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

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1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Stempel DA, Szefler SJ, Pedersen S, et al. Safety of adding salmeterol to fluticasone propionate in children with asthma. N Engl J Med 2016;375: DOI: /NEJMoa

2 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.

3 2011N112074_01 CONFIDENTIAL GlaxoSmithKline group of companies Division: Worldwide Development Retention Category: GRS019 Information Type: Clinical Protocol Title: Compound Number: Development Phase Effective Date: A 6-month safety and benefit study of inhaled fluticasone propionate/ salmeterol combination versus inhaled fluticasone propionate in the treatment of 6,200 pediatric subjects 4-11 years old with persistent asthma CCI18781+GR33343 IV 29-AUG-2011 Description: is a post-marketing safety and benefit study of ADVAIR that is requested by the United States Food and Drug Administration to assess the effect of inhaled fluticasone propionate (FP)/salmeterol combination (FSC) versus inhaled FP with respect to the composite endpoint of serious asthma-related outcomes. This study will be a multi-center, randomized, stratified, double-blind, parallel group, 6-month study in pediatric subjects 4-11 years of age with persistent asthma. Approximately 6,200 pediatric subjects will be randomized to 6-month double-blind treatment of either FSC 100/50mcg or FP 100mcg or FSC 250/50mcg or FP 250mcg. In addition to serious asthma-related outcomes (hospitalizations, endotracheal intubations, and deaths), asthma exacerbations, withdrawals from study treatment due to asthma exacerbation, rescue albuterol/salbutamol use, asthma symptoms, unscheduled asthma-related healthcare utilization, productivity, Childhood Asthma Control Test, and growth velocity will be assessed. Subject: ADVAIR, FLOVENT, GSK586129, CCI18781, GR33343, asthma, pediatric Author(s): Emmett, Amanda; Kral, Kenneth; Lee, Laurie A; Lincourt, William; Yun Kirby, Suyong Copyright 2011 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited. 1

4 2011N112074_01 SPONSOR SIGNATORY: CONFIDENTIAL Laurie A. Lee, MD Project Physician Leader, Pediatric LABA Safety Respiratory and Immuno-inflammation MDC Date 2

5 2011N112074_01 CONFIDENTIAL 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 Iron Bridge Road Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK Telephone: +44 (0) GlaxoSmithKline Research & Development Limited Five Moore Drive P.O Research Triangle Park, NC , USA Telephone: In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate company (or designee). Where applicable, the details of the Sponsor and contact person will be provided to the relevant regulatory authority as part of the clinical trial submission. Sponsor Medical Monitor Contact Information: Laurie A. Lee, MD Telephone: Sponsor Serious Adverse Events (SAE) Contact Information: Case Management Group, Global Clinical Safety and Pharmacovigilance Telephone: +44 (0) Fax: +44 (0) Regulatory Agency Identifying Number(s): IND Number , EudraCT Number

6 2011N112074_01 CONFIDENTIAL INVESTIGATOR PROTOCOL AGREEMENT PAGE For protocol number: 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 4

7 2011N112074_01 CONFIDENTIAL TABLE OF CONTENTS PAGE LIST OF ABBREVIATIONS... 8 PROTOCOL SUMMARY INTRODUCTION Background Rationale OBJECTIVE(S) INVESTIGATIONAL PLAN Study Design Discussion of Design SUBJECT SELECTION AND WITHDRAWAL CRITERIA Number of Subjects Inclusion Criteria Exclusion Criteria Withdrawal Criteria 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 Safety Safety Endpoints Adverse Events Definition of an AE Definition of a SAE Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs Potential Study Endpoints Pregnancy Medical Devices Time Period and Frequency of Detecting AEs and SAEs Prompt Reporting of Serious Adverse Events and Other Events to GSK Regulatory reporting requirements for SAEs

8 2011N112074_01 CONFIDENTIAL Medical History, Asthma/Asthma Exacerbation History, and Concomitant Drug Use Physical Examination Vital Signs Growth Monitoring of Asthma Status during the Study Efficacy Efficacy Endpoints Subgroup Efficacy Analyses Asthma Exacerbation Childhood Asthma Control Test Asthma Symptom Scores Rescue Albuterol/Salbutamol Use Productivity Asthma Control Days Unscheduled Asthma-related Healthcare Utilization Pharmacogenetics DATA MANAGEMENT DATA ANALYSIS AND STATISTICAL CONSIDERATIONS Hypotheses Study Design Considerations Sample Size Assumptions Composite Endpoint Rate for the Reference Group Risk Increase to Declare Non-inferiority Sample Size Estimation Data Analysis Considerations Analysis Populations Analysis Subgroups Analysis Data Sets Treatment Comparisons Primary Comparisons of Interest Interim Analysis Key Elements of Analysis Plan Safety Analyses Efficacy Analyses Primary Efficacy Endpoint Secondary Efficacy Endpoints Exploratory Efficacy Endpoints Efficacy Subgroup Considerations STUDY CONDUCT CONSIDERATIONS Posting of Information on Clinicaltrials.gov Regulatory and Ethical Considerations, Including the Informed Consent Process Quality Control (Study Monitoring) Quality Assurance Study and Site Closure Records Retention

