Evidence Synthesis and Mixed treatment comparisons of Asthma Treatments

Transcription

1 HEALTH OUTCOMES PROTOCOL UNIQUE IDENTIFIER HO / etrack # ABBREVIATED TITLE FINAL PROTOCOL APPROVED 5 th January 2015 FULL TITLE Evidence Synthesis and Mixed treatment comparisons of Asthma Treatments Protocol for Evidence Synthesis and Mixed Treatment Comparison for Evaluating Treatments for Asthma UPDATE PROJECT GSK ASSET DISEASE AREA SPONSORSHIP DIVISION/BUSINESS UNIT DEPARTMENT HO STUDY ACCOUNTABLE PERSON(S) CONTRIBUTING AUTHORS RETENTION CATEGORY INFORMATION TYPE KEY WORDS / MESH HEADINGS / META DATA Relvar (Fluticasone Furoate and Vilanterol (FF/VI) GW GW Asthma GSK Sponsored Pharma / Research & Development Global Health Outcomes Mixed Treatment Comparison Asthma Evidence synthesis Systematic review Meta-analysis Mixed treatment comparison Efficacy Effectiveness Safety Tolerability

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3 PROTOCOL SYNOPSIS (Complete protocol first; then cut/paste into the Synopsis) Unique Identifier Abbreviated Title GSK Product Rationale Objectives (Primary, Secondary & Exploratory) HO / etrack # Evidence Synthesis and Mixed treatment comparisons of Asthma Treatments UPDATE PROJECT Relvar (Fluticasone Furoate and Vilanterol (FF/VI) GW GW Payers, HTA bodies and other decision makers in many countries require a formal comparison of clinical efficacy of Relvar/Breo (FF/VI) with other available ICS/LABAs. This cannot be provided from direct head to head studies alone. This protocol is for an evidence synthesis of therapies for the treatment of Asthma with the goal of identifying and synthesizing clinical trial evidence for Relvar/Breo (FF/VI) versus other available ICS/LABAs. The information from a recently completed literature review will be used to develop an integrated Bayesian evidence synthesis model. Primary Objectives This study will update the original MTC of FF/VI in comparison to alternative ICS/LABA s in asthma (carried out in 2013; HO ) with recent literature (studies published since December 2012). This is the original approved protocol and these same methods will be followed for the update project. To evaluate the relative treatment efficacy of FF/VI 92/22mcg and FF/VI 184/22mcg compared with fixed dosing of the alternative ICS/LABAs licensed for the treatment of asthma as listed above, based on improvement in lung function, measured as the mean change from baseline in morning Peak Expiratory Flow (PEF; L/min) (averaged over the study period), and mean change from baseline in FEV 1 (L). Secondary Objectives The objectives presented below are those included in this preliminary summary. Full details of all objectives will be presented in the final full technical report. To assess the relative treatment efficacy of FF/VI 92/22mcg and FF/VI 184/22mcg vs the listed comparators on mean rates of moderate/severe exacerbation To assess the relative treatment efficacy of FF/VI 92/22mcg and FF/VI 184/22mcg on health status as measured by mean change

4 from baseline in AQLQ total score versus the listed comparators To assess the probability that FF/VI 92/22mcg and FF/VI 184/22mcg are non-inferior to the listed comparators in the treatment of asthma, (i) based on improvement in lung function measured as mean change from baseline in morning mean PEF (averaged over the study period) and mean FEV 1 change from baseline, (ii) based on the event rate ratios of moderate/severe exacerbations, and (iii) based on change in health status as measured by AQLQ; the range of non-inferiority (NI) thresholds considered were selected based on clinical opinion and on NI thresholds from NI clinical trials identified in the literature. Please note that the definition of moderate/severe exacerbations in the MTC equates to the severe exacerbation definition used in the FF/VI studies. This exacerbation definition was mapped to the corresponding definition of an exacerbation in other studies, whether nominally labelled as all, moderate, severe or moderate/severe exacerbations (please refer to the MTC technical report for a complete description). Exploratory objectives After developing the evidence synthesis models to address the primary and secondary objectives, additional exploratory objectives will be investigated. The ability to perform the exploratory analyses and the determination of whether the exploratory analyses are relevant cannot be determined until after the primary and secondary objectives are addressed. The possible exploratory objectives are as follows: Whether more research would strengthen the evidence If more research would be desired, the following specific components of the additional studies will be investigated: a. The predictable probability of superiority, non-inferiority, equivalence, of the proposed Relvar studies b. Possible sample sizes and studies sequences (if applicable) c. Possible sample size(s) and study sequencing if exacerbations were used as primary study endpoint instead of lung function d. The proposed duration of the additional studies

5 Study Design Study Population and Sampling Methods A set of Bayesian, hierarchical, mixed-treatment comparisons (MTCs) will be developed. The models will incorporate known predictors of treatment outcome and the observed efficacy of treatment strategies evaluated in randomized clinical trials. The models will be used to make inferences on multiple measures of efficacy included in this protocol associated with existing therapies for Asthma. The inclusion and exclusion criteria for the MTC were determined by the targeted patient population for clinical trials of FF/VI, to enable a priori comparison of treatments in patient populations similar to those examined in the FF/VI study programme. The MTC includes studies of clinical efficacy and effectiveness in adolescent and adult ( 12 years) asthma patients of any race and gender, irrespective of the disease stage. Only Phase III or Phase IV parallel-group randomised controlled trials (RCTs), irrespective of blinding status, were included in the MTC. RCTs are the gold standard of clinical evidence, minimising the risk of confounding factors and allowing the comparison of the relative efficacy of interventions. The studies in Phase III and Phase IV of development gather relevant information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Post-market requirement and commitment studies gather additional information about a drug s safety, efficacy or optimal use. In addition, the Phase II programme for many combination drugs focuses on the individual components only. Overall inclusion criteria: Study only included patients 12 years old o in line with the FF/VI licensed indication applied for in Europe Study was over 8 weeks in duration o appropriate for allowing time for steroid to take effect and allow assessment of efficacy using endpoints of interest Patients were required to be on ICS or ICS/LABA at randomisation o in line with the FF/VI licensed indication applied for in Europe scenario analyses were also performed across all endpoints for studies that required patients to be on an ICS, but did not permit ICS/LABA, at randomisation Patients had to be uncontrolled / symptomatic at randomisation o in line with the FF/VI licensed indication applied for in Europe RCTs irrespective of blinding status, either Phase III or Phase IV. o As stated for the literature review (Error! Reference source not found.). Overall exclusion criteria:

6 Trial contains at least one study arm including flexible dosing or a range of doses o The objective of the MTC was to compare combinations used in fixed dosing regimens. Combining flexible dosing arms is problematic due to range of possible doses patient receives Studies in patients that were controlled / asymptomatic at randomisation o Studies were excluded if they had an explicit inclusion criterion targeting controlled/asymptomatic patients, or an explicit exclusion criterion excluding patients who were uncontrolled/asymptomatic at baseline o Furthermore, studies were excluded if they predominantly included stable patients (or required a history of stable asthma), if they had baseline averages of key GINA parameters not suggesting uncontrolled asthma, and/or if the status of control/symptom at randomisation was undefined or irretrievable. Data Source Data Analysis Methods The data used in the MTCs will be obtained from a systematic literature review of efficacy and effectiveness that was conducted separately. An independent protocol for the systematic review of the literature is available and has been included in Appendix to this Protocol Primary efficacy endpoint: FEV1: value at baseline and any specified time point, change from baseline, difference in change from baseline between groups, mean difference, AUC FEV1; Peak Expiratory Flow (PEF; L/min): changed from baseline, averaged over the study period. Secondary efficacy endpoints:

