected in clinical studies for detection of both ADA and NAB. See previous risk for mitigation strategy related to clinical safety risks. 17

121 2013N183405_02 Potential Risk of Clinical Significance Potential risk for adverse cardiovascular (CV) effects Data/Rationale for Risk Mepolizumab binding was restricted to human lymphoid tissues in an immunohistochemistry tissue binding study suggesting a low likelihood of non-pharmacologic effects on cardiovascular (CV) function. No AEs concerning cardiac conduction or repolarization evident in cynomolgus monkeys at doses at least 10-fold in excess of humans dosed at 10 mg/kg or 750 mg. No clinically relevant trends observed in ECG data in humans. In one study in subjects with severe refractory asthma, cardiac events were reported in similar frequencies across treatment groups with a small numerical increase observed in serious ischemic cardiac events in the mepolizumabtreated groups. However, an integrated safety analysis of all placebo-controlled multiple dose asthma trials showed similar frequency of SAEs reported overall from the cardiac and vascular system organ class (SOC). Additionally, similar findings were observed in other SOCs with thrombotic events (e.g., stroke in the Nervous System SOC). Mitigation Strategy Daily monitoring of SAE by medical monitor; regular systematic review of AE/SAE data from ongoing studies by a GSK safety review team. CV monitoring for study includes: ECG monitoring during the trial; Use of standardized CRFs to collect relevant data on CV events of interest (i.e., myocardial infarction, hospitalization for unstable angina and congestive heart failure, arterial thrombosis, pulmonary embolism and deep vein thrombosis); Use of an IDMC during the study. 18

122 2013N183405_02 Potential Risk of Clinical Significance Potential risk for increase in infections - theoretical concern with biologics; however, the pharmacological properties of mepolizumab suggest the risk is low. Data/Rationale for Risk No evidence of increased incidence of infections in any preclinical studies. Murine data demonstrate that IL-5 antagonism is unlikely to influence cellular or humoral immunity, particularly in response to parasitic infections. No mepolizumab-related effects on lymphocyte Immunophenotyping in monkeys or humans, including T-cell activation, distribution of CD4/CD8 subtypes or Th1/Th2 cytokine patterns, B-cells, NK cells or γδ-t-cells. An integrated safety analysis of all placebocontrolled multiple dose asthma trials showed SAEs reported in the infection and infestation SOC were 5/345 (1%) in placebo subjects and 18/754 (2%) in mepolizumab subjects. Infections reported to date across the mepolizumab development program are summarized in the IB; see Special Precautions and Warnings (for exclusion of subjects with underlying parasitic infections) and Undesirable Effects (for very common infections of nasopharyngitis, URTI, rhinitis and bronchitis reported in other patient Mitigation Strategy Daily monitoring of SAE by medical monitor; regular systematic review of AE/SAE data from ongoing studies by a GSK safety review team An IDMC will be utilized during the study Standard safety assessments to be conducted as outlined in protocols. 19

123 2013N183405_02 Potential Risk of Clinical Significance Data/Rationale for Risk Mitigation Strategy Potential risk for increase in malignancies - theoretical concern with biologics; however, blockade of IL-5 is not associated with generalized immunosuppression or impaired host resistance. Potential risk for rebound eosinophilia with associated clinical consequences populations) sections located in Section 6 titled Summary of Data and Guidance for the Investigator. Role of IL-5 and eosinophils in tumour surveillance is not fully characterised in the literature. No evidence of defective tumour surveillance in IL-5 or eosinophil-deficient mice. Direct assessment of the carcinogenic potential of long-term IL-5 blockade in rodent models not technically feasible. Malignancies reported to date across the mepolizumab development program are summarized in the IB. Early published data with Schering-Plough anti- IL5 mab suggested potential for rebound eosinophilia and disease exacerbation when treatment was stopped [Kim, 2004; Gevaert, 2006]; however, no standard definition of rebound was used and criteria for reporting were variable. There have been no verbatim reports of rebound from completed Daily monitoring of SAE by medical monitor; regular systematic review of AE/SAE data from ongoing studies by a GSK safety review team An IDMC will be utilized during the study. Standard safety assessments to be conducted as outlined in protocols Daily monitoring of SAE by medical monitor; regular systematic review of AE/SAE data from ongoing studies by a GSK safety review team IDMC will be utilized during the study. Standard safety assessments to be conducted as outlined in protocols 20

124 2013N183405_02 Potential Risk of Clinical Significance Data/Rationale for Risk Mitigation Strategy Study Procedures Inclusion of a placebo arm Blinding eosinophil counts clinical trials of subjects with asthma, atopic dermatitis and eosinophilic esophagitis. Furthermore, the data do not support an exaggerated return of symptoms after cessation of treatment. The objective of the study is to compare the efficacy and safety of mepolizumab versus placebo in COPD subjects receiving standardof-care therapy This study is a double-blind study which will be used to support approval for the use of mepolizumab in the reduction of moderate/severe COPD exacerbations. Unblinding eosinophil counts may compromise the integrity of the study. Because all subjects are receiving background standard-of-care therapy in this study the Sponsor considers inclusion of a placebo arm to be justified. Patients will be seen monthly by investigators specialized in COPD. IDMC will be utilized during the study. Neither the site nor GSK personnel will be sent results from the central laboratory for: i) absolute eosinophil count or ii) white blood count differentials (% neutrophil, lymphocyte, monocyte, eosinophil and basophil), for each subject s duration in the study for any visits post-randomisation. However, sites will be sent total white blood counts throughout the study Benefit Assessment Study will investigate the efficacy and safety of mepolizumab in the reduction of moderate/severe COPD exacerbations in subjects receiving standard of care 21

125 2013N183405_02 COPD treatment recommended for this population (i.e. with the severity and risk level defined per the protocol). Exacerbations are a major concern to COPD patients and lead to a worsening of the quality of life for subjects. A reduction of moderate and severe exacerbations will improve a patient s quality of life and may reduce hospitalizations. A primary benefit will be the identification of a COPD subgroup of frequent exacerbators whose eosinophil level predicts a response to IL-5 inhibition. One reason to believe that COPD subjects will respond to IL-5 inhibition is derived from a clinical trial in severe asthma (MEA112997) where a post-hoc analysis of mepolizumab in COPD-like patients showed a reduction in exacerbations indicating that that mepolizumab may reduce IL-5 and eosinophils in a well-defined COPD population and have an impact on reducing the rate of exacerbations. Data obtained from study will provide a robust evaluation of the efficacy and safety of mepolizumab in the reduction of moderate/severe COPD exacerbations with a view towards supporting a regulatory approval for mepolizumab for the reduction of COPD exacerbations in patients with severe COPD. While it is believed that mepolizumab will only affect subjects with eosinophil levels of at least 150cells/µl, there is limited data to support this in COPD subjects. Therefore in this study each treatment arm will have 2 strata based on the eosinophil cell count; At least150cell/µl at Visit 1 or a historic count in the previous year of >300 cells/l < 150cells/l at Visit 1 Subjects participating in this study will be required to attend monthly visits and therefore may benefit from the additional monitoring to their current standard of care Overall Benefit:Risk Conclusion Data from mepolizumab preclinical and clinical development demonstrate the ability of mepolizumab to inhibit IL-5, and consequently treat inflammatory conditions linked to an eosinophil signal, such as COPD subjects predisposed for future exacerbations. To date, the safety profile of mepolizumab across other programs has been favorable in all patient populations studied and AEs reported commonly have been manageable with minimal medical intervention. Furthermore, preclinical data and the observed safety profile in over 1200 subjects receiving mepolizumab in clinical trials to date has not identified a safety concern that would preclude the investigation in COPD. Therefore investigation of the efficacy, safety, and tolerability of mepolizumab is thereby justified in study. 22

126 2013N183405_02 2. OBJECTIVE(S) Primary Objective To evaluate the efficacy and safety of mepolizumab 100 mg subcutaneous (SC) given every 4 weeks compared to placebo on the frequency of moderate and severe exacerbations in COPD subjects at high risk of exacerbations despite the use of optimized standard of care background therapy. Secondary Objective To evaluate other efficacy assessments of mepolizumab 100 mg subcutaneous (SC) compared to placebo on changes in health care utilization, COPD symptoms, quality of life, and lung function. 3. INVESTIGATIONAL PLAN 3.1. Study Design Schema 3.2. 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 2), are essential and required for study conduct. 23

127 2013N183405_02 This is a multi-center, randomized, placebo-controlled, double-blind, parallel group trial evaluating mepolizumab 100 mg against placebo given every 4 weeks through subcutaneous (SC) injection. The target global enrolment is approximately 800 randomized subjects. The total duration of subject participation will be approximately 62 weeks, consisting of a 1 to 2 week screening period, 52-week treatment period and 8- week follow-up period. Subjects will initially participate in a pre-screening visit (Visit 0) where the details about the study and procedures will be explained through the informed consent process. Subjects who meet all inclusion criteria and none of the exclusion criteria at Visit 1 will enter a 1 to 2 week screening period during which time subjects will remain on a stable dose of their current COPD therapy. Laboratory assessments will be collected at Visit 1 and will include a hematology assessment for determination of baseline eosinophil level. The site must receive the results of the Visit 1 laboratory assessments (e.g. blood eosinophils) prior to the determining eligibility at Visit 2. Baseline patient reported electronic diary (ediary) data will be captured during the screening period and subjects must meet the ediary compliance requirement to be eligible for randomization. Subjects must understand and agree to completion of the ediary on a daily basis in the morning to be considered for this study. Site personnel must train subjects on the proper use of the ediary at Visit 1. Baseline subject reported electronic diary (ediary) data will be captured during the screening period and subjects must meet the ediary compliance requirement to be eligible for randomization. Subjects must understand and agree to completion of the ediary on a daily basis in the morning to be considered for this study. Site personnel must train subjects on the proper use of the ediary at Visit 1. The ediary will capture daily COPD symptoms, rescue medication use, and activity level, as well as patient reported outcomes and this information will be transmitted daily. Sites will have real time access to subject symptom data. Study inclusion criteria require a history of regular use of at least one triple COPD standard of care (SoC) option (as defined in inclusion criteria) for at least 12 months prior to screening. In addition, for at least 3 months prior to screening, each subject must have a history of use of a specific inhaled triple SoC regimen (ICS + long acting beta 2 -agonist (LABA) + long acting muscarinic antagonist (LAMA)). Subjects are also required to have a history of at least 2 moderate or 1 severe exacerbation in the 12 months prior to Visit 1 and one of the exacerbations had to have occurred while treated with ICS + LABA + LAMA. All subjects will continue on their baseline optimized SoC COPD medications throughout the entire duration of the study regardless of treatment arm assignment. If for medical reason the subject must change their baseline SoC COPD medication the primary investigator should discuss with the GSK medical monitor. Eligible subjects will be randomized 1:1 to mepolizumab 100 mg or placebo. Randomization will be stratified based on baseline eosinophil levels. Investigational Product (IP) will be administered as one SC injection given every 4 weeks. The first dose will be administered at Visit 2 (Week 0) and the last dose administered at Week 48 (Visit 14). For those subjects randomized to mepolizumab, 13 doses will provide therapeutic coverage for 52 weeks (4 weeks following the last dose). The Exit Visit (Visit 15, Week 52) will occur 4 weeks after last administration of study treatment. Study treatment will not be administered at this visit. The primary efficacy endpoint will be evaluated from 24

128 2013N183405_02 Visit 2 (Week 0) to Visit 15 (Week 52). All subjects will be requested to return for a Follow-up Visit (Visit 16) approximately 12 weeks after their last dose of investigational product (and approximately 8 weeks after Visit 15) to conduct safety assessments and collect an immunogenicity sample. Serious adverse events (SAEs) reported from ongoing clinical studies with mepolizumab are reviewed daily by the project Medical Monitor. Additionally, regular, systematic reviews of emerging safety data from all clinical studies are conducted by an in-house multi disciplinary Safety Review Team (SRT) which provides a central and dedicated forum for review of emerging data which could impact subject safety. The SRT, which includes the project Medical Monitor, other physicians assigned to the project, clinical scientists and a statistician, reviews blinded and unblinded (i.e., from open-label trials) safety data from ongoing clinical studies with mepolizumab on a regular basis and conducts a comprehensive evaluation of the safety data upon completion of each study. Moreover, an integrated analysis of safety across the program is completed annually when additional safety data are available from completed studies. A re-assessment of benefit risk and the current Developmental Core Safety Information (DCSI) is completed at each SRT meeting subsequent to review of new data. Additionally, an adjudication committee and an Independent Data Monitoring Committee (IDMC) will be utilized during the study. There is also a standard and comprehensive process for the reporting and management of Sentinel Events. A Sentinel Event is an SAE that is not necessarily drug-related, but that has been associated historically with adverse reactions for other drugs, and is therefore worthy of heightened pharmacovigilance. Sentinel Events include acquired long QT syndrome, agranulocytosis, anaphylactic and anaphylactoid reactions, hepatotoxicity, renal failure, seizures, and Stevens Johnson syndrome/toxic epidermal necrolysis. Subsequent to the reporting of a Sentinel Event, the Medical Monitor promptly notifies the SRT and the GSK Global Safety Board and leads a thorough and comprehensive follow-up of the Sentinel Event with collection of all relevant data. 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 Discussion of Design This study is designed to evaluate the efficacy and safety of mepolizumab, over 52 weeks, in subjects who exacerbate despite regular use of maximal tolerated therapy, appropriate for severe COPD patients, in the 12 months prior to study start. Optimized SoC therapy must include a history of regular use of at least one triple COPD standard of care (SoC) option (per inclusion criteria) for at least 12 months prior to screening. Subjects are also required to have a history of at least 2 moderate or 1 severe exacerbation in the 12 months prior to Visit 1 and one of the exacerbations had to have occurred while using inhaled triple therapy (i.e. while the subjects was treated with ICS + LABA+ LAMA). Prior to study medication eligibility requirements and exacerbation history requirements are more fully defined in Section