9 2011N112074_01 CONFIDENTIAL 9.7. Provision of Study Results to Investigators, Posting to the Clinical Trials Register and Publication Data Monitoring Committee Other Committees REFERENCES APPENDICES Appendix 1: PGx

10 2011N112074_01 LIST OF ABBREVIATIONS CONFIDENTIAL AC AE AM ALT CARE CI CiC CRF CYP3A4 DMC DNA ecrf ECG ED ediary EW FDA FP FSC FU GCP GCSP GINA GSK NIH IB ICH ICS IEC INR IP IRB IVD IVRS LABA LSLV LTRA MAO MDI MedDRA MSDS NDI OCS PEF PGx PRN Adjudication Committee Adverse event Ante meridiem (before noon) Alanine aminotransferase Childhood Asthma Research and Education Confidence interval Children in care Case report form Cytochrome P450 3A4 Data Monitoring Committee Deoxyribonucleic acid Electronic case report form Electrocardiogram Emergency department Electronic diary Early withdrawal Food and Drug Administration Fluticasone propionate Fluticasone propionate/salmeterol combination Follow-up Good clinical practice Global Clinical Safety and Pharmacovigilance Global Initiative for Asthma GlaxoSmithKline National Institute of Health Investigator s brochure International Conference on Harmonisation Inhaled corticosteroid Independent Ethics Committee International normalized ratio Investigational product Institutional review board In vitro diagnostic Interactive voice response system Long-acting beta 2 -agonist Last subject s last visit Leukotriene receptor antagonist Monoamine oxidase metered-dose inhaler Medical Dictionary for Regulatory Activities Material safety data sheet National Death Index Oral corticosteroid Peak expiratory flow Pharmacogenetic Pro Re Nata, as needed 8

11 2011N112074_01 PSC PT RAP SABA SAE SMQ SNP SOC SPM SSDI ULN CONFIDENTIAL Pediatric Steering Committee Preferred term Reporting analysis plan Short-acting beta 2 -agonist Serious adverse event Standardised MedDRA Query Single nucleotide polymorphism System organ class Study Procedures Manual Social Security Death Index Upper limit of normal Trademark Information Trademarks of the GlaxoSmithKline group of companies ADVAIR DISKUS FLOVENT DISKUS Trademarks not owned by the GlaxoSmithKline group of companies Xolair 9

12 2011N112074_01 PROTOCOL SUMMARY Rationale CONFIDENTIAL Safety assessments from studies in adults with asthma using long-acting beta 2 -agonists (LABAs) in single inhaler presentations have been associated with an increased risk for rare respiratory-related events including asthma-related death and intubation [Nelson, 2006; Castle, 1993]. These studies in adults suggest that the increased risk was primarily associated with subjects who were not receiving inhaled corticosteroids (ICSs), or who received inadequate doses of ICS. The data, though, are inadequate to demonstrate that the addition of an ICS to a LABA mitigates the risk that has been observed in studies of LABAs. In a study with formoterol in children <12 years of age where concurrent ICS use was high but not compulsory, the use of LABA was associated with an increased risk for asthma-related hospitalization [Bensch, 2002]. Therefore, the US product label was changed to reflect safety concerns for patients treated with LABA medicines. While the safety profile of salmeterol used in a fixed-dose combination with fluticasone propionate (FP) has not shown an association with these same risks in adults, adolescents or children, despite extensive study in clinical trials and use worldwide [GlaxoSmithKline Briefing Information, 2008], there remains a public health debate whether the safety profile of fixed combination medications are fully established in the absence of a large, well-designed randomized controlled trial (RCT) to evaluate the occurrence of these rare events. In order to assess the safety of salmeterol in combination with FP, this randomized, double-blind study will compare inhaled FP/salmeterol combination (FSC) with inhaled FP via the composite endpoint of serious asthma-related outcomes (hospitalizations, endotracheal intubations, or deaths). In addition, efficacy data will be collected for both inhaled FSC and FP. Objective(s) The primary objective is to evaluate whether the addition of a LABA to an ICS (FSC) therapy is non-inferior in terms of risk of serious asthma-related events (asthma-related hospitalizations, endotracheal intubations, and deaths) compared with ICS alone (FP) in pediatric subjects (age 4-11 years) with persistent asthma. To declare non-inferiority, the relative risk of serious asthma-related events associated with LABA plus ICS compared with ICS alone must be less than 2.7 (a 2.7-fold increase), based on the upper bound of the 95% confidence interval (CI) on the estimate of relative risk. Additional safety measures include withdrawals from study treatment due to asthma exacerbation, adverse events leading to withdrawal from the study treatment, growth velocity, and serious adverse events (SAEs). A secondary objective of the study is to evaluate whether the addition of LABA to ICS therapy (FSC) is superior to ICS therapy alone (FP) in terms of measures of efficacy in pediatric subjects (age 4-11 years) with persistent asthma. The primary measure of efficacy is the occurrence of a severe asthma exacerbation. To declare superiority, the 10