7 Exacerbations: Mean rate of exacerbations per patient per year or annualised total number of exacerbations experienced over the course of the study (moderate/composite of moderate and severe/severe); Mean rate of exacerbations per patient per year or annualised total number of exacerbations experienced over the course of the study (any exacerbation as per study definition) Asthma control: Asthma Quality of Life Questionnaire (AQLQ12+); Mini AQLQ; AQLQ (S); averaged total score change from baseline Note on Exacerbations Contrarily to other endpoints, the definitions of exacerbations vary across studies. The definition of exacerbations in the MTC reflects the various definitions used in the trials; in other words, the inclusion of each study in the MTC will not be based on the use of a particular specific definition of exacerbations. Studies differ in their recording practice for exacerbation endpoints. Definitions used in the trials include the following: deterioration in asthma leading to hospitalisation/emergency (or equivalent) treatment and/or the need for oral corticosteroid treatment for at least three days deterioration in asthma requiring treatment with an oral corticosteroid or an emergency department visit or hospitalization clinical exacerbation requiring emergency treatment or hospitalization exacerbation requiring emergency treatment, hospitalization, or use of an asthma medication not allowed by the protocol. Such definitions assume that exacerbation, in fact, is a composite endpoint comprising of any exacerbation of any level of severity. In other studies, exacerbations are explicitly classified or reported as severe, moderate or mild. Importantly, some studies use explicit definition of the severity of exacerbation endpoints as a restriction to the type of exacerbation data collected. So in some studies, the composite endpoint includes exacerbations of any severity, i.e. mild, moderate or severe; in other studies, the composite includes exacerbations that are moderate or severe. Classification criteria may also vary by study. For example, severe exacerbations are defined as deterioration in asthma requiring emergency hospital treatment or alternatively, any hospitalizations. Moderate exacerbations required administration of additional inhaled corticosteroids, bronchodilators and/or oral corticosteroids,

8 or alternatively, as worsening of asthma leading to a prescription for a short use of oral corticosteroids. Mild exacerbations are deterioration in asthma requiring an increase in the use of relief medication which the physician considered to be clinically relevant. Definition of outputs of the MTC The results of the mixed treatment comparison will be expressed on the original scale of the data extracted from the systematic review. MTC endpoints are FEV1, exacerbations, QOL scores. FEV1 is expressed in Litres and is a continuous outcome. Treatment effects calculated in the MTC will be expressed as treatment differences (for treatment X compared to treatment Y) in mean difference from baseline to last measurement. Exacerbations are a count variable and are expressed either as total number of exacerbations (with treatment X and Y), yearly exacerbation rates (exacerbations per patient year, for treatment X and Y) or as relative risk ratio or odds ratios for treatment X vs treatment Y. The total number of exacerbations will be recalculated from the data extracted from the literature. Treatment effects calculated in the MTC will be expressed as risk ratios for treatment X compared with treatment Y. QOL measures will be analysed based on the original measurement scale in the varjous instruments. Efficacy will be reported as the difference in group means in the absolute change in score between baseline and end of follow-up. Credible limits (CrL, 95%) and posterior distribution will be estimated for each endpoint.

9 Sample Size and Power Limitations While the use of Bayesian hierarchical models require a number of assumptions (e.g., exchangeability of information at each level of the hierarchy, prior information), the ability of the model to incorporate the structure and limitations of the available information allows greater model validity than other approaches (e.g., traditional frequentist multi-level modeling). These models are very robust, because they are so flexible. This mitigates to some degree typical worries regarding model dependencies and the validity of initial assumptions. When using such a model to make mixed treatment comparisons, one must often make assumptions about the additivity of treatment effects across studies. For example, if treatment A is compared to treatment B in one study and treatment B is compared to treatment C in another study, then an assumption of the additivity of treatment effects is needed to make any comparison between A and C. This can be a difficult assumption to test because of the lack of repeated single trials. All assumptions will be laid out in detail and explained thoroughly in the final study report.

10 TABLE OF CONTENTS

11 ABBREVIATIONS

12 1. INTRODUCTION/BACKGROUND Payers, HTA bodies and other decision makers in many countries require a formal comparison of clinical efficacy of Relvar/Breo (FF/VI) with other available ICS/LABAs. This cannot be provided from direct head to head studies alone. This protocol is for an evidence synthesis of therapies for the treatment of Asthma with the goal of identifying and synthesizing clinical trial evidence for Relvar/Breo (FF/VI) versus other available ICS/LABAs. The information from a recently completed literature review will be used to develop an integrated Bayesian evidence synthesis model. 2. OBJECTIVES 2.1. Primary This study will update the original MTC of FF/VI in comparison to alternative ICS/LABA s in asthma (carried out in 2013; HO ) with recent literature (studies published since December 2012). This protocol displays the original methodology and these methods will be followed for the update project. To evaluate the relative treatment efficacy of FF/VI 92/22mcg and FF/VI 184/22mcg compared with fixed dosing of the alternative ICS/LABAs licensed for the treatment of asthma as listed above, based on improvement in lung function, measured as the mean change from baseline in morning Peak Expiratory Flow (PEF; L/min) (averaged over the study period), and mean change from baseline in FEV 1 (L) Secondary The objectives presented below are those included in this preliminary summary. Full details of all objectives will be presented in the final full technical report. To assess the relative treatment efficacy of FF/VI 92/22mcg and FF/VI 184/22mcg vs the listed comparators on mean rates of moderate/severe exacerbation To assess the relative treatment efficacy of FF/VI 92/22mcg and FF/VI 184/22mcg on health status as measured by mean change from baseline in AQLQ total score versus the listed comparators To assess the probability that FF/VI 92/22mcg and FF/VI 184/22mcg are non-inferior to the listed comparators in the treatment of asthma, (i) based on improvement in lung function measured as mean change from baseline in morning mean PEF (averaged over the study period) and mean FEV 1 change from baseline, (ii) based on the event rate ratios of moderate/severe exacerbations, and (iii) based on change in health status as measured by AQLQ; the range of non-inferiority (NI) thresholds considered were

13 selected based on clinical opinion and on NI thresholds from NI clinical trials identified in the literature. Please note that the definition of moderate/severe exacerbations in the MTC equates to the severe exacerbation definition used in the FF/VI studies. This exacerbation definition was mapped to the corresponding definition of an exacerbation in other studies, whether nominally labelled as all, moderate, severe or moderate/severe exacerbations (please refer to the MTC technical report for a complete description).

14 2.3. Exploratory After developing the evidence synthesis models to address the primary and secondary objectives, additional exploratory objectives will be investigated. The ability to perform the exploratory analyses and the determination of whether the exploratory analyses are relevant cannot be determined until after the primary and secondary objectives are addressed. The possible exploratory objectives are as follows: Whether more research would strengthen the evidence If more research would be desired, the following specific components of the additional studies will be investigated: 1. The predictable probability of superiority, non-inferiority, equivalence, of the proposed Relvar studies 2. Possible sample sizes and studies sequences (if applicable) 3. Possible sample size(s) and study sequencing if exacerbations were used as primary study endpoint instead of lung function 4. The proposed duration of the additional studies 3. RESEARCH METHODOLOGY 3.1. STUDY DESIGN A set of Bayesian, hierarchical, mixed-treatment comparisons (MTCs) will be developed. The models will incorporate known predictors of treatment outcome and the observed efficacy of treatment strategies evaluated in randomized clinical trials. The models will be used to make inferences on multiple measures of efficacy included in this protocol associated with existing therapies for Asthma STUDY POPULATION The systematic literature review (see Asthma Systematic Literature Review Technical Report) identified 96 randomised studies of an ICS/LABA against a comparator. These were used as the starting point for the study eligibility assessment for the MTC. The inclusion and exclusion criteria for the MTC were determined by the targeted patient population for clinical trials of FF/VI, to enable a priori comparison of treatments in patient populations similar to those examined in the FF/VI study programme. The MTC includes studies of clinical efficacy and effectiveness in adolescent and adult ( 12 years) asthma patients of any race and gender, irrespective of the disease stage. Only Phase III or Phase IV parallel-group randomised controlled trials (RCTs), irrespective of blinding status, were included in the MTC. RCTs are the gold standard of clinical evidence, minimising the risk of confounding factors and allowing the comparison of the relative efficacy of interventions. The studies in Phase III and Phase IV of development gather relevant information about safety and effectiveness by