129 2013N183405_02 All subjects will continue on their baseline optimized SoC COPD medications throughout the entire duration of the study regardless of treatment arm assignment. If for medical reason the subject must change their baseline SoC COPD medication the primary investigator should discuss with the medical monitor. Allowing use of optimized SoC therapy supports inclusion of a placebo group contributing to a favorable benefit:risk profile for participating subjects. The 1 to 2 week run-in period allows for the assessment of subject understanding of and compliance with the daily ediary, to establish baseline diary symptoms, and to allow adequate time for receipt of results from assessments collected at Visit 1. The study will be stratified based on blood eosinophil levels with the aim of recruiting equal numbers of subjects in the two strata to each treatment group. Subjects will be assigned to strata according to the following: Eosinophils 150 cells/l at Visit 1 or a historic eosinophil level in the preceding 12 months 300 cells/l, or Eosinophils <150 cells/l at Visit 1 The eosinophil count level, although determined primarily in severe asthmatics, is thought to be appropriate also for COPD. The study duration permits the evaluation of mepolizumab across seasonal periods. The protocol objective is to collect data over the full study period, whether subjects continue on investigational product (IP) and complete the study in-full, or even in the case of premature discontinuation from IP. However, the decision to continue in the study after premature discontinuation from IP remains the prerogative of the subject. Subjects who agree to continue in the study after premature discontinuation from IP (for any reason) will continue to be contacted by the study site, either through in clinics visit or by phone as agreed with the subject, on a monthly basis (aligned to their previous study schedule) until the end of their planned 52-week participation to enable capture of post-treatment assessments Dose Rationale The rationale for the mepolizumab selected dose to be studied in this trial in COPD is based on the evidence that the levels of IL-5 and eosinophils in the sputum of severe asthma and severe COPD patients are comparable and a steroid treatment approach aimed at reducing sputum eosinophils led to a reduction in exacerbations in both asthma and COPD patients compared to optimizing symptoms alone [Bafadhel 2012, Siva 2007, Green 2002] The dose selection is based on previous experience from a phase 2b/3 placebo controlled study (MEA112997) that demonstrated the safety and efficacy of mepolizumab at doses of 75mg, 250mg and 750mg administered IV, every 4 weeks, over a 52-week treatment period in patients with severe refractory asthma. Mepolizumab reduced blood and sputum eosinophils in a dose-related manner. Mepolizumab reduced the frequency of exacerbations similarly across the 3 doses studied. The absence of dose response implies 26

130 2013N183405_02 that the reduction in blood eosinophils achieved with mepolizumab 75 mg IV every four weeks was adequate to confer the desired clinical benefit in a severe asthma patient population. This study also demonstrated that mepolizumab had an acceptable safety profile in severe asthma patients across a 10-fold dose range. MEA114092, a dose ranging PK/PD study, studied 4 doses of mepolizumab administered by IV and SC injection, every 4 weeks, in adult patients with asthma and elevated blood eosinophils. The study included a low dose of 12.5 mg SC along with 125 mg SC, 250 mg SC, and 75 mg IV. The absolute bioavailability of mepolizumab administered SC into the upper arm is approximately 75% [GlaxoSmithKline Document Number CM2003/00010/08]. Similarly to MEA112997, this study demonstrated a dose related decrease in the blood and sputum eosinophil ratio to baseline with increasing dose of mepolizumab. The 12.5 mg SC dose showed a notably lower degree of eosinophil reduction and clearly differentiated from the other SC doses, and from the 75 mg IV dose. A non-linear inhibition dose-response model based on blood eosinophil counts at Week 12, identified 99 mg SC (approximately 75 mg IV) every 4 weeks as the ID90 (i.e., dose providing 90% of the maximum blood eosinophil reduction achievable by the drug) for blood eosinophil reduction. The data from MEA and MEA demonstrate concordance in the blood eosinophil reduction at 75 mg IV dose. Mean MEA data super-imposed on the mepolizumab - blood eosinophil dose response curve developed from MEA data were reasonably captured by the model. Together the results from these studies demonstrated that 75 mg IV (100 mg SC) is the minimum appropriate dose based on blood eosinophils and it is therefore not considered necessary to assess a dose lower than 75 mg IV/100 mg SC in further Phase 3 studies. Based on the absolute bioavailability of SC mepolizumab, combined with the dose response established on blood eosinophil count, a 100 mg SC regimen as the targeted effective dose is included in this trial. A SC route of administration is more convenient to administer compared to IV and is generally preferred by patients. An additional higher dose of mepolizumab (300 mg) is included in Study MEA117113, to include an assessment of dose-ranging of mepolizumab in a COPD population at high risk for exacerbations and to collect additional safety data over the one-year study period. The 300 mg SC dose corresponds approximately to a 250 mg IV dose that was used in previous studies demonstrating favorable safety margin and tolerability. 4. SUBJECT SELECTION AND WITHDRAWAL CRITERIA 4.1. Number of Subjects Number of Randomised Subjects:

131 2013N183405_ Eligibility Criteria 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 or IB supplement [GlaxoSmithKline Document Number CM2003/00010/08]. 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. COPD diagnosis: Subjects with a clinically documented history of COPD for at least 1 year in accordance with the following definition by the American Thoracic Society/European Respiratory Society [Celli, 2004] 2. Severity of COPD: Subjects must present with the following: A measured pre and post-salbutamol FEV 1 /FVC ratio of <0.70 at Visit 1 to confirm the diagnosis of COPD A measured post-salbutamol FEV 1 > 20% and 80% of predicted normal values calculated using NHANES III reference equations [Hankinson 1999, Hankinson, 2010] at Visit 1 3. History of exacerbations: A well documented history (e.g., medical record verification) in the 12 months prior to Visit 1 of: OR at least two moderate COPD exacerbations. Moderate is defined as the use of systemic corticosteroids (intramuscular (IM), intravenous, or oral) and/or treatment with antibiotics. at least one severe COPD exacerbation. Severe is defined as having required hospitalization Note: At least one exacerbation must have occurred while the subject was taking ICS plus LABA plus LAMA. Note: Prior use of antibiotics alone does not qualify as a moderate exacerbation unless the use was specifically for the treatment of worsening symptoms of COPD. 4. Concomitant COPD therapy: A well documented requirement for optimized standard of care (SoC) background therapy that includes ICS plus 2 additional COPD medications (i.e., triple therapy) for the 12 months prior to Visit 1 and meets the following criteria: 28

132 2013N183405_02 Immediately prior to Visit 1, minimum of 3 months of use of an a) inhaled corticosteroid at a dose 500 mcg/day fluticasone propionate dose equivalent plus b) LABA and c) LAMA. For subjects who are not continually maintained on ICS plus LABA plus LAMA for the entire 12 months prior to Visit 1 use of following is allowed (but not in the 3 months immediately prior to Visit 1): inhaled corticosteroid at a dose 500 mcg/day fluticasone propionate dose equivalent plus a LABA or a LAMA and use of at least one other class of COPD medication suggested by the 2013 GOLD guidelines for patients who are prone to exacerbation (i.e., phosphodiesterase-4-inhibitors, methylxanthines, or a combination of short acting beta 2 -agonist and short acting muscarinic antagonist). Note: Subjects must be willing to stay on their SoC COPD medication for the duration of the study. 5. Informed Consent: Able to give written informed consent prior to participation in the study, which will include the ability to comply with the requirements and restrictions listed in the consent form. Subjects must be able to read, comprehend, and write at a level sufficient to complete study related materials. 6. Gender: Male or Eligible Female To be eligible for entry into the study females of child bearing potential (FCBP; see Appendix 1 for definition) must commit to consistent and correct use of an acceptable method of birth control from the time of consent, for the duration of the trial, and for 4 months after last study drug administration. See Appendix 1 for a listing of acceptable methods of birth control. 7. Age: At least 40 years of age at Visit 1 8. Smoking status: Subject with confirmed COPD are eligible to participate independent of their smoking status and smoking history, i.e. current smokers, never smokers or ex-smokers can be enrolled into the study. Note: Pipe and/or cigar use cannot be used to calculate pack-year history. Current smokers are defined as those with a history of cigarette smoking of 10 pack-years [number of pack years = (number of cigarettes per day / 20) x number of years smoked (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years)]. Former smokers are defined as those who meet the definition of a current smoker but have stopped smoking for at least 6 months prior to Visit 1. Never smokers are those that do not meet the definition of a current or former smoker. French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category. 29

133 2013N183405_ 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. Asthma: Current and Former Smokers: Subjects with a current diagnosis of asthma (those with a prior history are eligible if they meet inclusion criteria for a current diagnosis of COPD) Never-Smokers: Subjects with any history of asthma 2. Other respiratory disorders: The investigator must judge that COPD is the primary diagnosis accounting for the clinical manifestations of the lung disease. Subjects with α1-antitrypsin deficiency as the underlying cause of COPD are excluded. Also, excluded are subjects with active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, primary pulmonary hypertension, interstitial lung diseases or other active pulmonary diseases. Subjects are also excluded if maintenance use of bi-level positive airway pressure is required for the treatment of respiratory disorder. 3. COPD stability: Subjects with pneumonia, exacerbation, lower respiratory infection within the 4 weeks prior to Visit Lung resection: Subjects with lung volume reduction surgery within the 12 months prior to Visit Pulmonary rehabilitation program: Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1. Subjects who are in the maintenance phase of a pulmonary rehabilitation program are not excluded. 6. Oxygen: Subjects receiving treatment with oxygen more than 4.0L/min. While breathing supplemental oxygen, subjects should demonstrate an oxyhemoglobin saturation greater than or equal to 89% lead ECG finding: An abnormal and significant ECG finding from the 12-lead ECG conducted at Visit 1 if considered to be clinically significant by the Investigator. Specific ECG findings that preclude subject enrolment are found in Appendix lead ECGs will be over-read by a centralized independent cardiologist to assist in consistent evaluation of subject eligibility. Results from the 12-lead ECG over-read must be received prior to assessing eligibility at Visit Unstable or life threatening cardiac disease: Subjects with any of the following would be excluded: Myocardial infarction or unstable angina in the last 6 months Unstable or life threatening cardiac arrhythmia requiring intervention in the last 3 months New York Heart Association (NYHA) Class IV Heart failure 30

134 2013N183405_02 9. Other diseases/abnormalities: Subjects with (historical or) current evidence of clinically significant, neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or haematological abnormalities that are uncontrolled. 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. 10. Eosinophilic disease: Subjects with other conditions that could lead to elevated eosinophils such as Hypereosinophilic syndromes including Eosinophilic Granulomatosis with Polyangiitis (EGPA, also known as Churg-Strauss Syndrome), or Eosinophilic Esophagitis. 11. Parasitic infection: Subjects with a pre-existing helminthes infestation within 6 months prior to Visit 1 are also excluded. 12. Malignancy: A current malignancy or previous history of cancer in remission for less than 12 months prior to Visit 1 (Subjects that had localized carcinoma of the skin or cervix which was resected for cure will not be excluded). Note for South Korea: Korean subjects with a diagnosis of malignancy within 5 years of Visit 1 are excluded 13. Immunodeficiency: A known immunodeficiency (e.g human immunodeficiency virus HIV), other than that explained by the use of corticosteroids taken for COPD. 14. Liver disease: Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices, or persistent jaundice), cirrhosis, and known bilary abnormalities (with the exception of Gilbert s syndrome or asymptomatic gallstones). Chronic stable hepatitis B and C are acceptable if subject otherwise meets entry criteria (e.g., presence of hepatitis B surface antigen or positive hepatitis C test result within 3 months of screening) 15. Monoclonal antibodies: Subjects who have received any monoclonal antibody within 5 half-lives of Visit Investigational medications: Subjects who have received an investigational drug within 30 days of Visit 1, or within 5 drug half-lives of the investigational drug, whichever is longer (this also includes investigational formulations of a marketed product). 17. Hypersensitivity: Subjects with a known allergy or intolerance to another monoclonal antibody or biologic including history of anaphylaxis to another biologic 18. Inability to read: In the opinion of the investigator, any subject who is unable to read and/or would not be able to complete study related materials. 19. 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. 20. 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. 31

135 2013N183405_ Drug or alcohol abuse: A known or suspected history of alcohol or drug abuse within 2 years prior to Visit Previous participation: Subjects who have previously participated in any study of mepolizumab. 23. Affiliation with Investigator Site: Is an investigator, sub-investigator, study coordinator, employee of a participating investigator or study site, or immediate family member of the aforementioned that is involved in this study Randomization Criteria In order to be randomized to study drug the subject must meet the following randomization criteria at Visit 2: 1. Blood eosinophils: While there is no threshold for enrolment, information on eosinophil level should be obtained prior to randomization. 2. Electronic Diary Compliance: Compliance with completion of the ediary defined as completion of all questions on 5 or more days out of the 7 days immediately preceding Visit lead ECG: No evidence of an abnormal and significant ECG finding from the 12- lead ECG conducted at Visit 1 as indicated on the over-read provided by the centralized independent cardiologist. Subjects with a QTcF 450 msec are not eligible. For subjects with a QRS interval 120msec, those with QTcF 480 msec are not eligible. Specific ECG findings that preclude subject eligibility are listed in the Appendix Abnormal chest X-ray (or CT scan): No chest X-ray (or CT scan) that reveals evidence of clinically significant abnormalities other than those believed to be due to the presence of COPD. If a chest X-ray or CT scan is not available within 6 months prior to Visit 1, then a chest X-ray must be taken at Visit 1 and the results reviewed prior to randomization. For sites in Germany: If a chest X-ray (or CT scan) within 6 months prior to Screening (Visit 1) is not available, the subject will not be eligible for the study. 5. Laboratory abnormality: No evidence of clinically significant abnormality in the haematological, biochemical, or urinalysis screen at Visit 1, as judged by the investigator. 6. Hepatitis B: Subjects who are HBsAg positive or HBcAb positive must not have a HBV DNA level 2000 IU/ml. 7. Liver function test: Subjects must meet the following based on results from sample taken at Visit 1: Alanine aminotransferase (ALT) <2x ULN (upper limit of normal) Alkaline Phosphatase (Alk Phos) 2x ULN Bilirubin 1.5x ULN (isolated bilirubin>1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) 32