13 2011N112074_01 CONFIDENTIAL relative risk of an asthma exacerbation associated with LABA plus ICS compared with ICS alone must be less than 1.0 (unity), based on the upper bound of the 95% CI on the estimate of relative risk. Additional efficacy measures include rescue albuterol/salbutamol use, asthma symptoms, unscheduled asthma-related healthcare utilization, productivity, and the Childhood Asthma Control Test. Study Design This study will be a multi-center, randomized, stratified, double-blind, parallel group, 6- month study in pediatric subjects with persistent asthma. The study will randomize approximately 6,200 subjects with adequate representation throughout the ages of 4 to 11 years. Potential subjects will be screened at Visit 1 to assess eligibility. At Visit 2, subjects will be randomized to 6-month double-blind treatment of either FSC 100/50mcg or FP 100mcg or FSC 250/50mcg or FP 250mcg based on their asthma control status as determined by assessment of the Childhood Asthma Control Test, number of exacerbations in the prior year, and their prior asthma medication use. Subjects will return to the clinic in 2 weeks (Visit 3), 2 months (Visit 4), 4 months (Visit 5), and 6 months (Visit 6). All subjects will be provided with albuterol/salbutamol (short-acting beta 2 -agonist) for quick relief of asthma symptoms and instructed in how and when to administer it. During the double-blind treatment period, subjects/caregivers will call daily into an Interactive Voice Response System (IVRS) to record subjects asthma symptom score, rescue albuterol/salbutamol use (other than pre-exercise treatment), nighttime awakenings due to asthma, and work (caregiver) or school/daycare (subject) missed due to asthma. Subjects will be contacted by the study site via telephone monthly at 1, 3, and 5 months post-randomization to monitor asthma status and query concerning the study outcomes of interest. Subjects will receive a follow-up telephone call to query SAEs approximately 1 week after the end-of-treatment/early withdrawal visit for both subjects who complete 6-month double-blind study treatment and subjects who end their study treatment prematurely prior to completing 6-month treatment period (withdrawn early from study treatment). All randomized subjects will be tracked for the duration of the intended study period (i.e., 6 consecutive months following randomization) for the primary outcome of interest for the study (i.e., serious asthma-related outcome [hospitalization, endotracheal intubation, or death]). Study Endpoints/Assessments The primary safety endpoint is the number of subjects experiencing an event in the composite endpoint of serious asthma-related outcomes (hospitalizations, endotracheal intubations, or deaths) over the 6-month study treatment period. Secondary safety endpoints are asthma-related hospitalizations, endotracheal intubations, and deaths, and withdrawals from study treatment due to asthma exacerbation. 11

14 2011N112074_01 CONFIDENTIAL Other safety assessments include adverse events leading to withdrawal from the study treatment, growth velocity, and SAEs. The primary efficacy endpoint is asthma exacerbations (defined as deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days or a single depot corticosteroid injection). Secondary efficacy endpoints are rescue-free days and asthma control days. Exploratory efficacy endpoints include, rescue albuterol/salbutamol use, symptom-free days, unscheduled asthma-related healthcare utilization, productivity (i.e., days of work [caregiver] or school/daycare [subject] missed due to asthma), and Childhood Asthma Control Test scores. 12

15 2011N112074_01 1. INTRODUCTION 1.1. Background CONFIDENTIAL Asthma is a chronic disease of the airways characterized by inflammation, bronchoconstriction, and airway hyper-responsiveness. Fluticasone propionate (FP), an inhaled corticosteroid (ICS), has been shown to be effective in the treatment of the inflammatory component of the disease, and salmeterol, a long-acting beta 2 -agonist (LABA), has been shown to be effective in alleviating smooth muscle contraction. A variety of asthma medications, generally targeting the inflammatory and/or obstructive components of the disease, may be selected for the treatment of asthma. The evidencebased asthma treatment guidelines recommend a stepwise approach to treat asthma where medications are increased or decreased when appropriate to gain and maintain disease control. For patients with persistent asthma symptoms, the preferred initiating controller medication (step 2 in the step-wise treatment paradigm) is low-dose ICS to target the inflammatory process in asthmatic airways. For children and adolescents 5 years of age on low-dose ICS whose asthma is uncontrolled, low-dose ICS plus adjunctive therapy (e.g., LABA, leukotriene receptor antagonist [LTRA], theophylline) or monotherapy with medium-dose ICS, may all be considered as step 3 care [GINA, 2009; NIH, 2007]. Due to the lack of comparative data for children ages 5 to 11 years, the step 3 care options are considered equivalent. Pediatric studies have shown the benefit of adding a LABA to low ICS dose in children with persistent asthma symptomatic on low-dose ICS [de Blic, 2009; Gappa, 2009]. In children as young as 4 years of age, adding a LABA to low ICS dose resulted in a greater improvement in morning peak expiratory flow (AM PEF) compared to doubling the ICS dose in both studies. Additionally, a study conducted by the Childhood Asthma Research and Education (CARE) Network showed that, in children symptomatic on FP 100mcg BID, the addition of LABA to ICS was most likely to produce the best response compared with the addition of montelukast to ICS or doubling the dose of ICS [Lemanske, 2010b] Rationale Safety assessments from studies in adults with asthma using LABA in single inhaler presentations have been associated with an increased risk for rare respiratory-related events including asthma-related death and intubation [Nelson, 2006; Castle, 1993]. These studies in adults suggest that the increased risk was primarily associated with subjects who did not report receiving ICS at baseline, or who received inadequate doses of ICS. The data, though, are inadequate to demonstrate that the addition of an ICS to a LABA mitigates the risk that has been observed in studies of LABAs. In a study with formoterol in children <12 years of age where concurrent ICS use was high but not compulsory, the use of LABA was associated with an increased risk for asthma-related hospitalization [Bensch, 2002]. Therefore, the US product label was changed to reflect safety concerns for patients treated with LABA medicines. 13