15 studying different populations and different dosages and by using the drug in combination with other drugs. Post-market requirement and commitment studies gather additional information about a drug s safety, efficacy or optimal use. In addition, the Phase II programme for many combination drugs focuses on the individual components only. Overall inclusion criteria: Study only included patients 12 years old o in line with the FF/VI licensed indication applied for in Europe Study was over 8 weeks in duration o appropriate for allowing time for steroid to take effect and allow assessment of efficacy using endpoints of interest Patients were required to be on ICS or ICS/LABA at randomisation o in line with the FF/VI licensed indication applied for in Europe scenario analyses were also performed across all endpoints for studies that required patients to be on an ICS, but did not permit ICS/LABA, at randomisation Patients had to be uncontrolled / symptomatic at randomisation o in line with the FF/VI licensed indication applied for in Europe RCTs irrespective of blinding status, either Phase III or Phase IV. o As stated for the literature review (Error! Reference source not found.). Overall exclusion criteria: Trial contains at least one study arm including flexible dosing or a range of doses o The objective of the MTC was to compare combinations used in fixed dosing regimens. Combining flexible dosing arms is problematic due to range of possible doses patient receives Studies in patients that were controlled / asymptomatic at randomisation o Studies were excluded if they had an explicit inclusion criterion targeting controlled/asymptomatic patients, or an explicit exclusion criterion excluding patients who were uncontrolled/asymptomatic at baseline o Furthermore, studies were excluded if they predominantly included stable patients (or required a history of stable asthma), if they had baseline averages of key GINA parameters not suggesting uncontrolled asthma, and/or if the status of control/symptom at randomisation was undefined or irretrievable. All arms from included studies were incorporated into the MTC, with the exception of the OPTIMA trial, 61 which explicitly reported results for different arms based on prior treatment. Thus it was possible to exclude group A arms, which randomised only steroid naïve patients, a population not considered appropriate for comparison. Study HZA (11533), a phase IIIa safety study was not included in the systematic literature review in error but was considered for inclusion in the MTC. For analysis of each endpoint, the study had to report the endpoint in a suitable format for analysis. For FEV 1, PEF and AQLQ this was mean change from baseline. The exacerbation model uses number of events and person years of follow-up as inputs so required either

16 rate of exacerbations (plus number of exacerbation events) or number of exacerbation events (plus patient years of follow up). The former was used in preference where available as it was expected to already be adjusted for follow-up, whilst the latter required an assumption about mean study participation. In addition, for the exacerbation rate analysis, a study was excluded if it excluded patients with a history of exacerbations over a period >6 months (note; a period of 6 months for excluding exacerbating patients was considered likely to be a safety criterion rather than specifically aiming to enroll patients with a low exacerbation risk). Studies were also excluded if the definition of exacerbation differed considerably from the definition of a severe exacerbation used in FF/VI studies (see definition in Error! Reference source not found.), or if patients were withdrawn after experiencing an exacerbation during the trial period. A sensitivity analysis was conducted relaxing the latter exclusion criterion, which will be presented in the technical report. Studies were only included in the PEF analysis if they reported mean change from baseline averaged over the period of the whole trial, rather than from baseline to a specific timepoint, a measure which has greater variability. There is no immediate relationship between average PEF over time (trial period) and PEF at a particular timepoint (end of study). For GSK-sponsored studies, the Clinical Study Reports (CSRs) were reviewed for data not contained in the publications, where necessary and the data were extracted where possible. For FF/VI studies, CSRs were used for all endpoints. Interventions for inclusion Interventions included in the MTC are the following: FF/VI 92/22mcg versus each of the following medium dose ICS/LABA: o FP/S 250/50mcg (220/42mcg) BID o BUD/F 400/12mcg (320/9mcg) BID o BDP (extra fine)/for 200/12mcg (169.2/10mcg) BID o FP/F 250/10mcg (230/9mcg) BID o MOM/F 200/10mcg BID FF/VI 184/22mcg versus each of the following high dose ICS/LABA: o FP/S 500/50mcg (440/42mcg) BID o BUD/F 800/24mcg (640/18mcg) BID o FP/F 500/20mcg (460/18mcg) BID o MOM/F 400/10mcg BID. Treatment arms within and across clinical trials were included in the same group for comparison if they delivered the same dose per administration (irrespective of number of puffs per administration) and same number of administrations per day, irrespective of device (e.g. FP/S Evohaler and Acculaher/Diskus were grouped). This meant that closed and open ICS/LABA combinations were also grouped together.

17 ELIGIBILITY CRITERIA include ICD-9 & NDC Codes Inclusion Criteria bulleted Exclusion Criteria bulleted SAMPLING random, systematic or convenience 3.3. DATA SOURCE / DATA COLLECTION The data used in the MTCs will be obtained from a systematic literature review of efficacy and effectiveness that was conducted separately. The additional data incorporated by the MTC update was identified by an update of the systematic literature review. The systematic literature review upate followed the PICO and methods as per the original review (displayed in the table below), however the publication timeframe started at December 2012 and ended in September An independent protocol for the systematic review of the literature is available and has been included in Appendix 3 to this Protocol., The main methodological features of the literature review are listed in the table below as part of this protocol. PICO and methods for the systematic literature review Objectives and research questions Objective Studies to include Primary objective To systematically assess the available clinical evidence base on all classes of inhaled therapies in the maintenance treatment for asthma Sub objectives To assess the evidence base on clinical effectiveness of Relvar vs. other ICS/LABAs combination therapies in asthma To assess the evidence base on clinical effectiveness of Relvar vs. ICS monotherapy in asthma To assess the evidence base on clinical effectiveness of Relvar vs. other monotherapies in asthma Study designs RCTs (Phase III and phase IV parallel-group studies, irrespective of blinding status) Systematic reviews (for bibliographic searching of relevant RCTs) Population Age: Adolescents and adults ( 12 years) Gender: Any Race: Any Disease: Asthma Disease stage: Any (mild, moderate, or severe) Interventions ICS Triamcinolone Betamethasone Mometasone FF Fluticasone propionate LABA Salmeterol Budesonide Beclometasone Flunisolide Ciclesonide Dexamethasone cipecilate Olodaterol Abediterol