136 2013N183405_02 8. Pregnancy: No subjects who are pregnant or breastfeeding. Subjects should not be enrolled if they plan to become pregnant during the time of study participation 4.3. Pre-Screening/Screening/Run-in Failures A subject will be assigned a subject number at the time the informed consent is signed. A subject who is assigned a subject number but does not have a Visit 1 procedure will be considered a pre-screen failure. The study interactive voice response system (IVRS) will be contacted to report pre-screen failures. The following information will be collected for subjects who are pre-screen failures: Date of ICF signature Demographic information including race, age, and gender Child bearing status assessment for all potential female subjects Subject number Details of COPD medications within 3 months of Visit 0 Details of COPD exacerbations during pre-screening period (yes/no status) Serious Adverse Events information only for any SAE considered as related to study participation (e.g., study treatment, protocol mandated procedures, invasive tests, or change in existing therapy) Investigator signature page Any subject who performs a Visit 1 procedure but no Visit 2 procedures will be designated as a screen failure. RAMOS will be contacted to report screen failures. In addition to the information above, the following information will be collected for screen failures: Date of screening visit Reason for screen failure Any subject who completes Visit 1 and enters the screening period, and completes at least one Visit 2 procedure but is not randomized is classified as a run-in failure. IVRS will be contacted to report run-in failures. In addition to the information above, the following information will be collected for run-in failures: Date of randomization visit 33

137 2013N183405_02 Reason for run-in failure Additional information related to data collection for pre-screen failures, screen failures, and run-in failures can be found in the ecrf completion guidelines. Re-screening of subjects will be allowed only upon approval by the GSK medical monitor Investigational Product (IP) Discontinuation Criteria Subjects that permanently stop IP are not required to withdraw from the study. If for any reason a subject must permanently stop IP every effort should be made by the PI/staff to keep the subject in the study to collect important efficacy and safety data. A subject will be considered to have completed study treatment if he/she continues to take study treatment until Visit 14 (Week 48) and completes Visit 15 (Week 52). A subject will be considered to have completed the study if they continue to participate in the study until Visit 15 (Week 52) regardless of whether they continue to take IP Protocol defined Stopping IP Criteria A subject must be permanently discontinued from IP if any of the following stopping criteria are met: Liver Chemistry: Meets any of the protocol-defined liver chemistry stopping criteria as defined in Section Hepatitis B Positive Subjects: If HBV DNA increases from baseline by 1 log and levels are 2000 IU/ml. Subjects who are discontinued from IP should be evaluated by the primary Investigator to determine if treatment with nucleoside analogues should be initiated (See Appendix 3). Pregnancy: Positive pregnancy test ECG: ECGs are required at specified study visits (see Table 2). Subjects should discontinue study treatment if any of the following QTcF or QT findings, as outlined in Appendix 4, are observed. Results from ECG central over-read will indicate if a subject meets protocol defined discontinuation from IP criteria. If additional ECGs are performed at the discretion of the investigator during the study these criteria also apply. QTcF >500 msec Uncorrected QT >600 msec Change from baseline: QTcF > 60 msec These criteria should be based on the average QTcF value of triplicate ECGs. For example, if an ECG demonstrates a prolonged QT interval, obtain two more ECGs 34

138 2013N183405_02 over a brief period, and then use the averaged QTcF values of the three ECGs to determine whether the subject should be discontinued from IP. Additional ECG criteria that would result in premature discontinuation from IP are presented in Appendix 4. For subjects with underlying prolonged QRS interval ( 120 msec) discontinuation from IP due to QTc is based on the QTcF value at baseline (Visit 2; see Table below): Baseline (Visit 2) QTcF Inclusion Criteria During Study Premature IP Discontinuation Criteria <450 msec with QRS <120 msec 500 msec with QRS <120 msec msec with QRS 120 msec 530 msec with QRS 120 msec Non-Compliance with daily diary: Subjects must be compliant in completing their daily diary between each pair of on-treatment visits. Subjects who are non-compliant should be re-educated on the requirement for daily diary entry compliance. Subjects who continue to be non-compliant after multiple visit assessments may be permanently discontinued from IP after consultation with the GSK clinical team Permanent Discontinuation from IP Subjects have the right to stop taking IP before the end of the study. A subject may also be asked to stop IP at the investigator s discretion. Subjects who have permanently discontinued IP are not required to withdraw from the study. Subjects who have permanently discontinued IP and have not withdrawn consent may continue in the study and will complete all remaining protocol specified visits by continued in-clinic visits or by phone contact. In the event that a subject permanently discontinues IP before the end of the randomized treatment period (i.e. Visit 15), every effort will be made by the investigator to encourage the subject to remain in the study and to complete all remaining study visits. Subjects will be provided with the option to continue to have regularly scheduled in-clinic visits or to have regularly scheduled phone visits. The Investigator must document the reason for discontinuation of IP in the ecrf. The PI/site staff should continue contact with the subject at the protocol designated visit time intervals to complete study assessments. If a subject discontinues from IP while attending a scheduled visit the Discontinuation from IP Visit assessments should be completed. Otherwise, the investigator should make every effort to have the subject return to the clinic as soon as possible after the subject permanently discontinues IP in order to complete the Discontinuation from IP Visit. The subject will then be followed up monthly, at regularly scheduled intervals, either by inclinic visit or scheduled phone contact. The required study assessments at the off-ip visits will depend on whether the subject is attending an in-clinic visit or a scheduled phone visit. At a minimum an assessment of exacerbations, SAEs, and concomitant medications will be completed. 35

139 2013N183405_02 In addition to the monthly follow-up in-clinic visit or monthly phone contact a safety Follow-up Visit should be completed as described in Section 4.6. The primary reason for discontinuation from IP will be recorded in the ecrf Withdrawal Criteria For this study there are no pre-determined protocol specific study withdrawal criteria (see Section for protocol defined stopping IP criteria). Every effort should be made by the investigator to keep the subject in the study. However a subject may voluntarily withdraw from participation in this study at any time. The investigator may also, at his or her discretion, withdraw a subject from further study participation. Subjects who are withdrawn from the study will not be replaced Withdrawal from Study Subjects have the right to withdraw from the study and to withdraw their consent for further participation in the study (i.e. this precludes continued data collection). The Investigator must document the reason (if specified by the subject) for withdrawal of consent in the ecrf. Subjects who wish to withdraw from further participation in the study should be encouraged to return to the clinic as soon as possible to complete the Withdrawal from Study Visit and also to complete the safety follow-up visit in order to collect important safety information. No further study visits or study-related telephone contacts can be conducted unless the subject s consent allows for contact after withdrawing from the study then every effort should be made by the Investigator and site to determine the subject s survival status at the end of the study Study Withdrawal assessments Subjects who are on IP and wish to withdraw from further participation in the study should be encouraged to return to the clinic as soon as possible to complete the Withdrawal from Study Visit assessments (see Table 2) and to complete the safety follow-up Visit as described in Section 4.6. Subjects who have previously discontinued IP (and have already completed their Discontinuation from IP Visit) but then decide that they no longer wish to participate in the study, may withdraw from the study by contacting the site by telephone to notify the site of their intention to withdraw; no additional safety follow-up visit is required Lost to Follow-up 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 36

140 2013N183405_02 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 (e.g., 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. Every effort should be made to collect survival status (whether the subject is still alive). Note: If contact is lost with the subject, only the specific additional actions as clearly outlined in each subjects Informed Consent form (e.g. attempt contact with subject s listed contact and/or a primary care physician; request access to the subject s medical record) should be attempted to collect survival status Reasons for Study Withdrawal The primary reason for study withdrawal will be recorded in the ecrf. When a subject withdraws consent, the Investigator must document the reason (if specified by the subject) in the ecrf Follow up Visit A Follow-up Visit will be conducted 12 weeks following last dose of IP. The follow-up contact must be done by an in clinic visit. The procedures to be conducted at the Followup Visit are listed in the T&E table (Table 2). 5. STUDY TREATMENTS 5.1. Investigational Product and Other Study Treatment Mepolizumab (SB ) is a fully humanized IgG antibody (IgG1, kappa) with human heavy and light chain frameworks. Mepolizumab will be provided as a lyophilised cake in sterile vials for individual use. The vial will be reconstituted with Sterile Water for Injection, just prior to use. Further details of dose preparation and administration can be found in the Investigator s Brochure (IB), the Study Procedures Manual (SPM), and in the unblinded reference manual. The contents of the label will be in accordance with all applicable regulatory requirements. Under normal conditions of handling and administration, investigational product is not expected to pose significant safety risks to site staff. Take adequate precautions to avoid direct eye or skin contact and the generation of aerosols or mists. Notify the monitor of any unintentional occupational exposure. A Material Safety Data Sheet (MSDS) 37

141 2013N183405_02 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. Mepolizumab will be provided by GSK as open-label product to the unblinded site staff. Unblinded site staff are required for this study. Unblinded site staff will be responsible for receipt, storage, reconstitution, and labelling, and accountability of investigational product. Mepolizumab must be stored in a secure area. Access to mepolizumab will be limited to the investigator s authorized unblinded site staff. Mepolizumab must be stored under the appropriate physical conditions which includes storage in a refrigerator or at a temperature of 2-8C and protected from light. Maintenance of a temperature log (manual or automated) is required. The placebo in this study will be 0.9% sodium chloride solution and will be provided by the study site. Mepolizumab will be reconstituted using sterile water for injection and swirled gently to enable complete dissolution of the product. Detailed instructions for product preparation can be found within the unblinded reference manual. Once prepared by unblinded site staff the active treatment will be indistinguishable from the placebo. Further details on preparation of investigational product are provided in the unblinded reference manual. Investigational product must be dispensed or administered only to subjects enrolled in the study and in accordance with the protocol. Blinded site staff will administer investigational product by SC injection. Additional instruction on product administration can be found in the SPM. Investigational Product should be administered after other Visit assessments have been completed. Refer to Table 2 for the list of assessments that must be completed at each Visit (Table 2). Procedures must be in place to ensure the blind is maintained by any site staff involved in administration of the drug or clinical care or assessment of the subject, and by the subject themselves. Safety monitoring of subjects will occur during SC administration and for one hour after the end of injection. Such monitoring will include general safety monitoring including monitoring for both systemic hypersensitivity (i.e., allergic/ige-mediated and nonallergic) and local site reactions. Trained rescue personnel and rescue medications/equipment must be available for use at all times. See Appendix 8 for additional information. Salbutamol metered dose inhaler (MDI) for use as rescue medication throughout the study will be sourced by GSK for centers in the United States of America. For all other centers it will be sourced locally where possible. 38

142 2013N183405_ Treatment Assignment At Visit 2 (Week 0) those subjects who meet the randomization eligibility criteria will be randomized in a 1:1 ratio to receive one of the following treatments every 4 weeks for a total of 13 doses: Mepolizumab 100 mg SC Placebo SC The study will be stratified based on blood eosinophil levels with the aim of recruiting equal numbers of subjects in the two strata to each treatment group. Subjects will be assigned to strata according to the following: Eosinophils 150 cells/l at Visit 1 or a historic eosinophil level in the preceding 12 months 300 cells/l, or Eosinophils <150 cells/l at Visit 1 Subjects will be assigned to study treatment in accordance with the randomization schedule. Subcutaneous preparations of mepolizumab will be administered by a designated blinded member of the site staff. To ensure the blind of those involved in the evaluation of the study is maintained at all times, mepolizumab must be prepared by a designated unblinded member of staff who remain independent of the study assessments. A unique Subject Number will be assigned to subjects who have consented. This unique subject number will be used to identify the individual subject throughout the study and will not be re-assigned to any other subject. Subjects will be assigned to study treatment in accordance with the randomization schedule. Once a randomization number has been assigned to a subject, it cannot be reassigned to any other subject in the study. The randomization schedule will be generated using the GSK validated randomisation software RandAll NG. Subjects will be randomized using an IVRS. The study will be randomized separately for each country and the randomisation will be stratified according to whether or not the subject has elevated eosinophils (defined as either a blood eosinophil count of 150 cells/l at baseline or a count of 300 cells/l within the past 12 months). Equal numbers of subjects will be allocated to each treatment and equal numbers of subjects will be assigned to the two eosinophil strata. Details of how to use the IVRS to register and randomize subjects will be provided in the SPM. 39

143 2013N183405_ Blinding 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, 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 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 Treatment Compliance All doses of study treatment will be administered at the study site by designated site staff. Drug dispensing/accountability logs will be maintained by a designated unblinded member of the site staff Concomitant Medications and Non-Drug Therapies Permitted Medications and Non-Drug Therapies All concomitant medications taken during the treatment phase of the study will be recorded in the electronic case report form (ecrf). The minimum requirement is that the drug name and the dates of administration (start and stop dates) must be recorded. The following COPD medications are permitted during the treatment period while the subject is on IP: 40

144 2013N183405_02 Salbutamol MDI (study supplied), or nebules, for prn rescue use (must be withheld for at least 4 hours prior to spirometry testing) Ipratropium bromide MDI, or nebules, for prn rescue use (must be withheld for at least 4 hours prior to spirometry testing) If taken as standard of care therapy prior to Visit 1 the following are permitted and should be maintained at a stable dose for the duration of the treatment period: o inhaled corticosteroids (ICS) o inhaled long-acting muscarinic antagonists (LAMA) o inhaled long-acting beta 2 -agonists (LABA) o methylxanthines o phosphodiesterase-4 (PDE-4) inhibitor o oral corticosteroids (chronic use) Oral or injectable corticosteroids (short course <14 days) only for the short term treatment of COPD exacerbations and/or pneumonia Antibiotics (short course <14 days) for the short term treatment of COPD exacerbations and/or pneumonia Mucolytics such as acetylcysteine Long term oxygen therapy (LTOT). To be eligible to enter the study subjects who are on LTOT must be using at a flow rate of 4 liters/minute over 24 hours. However, oxygen therapy may be adjusted as deemed medically necessary at any time during the study. Oxygen therapy must be captured on the concomitant medication page of the ecrf. Supplemental oxygen is recommended for patients who exhibit oxyhemoglobin desaturation with rest or exertion (e.g. SaO2 88%) Maintenance phase of pulmonary rehabilitation treatment (subjects are not allowed to initiate treatment during the study). The following non-copd medications are permitted during the study (for example): Medications for rhinitis (e.g. intranasal corticosteroids, antihistamines, cromolyn, nedocromil, nasal decongestants) Topical and ophthalmic corticosteroids Unplanned localized corticosteroid injections (e.g. intra-articular and epidural) Vaccinations (Influenza vaccine, Pneumonia vaccine, Shingles vaccine, etc). Administration of influenza and pneumonia vaccines should be considered based on clinical discretion of the investigator and local/national guidelines. Influenza vaccines and pneumonia vaccines will be captured on the concomitant medication pages of the ecrf) Allergy immunotherapy Antibiotics for short-term treatment (14 days) of acute infections. Long term treatment with antibiotics is not allowed Systemic and ophthalmic beta-blockers Smoking cessation treatments Cough suppressants Anti-depressants and anxiolytics Continuous Positive Airway Pressure (CPAP) 41