16 2011N112074_01 CONFIDENTIAL A systematic review of GlaxoSmithKline s (GSK) randomized controlled trials was conducted in 2008 [GlaxoSmithKline Briefing Information, 2008] to summarize the efficacy and risks of asthma control provided by salmeterol administered with ICS in adults and children. The results from this review demonstrated that treatment with salmeterol plus ICS resulted in greater benefit in lung function compared with ICS or ICS plus other treatment (e.g., montelukast). Similar results were seen for symptom-free days, rescue-free days, and quality of life in adults and children. Concurrent use of salmeterol and ICS was also shown to significantly reduce exacerbations requiring treatment with systemic corticosteroids. The results from the systematic review of GSK trials also demonstrated that the use of salmeterol used in a fixed dose combination with FP did not show an association with the risk for asthma-related death in adults, adolescents or children in randomized controlled clinical trials and observational studies [FDA Briefing Information, 2008]. However, there remains a public health debate whether the use of a LABA with an ICS increases the risk of serious asthma outcomes [Chowdhury, 2010; Lemanske, 2010a]. In order to assess the safety of salmeterol in combination with FP, this randomized, double-blind study will compare inhaled FP/salmeterol combination (FSC) with inhaled FP via the composite endpoint of serious asthma-related outcomes (hospitalizations, endotracheal intubations, or deaths). In addition, efficacy data will be collected for both inhaled FSC and FP. These assessments will be used to assess asthma stability and provide clinical measures to help monitor subject safety during the study period as well as to provide efficacy data of inhaled FSC and FP. 2. OBJECTIVE(S) Primary Objective The primary objective is to evaluate whether the addition of a LABA to an ICS (FSC) therapy is non-inferior in terms of risk of serious asthma-related events (asthma-related hospitalizations, endotracheal intubations, and deaths) compared with ICS alone (FP) in pediatric subjects (age 4-11 years) with persistent asthma. To declare non-inferiority, the relative risk of serious asthma-related events associated with LABA plus ICS compared with ICS alone must be less than 2.7 (a 2.7-fold increase), based on the upper bound of the 95% confidence interval (CI) on the estimate of relative risk. Additional safety measures include withdrawals from study treatment due to asthma exacerbation, adverse events (AEs) leading to withdrawal from the study treatment, growth velocity, and serious adverse events (SAEs). Secondary Objective A secondary objective of the study is to evaluate whether the addition of LABA to ICS therapy (FSC) is superior to ICS therapy alone (FP) in terms of measures of efficacy in pediatric subjects (age 4-11 years) with persistent asthma. The primary measure of efficacy is the occurrence of a severe asthma exacerbation. To declare superiority, the relative risk of an asthma exacerbation associated with LABA plus ICS compared with 14

17 2011N112074_01 CONFIDENTIAL ICS alone must be less than 1.0 (unity), based on the upper bound of the 95% CI on the estimate of relative risk. Additional efficacy measures include rescue albuterol/salbutamol use, asthma symptoms, unscheduled asthma-related healthcare utilization, productivity, and the Childhood Asthma Control Test. 3. INVESTIGATIONAL PLAN 3.1. Study Design Figure 1 Study Schematic Protocol waivers or exemptions are not allowed. Therefore, adherence to the study design requirements, including those specified in the Time and Events Table, are essential. This study will be a multi-center, randomized, stratified, double-blind, parallel group, 6- month study in pediatric subjects with persistent asthma. The study will be conducted in multiple countries. The study will randomize approximately 6,200 subjects with adequate representation throughout the ages of 4 to 11 years. Eligibility Assessments and Randomization Eligibility for participation will be based on pre-study asthma medications, assessment of asthma control based on Childhood Asthma Control Test; (see Section 6.3.4) at Visit 1, and a history of an asthma exacerbation requiring systemic corticosteroids in the previous year. Potential subjects will be screened at Visit 1 to assess eligibility. Subjects will be provided with albuterol/salbutamol (short-acting beta 2 -agonist [SABA]) for quick relief of asthma symptoms and instructed in how and when to administer it. During the 15