18 Formeterol Bambuterol, R-bambuterol, levobambuterol Indacaterol LAMA Tiotropium Aclidinium Combination products (open and closed) Horizon, Relovair, Relvar, Breo (FF + VI) Symbicort, Rilast, Vannair (budesonide + formoterol) Advair, Seretide, Viani (salmeterol + fluticasone propionate) Zenhale, Dulera (mometasone + formoterol) Clenbuterol VI Oxytropium Glycopyrronium/glycopyrrolate Umeclidinium AZD-8683 Flutiform, Avessa (fluticasone propionate + formoterol) Fostair, Innovair (beclometasone + formoterol) Mometasone + indacaterol Formoterol + glycopyrrolate Corticosteroid + LAS (abediterol) Any (open) dual ICS/LABA combination in separate inhalers Comparators Any other active treatment (either other included interventions or non relevant interventions) Placebo or BSC Language No restriction on language List of non-english studies of interest to be provided to GSK Publication Database: Database inception to present date timeframe Conference proceedings: (last 3 years) Data sources Databases Embase MEDLINE MEDLINE In-Process CENTRAL Conference Conferences will be hand-searched for the last 3 years: proceedings American Thoracic Society European Respiratory Society American College of Chest Physicians Other data sources Bibliographic search of included systematic reviews Clinical controlled trails (Link: FDA website EMA website Information to extract* Study information Study research question Analysis type (ITT/mITT/PP) Study setting Funding source Study methods including number of centres and country Primary and secondary endpoints (including clinical, safety, and QoL) Study phase Concomitant medications Eligibility criteria (inclusion/exclusion: Study duration/trial length list of all the criteria as reported in publication) Blinding status (blinding methods, description of blinding procedures) Number of patients enrolled Statistical method Number of patients randomised Number of patients analysed Treatment details Treatment arms Number of patients randomised (per Treatment protocol and dosing treatment arm) details (including average dose Route of administration received and administration details) Study population Age (mean) Prior treatment Percentage of patients with age <18 Reversibility % years Patients above reversibility thresholds Disease duration FEV1/FVC Male patients (percent) Percentage of patients with allergies Race (percent) Salbutamol use Co-morbidities Efficacy outcomes Prebronchodilator FEV1: value at baseline and any specified time point, change from

19 baseline, and difference in change from baseline between groups For all the efficacy and PRO/QoL outcomes, values at baseline, any specified time point, change from Postbronchodilator FEV1: value at baseline and any specified time point, change from baseline, difference in change from baseline between groups, percentage of patients achieving an increase in postbronchodilator FEV1 of 12% and 200 ml above baseline post-dose on treatment day 1, and time to onset of bronchodilator effect (time to postbronchodilator FEV1 of 12% and 200 ml above baseline at any time) baseline and difference from Peak FEV1: value at baseline and any specified time point, change from baseline, and difference in change from baseline between groups change in baseline between treatment groups to be Trough FEV1: value at baseline and any specified time point, change from baseline, difference in change from baseline between groups, and percentage of patients achieving an increase in trough FEV1 of 100 ml above baseline extracted along with any measure AUC- FEV1: value at baseline and any specified time point, change from baseline, difference in change from baseline between groups of variability reported (CI, SD, SE) and their Daily trough PEF averaged over the treatment period at AM or PM: value at baseline and any specified time point, change from baseline, difference in change from baseline between groups definitions and associated risk ratio (RR)/hazards Use of rescue medication: type of rescue medication, mean number of rescue medications per patient, number of patients using rescue medications, and number of doses taken in a specified time period) ratio (HR) if Rescue-free 24-hour periods during treatment period for each treatment group reported. Symptom-free 24-hour periods during treatment period for each treatment group Number of patients with exacerbations (moderate/composite of moderate and severe/severe) Data reported as Total number of exacerbations experienced over the duration of the study graphs will be (moderate/composite of moderate and severe/severe) extracted from the Mean rate of exacerbations per patient per year (moderate/composite of moderate charts, when and severe/severe) possible, and Time to first exacerbation (moderate/composite of moderate and severe/severe) flagged as such. Exercise capacity (6 minute walk test, incremental shuttle walk test) Global Assessment of Change Questionnaire Number of respondents according to Global Assessment of Change Questionnaire St. George s Respiratory Questionnaire for asthma (SGRQ) Number of respondents according to MCID SGRQ 4 point change Asthma control test (ACT) Proportion of patients with ACT 20 at specific time point Asthma Quality of Life Questionnaire (AQLQ12+) Mini AQLQ AQLQ (S) Acute AQLQ Asthma Control Questionnaire (ACQ) Asthma Control Diary (ACD) Marks Asthma Quality of Life Questionnaire (MAQLQ) Living With Asthma Questionnaire (LWAQ) St. Georges Respiratory Questionnaire (SGRQ) EuroQol 5D (EQ-5D) Short Form 36 (SF-36) St. Georges Respiratory Questionnaire Asthma Impact Survey Asthma Therapy Assessment Questionnaire Perceived Control of Asthma Questionnaire Asthma Outcomes Monitoring System Asthma Control Scoring System Asthma Quality of Life Utility Index Asthma Symptom Utility Index Asthma Questionnaire 20 Royal College of Physicians 3 questions Lara Asthma Symptom Scale Asthma Self-efficacy Scale Work Productivity and Activity Impairment: Asthma Any other reported efficacy endpoint, if not one of the above Safety outcomes Any adverse events Nausea Any serious adverse events Bronchitis Any treatment-related adverse events Cough Oral candidiasis Hypertension Oropharyngeal candidiasis Nasopharyngitis

20 Tolerability outcomes Myocardial infarction Arrhythmia Congestive heart failure Pneumonia Bone fractures Dry mouth All withdrawals Withdrawal due to adverse events Oropharyngeal pain Pharyngitis Respiratory tract infection Rhinitis Sinusitis Withdrawal due to lack of efficacy Time to withdrawal Critical appraisal NICE checklist CONSORT checklist Assessment of the quality of reporting of RCTs will be carried out using recommendations from the NICE single technology appraisal (STA) manufacturer s template (NICE STA 2009; Cochrane Handbook 2009). Additionally, the Consort 2010 checklist of information to include when reporting a randomised controlled trial will also be filled (Moher 2012).

21 ENDPOINTS Primary Endpoint(s) The primary objective is to evaluate the relative treatment efficacy of FF/VI 92/22mcg and FF/VI 184/22mcg compared with fixed dosing of the alternative ICS/LABAs licensed for the treatment of asthma as listed above, based on improvement in lung function, measured as the mean change from baseline in morning Peak Expiratory Flow (PEF; L/min) (averaged over the study period), and mean change from baseline in FEV 1 (L) Secondary Endpoint(s) Exacerbations: Mean rate of exacerbations per patient per year or annualised total number of exacerbations experienced over the course of the study (moderate/composite of moderate and severe/severe); Mean rate of exacerbations per patient per year or annualised total number of exacerbations experienced over the course of the study (any exacerbation as per study definition) Note on Exacerbations Contrarily to other endpoints, the definitions of exacerbations vary across studies. The definition of exacerbations in the MTC reflects the various definitions used in the trials; in other words, the inclusion of each study in the MTC will not be based on the use of a particular specific definition of exacerbations. Studies differ in their recording practice for exacerbation endpoints. Definitions used in the trials include the following: deterioration in asthma leading to hospitalisation/emergency (or equivalent) treatment and/or the need for oral corticosteroid treatment for at least three days deterioration in asthma requiring treatment with an oral corticosteroid or an emergency department visit or hospitalization clinical exacerbation requiring emergency treatment or hospitalization exacerbation requiring emergency treatment, hospitalization, or use of an asthma medication not allowed by the protocol. Such definitions assume that exacerbation, in fact, is a composite endpoint comprising of any exacerbation of any level of severity. In other studies, exacerbations are explicitly classified or reported as severe, moderate or mild. Importantly, some studies use explicit definition of the severity of exacerbation endpoints as a restriction to the type of exacerbation data collected. So in some studies, the composite endpoint includes exacerbations of any severity, i.e. mild, moderate or severe; in other studies, the composite includes exacerbations that are moderate or severe. Classification criteria may also vary by study. For example, severe exacerbations are defined as deterioration in asthma requiring emergency hospital treatment or alternatively, any hospitalizations. Moderate exacerbations required administration of additional inhaled corticosteroids, bronchodilators and/or oral corticosteroids, or alternatively, as worsening of asthma leading to a prescription for a short use of oral corticosteroids. Mild

22 exacerbations are deterioration in asthma requiring an increase in the use of relief medication which the physician considered to be clinically relevant. All definitions of exacerbations used in the MTC are reported in Appendix 1 and listed by study. Exacerbations were defined as composite endpoints of multiple types of resource use (oral corticosteroids, antibiotics, hospital visit, ER visit, any inclusion of health care resource utilization HCRU). No studies will be excluded a priori because of definitions of exacerbations. Primary analysis will be based on moderate and severe exacerbations. An assessment of comparability of definitions will be done to explicitly state how differences between definitions of exacerbations across studies will be handled. Sensitivity analyses will be developed for different definitions of exacerbations, as per Appendix 1. Asthma control: Asthma Quality of Life Questionnaire (AQLQ12+); Mini AQLQ; AQLQ (S); averaged total score change from baseline The AQLQ is a validated 32-item instrument organized in 4 domains (symptoms, activity limitation, emotional function and environmental stimuli). The activity domain contains 5 patient-specific questions, which allows patients to select 5 activities in which they are most limited and these activities will be assessed at each follow-up. Patients are asked to think about how they have been during the previous two weeks and to respond to each of the 32 questions on a 7-point scale (7 = not impaired at all - 1 = severely impaired). The overall AQLQ score is the mean of all 32 responses and the individual domain scores are the means of the items in those domains.