145 2013N183405_ Prohibited Medications and Non-Drug Therapies Medications noted as part of exclusion criteria are prohibited for the duration of the treatment period. Eligible subjects are expected to continue their baseline COPD medications during the run-in period. On the morning of the screening visit (Visit 1) subjects will refrain from taking their morning dose of their usual COPD medications until instructed to do so by clinic personnel. Rescue medication (i.e. salbutamol or ipratropium) must be withheld for at least 4 hours before visits when spirometry is required (see Table 2) and prior to reversibility testing at Visit 1. COPD medications and non-drug therapies that are prohibited during the randomized portion of the study: Acute phase of pulmonary rehabilitation (at any time during the study including run-in) Long term systemic antibiotic therapy (antibiotics used for <14 days for acute infections or for exacerbations or pneumonia are allowed) Omalizumab [Xolair] Other monoclonal antibodies Experimental anti-inflammatory drugs (non biologicals) Immunosuppressive medications including but not limited to o Corticosteroids intramuscular, long-acting depot if used to treat a condition other than COPD o Methotrexate, troleandomycin, cyclosporine, azathioprine o Oral gold o Chemotherapy used for conditions other than COPD o Regular systemic (oral or parenteral) corticosteroids for the treatment of conditions other than COPD Other investigational products (subjects must have not received investigational products for 1 months or 5 half-lives prior to Visit 1, whichever is longer) Bilevel positive airway pressure (BiPAP) is not permitted Radiation therapy is excluded for 12 months prior to visit one and throughout the study 42

146 2013N183405_ Treatment after the End of the Study The investigator is responsible for ensuring that consideration has been given to the poststudy care of the patient s medical condition whether or not GSK is providing specific post study treatment Treatment of Study Treatment Overdose The dose of mepolizumab considered to be an overdose has not been defined. There are no known antidotes and GSK does not recommend a specific treatment in the event of a suspected overdose. The investigator should use clinical judgement in treating the symptoms of a suspected overdose. 43

147 2013N183405_02 6. STUDY ASSESSMENTS AND PROCEDURES Table 2 Time and Events Protocol Activity Screen/Run-in Randomized Treatment (visit window is ± 7 days) V0 a V1 V2 b V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 Exit Visit Withdrawal Discontinue from IP Visit c Withdraw from study Visit c Pre-screening V1(S) Week Week Week Week Week Week Week Week Week Week Week Week Week Week Study Day 1 Procedures Written Informed Consent/PGx consent X d Demography/child bearing status assessment X Medical history including cardiovascular, COPD, X and exacerbation Concomitant Medication Assessment X X X X X X X X X X X X X X X X X X X Inclusion/Exclusion Criteria e X X CCI X mmrc X Smoking Status X X X X X Smoking Cessation Counseling X X Parasite Screening f X Register Visit in RAMOS/IVRS X X X X X X X X X X X X X X X X X X X Efficacy Assessements Spirometry X X X X X X X X X X Follow Up V16 Week 60 44

148 2013N183405_02 Protocol Activity Screen/Run-in Randomized Treatment (visit window is ± 7 days) V0 a V1 V2 b V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 Exit Visit Withdrawal Discontinue from IP Visit c Pre-screening V1(S) Week Week Week Week Week Week Week Week Week Week Week Week Week Week Study Day 1 Reversibility Testing X ediary data review X X X X X X X X X X X X X X X X Exacerbation and Healthcare Utilization X X X X X X X X X X X X X X X Assessment SGRQ-C X X X X X X X EQ-5D-5L X X X X X CAT X X X X X X X X X X X X X X X X Subject global rating of activity level Subject global rating of activity change Clinician rated response to therapy Subject rated response to therapy Safety Assessments Adverse Events/Serious Adverse Event Assessment X X X X X X X X X X X X X X X X Withdraw from study Visit c X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X Medical Problems Diary Review X X X X X X X X X X X X X X X COPD symptoms summary report review X X X X X X X X X X X X X X X X Physical Examination X g X h X h X g X h X g Xg X g Vital Signs (including pulse oximetry) X X X X X X X X X X X X X X X X X X Follow Up V16 Week 60 45

149 2013N183405_02 Protocol Activity Screen/Run-in Randomized Treatment (visit window is ± 7 days) V0 a V1 V2 b V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 Exit Visit Withdrawal Discontinue from IP Visit c Withdraw from study Visit c Pre-screening V1(S) Week Week Week Week Week Week Week Week Week Week Week Week Week Week Study Day 1 ECG X X X X X X X X Chest x-ray X i Laboratory Assessments Hematology with differential j X X X X X X X X X X X X X X X X X X Clinical Chemistry s X X X k X k X X X X X X X Clinical chemistry with lipoproteins (fasting) l X X X X X Urine Pregnancy Test m X X X X X X X X X X X X X X X X X X PGx Sampling (blood) X n Hepatitis B and C testing o X LFT testing (only in hepatitis B positive subjects) p X X X X X X X X X X X X X X X X Pharmacokinetic Sample q X X X X X X X Immunogenicity sample X X X X X X Exploratory Lab Assessments Total IgE X Blood Biomarker X X X X X Serum IL-5 X X X Study Supplies and Investigational Product Electronic Diary X r registration and training Electronic Diary close out X X Administer Investigational Product X X X X X X X X X X X X X Follow Up V16 Week 60 46

150 2013N183405_02 Protocol Activity Screen/Run-in Randomized Treatment (visit window is ± 7 days) V0 a V1 V2 b V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 Exit Visit Withdrawal Discontinue from IP Visit c Withdraw from study Visit c Pre-screening V1(S) Week Week Week Week Week Week Week Week Week Week Week Week Week Week Week Study Day 1 Dispense Rescue Salbutamol X X X X X X X X X X X X X X Collect Used Rescue Salbutamol X X X X X X X X X X X X X X X Complete electronic Case Report Form (ecrf) X X X X X X X X X X X X X X X X X X a. The pre-screening visit (Visit 0) can occur on the same day as the screening visit (Visit 1) but must be completed prior to initiating any Visit 1 procedures. b. Visit 2 can occur 1 to 2 weeks after Visit 1. Results from Visit 1 procedures must be available for review of randomization criteria. c. See definition in Section 4.4 and Section 4.5 for additional information. d. Informed consent for optional PGx (pharmacogenetics) research must be obtained before collecting a sample. e. Inclusion and Exclusion criteria should be assessed at Visit 1 and Randomization Criteria assessed at Visit 2. f. Parasitic screening is only required in countries with high-risk or for subjects who have visited high-risk countries in the past 6 months. Sites should use local laboratories. g. A comprehensive physical exam should be conducted. See Section for specific details of the comprehensive physical exam. h. A brief physical exam should be conducted. See Section for specific details of the brief exam. i. Only required if results from a chest x-ray or CT-scan, taken within the past 6 months, is not available. j. Differential results will be blinded from Visit 3 onwards. k. Liver panel only l. Subject must be in fasting state. If subject has not fasted they may return to the clinic to provide this sample. m. Pregnancy testing is only required for females of child bearing potential. An assessment must be made at baseline to determine child bearing potential of each female study participant (see Section ). n. PGx consent must be obtained prior to collecting the PGx blood sample. The PGx sample can be collected at any visit post-randomization (i.e. at Visit 3 or any visit after Visit 3). o. If hepatitis C positive confirmation by testing the same sample is required. See Quest manual for details. For subjects who are HBsAg positive or HBcAb positive reflexive testing must be conducted to assess HBV DNA p. If ALT 3X ULN, reflexive testing should be conducted for HBV-DNA q. PK samples must be taken pre-dose r. Thorough ediary training should be conducted at Visit 1 and throughout the study on an as-needed basis s. Clinical chemistry will include analytes and liver chemistry monitoring as detailed in the SPM. Follow Up V16 47

151 2013N183405_ Critical Baseline Assessments Subjects should conduct the pre-screening visit (Visit 0) up to 30 days prior to the screening visit (Visit 1). A subject number will be assigned at this time of signing informed consent. During the pre-screening Visit, study designated personnel should provide informed consent, and pharmacogenetics (PGx) informed consent, to potential study participants. Site staff will review with the subject any study related procedures that must be taken prior to the next visit (i.e., fasting for lab assessments, withholding of SABA or SAMA for 4 hours and withholding of COPD medication on the morning of Visit 1, etc) Pre-screening Visit Subjects can complete pre-screening and screening visits on the same day. Once the informed consent process is complete, and the subject has agreed to participate by signing the informed consent documents, additional pre-screening assessments can be conducted. The pre-screening assessment will include the collection of demographic information (including race, age, and gender), an assessment of child bearing status for all potential female study participants, and an assessment of COPD medication use in the 3 months prior to study Critical Procedures Performed at Visit 1 (Screening) The required order of completion of these assessments can be found in the SPM. Medical history including but not limited to COPD history (comprised of date of diagnosis and COPD type [emphysema and/or chronic bronchitis]), smoking status, history of diabetes, history of hypertension, history of osteoporosis, and history of cataracts. See ecrf completion guidelines for additional information of the data that will be captured. Cardiovascular (CV) medical history/risk factors and CV medication history will be assessed at screening. This assessment must include a review of the subject s blood pressure, smoking history, cardiovascular medical conditions, and family history of premature cardiovascular disease. Current and prior COPD medication history used in the 12 months prior to Visit 1 COPD exacerbation history in the 12 months prior to Visit 1 including the recording of COPD maintenance medications taken at the time of exacerbation and details of exacerbation treatment A comprehensive physical exam (see Section for details) Vital sign measurement including measurement of pulse rate, blood pressure, body temperature, and pulse oximetry. Comprehensive training on the electronic diary including subject in office completion of the training diary and a practice data transmission. 48

152 2013N183405_02 Completion of questionnaires outlined in Table 2, including baseline assessment with modified Medical Research Council grading system (mmrc; see Section ) and the Charlson co-morbidity index (CCI; see Section ), prior to spirometry. Pulmonary function tests including bronchodilator responsiveness testing Chest X-ray or if available review of chest x-ray conducted in the prior 6 months Resting 12 lead ECG Inclusion/exclusion criteria assessment Determination and documentation in source of child bearing potential for female subjects (see definition in Section ). If child bearing potential is questionable an assessment of follicle stimulating hormone (FSH) and estradiol should be obtained and analyzed to confirm childbearing potential. A pregnancy test is required for females of child bearing potential (FCBP) at screening and prior to randomization and at each scheduled study visit prior to the administration of investigational product Laboratory testing as indicated in Section which includes but not limited to the following: Clinical Chemistry including glucose and potassium Hematology with differential Hepatitis B and Hepatitis C screening. For those who are Hepatitis B positive (surface antigen or core antibody) reflexive testing will be performed to assess Hepatitis B virus (HBV-DNA) load to determine eligibility and/or required on treatment monitoring. Parasitic screening (only in countries with a high risk or in subjects who have visited a high risk country) Modified Medical Research Council Grading System (mmrc) The subject s degree of dyspnea to different levels of activity will be rated on the five point mmrc scale. The mmrc, administered by an interviewer, asks subjects to rate how breathless they are on a 5-point Guttman scale Charlson Co-morbidity index (CCI) The Charlson Co-morbidity Index contains 19 categories of co-morbidity and predicts the ten-year mortality for a patient who may have a range of co-morbid conditions. Each condition is assigned with a score of 1, 2, 3, or 6 depending on the risk of dying associated with this condition. 49

153 2013N183405_ Definition of child bearing and non-child bearing potential Females of childbearing potential are defined as females with functioning ovaries (i.e., post-menarche, premenopausal women with no documented impairment of oviductal or uterine function that would cause sterility). This category includes females with oligomenorrhea, females who are peri-menopausal, and young females who have begun to menstruate (adolescents). The information on the lack of impairment of oviductal or uterine function that would cause sterility can come from the site personnel s: Review of subject s medical records Medical examination of the subject Interview with the subject on her medical history. Females of non-childbearing potential are defined as females with functioning ovaries and with a documented tubal ligation or hysterectomy; or females who are postmenopausal defined as 12 months of spontaneous amenorrhea with an appropriate clinical profile, e.g., age appropriate, >45 years, in the absence of hormone replacement therapy (HRT). In questionable cases a blood sample for follicle stimulating hormone (FSH) and estradiol will be obtained and analyzed to confirm childbearing potential. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods listed above for females of childbearing potential if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks should elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method Critical Procedures Performed at Visit 2 (Randomization) Review the results of assessments collected at Visit 1, including laboratory and safety assessments and re-assess subject eligibility. Review of electronic diary (ediary) data and compliance. Address any concerns the subject may have with the completion of the daily ediary. Conduct additional training if deemed necessary. Complete Questionnaires as indicated in Table 2. Questionnaires must be completed prior to the administration of Investigational Product. Conduct spirometry. Spirometry must be completed prior to the administration of Investigational Product. Conduct laboratory assessments as listed in Table 2. Laboratory assessments must be collected prior to administration of Investigational Product. 50

154 2013N183405_02 This visit includes chemistry plus lipoprotein panel. The subject must have fasted. Administer Investigational Product Train subjects on the completion of the medical problems and healthcare utilization worksheets. Provide worksheets and instruct subject to return worksheets at the next visit. Safety monitor subjects for the protocol specified time following administration of Investigational Product. See Section Efficacy Primary Efficacy Endpoint Frequency of moderate/severe exacerbations. Moderate exacerbations are defined as COPD exacerbations that require either systemic corticosteroids (intramuscular (IM), intravenous, or oral) and/or antibiotics. Severe exacerbations are defined as COPD exacerbations requiring hospitalization or result in death Secondary Efficacy Endpoints Time to first moderate/severe exacerbation Frequency of COPD exacerbations requiring emergency department (ED) visits and/or hospitalizations Change from baseline mean total St. George s Respiratory Questionnaire-COPD (SGRQ-C) score Change from baseline COPD assessment test (CAT) score Other Efficacy Endpoints Frequency of moderate COPD exacerbation Frequency of severe COPD exacerbations Occasions of rescue medication use Proportion of SGRQ-C responders Change from baseline in FEV 1 and FVC Change from baseline EQ-5D-5L Frequency of COPD exacerbations requiring re-hospitalization within 30 days 51