18 2011N112074_01 CONFIDENTIAL treatment period, subjects/caregivers will call daily into an Interactive Voice Response System (IVRS) to record subjects asthma symptom score, rescue albuterol/salbutamol use (other than pre-exercise treatment), nighttime awakenings due to asthma, and productivity. At Visit 2, subjects will be randomized to either inhaled FP 100mcg or FSC 100/50mcg or FP 250mcg or FSC 250/50mcg based on the Childhood Asthma Control Test, number of exacerbations in the prior year and their prior asthma medication use (more detail in Section 5.2). Subjects will be instructed to self-administer study medication (parental [guardian] observation will be encouraged) as one inhalation from their inhaler each morning and evening at approximately 12 hours apart and approximately at the same time each day. Clinic Visits and Study Assessments Subjects will return to the clinic in 2 weeks (Visit 3), 2 months (Visit 4), 4 months (Visit 5), and 6 months (Visit 6). During the double-blind treatment period, subjects/caregivers will call daily into the IVRS to record subjects asthma symptom score, rescue albuterol/salbutamol use (other than pre-exercise treatment), nighttime awakenings due to asthma, and work (caregiver) or school/daycare (subject) missed due to asthma. The Childhood Asthma Control Test will be administered at Visits 1, 4, 5, 6, and early withdrawal (EW). Subjects will be contacted by the study site via telephone at 1, 3, and 5 months post-randomization to monitor asthma status and query concerning the study outcomes of interest. Subjects will be dispensed an adequate treatment supply of blinded study medication and rescue albuterol/salbutamol. Ability to use study treatments will be assessed. All blinded study treatment devices will include dose counters to assess subject adherence to study medication throughout the treatment period. At the final study clinic visit (end-oftreatment visit; Visit 6), the investigator will prescribe appropriate asthma therapy and request that the parents (guardians) communicate this information to the child s asthma healthcare provider. Subjects will receive a follow-up telephone call to query SAEs approximately 1 week after the end-of-treatment for both subjects who complete 6-month study treatment and subjects who end their study treatment prematurely prior to completing 6-month treatment period (withdrawn early from study treatment). Refer to Table 3. Time and Events Table (Section 6) for study assessments and procedures associated with each clinic visit. Follow-up of Subjects for 6 Months for the Primary Outcome All randomized subjects will be tracked for the duration of the intended study period (i.e., 6 consecutive months following randomization) for the primary outcome of interest for the study (i.e., serious asthma-related outcome [hospitalization, endotracheal intubation, or death]). 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. 16

19 2011N112074_01 CONFIDENTIAL 3.2. Discussion of Design Regulatory Perspective The Food and Drug Administration (FDA) requested that all manufacturers of LABAcontaining products, including GlaxoSmithKline, conduct a post-marketing safety study, which was discussed at the FDA Advisory Committee meeting on March 10-11, is a post-marketing safety and benefit study of ADVAIR containing salmeterol (LABA) in children 4-11 years of age with persistent asthma. Study Population Given the rare nature of the primary outcome of interest (serious asthma-related events), subjects with persistent asthma and a history of an asthma exacerbation in the preceding year broadly characterize eligibility criteria for the study. Eligibility for participation will be based on pre-study asthma medications and an assessment of both the impairment (Childhood Asthma Control Test) and the risk (asthma exacerbations in the previous year) domains of asthma control. Subjects receiving SABA only, LTRA, theophylline, or cromolyn as monotherapy whose asthma is currently controlled (Childhood Asthma Control Test 20) are not eligible. Subjects receiving SABA only, LTRA, theophylline or cromolyn as monotherapy whose asthma is currently not well-controlled (Childhood Asthma Control Test 19) are eligible if they have had two or more asthma exacerbations in the previous year. They demonstrate a lack of asthma control in both the impairment and the risk domains. These subjects will receive a step-up randomized study treatment. Subjects receiving low-dose ICS monotherapy whose asthma is currently not wellcontrolled (Childhood Asthma Control Test 19) and have had at least one asthma exacerbation in the prior year are eligible. They demonstrate a lack of asthma control by the impairment domain or both the impairment and the risk domains. These subjects will receive a step-up randomized study treatment. Subjects on low-dose ICS monotherapy whose asthma is currently controlled (Childhood Asthma Control Test score 20) are eligible if they have had two or more asthma exacerbations in the previous year. They demonstrate a lack of asthma control by the risk but not the impairment domain. These subjects will receive either a step-up or stepneutral randomized study treatment. Subjects receiving medium-dose ICS monotherapy or a low-dose ICS-containing asthma regimen are eligible if they have had at least one asthma exacerbation in the previous year. These subjects will receive either a step-up, step-neutral, or step-down randomized study treatment based on both the impairment and risk domains of asthma control. A step-neutral asthma therapy is appropriate in these subjects given that a differential response to asthma regimens has been demonstrated in subjects with persistent asthma [Lemanske, 2010b]. A step-down in therapy is in alignment with asthma treatment guidelines for patients with well-controlled asthma. 17