23 Exploratory Endpoint(s) 3.4. SAMPLE SIZE / POWER CALCULATIONS 3.5. HYPOTHESES Definition of outputs of the MTC The results of the mixed treatment comparison will be expressed on the original scale of the data extracted from the systematic review. All analyses will be based on the study ITT populations. MTC endpoints are FEV1, PEF, exacerbations, and AQLQ scores. FEV1 is expressed in Litres and is a continuous outcome. Treatment effects calculated in the MTC will be expressed as treatment differences (for treatment X compared to treatment Y) in mean difference from baseline to last measurement. Peak Expiratory Flow (PEF; L/min) will be evaluated based on morning assessments. Treatment effects calculated in the MTC will be expressed as treatment differences (for treatment X compared to treatment Y) in mean difference from baseline to last measurement in the average PEF over the study period, Exacerbations are a count variable and are expressed either as total number of exacerbations (with treatment X and Y), yearly exacerbation rates (exacerbations per patient year, for treatment X and Y) or as relative risk ratio or odds ratios for treatment X vs treatment Y. The total number of exacerbations will be recalculated from the data extracted from the literature. Treatment effects calculated in the MTC will be expressed as risk ratios for treatment X compared with treatment Y. QOL measures will be analysed based onaqlq total score change from baseline.. Efficacy will be reported as the difference in group means in the absolute change in score between baseline and end of follow-up. Credible limits (CrL, 95%) and posterior distribution will be estimated for each endpoint. 4. DATA ANALYSIS CONSIDERATIONS Developing standard language. Top level description of primary, secondary & exploratory analyses; derived/transformed; missing data management summarize univariate data; including age, gender and race for entire population ** CT.gov requirement; multivariate analyses will be transformed using appropriate technique if abnormally distributed prior to analysis). While shell tables are not required, consider these as you think through your endpoints & analyses, groups, etc. Develop a separate Statistical Analysis Plan Evidence Synthesis Models The role of the modeling is to build a network model which allows the analysis of multiple studies with overlapping drugs. Within this single model many different questions

24 can be addressed. Individual drugs may be compared, or a group of drugs may be compared, i.e. determining the best drug or the likelihood a drug is in the top 5, etc. Therefore, this single model is the generator of many of the analysis results. For all comparators in the analysis, information on treatment outcomes is only available at the study level. Therefore, the information available will be averaged over the trial and treatment arm (e.g., primary and secondary outcomes, patient characteristics and other covariates). The general formulation of the model is made up of multiple parts. The first is the outcome variable, the second is the study structure, the third is the treatment characterization, and the fourth is the treatment of covariates and populations. The generic analytical mathematical structure used in the MTC is: Y = Study + Treat + Covariate The outcome variable, Y, represents the clinical outcome, FEV, exacerbations, health status etc.. This can be a continuous variable, dichotomous variable, a time-to-event variable, or even a repeated measures analysis. A common mathematical structure will be created to handle the type of intrinsic uncertainty created by the outcome variable. Typically the modeling assumptions for the remaining aspects of the evidence synthesis will remain constant for example, the same assumptions about study effects will be made in the modeling of a continuous or dichotomous variable. Model Study Effects The key to most mixed treatment comparisons are the possibly disparate studies utilized. The mathematical handling of the studies plays a critical role in the results of the analysis. Two standard types of models will be used in this MTC, borrowing the terminology used for meta-analyses: fixed and random effects models. Fixed effect models assume an independent parameter for each study in the dataset. In practice, this means that a distribution will be assigned to each study and these studies effects will be allowed to vary independently. Because this type of model is naïve and because of the overlapping nature of studies, this model may yield numerically unstable results. For the reason above, in this MTC, the base case will be estimated using a statistical approach referred to as hierarchical model or random effects model. This is a powerful way of treating the studies as coming from a common distribution of studies, hence there the common link to the studies is explicitly modeled, assigning one distribution to the population of parameters; this approach allows understanding of the variability from studyto-study, and using this in the analysis of each study. A hierarchical model is the standard model used in mixed treatment comparisons and evidence syntheses as it is expected to have better performance and properties that the simple fixed effects model. A hierarchical model will be built as in the following paragraphs. Model studies Each study will be characterized by a study parameter, Study = a S for S=1,, N S. Each study is then modeled with a distribution, creating the multi-level, or hierarchical,

25 approach: a S ~ N ( m,s 2 ) The population of studies is then modeled with the above distribution, which can be used to draw conclusions about possible new studies. The two parameters, µ and 2, are then modeled with a second-level (hyper) prior. The analysis creates a posterior distribution for these hyper-parameters, µ and 2. The posterior also uses the population of studies to individually estimate each study, resulting in better estimates, and smaller standard errors. Study duration may be explicitly considered as a study stratification variable when relevant. Model Treatment Effects The modeling of the treatment effect can also vary. The most straightforward assumption is that each treatment has its own parameter. This is straightforward because it allows comparisons between treatments that are not dependent on the study or population. Model 1. Will be estimated assuming Independent prior distributions. A single parameters for each treatment is selected and they are modeled independently However, depending on heterogeneity that will be identified in the data, more elements may be taken into account. If heterogeneity of the study data identified is large, then the treatment effect can depend on population, study, or time-point. Assumptions used in the base case are as follows: 1. Treatment doses will be assumed as independent treatments, i.e. the model will not be used to model a dose-response relationship. This is because in asthma, treatment doses are part of clinical escalation protocols and are prescribed to patients with different characteristics at baseline Combination treatments, both open and closed combinations, will be considered one treatment If required, an alternative modeling approach will be designed, including the following scenarios: Model 2: Interaction with population or study. The parameters for each treatment will be modeled as specific parameters to a study or a population subset. This approach is in fact equivalent to stratification in a standard meta-analytical approach. A model the effect of treatment 1 with µ 11, µ 12,, µ 1S, where each µ is the effect for Treatment 1 in each study (explicitly allowed to vary). Within this model the effects for each treatment within each study are modeled hierarchically. The same type of model will be used to incorporate study effects being dependent on the population. Model 3: Treatment class hierarchical model. Treatment will also be modeled as a member of a treatment class (drug class for example). So, the individual treatment effect, µ T, will be modeled with a hierarchical distribution depending on the drug-class: ( ). 2 q T ~ N m Class,s Class This allows the analysis of each treatment to be modeled within its drug-class. This model aids in the estimating of each treatment effect, but also allows drug-class level variables to be estimated, i.e. estimates of the mean and standard deviation for a drug-class.