155 2013N183405_ Spirometry and Bronchodilator Responsiveness Testing Spirometry Spirometry measurements will be obtained using spirometry equipment that meets or exceeds the minimal performance recommendations of the ATS [Miller, 2005]. All subjects will have spirometry performed at Screening and scheduled clinic visits during the treatment period as indicated in Table 2. For FEV 1 and FVC determinations, at least 3 acceptable spirometry efforts (with no more than 8) should be obtained. Acceptable spirometry efforts should have a satisfactory start of test and end of test (i.e. a plateau in the volume-time curve) and be free from artifacts due to cough, early termination, poor effort, obstructed mouthpiece, equipment malfunction, or other reasons [Miller, 2005]. The largest FEV 1 and FVC from the 3 acceptable efforts should be recorded, even if they do not come from the same effort. Additional details about acceptable, quality, spirometry testing are provided in the SPM. Spirometry must be performed as follows: Started approximately between 6:00AM and 11:00 AM After completing questionnaires at Visits where these assessments are captured (as specified in Table 2) After withholding salbutamol for 4 hours After withholding ipratropium for 4 hours After withholding the morning dose of usual COPD medications Prior to IP dosing Subjects should refrain from smoking for 1 hour prior to each pulmonary function test Subjects should abstain from drinking beverages with high levels of caffeine such as tea and coffee for 2 hours prior to each pulmonary function test A full description of the timing and conduct of spirometry procedures is provided in the SPM Bronchodilator Responsiveness Testing At the screening visit (Visit 1), both pre- and post-salbutamol spirometry will be obtained to determine subject eligibility. Bronchodilator responsiveness testing will be completed as follows: Following pre-salbutamol spirometry (three acceptable spirometry efforts), the subject will self-administer 4 puffs of salbutamol MDI. Three acceptable spirometry 52

156 2013N183405_02 efforts will be obtained approximately 10 to 30 minutes after salbutamol administration Diary Assessment Subjects will be trained at Screening (Visit 1) on the completion of daily questions through an electronic diary (edairy). The ediary should be completed each morning during the study starting the morning after Visit 1. Each day the subject will be asked to respond to questions about the following: Number of nighttime awakenings due COPD symptoms Use of supplemental rescue medication Major symptoms of COPD exacerbations concerning the subject s dyspnea, sputum volume, sputum purulence (color) Minor symptoms of COPD exacerbations: cough, wheezing, sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause Daily activity Site staff will have access to the subject COPD symptom summary report through a webbased portal. When symptoms meet a pre-defined threshold, the subject will be notified, through the ediary, to consult their study site. The primary Investigator should review the COPD symptom summary report at least monthly prior to the subject's scheduled in clinic visit. The COPD symptom summary report should be reviewed at any time the primary Investigator has concerns about worsening of the subject's condition. Investigator judgment should be used in deciding whether to report the signs and symptoms (and/or determined diagnosis) recorded in the daily diary as an AE/SAE in the ecrf. Refer to Section and Section for definitions of AE and SAE, respectively. Subjects compliance with completion of the daily diary should be reviewed at each clinic visit subject who are non-compliant should be re-educated on the importance for compliance. Every effort will be made to re-educate those subjects who continue to be non-compliant. The ediary will also be used to administer patient reported outcomes during clinic visits. Details regarding completion of the ediary are located in the SPM. 53

157 2013N183405_ Moderate and Severe COPD Exacerbations Moderate exacerbations are defined per protocol as clinically significant exacerbations that require treatment with oral/systemic corticosteroids and/or antibiotics. Severe exacerbations are defined per protocol as clinically significant exacerbations that require in-patient hospitalization (i.e., 24 hours) or result in death. The decision to treat moderate exacerbations should be corroborated by review of data from the daily symptoms ediary to confirm that the exacerbation was associated with deterioration of symptoms. For safety reasons alerts will be programmed into the ediary to encourage the subject to contact the investigator if their COPD symptoms worsen. The site will also receive notification of the alert. An alert itself will not be classified as a moderate exacerbation unless it resulted in subsequent treatment for the worsening of symptoms meeting the definition above Symptom Defined COPD Exacerbations Symptom-defined exacerbation will be identified using the following criteria. Worsening of two or more of the following major symptoms for at least two consecutive days: OR Dyspnea Sputum volume Sputum purulence (color) Worsening of any one major symptom together with any one of the following minor symptoms for at least two consecutive days: Sore throat Colds (nasal discharge and/or nasal congestion) Fever (oral temperature > 37.5 C) without other cause Increased cough Increased wheeze Site staff will have access to a symptom summary report through a web-based portal. The symptoms summary report will indicate when symptoms meet the above criteria. If a subject is determined to have an exacerbation it should be treated per protocol as described in Section

158 2013N183405_ Exacerbation Treatment If in the opinion of the investigator/treating physician the exacerbation is severe enough to warrant the need for oral corticosteroids (with or without antibiotics) the following guidelines should be used. The duration of treatment with oral corticosteroids should be 14 days (dose and type according to local practice) The duration of treatment with oral corticosteroids should not exceed 14 days unless given approval by the sponsor or representative Any course of oral corticosteroids started within 7 days of finishing a previous course will be considered as treatment for a single exacerbation If, in the opinion of the investigator/treating physician there is evidence of respiratory bacterial infection that warrants treatment with antibiotics the following guidelines should be followed: The duration of treatment with antibiotics should be 7 to 14 days (dose and type according to local practice). If first line antibiotic treatment fails and additional antibiotics are used, the total duration of antibiotic treatment should not exceed 30 days unless given approval by the sponsor or representative. Any course of antibiotics started within 7 days of finishing a previous course will be considered as treatment for a single exacerbation. Use of antibiotics for the treatment of upper or lower respiratory tract infections is not considered a COPD exacerbation unless worsening of COPD symptoms meets the criteria noted in Section All medications used for the treatment of exacerbations must be recorded in the source documents and the exacerbation page of the ecrf. Exacerbations should not be recorded in the AE section of the ecrf unless they meet the definition of an SAE St. George's Respiratory Questionnaire for COPD patients The SGRQ-C is a 40-item patient questionnaire, designed to measure health impairment by addressing the frequency of respiratory symptoms (questions 1-7) and the patient's current state (questions 8-14). The SGRQ-C is derived from the original SGRQ, and produces scores equivalent to the SGRQ instrument [Meguro, 2007]. The questionnaire (and all other visit questionnaires, as noted in the T&E table) should be completed before any other visit procedures. The questionnaire should be completed in a quiet area free from distraction while sitting at a table or a desk. Site staff should explain to the subject the importance of completing of the questionnaire for clinicians and researchers to understand how COPD affect their daily lives. The subject should be asked to complete the questionnaire as honestly as they can and stress that there are no right or wrong answers. Explain that they must answer every question. The SGRQ-C is designed for supervised self-administration which means that the subject should answer the 55

159 2013N183405_02 questionnaire by themselves but that site staff can provide advice if required. It is appropriate to help clarify a question but do not provide an answer. If patients have difficulty reading questions may be read out loud. However, you may not challenge the subject's response. Subjects must complete the questionnaire while in the clinic for their scheduled study visit. The SGRQ-C should be administered at Randomization (Visit 2) and at additional visits indicated in the Time and Events table (Table 2) EQ-5D-5L The EQ-5D-5L questionnaire will be completed by subjects at randomization and at additional visits as indicated Table 2. The EQ-5D-5L is a standardized instrument for use as a measure of health utility. It is designed for self-completion and is cognitively simple, taking only a few minutes to complete. The EQ-5D-5L is a two-part self-assessment questionnaire. The first part consists of five items covering five dimensions (mobility, self care, usual activities, pain/discomfort, and anxiety/depression). Each dimension is measured by a five-point Likert scale (no problems, slight problems, moderate problems, severe problems, and extreme problems). Respondents are asked to choose one level that reflects their "own health state today" for each of the five dimensions. Respondents can be then classified into one of 243 distinct health states. The second part is a 20-cm visual analogue scale (EQ-VAS) that has endpoints labelled "best imaginable health state" and "worst imaginable health state "anchored at 100 and 0, respectively. Respondents are asked to indicate how they rate their own health by drawing a line from an anchor box to that point on the EQ-VAS which best represents their own health on that day. EQ-5D-5L health states are converted to a single summary index by applying a formula that essentially attaches weights to each of the levels in each dimension. The formula is based on the valuation of EQ-5D health states from general population samples COPD Assessment Test The COPD Assessment Test (Jones, 2009; Jones, 2012) 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 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 Higher scores indicate greater disease impact. The CAT should be completed at each scheduled in clinic visit as indicated in Table 2. 56

160 2013N183405_ Safety Safety assessment and endpoints Incidence of adverse events including systemic (i.e., allergic/ige mediated and non-allergic) and local site injection-related reactions reported throughout the 52- week treatment period. o Systemic reactions can be allergic or non-allergic in nature and are typically mild to moderate in intensity, generally develop within several hours of the injection, and are most commonly associated with a complex of symptoms including chills, fever, nausea, vomiting, asthenia, headache, skin rash, pruritus, urticaria, arthralgia/myalgia, hypotension/hypertension, dizziness, bronchospasm, dyspnea or cough. Subjects must be monitored during IP administration and for 1 hour post-administration. o Anaphylaxis, the most severe form of hypersensitivity reactions will be assessed using the diagnostic criteria outlined by the 2006 Joint NIAID/FAAN Second Symposium on Anaphylaxis [Sampson, 2006; See Appendix 8]. Vital signs including blood pressure, body temperature, pulse rate, and pulse oximetry ECG measurements Mortality (all cause, respiratory, cardiovascular) Immunogenicity Hematological and clinical chemistry parameters throughout the 52-week treatment period and the 8-week follow up period Hepatitis B screening and monitoring Chronic stable hepatitis B is acceptable if the subject otherwise meets entry criteria (see Section 4). For subjects who are Hepatitis B surface antigen positive or hepatitis B core antibody positive with HBV DNA levels of < 2000 IU/ml at baseline, monthly liver monitoring will be required and must continue for 12 weeks after last dose of study treatment. Additional information required liver function testing is provided in Section Liver chemistry stopping and follow up criteria Phase III-IV liver chemistry stopping and follow up criteria have been designed to assure subject safety and evaluate liver event etiology (in alignment with the FDA premarketing clinical liver safety guidance). Phase III-IV liver chemistry stopping criteria 1-5 are defined below and are presented in a figure in Appendix 7: 57

161 2013N183405_02 1. ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) (or ALT 3xULN and INR>1.5, if INR measured) NOTE: if serum bilirubin fractionation is not immediately available, discontinue IP for that subject if ALT 3xULN and bilirubin 2xULN. Serum bilirubin fractionation should be performed if testing is available. If testing is unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 2. ALT 8xULN. 3. ALT 5xULN but <8 xuln persists for 2 weeks 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 discontinue IP for that subject Report the event to GSK within 24 hours of learning its occurrence Complete the liver event CRF and SAE data collection tool if the event also meets the criteria for an SAE. All events of ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 3xULN and INR>1.5, if INR measured); INR measurement is not required and the threshold value stated will not apply to patients receiving anticoagulants), termed Hy s Law, must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis). NOTE: if serum bilirubin fractionation is not immediately available, discontinue IP for that subject if ALT 3xULN and bilirubin 2xULN. Serum bilirubin fractionation should be performed if testing is available. If testing is unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. Complete the liver imaging and/or liver biopsy CRFs if these tests are performed Perform liver event follow up assessments, and monitor the subject until liver chemistries resolve, stabilise, or return to baseline values as described below. Discontinue IP (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 58

162 2013N183405_02 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 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 assessments described below: Viral hepatitis serology including: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); For subjects who were hepatitis B surface antigen positive or hepatitis B core antibody positive at baseline HBV DNA testing is also required; 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 one week of the liver event. 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 59

163 2013N183405_02 the last dose is unclear, provide the subject s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected within a week of the liver event, 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]). 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) [LeGal, 2005]. Liver imaging (ultrasound, magnetic resonance, or computerised tomography) to evaluate liver disease 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 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 60

164 2013N183405_02 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/selfharming intent. This should be reported regardless of sequelae. Lack of efficacy or failure of expected pharmacological action per se will not be reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae resulting from lack of efficacy will be reported if they fulfil the definition of an AE or SAE. Events that do not meet the definition of an AE include: Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to the procedure is an AE Situations where an untoward medical occurrence did not occur (social and/or convenience admission to a hospital) Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen The disease/disorder being studied, or expected progression, signs, or symptoms of the disease/disorder being studied, unless more severe than expected for the subject s condition 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 61

165 2013N183405_02 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 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 jeopardise the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These should also be considered serious. Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 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 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: 62

166 2013N183405_02 Acquired Long QT Syndrome Agranulocytosis/Severe Neutropenia Anaphylaxis & Anaphylactoid Reactions Hepatotoxicity Acute Renal Failure Seizure Stevens Johnson syndrome/toxic epidermal necrosis 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 judgment of the investigator are to be recorded as AEs or SAEs. However, any clinically significant safety assessments that are associated with the underlying disease, unless judged by the investigator to be more severe than expected for the subject s condition, are not to be reported as AEs or SAEs Cardiovascular Events Investigators will 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. 63

167 2013N183405_ 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 Pregnancy Any pregnancy that occurs during study participation must be reported using a clinical trial pregnancy form. To ensure subject safety, each pregnancy must be reported to GSK within 2 weeks of learning of its occurrence. The pregnancy must be followed up to determine outcome (including premature termination) and status of mother and child. Pregnancy complications and elective terminations for medical reasons must be reported as an AE or SAE. Spontaneous abortions must be reported as an SAE. Any SAE occurring in association with a pregnancy, brought to the investigator s attention after the subject has completed the study and considered by the investigator as possibly related to the study treatment, must be promptly reported to GSK Time Period and Frequency of Detecting AEs and SAEs The investigator or site staff is responsible for detecting, documenting and reporting events that meet the definition of an AE or SAE. AEs will be collected from the start of study treatment and until the follow up contact. SAEs will be collected over the same time period as stated above for AEs. However, any SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant medication, will be recorded from the time a subject consents to participate in the study up to and including any follow up contact. All SAEs will be reported to GSK within 24 hours, as indicated in Section 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? Have you had any (other) medical problems since your last visit/contact? Have you taken any new medicines, other than those provided in this study, since your last visit/contact? 64