20 2011N112074_01 CONFIDENTIAL Subjects receiving a medium-dose ICS-containing asthma regimen whose asthma is currently controlled (Childhood Asthma Control Test score 20) are eligible if they have had only one asthma exacerbation in the previous year. They demonstrate asthma control in both the impairment and risk domains. These subjects will receive either a step-down or step-neutral randomized study treatment. Subjects receiving a medium-dose ICS-containing asthma regimen whose asthma is currently not well-controlled (Childhood Asthma Control Test score 19) are not eligible. Choice of Control Treatment Arm The primary objective of this study is to evaluate whether a LABA added to an ICS (FSC) is non-inferior in terms of the risk of serious asthma-related events (asthmarelated-hospitalizations, endotracheal intubations, and deaths) compared with ICS alone (FP) in pediatric subjects (age 4-11 years) with persistent asthma. Therefore, FP alone is the appropriate choice of control to assess the safety of FSC (ICS/LABA combination). Both ICS alone and ICS plus LABA are recommended therapy for patients with persistent asthma [GINA, 2009; NIH, 2007]. ICS Treatment doses The study includes FP 250mcg either as FSC 250/50mcg or FP 250mcg as two of four possible treatments. FP 250mcg and FSC 250/50mcg are not currently indicated in children 4-11 years of age according to the US approved product information [ADVAIR DISKUS US product label 2011; FDA Briefing Information, 2008; FLOVENT DISKUS US product label 2010], although they are in alignment with stepwise therapeutic guidelines [GINA, 2009; NIH, 2007]. Accordingly, for selected subjects whose asthma is not well-controlled on low-dose ICS (FP 100) or low-dose ICS/LABA (FSC 100/50), higher than US-labelled doses of FP are appropriate study treatments. The maximum daily dose of FP in this study will be 500mcg/day. The potential clinical benefits of higher ICS doses in children who are symptomatic on low-dose ICS include improved lung function, reduced asthma symptoms, and reduced need for rescue medication use [de Blic, 2009; Gappa, 2009; Lemanske, 2010b; Vaessen- Verberne, 2010]. The potential for systemic effects such as decrease in growth rates exist. The potential risks of higher than approved FP doses in children 4-11 years of age are balanced by the necessity of maintaining asthma control in this patient population given limited treatment options and by the knowledge gained from a large-scale safety study. Potential Risk Associated with the Sample Size Assumption around Background Rate The background rate for the composite endpoint of asthma-related hospitalization, endotracheal intubation, or death has a significant impact on the determination of the sample size for this study. If, for example, the observed number of subjects experiencing an event in the composite endpoint is approximately half of what is expected, the power 18

21 2011N112074_01 CONFIDENTIAL of the study to declare non-inferiority at the pre-specified acceptable margin of increased risk will be severely compromised. 4. SUBJECT SELECTION AND WITHDRAWAL CRITERIA 4.1. Number of Subjects Screening and Randomization Assuming a screen failure rate of 35%, approximately 9,500 subjects will need to be screened. A total of approximately 6,200 subjects will be randomized for the study. Screen Failures A subject who is assigned a subject number, but is not randomized to study treatment, has failed screening. The following information will be collected for subjects who fail screening: Demographic information including race, age, and gender, Reason for screen failure (inclusion/exclusion criteria and screening failure), SAE information, and Investigator signature Subjects who do not meet all inclusion criteria or meet any of the exclusion criteria will not be eligible for randomization. Re-screening Subjects who do not meet entry criteria may be eligible for re-screening once at least 4 weeks after the initial screening. Subjects must meet all inclusion criteria and none of the exclusion criteria at the time of randomization Inclusion Criteria Specific information regarding warnings, precautions, contraindications, AEs, and other pertinent information on the GSK investigational product (IP) or other study treatment that may impact subject eligibility is provided in the Investigator Brochure and respective product labels [GlaxoSmithKline Document Number RM2007/00413/03; ADVAIR DISKUS product label, 2011; FDA Briefing Information, 2008; FLOVENT DISKUS product label, 2010, in respective countries]. Deviations from inclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential. Subjects eligible for enrolment in the study must meet all of the following criteria: 19

22 2011N112074_01 CONFIDENTIAL 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. 1. Informed consent Subject s legal guardian must be able and willing to give written informed consent to take part in the study. If applicable, subject must be able and willing to give assent to take part in the study according to the local requirement. Subject and their legal guardian understand that the study requires them to be treated on an outpatient basis. Subject and their legal guardian understand that they must comply with study medication and study assessments including recording of symptom scores and rescue albuterol/salbutamol use, attending scheduled study visits, and being accessible by a telephone call. 2. Age: 4-11 years of age at Visit 1 3. Gender: Male or eligible female Female subjects should not be enrolled if they are pregnant, lactating or plan to become pregnant during the time of study participation. All females of childbearing potential must have a negative urine pregnancy test result prior to randomization to continue in the study. Females who become pregnant during the course of the study will be discontinued and the pregnancy outcome followed (see Section 6.2.5) Females of childbearing potential are Females, regardless of their age, with functioning ovaries and no documented impairment of oviductal or uterine function that would cause sterility This category includes young females who have begun to menstruate, females with oligomenorrhea, and females who are perimenopausal. 4. Asthma diagnosis: Asthma, defined by the regional asthma guidelines (i.e., NIH, GINA, etc.), for at least 6 months prior to Visit 1. Asthma is defined as a chronic inflammatory disorder associated with airway hyperresponsiveness and reversible airways obstruction that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing. If the subject is naïve to the study site, the subject/guardian must self-report a physician diagnosis of asthma and the investigator must confirm by review of medical history with the subject/guardian. 5. Ability to answer questions regarding asthma control (with assistance of his/her parents [guardians], if needed), and use a metered-dose inhaler (MDI) and DISKUS effectively. 20