26 Model 4: Treatment and covariates model. The modeling of the covariates is usually done in two ways. The first is the fixed effect approach and the second is to model the interaction with treatment (described in the treatment section above). The standard approach to modeling covariates is to create a coefficient for each covariate. The following covariates will be considered: Percentage of patients <18 years of age Asthma severity at baseline (eligibility). Prior therapy: Inhaled corticosteroids Prior therapy: Short acting beta agonist Disease status (Controlled) % reversibility of FEV1 at baseline Additional exploration may include an analysis of the impact of study duration on treatment effects. Studies are expected to present heterogeneity at baseline driven by inclusion criteria around asthma severity. For both these factors, adjusted models will be used to explore the impact of the mean of selected covariates at baseline and whether or not covariates could potentially drive differences in treatment effects. The interaction between covariates (population) and treatment is rarely possible without the availability of subject level data therefore interaction terms will not be considered in this MTC. A general test f model fit (standard model fitting diagnostics, deviance information criterion (DIC) and Bayesian Information Criterion (BIC)) will be applied to assess and capture sensitivity to assumptions, i.e. evaluating the to determine if a hierarchical aspect is necessary, and provide sensitivity analyses when warranted. General Modeling Strategy We will use the above structure to address the modeling of the studies, treatment, and covariates. Before addressing any individual analysis we structure the standard modeling. We will refer to scenarios as the modeling of an endpoint, treatment subsets, and specific covariates. The default modeling approach for each scenario is: 1. Standard modeling of each variable: a. Normal distribution model for continuous outcomes b. Logistic link function for dichotomous outcomes c. Exponential modeling for time-to-event d. Poisson Model for count data 2. Hierarchical additive study effects 3. Fixed effects for each treatment 4. Coefficients for each covariate. This modeling will allow general conclusions on the comparisons, ranking, and ordering of

27 different treatments. Specifically the modeling will allow us to address the following research questions: The relative treatment effect (non-inferiority) of Relvar vs. other ICS/LABA combination therapies (primary). The rank of Relvar in comparison with other ICS/LABAs (secondary): In addition to the posterior quantities used to assess non-inferiority, the model will provide the probability that each of the treatments is the best, second best, etc., among the population of treatments allowing ranking of Relvar in comparison with other ICS/LABAs. The role of heterogeneity in study design (sample size, differences in endpoints definitions, trial duration, population characteristics) in the observed variability of trial results (secondary) Several approaches to the assessment of heterogeneity in the study design will be attempted. First, as part of the systematic review, a qualitative summary of the variability of demographics at the study level (population characteristics) will be provided The second aspect is how much variability in efficacy/safety is realized across studies. In Bayesian frameworks, there is no explicit assessment of heterogeneity other than that based on the properties and convergence of the model. An index of heterogeneity is not available for more complex frameworks than the head to head comparisons assuming fixed effects. In a Bayesian hierarchical model, a more appropriate measure criterion is the explicit modeling of the heterogeneity across studies, summarized by the between study variability (with relevant posterior summaries, such as the posterior mean and standard deviation of the study-to-study heterogeneity). Selection of Priors Priors will be elicited based on the views from the clinical asthma experts, and if appropriate, from large epidemiological studies conducted by GSK or other appropriate sources. The strategy of prior development in this MTC is the following. First priors are separated into two components one is a modeling choice, like a hierarchical model, which allows for the needed heterogeneity. This aspect of prior development will be incorporated in the model development. The second component is the selection of priors for the hierarchical hyperparameters. For these prior specifications we will use the following staged approach: 1. Base case analysis: non-informative priors for all parameters will be developed. These priors will be selected to allow the empirical information to shape the posterior completely. This approach achieves an added level of external validity, in that it eschews subjective information, and has a level of objectivity to it. The priors selected in this strategy may play an important role (data dependent through the hierarchical model). A sequence of priors will be created, different from those selected above, to assess the role of sensitivity analyses. These

28 priors will span the space of priors from strong to weak. We will present the results of the analyses for the range of priors in the sensitivity analyses to explore the sensitivity of the results to the prior distributions. 2. Expert opinion elicitation: there are a number of parameters for which prior information will play an important role and potentially affect decisions. These will typically be heterogeneity parameters. These variance components are important parts of the model and allow it to range from a pooling model to a completely separate model. Because of this importance, we will develop internal GSK priors prospectively on these critical parameters. This will be done using a sequence of qualitative discussions, simulation results, and leveraging our prior construction experience. The range of priors in this analysis will be used for measuring prior sensitivity. SEE APPENDIX 2 for DETAILED STATISTICAL ANALYSIS PLAN

29 5. LIMITATIONS While the use of Bayesian hierarchical models require a number of assumptions (e.g., exchangeability of information at each level of the hierarchy, prior information), the ability of the model to incorporate the structure and limitations of the available information allows greater model validity than other approaches (e.g., traditional frequentist multi-level modeling). These models are very robust, because they are so flexible. This mitigates to some degree typical worries regarding model dependencies and the validity of initial assumptions. When using such a model to make mixed treatment comparisons, one must often make assumptions about the additivity of treatment effects across studies. For example, if treatment A is compared to treatment B in one study and treatment B is compared to treatment C in another study, then an assumption of the additivity of treatment effects is needed to make any comparison between A and C. This can be a difficult assumption to test because of the lack of repeated single trials. All assumptions will be laid out in detail and explained thoroughly in the final study report. 6. STUDY CONDUCT, MANAGEMENT & ETHICS 6.1. ETHICS/IRB APPROVAL Non interventional study 6.2. INFORMED CONSENT Non interventional study 6.3. DATA PRIVACY Only published trial data used 6.4. PERSONALLY IDENTIFIABLE INFORMATION (PII) No PII used 6.5. AE REPORTING Only previously published or disclosable analyses used 6.6. DATA STORAGE/ARCHIVAL All data will be stored according to GSK policy & archived to PIER with appropriate metadata. 7. EXTERNAL INVOLVEMENT 7.1. Third Party Supplier (Company Name, Address & Staff Names/ /Phone)

30 7.2. External Expert/Health Care Professionals (Consultants & Research PIs) CID ## consultant, not government employee

31 MILESTONES MILESTONE GUIDANCE OR POLICY REQUIREMENT FORECAST DATE MM-YYYY Forecast Final Protocol Approval Forecast GSK CSR Protocol Summary FPA Actual + 30 days Forecast Statistical Analysis Plan Approved Forecast Statistical Analysis Complete Forecast Final Study Report Complete SAC Actual + 6 months Forecast GSK CSR Results Summary Posting SAC Actual + 8 months Forecast Manuscript Submission SAC Actual + 18 months

32 DATA DISSEMINATION PLAN Attach the Manuscript & Congress Presentation Data Dissemination Plan (DDP) in the MCQP DDP Powerpoint template. Should include the following information: MANUSCRIPT PUBLICATION(S) Note: Only 1 primary manuscript per study is permitted unless approval from Medical. STUDY ID PUBLICATION SHORT TITLE LEAD AUTHOR STUDY ACCOUNTABLE PERSON ESTIMATED SUBMISSION DATE (< SAC + 18 months) TARGET JOURNAL CONGRESS PRESENTATION(S) STUDY ID ABSTRACT SHORT TITLE PRESENTER POSTER OR ORAL PRESENTATION CONGRESS CONGRESS LOCATION CONGRESS DATE DISCLOSURE PLAN GSK CSR PROTOCOL SUMMARY (FPA + 30 DAYS) GSK CSR RESULTS SUMMARY (SAC + 8 MONTHS) FULL PROTOCOL POSTING DATE (Manuscript submission actual + 30 days) FORECAST