168 2013N183405_ Prompt Reporting of Serious Adverse Events and Other Events to GSK SAEs, pregnancies and liver function abnormalities meeting pre-defined criteria will be reported promptly by the investigator to GSK as described in the following table once the investigator determines that the event meets the protocol definition for that event. Initial Reports Follow-up Information on a Previous Report Type of Event Time Frame Documents Time Frame Documents All SAEs 24 hours SAE data collection tool 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 Pregnancy 2 weeks Pregnancy Notification Form Liver chemistry abnormalities for Phase I to IV: ALT3xULN and Bilirubin2xULN (>35% direct) (or ALT3xULN and INR>1.5, if INR measured) 1 24 hours 2 SAE data collection tool. Liver Event CRF and Liver Imaging and/or Liver Biopsy CRFs, if applicable 3 Remaining liver chemistry abnormalities Phase III to IV: ALT8xULN; ALT3xULN with 24 hours 2 Liver Event Documents hepatitis or rash or (defined above) 3 3xULN and <5xULN that persists4 weeks 24 hours Updated SAE data collection tool Initial and follow up 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 2 weeks Pregnancy Follow-up Form 24 hours Updated SAE data collection tool/ Liver Event Documents 3 24 hours Updated Liver Event Documents 3 65

169 2013N183405_02 Initial Reports Follow-up Information on a Previous Report Type of Event Time Frame Documents Time Frame Documents ALT5xULN plus bilirubin <2xULN ALT5xULN and bilirubin <2xULN that persists 2 weeks ALT3xULN and <5x ULN and bilirubin <2xULN 24 hours 2 Liver Event Documents (defined above) do not need completing unless elevations persist for 2 weeks or subject cannot be monitored weekly for 2 weeks 3 24 hours 2 Liver Event Documents (defined above) 3 24 hours 2 Liver Event Documents (defined above) do not need completing unless elevations persist for 4 weeks or subject cannot be monitored weekly for 4 weeks 3 24 hours Updated Liver Event Documents, if applicable 3 24 hours Updated Liver Event Documents 3 24 hours Updated Liver Event Documents, if applicable 3 1. INR measurement is not required; if measured, the threshold value stated will not apply to patients receiving anticoagulants. 2. GSK must be contacted at onset of liver chemistry elevations to discuss subject safety 3. Liver Event Documents (i.e., Liver Event CRF and Liver Imaging CRF and/or Liver Biopsy CRF, as applicable) should be completed as soon as possible. The method of 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. The investigator is obligated to assess the relationship between investigational product and the occurrence of each AE/SAE. A "reasonable possibility" is meant to convey that there are facts/evidence or arguments to suggest a causal relationship, rather than a conclusion that a relationship to the investigational product cannot be ruled out. The investigator will use clinical judgment to determine the relationship. Alternative causes, such as natural history of the underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of the event to the investigational product will be 66

170 2013N183405_02 considered and investigated. The investigator will also consult the Investigator Brochure (IB) to assist in the determination of his/her assessment 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 Other Safety Outcomes Laboratory Assessments All protocol required laboratory assessments, as defined in Table 2, must be performed by the central laboratory, Quest Diagnostics. All lab assessments must be completed prior to injection of investigational product. Laboratory assessments must be conducted in accordance with the Central Laboratory Manual and Protocol Time and Events Schedule. Laboratory requisition forms must be completed and samples must be clearly labelled with the subject number, protocol number, site/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. All study-required laboratory assessments will be performed by a central laboratory. Routine non-fasting clinical chemistry including serum glucose and serum potassium levels will be performed at screening (Visit 1), and at clinic treatment visits indicated in the Time and Events table (Table 2). In the event of premature discontinuation from the 67

171 2013N183405_02 study a sample should be collected at the premature discontinuation visit. Samples should also be collected at follow-up visit as specified in Table 2 In addition to routine clinical chemistry subjects must provide a fasted blood sample on Visit 2, Visit 8, and Visit15 or premature discontinuation for an assessment of lipoproteins. A blood sample for Hematology with differential will be collected at every study visit, including premature discontinuation (if required) and at the follow-up visit. The results of the differential will be blinded to the study site staff and Sponsor after Visit Physical Exam A comprehensive physical exam will be performed at Visit 1, Visit 8, Visit 15 or Withdrawal. The physical exam will be conducted by the primary investigator or a qualified designee at the visits specified in Table 2 The comprehensive physical exam will include an assessment of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and extremities and will include a comprehensive medical history, and COPD history. A brief physical exam will be conducted at visits specified in Table 2 and will include an assessment of the skin, lungs, cardiovascular system and abdomen (liver and spleen) Vital Signs Vital signs including pulse oximetry will be performed at all study visits. At Screening (Visit 1) vital signs must be taken prior to spirometry. At randomization (Visit 2) and on subsequent Visits as indicated in Table 2, vital signs must be performed prior to administration of study medication and prior to spirometry. Blood pressure (systolic and diastolic) and pulse rate will be measured in the sitting position after approximately 5 minutes rest. A single set of values will be collected and recorded in the source documentation and ecrf. Oxygen saturation should be measured by pulse oximetry as part of the vital signs assessment at each visit. A single value will be collected and recorded in the source documentation and ecrf. Body temperature should also be measured Medical Problems and Concomitant Medications Subjects will be instructed to record any medical problems and the medications used to treat them over each day. These entries will be reviewed by the study coordinator at each study visit and recorded in the ecrf as adverse events as appropriate. 68

172 2013N183405_ Lead ECG All sites will use standardized ECG equipment provided by a centralized external vendor. A single 12-lead ECG and rhythm strip will be recorded after measurement of vital signs and prior to spirometry. Recordings will be made at time points outlined in Table 2. All ECG measurements will be made with the subject in a supine position having rested in this position for approximately 5 minutes before each reading. The investigator, a designated sub-investigator or other appropriately trained site personnel will be responsible for performing each 12-lead ECG. The investigator must provide his/her dated signature on the original paper tracing, attesting to the authenticity of the ECG machine interpretation. All ECGs will be electronically transmitted to an independent cardiologist (contracted by GSK) and evaluated. The independent cardiologist, blinded to treatment assignment, will be responsible for providing measurements of heart rate, QT intervals and an interpretation of all ECGs collected in this study. A hard copy of these results will be sent to the investigator. The investigator must provide his/her dated signature on the confirmed report, attesting to his/her review of the independent cardiologist s assessment. Details of the cardiac monitoring procedures will be provided by the centralized cardiology service provider Pneumonia All pneumonias should be confirmed by the presence of new infiltrate on chest x-ray and captured on the AE/SAE page and on the pneumonia page of the ecrf. Investigators and site staff should remain vigilant for the possible development and diagnosis of pneumonia as the clinical features of such infections overlap with the symptoms of COPD exacerbations. For all suspected cases of pneumonia, Investigators must confirm the diagnosis by obtaining a chest x-ray or documentation of the result of a chest x-ray performed outside of the clinic site. Appropriate therapy should be initiated for confirmed pneumonia. Confirmation by chest x-ray should occur within 48 hours of suspected pneumonia Health Outcomes All patient reported outcomes should be administered at the beginning of a study visit before spirometry and before administration of IP. SGRQ-C should be administered first followed by EQ-5D-5L, CAT, and Patient Global Rating of activity limitation and impression of change and Subject rated response to therapy, according to the scheduled outlined in Table 2. 69

173 2013N183405_ Health Outcome Assessments Not Included as Primary or Key Secondary Endpoints Healthcare Resource Utilization All unscheduled COPD-related health care utilization will be recorded including telephone contacts, specialist nurse visits, visits to a physician s office, home visits (day and night time), outpatient visits, visits to urgent care, visits to the emergency department, and hospitalizations associated with the subject s exacerbations will be recorded in the ecrf. Hospitalization data should be stratified by ward type (e.g; ICU, high dependency and usual care). Hospital length of stay in each type of ward will also be recorded. The resource utilization worksheet used by the patient to record all health care contacts experienced since the last visit will be presented to the investigator (or designated coordinator) at the visits indicated in Table 2 The investigator (or designated coordinator) should ask the subject if any of the health care contacts that are recorded on the worksheet were due to a COPD exacerbation. The investigator can refer to his/her records to verify or supplement information given by the subject, if necessary. If any unscheduled healthcare contact is due to a COPD exacerbation, then the COPD Exacerbation section of the ecrf must be completed. Details regarding completion of the Healthcare Utilization worksheet are located in the SPM Additional Health Outcomes Assessments Change from baseline in rating of activity limitation Change from baseline in subject's impression of change Change in clinician and subject response to therapy Rating of Activity Limitation and Impression of Change Subjects will complete the Global Rating of Activity limitation as outlined in Table 2. This single global question will ask subjects to rate their activity limitation on a fourpoint scale (not limited, slightly limited, limited, very limited). Subjects will complete an activity specific Global Impression of Change question as outlined in Table 2. Response options will be on a 7 point Likert scale ranging from much better to much worse Clinician/Subject Rated Response to Therapy The clinician and the subject will be asked to rate the response to therapy at the visits specified in the Time and Events schedule (Table 2). This is an overall evaluation of response to treatment, conducted separately by the investigator and the subject using a 70

174 2013N183405_02 rating scale. In this rating scale, a seven-point scale score is used with the following definitions: 1 = significantly improved 2 = moderately improved 3 = mildly improved 4 = no change 5 = mildly worse 6 = moderately worse 7 = significantly worse. The subject will indicate their response on a paper questionnaire which will be transcribed into the ecrf by study designated site staff Pharmacokinetics/Pharmacodynamics/Biomarker(s) Blood samples for analysis of mepolizumab plasma concentration will be obtained as per the Time and Events table (Table 2). Samples should be obtained prior to dosing on dosing days. The date and exact time of collection for each sample will be documented in the ecrf. Details for collection and processing of samples may be found in the SPM. Plasma analysis will be performed under the control of GSK PTS-DMPK/Scinovo, the details of which will be included in the Study Procedures Manual. Concentrations of mepolizumab will be determined in plasma samples using the currently approved bioanalytical methodology. Raw data will be archived at the bioanalytical site (detailed in the SPM) Pharmacodynamics Blood eosinophil counts will be recorded as part of standard haematological assessments performed at visits specified in the Time and Events Table (Table 2). After Visit 2 blood eosinophil counts will be blinded to the Sponsor and site staff Immunogenicity Blood samples will be collected prior to dosing at visits specified in the Time and Events Table (Table 2). Samples will be analysed for the presence of anti-mepolizumab antibodies and neutralizing antibodies. Further details regarding sample collection and processing may be found in the lab manual and the SPM Pharmacogenetic Research Information regarding pharmacogenetic (PGx) research is included in Appendix 5. 71

175 2013N183405_ Novel Biomarkers After completion of the clinical trial, investigations will be performed on samples collected during the course of the trial to detect factors or profiles that correlate with other measures of response to treatment with mepolizumab or with COPD status. The results gained may also be of application for medically related conditions. Performance of these investigations may be conditional on the results of the clinical trial and samples may be selected for analysis on the basis of the clinical outcome. Unless stated otherwise, these investigations may be performed irrespective of whether a response to mepolizumab is observed. Comparative examination of pre-dosing profiles of participants may uncover known or novel candidate biomarkers/profiles which could be used to predict response to treatment with mepolizumab or provide new insights into COPD and medically related conditions. Comparative examination of post-dosing profiles in conjunction with pre-dosing profiles may yield known and novel candidate biomarkers/profiles and new insights which relate to the action of mepolizumab. All samples will be retained for a maximum of 15 years after the last subject completes the trial. Novel candidate biomarkers and subsequently discovered biomarkers of the biological response associated with COPD or medically related conditions and/or the action of mepolizumab may be identified by application of: Proteome analysis of plasma serum samples. 7. DATA MANAGEMENT For this study subject data will be entered into GSK defined electronic case report forms (ecrfs), transmitted electronically to GSK or designee and combined with data provided from other sources in a validated data system. Management of clinical data will be performed in accordance with applicable GSK standards and data cleaning procedures to ensure the integrity of the data, e.g., removing errors and inconsistencies in the data. Adverse events and concomitant medications terms will be coded using MedDRA and an internal validated medication dictionary, GSKDrug. An appropriate medical dictionary that covers all approved drugs in studies where Japan is participating will be referenced. Electronic CRFs (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. 72

176 2013N183405_02 8. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 8.1. Hypotheses This study is designed to test the superiority of mepolizumab 100mg SC vs placebo for the group of subjects with elevated eosinophils and for all subjects in the study. The study will be stratified at randomisation according to whether or not the subject has elevated eosinophils (defined as either a blood eosinophil count of 300 cells/μl within the past 12 months or 150 cells/l at baseline). To control the experiment-wise Type 1 error rate of α=0.05, the α will be split such that 0.04 is assigned to treatment comparisons within the group with elevated eosinophils and the remaining 0.01 to treatment comparisons involving all subjects in the study. The multiple treatment comparisons planned between the primary and secondary endpoints within the group with elevated eosinophils and for all subjects in the study will be controlled using a hierarchical testing procedure; further details are given in Section Study Design Considerations Sample Size Assumptions The primary analysis in the group of subjects with elevated eosinophils is a comparison of the rate of moderate/severe exacerbations in those treated with mepolizumab 100mg SC vs placebo, this same analysis is also of interest using data from all subjects in the study. Within the group with elevated eosinophils, the null hypotheses used to test the superiority of the mepolizumab 100mg SC dose against placebo will be: H 0 : μ i = μ p where μ i is the exacerbation rate on the mepolizumab 100mg SC arm and μ p is the exacerbation rate on the placebo arm. The (one-sided) alternative hypothesis is that the exacerbation rate is lower on the mepolizumab arm: H a : μ i < μ p The estimated rate of moderate/severe exacerbations in the placebo arm is 2 exacerbations per annum (p.a.). With a two-sided 4% level of significance and a sample size of 200 randomized subjects per arm, it is estimated that within this group the smallest observed treatment effect which will result in a rejection of the null hypothesis of no difference is a reduction in exacerbation rate of 23%. Based on a true population reduction of 35%, there is a 90% 73