23 2011N112074_01 CONFIDENTIAL 6. In countries where the product label includes a warning regarding more serious chickenpox infections in patients using corticosteroids (refer to the local product labels for varicella vaccine, ADVAIR DISKUS, and FLOVENT DISKUS) and/or varicella immunization is recommended for the age group, the subject must have a history of clinical varicella infection or recipient of a varicella vaccine before receiving any study drug. In those countries, subjects without a history of clinical varicella disease must receive varicella vaccine prior to randomization, and should follow standard guidelines regarding timing of second dose, if indicated. 7. Subject must have history of at least one occurrence (self-report by subject/guardian) of treatment with systemic corticosteroid [3 or more days of oral corticosteroid (OCS) or an equivalent depot corticosteroid injection] for an asthma exacerbation within the prior 12 months, excluding the 4 weeks immediately preceding Visit 1 (see Section 4.3, Exclusion Criteria #7). 8. Currently being treated for asthma and no change in asthma therapy for the last 4 weeks from Visit 1 and Subjects must meet one of the following pre-study asthma medication, impairment domain (Childhood Asthma Control Test) and risk domain (asthma exacerbations) criteria to be eligible for enrolment (Table 1). Subjects on SABA alone, LTRA, theophylline, or cromolyn as monotherapy with Childhood Asthma Control Test score 19 at Visit 1 and have had 2 or more asthma exacerbations in the previous year, or Subjects on low-dose ICS monotherapy with Childhood Asthma Control Test score 20 at Visit 1 and have had 2 or more asthma exacerbations in the previous year, or Subjects on low-dose ICS monotherapy with Childhood Asthma Control Test score 19 at Visit 1 and have had at least 1 asthma exacerbation in the previous year, or Subjects on low-dose ICS and one or more adjunctive therapy (LABA, LTRA, or theophylline) with Childhood Asthma Control Test score 20 at Visit 1 and have had at least 1 asthma exacerbation in the previous year, or Subjects on low-dose ICS and one or more adjunctive therapy (LABA, LTRA, or theophylline) with Childhood Asthma Control Test score 19 at Visit 1 and have had at least 1 asthma exacerbation in the previous year, or Subjects on medium-dose ICS monotherapy with Childhood Asthma Control Test score 20 at Visit 1 and have had at least 1 asthma exacerbation in the previous year, or Subjects on medium-dose ICS monotherapy with Childhood Asthma Control Test score 19 at Visit 1 and have had at least 1 asthma exacerbation in the previous year, or Subjects on medium-dose ICS and one or more adjunctive therapy (LABA, LTRA, or theophylline) with Childhood Asthma Control Test score 20 at Visit 1 and have had only 1 asthma exacerbation in the previous year. 21

24 2011N112074_01 CONFIDENTIAL Note: Subjects receiving SABA only, LTRA, theophylline or cromolyn as monotherapy with Childhood Asthma Control Test 20 are not eligible. Subjects receiving medium-dose ICS and one or more adjunctive therapy (LABA, LTRA, or theophylline) with Childhood Asthma Control Test score 19 at Visit 1 are not eligible. To be eligible, subjects should not present signs of unstable asthma as described in Section 4.3, Exclusion Criterion #2. Subjects who are currently on high-dose ICS or high-dose ICS/LABA are not eligible for the study (Section 4.3, Exclusion Criterion #3). Subjects who had an asthma exacerbation within 4 weeks of Visit 1 or more than 4 asthma exacerbations in the last 12 months from Visit 1 are not eligible (Section 4.3, Exclusion Criterion #7). Table 1 Summary table of eligibility criteria Prior Asthma Therapy SABA, LTRA, theophylline or cromolyn Low-dose ICS monotherapy Low-dose ICS and one or more adjunctive therapy Medium-dose ICS monotherapy Medium-dose ICS and one or more adjunctive therapy Childhood Asthma Control Test score at Visit 1 One exacerbation in previous year Two or more exacerbations in previous year 20 Not eligible Not eligible 19 Not eligible Eligible 20 Not eligible Eligible 19 Eligible Eligible 20 Eligible Eligible 19 Eligible Eligible 20 Eligible Eligible 19 Eligible Eligible 20 Eligible Not eligible 19 Not eligible Not eligible 4.3. Exclusion Criteria Deviations from exclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential. Subjects meeting any of the following criteria must not be enrolled in the study: 1. History of life-threatening asthma: Defined for this protocol as an asthma episode that required intubation, hypercapnea requiring non-invasive ventilatory support, respiratory arrest, hypoxic seizures or asthma-related syncopal episode(s). 22

25 2011N112074_01 CONFIDENTIAL 2. Unstable asthma at Visit 1. Signs of unstable asthma include: Daily use of > 4 puffs of albuterol/salbutamol (other than pre-exercise treatment), 8 puffs of albuterol/salbutamol for 2 or more consecutive 24-hour periods in the 7 days preceding Visit 1, 2 nighttime awakenings due to asthma symptoms in the 7 days preceding Visit 1, or Investigator s discretion (reason should be recorded in source documents). 3. Subjects who are currently receiving high-dose ICS or ICS/LABA therapy to treat asthma symptoms. 4. Concurrent respiratory disease: Current evidence of pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, allergic bronchopulmonary aspergillosis, cystic fibrosis, bronchopulmonary dysplasia, or other severe respiratory abnormalities other than asthma. 5. Respiratory infection: Bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear (either culture-documented or suspected) that is not resolved at Visit 1 and that in the opinion of the investigator is expected to affect the subject s asthma status or the subject s ability to participate in the study. 6. Subjects with only exercise-induced asthma are excluded from participation in this study. 7. Asthma exacerbation: An asthma exacerbation requiring systemic (tablets, suspension or injection) corticosteroids within 4 weeks of Visit 1 or more than 4 separate exacerbations in the last 12 months from Visit 1. These include asthma exacerbations resulting from poor compliance with asthma medications. Each asthma exacerbation must be separated by >7 days from the discontinuation of OCS to be considered an individual event. 8. Asthma hospitalization: Hospitalization for asthma within 4 weeks of Visit 1 or more than 2 hospitalizations (defined as overnight admission) for asthma in the last 12 months from Visit 1. Each hospitalization must be separated by >7 days to be considered an individual event (ED visits < 24 hours in duration are not considered hospitalizations). 9. Other current evidence of clinically significant uncontrolled diseases/conditions of any body or organ system. Excluded diseases/conditions includes, but are not limited to the following: 23