33

34 Appendix 1: Definitions of exacerbations used in Asthma studies Author Description reported in study Definitions of 'All exacerbations' endpoint, when used Peters 2008 Berger 2010 Nathan 2010 Papi 2007 asthma exacerbations (defined as the use of oral or systemic corticosteroids, hospitalization, or an emergency department [ED] or urgent care visit caused by an asthma exacerbation) clinical exacerbation was defined as an exacerbation requiring emergency treatment, hospitalization, or use of an asthma medication not allowed by the protocol ATS/ERS statement definition for severe asthma exacerbation The recently published ATS/ERS guidelines2 provide the following definition for severe asthma exacerbations: Use of systemic corticosteroids or an increased dose from a stable maintenance level, for at least 3 days (courses of corticosteroid treatment separated by 1 week should be considered as separate incidences). Asthma-related hospitalization or emergency room visit, requiring use of systemic corticosteroids. In addition, the following criteria are being evaluated for further validation (the changes should persist for 2 days): Changes in PEF from baseline. Changes in asthma symptoms. Changes in 2-agonist use a mild exacerbation was defined as 2 consecutive days with: morning PEF more than 20% below the baseline value, or use of more than three additional inhalations of rescue salbutamol for a 24 h period when compared with baseline, or a night-time asthma symptoms score 3; a severe exacerbation was defined as: morning PEF more than 30% below the baseline value on 2 consecutive days, or a deterioration in asthma requiring administration of oral corticosteroids OC+hosp & emergency + urgent care OC+hosp & emergency + urgent care + medication Definitions of 'Severe exacerbations' endpoint, when used OC+hosp & emergency + urgent care OC; PEF<-30% baseline Definitions of Mild/moderate exacerbations' endpoint, when used changes in PEF, symptoms, b2- agonists MILD: PEF <=20% baseline; 3+ rescue puffs / 24h; nightime symptoms +3

35 Calhoun 2001 OPTIMA trial An asthma exacerbation was defined as any requirement for additional asthma medications other than those permitted by the protocol. Therefore, any requirement for supplemental oral or parenteral corticosteroids, as determined by each investigator, was considered an exacerbation. Patients were withdrawn from the study in the event of an asthma exacerbation first severe asthma exacerbation, defined as need for treatment with oral corticosteroids, as judged by the investigator, or hospital admission or emergency treatment for worsening asthma, or a decrease in morning PEF additional asthma medication not per protocol (including OC) OC; emergency admission; PEF<-25% baseline 25% from baseline (the mean values during the last 14 d of the run-in) on two consecutive days. Condemi 1999 Pearlman 2002 Berger 2002 Weiler 2005 Malmstrom 1999 Bodzenta- Lukaszyk 2011 Asthma exacerbations were defined as any asthma event that required treatment with oral or parenteral corticosteroids. Patients were withdrawn if they experienced more than two study-defined asthma exacerbations or had two exacerbations within a 30-day period. An asthma exacerbation was defined as any requirement for additional asthma medications other than those permitted by the protocol. Therefore, any requirement for supplemental oral or parenteral corticosteroids, as determined by each investigator, was considered an exacerbation. Patients were withdrawn from the study in the event of an asthma exacerbation. 12 weeks; An asthma exacerbation was defined as any event that required emergency care or an emergency room or hospital visit because of worsening of asthma; an unscheduled clinic visit requiring treatment with inhaled, oral, or parenteral corticosteroids, or nebulised albuterol; asthma medications other than study medication; the use of 12 or more puffs of albuterol in a 24-hour period; or the use of 10 or more puffs of albuterol on each of 2 consecutive days. No definition provided asthma attacks: defined as worsening asthma requiring oral corticosteroid treatment or an unscheduled visit to a physician, emergency department, or hospital Mildtomoderate exacerbations were: pre-dose morning PEFR > 30% below baseline on 2 consecutive days; night awakening due to asthma 2 consecutive days; or use of salbutamol rescue medication > 4 times per day for 2 consecutive days. Severe exacerbations were deterioration in asthma requiring additional therapy, or emergency visit or hospitalization due to asthma. any OC additional asthma medication not per protocol (including OC) OC+hosp & emergency + urgent care + medication attack': OC+hosp & emergency + urgent care OC+hosp & emergency + urgent care MILD/MODERATE: PEFR decrease up to 30% baseline; 2 days noghtime awakenings; rescue medication

36 Nathan 2012 Foresi 2005 Postma 2011 Johansson 2001 Boonsawat 2008 Chuchalin 2008 Mild-to-moderate exacerbations were defined as any of the following occurring for at least 2 consecutive days: i) pre-dose PEFR measurements more than 30% below the values measured at baseline, or ii) awakening during the night because of asthma, or iii) the use of additional rescue medication of more than three inhalations per day compared with baseline. Severe exacerbations were defined as the deterioration in asthma that required additional therapy (for example, systemic steroids), or an emergency visit or hospitalisation due to asthma. not specified exacerbation: defi ned as a. 30% decrease in PEF from baseline on 2 consecutive days or the need for oral corticosteroids, hospitalization, or emergency treatment of worsening asthma Exacerbations were categorised as mild (increased relief medication use), moderate [additional corticosteroids (inhaled and/or oral) and/or permitted bronchodilators] or severe (emergency hospital treatment). A moderate asthma exacerbation was defined as a deterioration in asthma requiring treatment with a short course of oral corticosteroids, based on a morning PEF >30% below the baseline value (defined as the mean of the values over the past 7 days prior to randomization) for 2 consecutive days, or in the investigator s opinion. A severe asthma exacerbation was defined as a deterioration in asthma symptoms requiring hospital admission. Patients who experienced more than two asthma exacerbations requiring treatment with oral corticosteroids, or any exacerbation that required hospitalization, were withdrawn from the study. Mild moderate and severe. Mild exacerbations were defined as morning PEF >20% below baseline on 2 consecutive days; use of additional reliever compared with baseline on more than three occasions per 24-hour period for 2 consecutive days; awakening at night as a result of asthma for 2 consecutive nights. Moderate exacerbations were defined as a deterioration in asthma requiring treatment with oral corticosteroids based on PEF >30% below baseline for 2 consecutive days or according to the investigator s opinion. Severe exacerbations were defined as deterioration in asthma requiring hospital admission. PEFR decrease up to 30% baseline; 2 days nightime awakenings; rescue medication OC+hosp & emergency + urgent care SEVERE: hospital admission SEVERE: hospital admission MILD/MODERATE: PEFR decrease up to 30% baseline; 2 days nightime awakenings; rescue medication MILD: increased medication MODERATE: OC / inhaled, Oral SEVERE: emergency hospital MILD/MODERATE: PEFR decrease up to 30% baseline; 2 days ; or Investigator's opinion MILD: PEFR decrease of at least 20% over baseline; 2 days; nightime awakenings ; MODERATE: deterioration in asthma + OC + PEF >30% below baseline CONCEPT trial An asthma exacerbation was defined as a worsening of asthma requiring hospital treatment or treatment with oral corticosteroids, either in the opinion of the investigator or based on a morning PEF <70% of the mean of the last 7 days in weeks 1 through 4 for >2 consecutive days. hospital treatment + OC + PEF < 70% from baseline