177 2013N183405_02 chance that the reduction will be greater than 23% and hence 90% power for demonstrating a statistically significant result for this assumed true population effect. To account for the loss of patient years data from subjects who withdraw early from the trial and for whom no follow-up data off-treatment is available, this sample size includes an additional 28 subjects per arm; this approximates to an additional 12.5% of patients years of data being collected. In total 400 subjects will be randomized to the group of subjects with elevated eosinophils, 200 to each treatment arm with a randomisation ratio of 1:1 placebo : mepolizumab 100mg SC. To allow for a comparison of treatments in the group of all subjects, an additional 400 subjects will be randomised into a group who do not fulfill the criteria of having elevated eosinophils (i.e. no evidence of a blood eosinophil count of 300cells/μL within the past 12 months and baseline eosinophil levels <150cells/μL), 200 to each treatment arm with a randomisation ratio of 1:1 placebo : mepolizumab 100mg SC. For the group of all subjects, with a two-sided 1% level of significance and a sample size of 400 subjects per treatment arm, it is estimated that the smallest observed treatment effect which will result in a rejection of the null hypothesis of no difference is a reduction in exacerbation rate of 20%. Based on a true population reduction of 30%, there is a 90% chance that the reduction will be greater than 20% and hence 90% power for demonstrating a statistically significant result for this assumed true population effect. Overall in this study, a total of 800 subjects will be randomised with a randomisation ratio of 1:1 placebo : mepolizumab 100mg SC. Randomisation will be stratified based on historical and baseline levels of eosinophils (see Section 5.2) with 400 subjects in the strata with elevated eosinophils and 400 in the strata with no evidence of elevated eosinophils. The above sample size calculation assumes the number of exacerbations p.a. follow a negative binomial distribution [Keene, 2007] with a dispersion parameter k=0.8. The estimated value for the dispersion parameter is based on data observed in a previous study (MEA112997). For patients who complete the study, exacerbations occurring on-treatment and within 4 weeks of the last dose will be included in the primary analysis. For subjects who withdraw early from the study, the intent is to continue collecting data on exacerbations for up to 52 weeks following randomization and include this in the primary analysis Sample Size Sensitivity The sample size in Section is based on assumed exacerbation rates in the placebo group and an expected reduction in this rate for subjects treated with mepolizumab. If the assumed placebo exacerbation rate or the expected reduction with mepolizumab differ then, at the given sample size there will be an effect on the power of the study.table 3 illustrates this effect on power in the group of subjects with elevated eosinophils (based on 172 subjects per arm, excluding the additional 28 subjects to account for early withdrawals, and a dispersion parameter k=0.8). 74

178 2013N183405_02 Table 3 Effect on power of varying placebo rates and reductions in rates with mepolizumab Placebo: Exacerbations rate p.a. % reduction in exacerbation rate p.a with mepolizumab 30% % % Sample Size Re-estimation No sample size re-estimation is planned for this study Data Analysis Considerations Analysis Populations All Subjects Enrolled Population (ASE) The All Subjects Enrolled Population will comprise all subjects enrolled and for whom a record exists on the study database. This population will be used for summarising reasons for screen and run-in failures. Intent-to-Treat Population (ITT) This population will consist of all randomised subjects who receive at least one dose of trial medication, and will be the primary population for all analyses of efficacy and safety data. In cases where there is a discrepancy between the treatment to which a subject was randomised and the treatment they actually received a profile of the subjects data will be produced. Intent-to-Treat Population with elevated eosinophils (ITT-EE) A subset of the ITT population, consisting of subjects with elevated eosinophils (ITT-EE) will be the primary population for the analyses of efficacy and safety data for subjects with elevated eosinophils. Intent-to-Treat Population without elevated eosinophils (ITT-nonEE) A subset of the ITT population, consisting of subjects without elevated eosinophils (ITTnonEE) will be used for descriptive analyses of efficacy and safety data for subjects without elevated eosinophils. Per Protocol Population (PP) The Per Protocol (PP) population will consist of all subjects in the Intent-to-Treat population who have not been identified as full protocol deviators with respect to criteria that are considered to impact the primary efficacy analysis. The decision to exclude a subject from the PP Population or exclude part of their data from the PP Population analyses will be made prior to breaking the blind. A 75

179 2013N183405_02 subset of this population, consisting of subjects with elevated eosinophils (PP-EE) will be used for a supplementary analysis of the primary endpoint in these subjects Analysis Data Sets All analyses will be carried out using all available data and will be detailed in the RAP Treatment Comparisons Primary Comparisons of Interest The primary treatment comparison of interest in this study is mepolizumab 100mg SC vs placebo. This treatment comparison will be made for the primary and key secondary endpoints in the group of subjects with elevated eosinophils and for all subjects in the study. To control for the multiplicity due to the two primary treatment comparisons of interest the overall of 0.05 will be split such that 0.04 is allocated to treatment comparisons for the group of subjects with elevated eosinophils and the remaining 0.01 is allocated to the treatment comparisons pertaining to all subjects in the study. Within the group of subjects with elevated eosinophils, a hierarchical testing procedure will be used to control for the multiple comparisons between the primary and key secondary endpoints. This will be carried out using a step-down closed testing procedure where inference for an endpoint in the predefined hierarchy will be dependent on statistical significance having been achieved for the previous endpoints in the hierarchy. For example, for the primary endpoint mepolizumab will be compared to placebo at a one-sided α=0.02 (two-sided α=0.04). Significance will be declared if this test demonstrates statistical significance at the one-sided 2.0% level. The next endpoint in the hierarchy (i.e. the first key secondary endpoint) will be tested only if this test is significant at the one-sided 2.0% level. This will ensure the error rate for comparisons within this group is no greater than 2.0% (one-sided). This same step-down procedure will be applied to the treatment comparisons involving all subjects in the study with significance being declared if a test demonstrates statistical significance at the one-sided α=0.005 level (two-sided α=0.01), this will ensure the error rate for comparisons involving all subjects in the study is controlled at 0.5% (one-sided). Further details are given in Section The hierarchy of endpoints to be tested is as follows: 1. Frequency of moderate/severe exacerbations (primary endpoint) 2. Time to first moderate/severe exacerbation 3. Frequency of COPD exacerbations requiring emergency department (ED) visit and/or hospitalization. 4. Change from baseline mean total St. George s Respiratory Questionnaire-COPD (SGRQ-C) score 5. Change from baseline COPD assessment test (CAT) score 76

180 2013N183405_ Other Comparisons of Interest There are no other treatment comparisons of interest within this study Interim Analysis No formal interim analyses of efficacy data are planned for this study. The schedule of any planned interim safety analyses and the analysis plan for the IDMC review are described in the charter which is available upon request. Only members of the IDMC and the independent statistical centre responsible for preparing results for the IDMC will have access to unblinded randomisation codes and any interim safety results. The study statistician, investigators, and GSK personnel involved in monitoring of the study will not be unblinded until the study completes as planned or is terminated Meta-analysis Exacerbations requiring emergency department visits and/or hospitalization occur infrequently and therefore it is likely that there will be insufficient patients recruited within this study to appropriately assess whether there is a reduction in these events with mepolizumab. Therefore a pre-specified meta-analysis of subject level data from this study and from Study MEA will be carried out once both studies have completed. Only data from the group of subjects with elevated eosinophils in this study will be included (study MEA is being conducted in parallel to this study and only recruits subjects with elevated eosinophils). The primary endpoint for this meta-analysis will be the frequency of COPD exacerbations requiring an emergency department visit and/or hospitalisation, with the frequency of COPD exacerbations requiring hospitalisation as a secondary endpoint. Analysis of these endpoints will follow the methods described below for the primary endpoint, with an additional covariate of study. The primary comparison of this fixed effects meta-analysis will be of mepolizumab 100mg SC vs. placebo. Further details with regard to this pre-specified meta-analysis will be documented in a RAP which will be finalised prior to the unblinding of treatment codes in either study Key Elements of Analysis Plan The primary analyses of efficacy will be performed on the ITT-EE population. The primary endpoint will also be analysed for the PP-EE population. Additional efficacy analyses will be carried out for all subjects in the study and for subjects with no evidence of elevated eosinophils. Full details of all analysis methods to be used will be provided in the RAP. 77

181 2013N183405_ Primary Analyses The primary endpoint for the group of subjects with elevated eosinophils and for all subjects in this study is the frequency of moderate or severe exacerbations expressed as an exacerbation rate p.a. All exacerbations from the start of treatment until 4 weeks after the last dose of study medication will be included in the primary analysis. In addition the study is designed to continue collecting exacerbation data for up to 52 weeks after randomization for subjects who have withdrawn early from the study, all exacerbation data collected for these subjects will also be included in the primary analysis. Exacerbations which are separated by less than 7 days will be treated as a continuation of the same exacerbation. The numbers of moderate/severe exacerbations are assumed to follow a negative binomial distribution. The primary analysis of the rate of moderate/severe exacerbations will use a generalised linear model with a log-link function. This model will include covariates of smoking status (current vs never/ex-smoker), number of exacerbations in previous year (as an ordinal variable), baseline disease severity (as % predicted FEV 1 ) and geographic region with log e (time in study) as an offset variable. The primary analyses will be performed on the ITT-EE population with supporting analyses in the PP-EE population. Additional analyses will be carried out for all subjects in the study and for subjects with no evidence of elevated eosinophils. Full details of the analysis methods to be used will be provided in the RAP Efficacy Analyses Key Secondary Endpoints The time to the first moderate/severe exacerbation will be analysed using a Cox s proportional hazards model allowing for covariates of smoking status (current vs never/ex-smoker), number of exacerbations in previous year (as an ordinal variable), baseline disease severity (as % predicted FEV 1 ) and geographic region. Summaries and graphs of the Kaplan-Meier estimates of the proportion of subjects with a moderate/severe exacerbation over time will be produced. Exacerbations that resulted in an ED visit or hospitalization will be analysed using the same methods as for the primary endpoint. Change from baseline in the St. George s Respiratory Questionnaire-COPD (SGRQ-C) total score will be analysed using mixed model repeated measures adjusting for baseline SGRQ-C, smoking status, geographic region, visit by baseline SGRQ-C interaction and visit by treatment group interaction. Change from baseline in the COPD assessment test (CAT) score will be analysed using mixed model repeated measures adjusting for baseline CAT score, smoking status, geographic region, visit by baseline CAT score interaction and visit by treatment group interaction. 78

182 2013N183405_ Other Endpoints See Section for a list of all other endpoints. Full details of any analyses to be performed on these endpoints will be provided in the RAP Safety Analyses The ITT-EE and the ITT-nonEE population will be used for the analysis of safety data. Summaries of data will include data from scheduled assessments only, all data will be reported according to the nominal visit for which it was recorded (i.e. no visit windows will be applied). Data from unscheduled visits will be included in overall and any post-baseline summaries. Further details will be provided in the RAP Extent of Exposure The number of subjects administered investigational product, the number of treatments administered and the number of days over which treatment was administered will be summarised Adverse Events Adverse Events (AEs) will be coded using the standard GlaxoSmithKline Medical Dictionary for Regulatory Activities (MedDRA) and will be grouped by system organ class. AEs will be summarised by frequency and percentage of subjects, by system organ class and preferred term within each treatment group. Separate summaries will be presented for all AEs, drug-related AEs, serious AEs (SAEs), AE s leading to permanent discontinuation of IP or withdrawal from study and for any AEs of special interest Clinical Laboratory Evaluations Haematology (including blood eosinophils) and clinical chemistry data will be summarized at each scheduled assessment. The proportion of values outside of the normal reference range and those meeting the criteria for potential clinical significance will also be summarised. Further details will be provided in the RAP Other Safety Measures Actual values and change from baseline for other scheduled safety assessments such as vital signs (pulse rate, systolic and diastolic blood pressure), 12-lead ECG parameters (QTcF, QTcB and heart rate) will be summarized at each scheduled visit. Further details will be provided in the RAP Immunogenicity Immunogenicity data will be summarised using appropriate descriptive statistics. 79

183 2013N183405_ Health Outcomes Analyses Full details of the analyses to be performed on all health outcomes endpoints will be given in the RAP Pharmacokinetic Analyses Blood samples will be collected to determine mepolizumab plasma concentrations as Visits specified in the Time and Events Table (Table 2). Sparse blood sampling is being implemented in this study. The mepolizumab plasma concentrations from this study will be evaluated using the population PK model developed based on previous mepolizumab data collected during mepolizumab clinical development. The analysis will be conducted using for example NONMEM 7 and will allow the determination for example of the population and/or individual systemic exposure, volume of distribution and clearance as well as characterise the between- and within subject variability. The effect of subjects characteristics such as, for example, body weight, age, sex, serum creatinine on mepolizumab systemic exposure will also be explored in order to explain the inter-subject variability in drug exposure. Pharmacokinetic data will be presented in graphical and/or tabular form and will be summarized descriptively. No statistical analysis of PK data will be carried out Pharmacodynamic Analyses Blood eosinophils ratio to baseline will be analysed using mixed model repeated measures adjusting for baseline, smoking status, geographic region, visit by baseline interaction and visit by treatment group interaction Values below the lower limit of quantification will be imputed as half the lower limit of quantification prior to analysis. Data will be log-transformed prior to analysis Pharmacokinetic/Pharmacodynamic Analyses If deemed appropriate, details of any PK/PD analyses to be performed will be given in the RAP Pharmacogenetic Analyses See Appendix 5 for details of Pharmacogenetics Analyses Novel Biomarker(s) Analyses The results of these biomarker investigations will be reported separately from the main clinical study report. All endpoints of interest from all comparisons will be descriptively and/or graphically summarised as appropriate to the data. 80

184 2013N183405_02 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 Regulatory and Ethical Considerations, Including the Informed Consent Process Prior to initiation of a study site, GSK will obtain favourable opinion/approval from the appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical Practice (GCP) and applicable country-specific regulatory requirements. The study will be conducted in accordance with all applicable regulatory requirements. The study will be conducted in accordance with ICH GCP, all applicable subject privacy requirements, and the ethical principles that are outlined in the Declaration of Helsinki 2008, including, but not limited to: Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and favourable opinion/approval of study protocol and any subsequent amendments. Subject informed consent. Investigator reporting requirements. GSK will provide full details of the above procedures, either verbally, in writing, or both. Written informed consent must be obtained from each subject prior to participation in the study. 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 5 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 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, 81

185 2013N183405_02 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 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 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 noncompliance. 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. 82