26 2011N112074_01 CONFIDENTIAL Uncontrolled hypertension 1 Uncontrolled hematologic, hepatic, neurologic, or renal disease Uncontrolled gastroesophageal reflux disease Immunologic compromise Cardiac arrhythmias Tuberculosis (current or untreated) 2 Congestive heart failure Cushing s disease Coronary artery disease Addison s disease Current malignancy Uncontrolled eosinophilic esophagitis Uncontrolled diabetes mellitus Uncontrolled thyroid disorder 1. Two or more measurements with systolic or diastolic BP above the 95% percentile reference value for the subjects height and weight 2. Subjects with a history of tuberculosis infection who have completed an appropriate course of anti-tuberculosis treatment may be suitable for study entry provided that there is no clinical suspicion of active or recurrent disease Significant is defined as any disease/condition that, in the opinion of the investigator, would put the safety of the subject at risk through study participation, or which would confound the interpretation of the study results if the disease/condition exacerbated during the study. 10. Neurological or psychiatric disease or history of drug or alcohol abuse (of a subject or his/her guardian) which in the opinion of the investigator could interfere with the subject s proper completion of the protocol requirements excludes study participation. 11. Investigational medications: A subject must not have participated in an interventional study or used any investigational drug for any disease state within 30 days prior to Visit Drug allergy: Any adverse reaction including immediate or delayed hypersensitivity to any beta 2 -agonist, sympathomimetic drug, or any intranasal, inhaled, or systemic corticosteroid therapy, or vehicle contained within these medications. 13. Severe hypersensitivity to cow s milk proteins. Any immediate hypersensitivity reaction such as urticaria, angioedema, rash, or bronchospasm to milk proteins. 14. Concomitant medications: Administration of prescription or over the counter medications that would significantly affect the course of asthma, or interact with sympathomimetic amines such as: anti-ige (omalizumab), anticonvulsants (barbiturates, hydantoins, carbamazepine); polycyclic antidepressants, betaadrenergic blockers; phenothiazines, monoamine oxidase (MAO) inhibitors, or diuretics. 15. Potent cytochrome P450 3A4 (CYP3A4) inhibitors: A subject is not eligible if he/she is receiving potent CYP34A inhibitor within 4 weeks of Visit 1 (e.g., ritonavir, ketoconazole, itraconzole). 16. Affiliation with investigator s site: A subject will not be eligible for this study if he/she is an immediate family member of the participating investigator, subinvestigator, study coordinator, or employee of the participating investigator. 17. Children in Care: A Child in Care (CiC) is a child who has been placed under the control or protection of an agency, organisation, institution or entity by the courts, 24

27 2011N112074_01 CONFIDENTIAL the government or a government body, acting in accordance with powers conferred on them by law or regulation. The definition of a CiC can include a child cared for by foster parents or living in a care home or institution, provided that the arrangement falls within the definition above. The determination of whether a child meets the definition of CiC should be made with the study centre staff in consultation with the responsible Institutional Review Board (IRB)/Independent Ethics Committee (IEC) Withdrawal Criteria Premature discontinuation from the study treatment occurs when a subject discontinues IP prior to completion of 6-month study treatment, either voluntarily or is withdrawn by the investigator. In case that any of the following events occur, a subject must stop study treatment and EW Visit procedures must be performed (Table 3. Time and Events Table [Section 6]): A subject becomes pregnant (subject will be contacted after expected due date for pregnancy outcome information). A subject has an AE that would, in the investigator s judgement, make continued participation in the study an unacceptable risk. A subject is hospitalized or intubated for asthma. A subject has >2 episodes of treatment for protocol-defined asthma exacerbations during the entire study (withdrawn upon experiencing a third asthma exacerbation). Each exacerbation must be separated by >7 days from the discontinuation of OCS to be considered an individual event. In the opinion of the investigator, a subject is judged to be significantly noncompliant with the requirements of the protocol. The treatment blind is broken for a subject by site personnel. Investigator s judgment that subject requires additional asthma medication over and above that allowed by the protocol to maintain long term asthma control. A subject voluntarily discontinues participation in this study. GlaxoSmithKline discontinues the study. The IRB/IEC denies continued approval of the study. Follow-up for Subjects Who Withdraw Early from the Study Treatment Subjects who end their study treatment prematurely prior to completing 6-month doubleblind treatment period (withdrawn early from study treatment) will be followed for the 6- month period from randomization for tracking of primary outcome of interest for the study (i.e., serious asthma-related outcome [hospitalization, endotracheal intubation, or death]). During this time, subjects will be contacted by the study site monthly to assess any serious asthma-related outcomes (i.e., asthma-related hospitalization, endotracheal intubation, and death). Subjects may choose to discontinue use of IP at any time, but full accountability for asthma-related hospitalization, endotracheal intubation, and death is required for all subjects for the 6 months following randomization. 25