186 2013N183405_ 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 Provision of Study Results to Investigators, Posting of Information on Publicly Available Clinical Trials Registers and Publication Where required by applicable regulatory requirements, an investigator signatory will be identified for the approval of the clinical study report. The investigator will be provided reasonable access to statistical tables, figures, and relevant reports and will have the opportunity to review the complete study results at a GSK site or other mutuallyagreeable location. GSK will also provide the investigator with the full summary of the study results. The investigator is encouraged to share the summary results with the study subjects, as appropriate. GSK will provide the investigator with the randomization codes for their site only after completion of the full statistical analysis. 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 83

187 2013N183405_02 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 Independent Data Monitoring Committee (IDMC) An IDMC will be utilised in this study to ensure external objective medical and/or statistical review of safety and/or efficacy issues in order to protect the ethical and safety interests of subjects and to protect the scientific validity of the study. The schedule of any planned interim analysis and the analysis plan for IDMC review is described in the charter, which is available upon request Adjudication Committee An adjudication committee will be established to independently review safety outcomes as further defined in the charter which is available upon request. The committee members will remain blinded to treatment. 84

188 2013N183405_ REFERENCES Bafadhel M,McKenna S, Terry S,Mistry V, Reid C, Haldar P, McCormick, M, Haldar K, Kebadze T, Duvoix A, et al. Acute exacerbations of COPD: identification of biological clusters and their biomarkers. Am J Respir Crit Care Med 2011;184: Bafadhel M., McCormick M., et al. Profiling of sputum inflammatory mediators in asthma and chronic obstructive pulmonary disease. Respiration (1): Bafadhel M., McKenna S., Terry S., Mistry V., Pancholi M., Venge P., Lomas D.A., Barer M.R., Johnston S.L., Pavord I.D., Brightling C.E. Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: A randomized placebo-controlled trial. Am J Resp Crit Care Med :1 (48-55) Brightling C.E., McKenna S., Hargadon B., Birring S., Green R., Siva R., Berry M., Parker D., Monteiro W., Pavord I., Bradding P. Sputum eosinophilia and the short term response to inhaled mometasone in chronic obstructive pulmonary disease. Thorax 2005; 60: Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004;23: Connors, A. F., Dawson, N. V., et al. Outcomes following acute exacerbation of severe chronic obstructive lung disease. The SUPPORT investigators (Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments). Am J Respir Crit Care Med (4 Pt 1): Dmitrienko A., Tamhane AC., Wiens BL., General Multistage Gatekeeping Procedures. Biom 2008: 50 (5): Donaldson G. C., Seemungal T.A., Bhowmik A., Wedzicha J.A et al. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax (10): Eltboli, O., Brightling, C.E., Eosinophils as diagnostic tools in chronic lung disease. Expert Rev Respir Med (1): Gevaert P, Lang-Loidolt D, Lackner A, et al. Nasal IL-5 levels determine the response to anti-il-5 treatment in patients with nasal polyps. J Allergy Clin Immunol. 2006; 118: GlaxoSmithKline Document Number CM2003/00010/08Compound ID SB Investigator s Brochure for Mepolizumab. Report Date 08-APR GOLD. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease.Revised 2013:

189 2013N183405_02 Green, R. H., C. E. Brightling, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet (9347): Hankinson JL, Kawut SM, Shahar E, Smith LJ, MD, Hinckley Stukovsky K, and Barr RG. Performance of American Thoracic Society-Recommended Spirometry Reference Values in a Multiethnic Sample of Adults: The Multi-ethnic Study of Antherosclerosis (MESA) Lung Study. Chest, 2010;137: 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: James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. Pharmacokinetics of Acetaminophen-Protein Adducts in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37(8): Jones, P., Harding, G., Berry, P., Wiklund, I., Chen, W-H., Leidy, N. Development and first validation of the COPD Assessment Test (CAT) Eur Respir J : Jones, P., Harding, G., Wiklund, I., Berry, P., Tabberer, M., Yu, R., Leidy, N. Tests of the Responsiveness of the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) Following Acute Exacerbation and Pulmonary Rehabilitation. Chest Keene ON, Jones MRK, Lane PW, Anderson J. Analysis of exacerbation rates in asthma and chronic obstructive pulmonary disease: example from the Tristan study. Pharmaceut. Statist. 2007; 6:89-87 Kim YJ, Prussin C, Martin B, et al. Rebound eosinophilia after treatment of hypereosinophilic syndrome and eosinophilic gastroenteritis with monoclonal anti IL-5 antibody SCH J Allergy Clin Immunol (6): LeGal 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): Meguro M, Barley EA, Spencer S et al. Development and validation of an improved COPD-Specific Version of the St. George Respiratory Questionnaire. Chest : Miller MR, Hankinson J, Odencrantz J, Standardisation of spirometry. Eur Respir J. 2005; 26: Saha S., Brightling CE. Eosinophilic airway inflammation in COPD. Int J Chron Obstruct Pulmon Dis 2006;1: Sampson HA., Munoz-Furlong A., Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: summary-report Second National Institute of 86

190

191 2013N183405_ APPENDICES Appendix 1: Acceptable Birth Control To be eligible for entry into the study, females of childbearing potential (FCBP) must commit to consistent and correct use of an acceptable method of birth control from the time of consent, for the duration of the trial, and for 4 months after the last study drug administration. Male partner who is sterile prior to the female subject s entry into the study and is the sole sexual partner for that female subject Abstinence from penile-vaginal intercourse. Abstinence is only acceptable as effective contraception in this trial when it is a lifestyle choice. Implants of levonorgestrel or etonogestrel Injectable progestogen Oral contraceptive (either combined or progestogen alone) Estrogenic vaginal ring Percutaneous contraceptive patches Any intrauterine device (IUD) with a documented failure rate of less than 1% per year. Male condom combined with a vaginal spermicide (foam, gel, film, cream, or suppository) Male condom combined with a female diaphragm, either with or without a vaginal spermicide (foam, gel, film, cream, or suppository) Females of childbearing potential are defined as females with functioning ovaries (i.e., post-menarche, premenopausal women with no documented impairment of oviductal or uterine function that would cause sterility). This category includes females with oligomenorrhea, females who are peri-menopausal, and young females who have begun to menstruate (adolescents). The information on the lack of impairment of oviductal or uterine function that would cause sterility can come from the site personnel s: Review of subject s medical records Medical examination of the subject Interview with the subject on her medical history. Females of non-childbearing potential are defined as females with functioning ovaries and with a documented tubal ligation or hysterectomy; or females who are postmenopausal defined as 12 months of spontaneous amenorrhea with an appropriate clinical profile, e.g. age appropriate, >45 years, in the absence of hormone replacement therapy (HRT). 88

192 2013N183405_02 In questionable cases a blood sample for follicle stimulating hormone (FSH) and estradiol will be obtained and analyzed to confirm childbearing potential. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods listed above for females of childbearing potential if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks should elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method. Based on the absence of an identified reproductive hazard from preclinical studies, absence of a genotoxic potential, and very low levels of mepolizumab that might be present in semen, there is no recognized risk for mepolizumab to affect human sperm or the fetus if transferred to a female partner via semen. Therefore, the use of condoms or other methods of contraception in the male study subject is not required. 89

193 2013N183405_ Appendix 2: ECG Exclusion Criteria for Screening and Pre- Dose Randomization An abnormal and clinically significant finding that would preclude a subject from entering the trial is defined as a 12-lead tracing that is interpreted as, but not limited to, any of the following: Sinus tachycardia 120bpm *Note: sinus tachycardia 110bpm should be confirmed by two additional readings at least 5 minutes apart Multifocal atrial tachycardia (wandering atrial pacemaker with rate >120bpm) Junctional tachycardia (heart rate >100bpm) Non-sustained and sustained tachycardia (>100bpm) Ventricular tachycardias (sustained, non-sustained (>3 up to 30 sec), polymorphic, or monomorphic) Atrial fibrillation with rapid ventricular response (rate >120bpm) Atrial flutter with rapid ventricular response (rate >120bpm) Ventricular flutter Ventricular fibrillation Torsades de Pointes Wide QRS tachycardia (diagnosis unknown) Evidence of Mobitz type II second degree or third degree atrioventricular (AV) block AV dissociation Trifascicular block QT >600msec For subjects with a QRS interval <120msec: QTc(F) 450msec or an ECG that is unsuitable for QT measurements (e.g., poor defined termination of the T wave). For subjects with a QRS interval 120msec: QTc(F) 480msec or an ECG that is unsuitable for QT measurements (e.g., poor defined termination of the T wave). *Note: All potentially exclusionary QTC prolongations should be confirmed by two additional readings at least 5 minutes apart. Myocardial infarction (acute or recent) *Note: Evidence of an old (resolved) myocardial infarction is not exclusionary. 90

194 2013N183405_ Appendix 3: Hepatitis B screening and monitoring 91

195 2013N183405_ Appendix 4: ECG Premature Discontinuation from IP Criteria An ECG finding that would result in subject premature discontinuation from IP postrandomization is defined as a 12-lead tracing that is interpreted as, but not limited to, any of the following: Increase in QTc (F) >60msec from baseline ECG Ventricular tachycardias (sustained, polymorphic, or monomorphic) Sustained supraventricular tachycardia (>100bpm) Ventricular flutter Ventricular fibrillation Torsades de Pointes Wide QRS tachycardia (diagnosis unknown) Uncorrected QT >600msec For subjects with a QRS interval <120msec: QTc(F) 500msec or an ECG that is unsuitable for QT measurements (e.g., poor defined termination of the T wave). For subjects with QRS interval 120msec: QTc(F) 530msec or an ECG that is unsuitable for QT measurements (e.g., poor defined termination of the T wave). *Note: All potentially exclusionary QTC prolongations should be confirmed by two additional readings at least 5 minutes apart. Myocardial infarction (acute or recent) *Note: Evidence of an old (resolved) myocardial infarction is not exclusionary. 92

196 2013N183405_ Appendix 5: 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 Abacavir HIV HLA-B* [Hetherington, 2002; 57:01 Mallal, 2002; (Human Mallal, 2008] Leukocyte Antigen B) Carbama zepine Seizure, Bipolar disorders & Analgesia Chung, 2010; Ferrell, 2008 HLA- B*15:02 Outcome 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*57:01 screening should supplement but must never replace clinical risk management strategies for abacavir hypersensitivity. Independent studies indicated that patients of East Asian ancestry who carry HLA-B*57:02 are 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*57:02 prior to initiating treatment with carbamazepine. 93

197 2013N183405_02 Drug Disease Gene Variant Irinotecan Cancer [Innocenti, UGT1A1* ; Liu, 2008; Schulz, 2009] Outcome Variations in the UGT1A1 gene can influence a patient s ability to break down irinotecan, which can lead to increased blood levels of the drug and a higher risk of side effects. A dose of irinotecan that is safe for one patient with a particular UGT1A1 gene variation might be too high for another patient without this variation, raising the risk of certain side-effects, that include neutropenia following initiation of Irinotecan treatment. The irinotecan drug label indicates that individuals who have two copies of the UGT1A1*28 variant are at increased risk of neutropenia. A genetic blood test is available that can detect variations in the gene. A key component to successful PGx research is the collection of samples during the conduct of clinical studies. Collection of whole blood samples, even when no a priori hypothesis has been identified, may enable PGx analysis to be conducted if at any time it appears that there is a potential unexpected or unexplained variation in response to mepolizumab. 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 mepolizumab. If at any time it appears there is potential variability in response in this clinical study or in a series of clinical studies with mepolizumab, the following objectives may be investigated the relationship between genetic variants and study treatment with respect to: 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. 94

198 2013N183405_02 Study Assessments and Procedures Blood samples can be taken for Deoxyribonucleic acid (DNA) extraction and used in PGx assessments. In addition to any blood samples taken for the clinical study, a whole blood sample (~6 ml) will be collected for the PGx research using a tube containing EDTA. It is recommended that the blood sample be taken at the first opportunity after a subject has been randomized (Visit 2) and provided informed consent for PGx research, but may be taken at any time while the subject is participating in the clinical study. 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 blood sample is taken on a single occasion unless a duplicate sample is required due to inability to utilize the original sample. The DNA extracted from the blood 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 mepolizumab 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 mepolizumab. Samples will be stored securely and may be kept for up to 15 years after the last subject completes the study or GSK may destroy the samples sooner. GSK or those working with GSK (for example, other researchers) will use samples collected from the study for the purpose stated in this protocol and in the informed consent form. Subjects can request their sample to be destroyed at any time. Subject Withdrawal from Study If a subject who has consented to participate in PGx research 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, 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 95

199 2013N183405_02 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 blood sample for PGx research has been collected and it is determined that the subject does not meet the entry criteria for participation in the clinical study, then the investigator should instruct the participant that their PGx sample will be destroyed. No forms are required to complete this process as it will be completed as part of the consent and sample reconciliation process. In this instance a sample destruction form will not be available to include in the site files. Pharmacogenetics Analyses Specific genes may be studied that encode the drug targets, or drug mechanism of action pathways, drug metabolizing enzymes, drug transporters or which may underpin adverse events, disease risk or drug response. These candidate genes may include a common set of ADME (Absorption, Distribution, Metabolism and Excretion) genes that are studied to determine the relationship between gene variants or treatment response and/or tolerance. In addition, continuing research may identify other enzymes, transporters, proteins or receptors that may be involved in response to mepolizumab treatment. The genes that may code for these proteins may also be studied. Genome-wide scans involving a large number of polymorphic markers (e.g., single nucleotide polymorphisms) at defined locations in the genome, often correlated with a candidate gene, may be studied to determine the relationship between genetic variants and treatment response or tolerance. This approach is often employed when a definitive candidate gene(s) does not exist and/or the potential genetic effects are not well understood. If applicable and PGx research is conducted, appropriate statistical analysis methods will be used to evaluate pharmacogenetic data in the context of the other clinical data. Results of PGx investigations will be reported either as part of the main clinical study report or as a separate report. Endpoints of interest from all comparisons will be descriptively and/or graphically 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 blood 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. 96

200 2013N183405_02 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 antiepilepticinduced skin reactions. Expert Opin. Drug Saf. 2010; 9: Ferrell PB, McLeod HL. Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations. Pharmacogenomics. 2008; 9: 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: 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 UDPglucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 2004; 22: 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: 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: 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; 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:

201 2013N183405_ Appendix 6: Country Specific Requirements No Country specific Requirements. 98

202 2013N183405_ Appendix 7: Liver Chemistry Stopping and Follow-up Criteria 99