37 Corren 2007 Aalbers 2004 Jung 2008 Bailey 2008 A clinical exacerbation requiring emergency treatment, hospitalization, or use of asthma medication not allowed by the protocol. Exacerbations, defined as oral steroid treatment for 3 days, emergency room (ER) visits and/or hospitalisation, deterioration in asthma symptoms requiring an emergency room visit and/or admission to hospital, or the need for oral steroid therapy. An asthma exacerbation during this period was defined as any of the following: (1) worsening of asthma that required treatment with an oral corticosteroid; (2) hospitalization for the treatment of asthma; (3) unscheduled urgent care for acute asthma symptoms that required intervention (e.g., unscheduled clinic visit, physician office visit, emergency room [ER] visit); (4) 30% decrease in FEV1 from the baseline obtained at the randomization visit; or (5) morning peak expiratory flow (AM PEF) below the AM PEF Stability Limit on any 2 consecutive days. The AM PEF Stability Limit was defined by a 30% decrease emergency treatment, hospitalisation, asthma medication (any) emergency treatment, hospitalisation, OC emergency treatment, hospitalisation, OC emergency treatment, hospitalisation,, FEV<-30% decrease from baseline; PEF <=30% (stability limit from baseline) Noonan 2006 Johnson 1994 COSMOS study Papi 2007 Clinical asthma exacerbations, a component of the predefined criteria for worsening asthma, were those requiring emergency treatment, hospitalisation or use of an asthma medication not allowed by the protocol not specified severe exacerbations: deterioration in asthma, resulting in hospitalisation/emergency room (ER) treatment, oral steroids for o3 days or an unscheduled visit (i.e. patient initiated) leading to treatment change. Mild, moderate and severe hospital / emergency treatment + asthma medication severe: hospital admission ; OC; change in treatment Sears 2008 EuroSMART study defined as hospitalisation or emergency room (ER) visit and/or use of oral corticosteroid for o3 days due to asthma first severe asthma exacerbation, defined as deterioration in asthma leading to a need for oral or systemic corticosteroids either for o3 days, and/or associated with hospitalisation, an emergency room visit or other patient-initiated unscheduled visits to a healthcare centre emergency treatment, hospitalisation, OC emergency treatment, hospitalisation, OC

38 Meltzer 2012 Severe exacerbation: An asthma deterioration was defined as a clinically judged deterioration (i.e. asthma attack resulting in emergency treatment, hospitalisation or treatmentwith additional, excluded asthma medication (i.e. systemic corticosteroids)) or a meaningful reduction in lung function (i.e. a decrease in FEV1 of.20% from baseline at any study visit or a decrease in PEF of.30% from baseline foro2 days consecutively at any time during the treatment period). emergency treatment, hospitalisation, OC; FEV <=80% of baseline; PEF <=70% from baseline MILD: nightime awakening + SABA; PEF<=75% of baseline Kuna 2007 moderate asthma exacerbation defined as any one of the following criteria: two consecutive nights with at least one nocturnal awakening due to asthma symptoms requiring SABA use; a decrease in 24-h PEF of o25% on two consecutive days of treatment; a clinically significant increase in short-acting bronchodilator use (two consecutive days of o8 units of SABA). Severe exacerbations were defined as deterioration in asthma resulting in hospitalisation or emergency room (ER) treatment, or the need for oral steroids for 3 days (as judged by the investigator) OC+hosp & emergency + urgent care Louis 2009 to first severe asthma exacerbation defined as deterioration in asthma leading to at least hospitalisation emergency room (or equivalent) or oral GCS treatment for at least 3 days OC+hosp & emergency + urgent care MILD: nightime awakening + SABA; PEF<=75% of baseline Mild exacerbation days, defined as a day with any one of the following: morning PEF 20% below baseline, daily as-needed medication use 2 inhalations above baseline or a night with an asthma-related awakening, were also calculated from diary-card data. Busse 2008 worsening asthma requiring oral corticosteroid treatment; OC Bodzenta- Lukaszyk 2012 Nelson 2000 Busse 2003 Bateman 2006 Pavord 2009 Severe asthma exacerbations were defined as exacerbations of asthma requiring treatment with oral or parenteral steroids or medical intervention. An asthma exacerbation was defined as any requirement for asthma medications other than those permitted by the protocol. defined as any worsening of asthma that required asthma medication beyond blinded study drugs or albuterol). moderate (requiring oral corticosteroids) and severe (requiring hospitalization) asthma exacerbations deterioration in asthma symptoms resulting in hospitalization/emergency room treatment and/or oral steroid use for 3 days), OC/ syst CS + medical assistance asthma medication non permitted asthma medication non permitted emergency treatment, hospitalisation, OC hospitalisation MODERATE: Ocs

39 Brown 2012 Koenig 2008 Quirce 2011 Asthma exacerbations were defined as requirement of oral/parenteral corticosteroids and/or emergency department visit and/or urgent care visit and/or hospitalization for asthma. Patients who experienced more than 2 exacerbations within 3 months or more than 5 exacerbations within 1 year during randomized treatment were discontinued from the study. 16 weeks; An exacerbation was recorded if, in the investigator s opinion, worsening asthma symptoms required treatment with any asthma medication in addition to blinded study medication or albuterol; Reported in 8% of 159 patients A severe asthma exacerbation was defined as deterioration in asthma leading to at least hospitalization or emergency room treatment for asthma or treatment with oral corticosteroids for at least three consecutive days emergency treatment, hospitalisation, OC asthma medication non permitted emergency treatment, hospitalisation, OC Busse 2001 START study Rabe weeks; An asthma exacerbation was defined as any event that required treatment with oral or parenteral steroid; severe exac as an event resulting in hospitalisation, emergency room treatment, or both, or the need for oral steroids for 3 days or more OCs / parenteral Cs emergency treatment, hospitalisation, OC Morice 2008 severe exacerbation (defined as asthma symptoms requiring oral steroids and/or hospitalization/ emergency room treatment for asthma) emergency treatment, hospitalisation, OC Papi 2012 A mild exacerbation was defined as 2 consecutive days with morning PEF readings more than 20% below the baseline value, the use of>3 additional inhalations of rescue salbutamol compared to baseline or OC; PEF <=70% from baseline MILD: nightime awakening + SABA; PEF<=80% of baseline Nieminen 1998 Dusser 2005 awakening at night due to asthma [14,15]. A severe exacerbation was defined as morning PEF readings more than 30% below baseline values on 2 consecutive days or the deterioration of asthma requiring administration of oral corticosteroids increased asthma symptoms requiring changes in therapy other than inhaled ß2-agonist rescue therapy. The occurrence of an exacerbation was not a dropout criterion. not specified symptoms + change in therapy (other than rescue)

40 Jenkins 2000 Ringdal 2002 A severe exacerbation of asthma was de ned as a deterioration in asthma requiring emergency hospital treatment. Exacerbations were de ned as moderate if they required administration of additional inhaled corticosteroids, bronchodilators and/or oral corticosteroids. A mild exacerbation was de ned as a deterioration in asthma requiring an increase in the use of relief medication which the physician considered to be clinically relevant. Mild K a deterioration in asthma requiringan increase in relief medication use, which the investigator deemed clinically relevant, or K PEFam 420% below baseline (mean of last 10 days of runin) for 2 consecutive days, or K 43 additional reliever inhalations per 24-h period with respect to baseline for 2 consecutive days, or K awakeningat night due to asthma for 2 consecutive days Moderate K PEFam430% below baseline on 2 consecutive days, or K a deterioration in asthma requiring administration of additional ICS (over and above studymedication) and/or oral corticosteroids Severe K a deterioration in asthma requiring emergency hospital treatment hospitalisaton emergency hospitalisation MILD: increase reliever MODERATE: OC/antibiotics / inhaled therapy SEVERE: Hospitalisation MILD: nightime awakening + SABA; PEF<=80% of baseline MODERATE: PEF<=70% of baseline Ringdal 2003 Strand 2004 Lundback 2006 Exacerbations were classi ed as mild (a deterioration in asthma requiring a clinically relevant increase in salbutamol use de ned asmore than three additional inhalations per 24-h periodwith respect to baseline for42 consecutive days), moderate (requiring oral corticosteroids and/or antibiotics) or severe (requiring a hospitalisation). A moderate asthma exacerbation was defined as a deterioration in asthma requiring administration of ICS over and above current study medication and/or oral corticosteroid and/or parenteral corticosteroid. A severe asthma exacerbation was defined as a deterioration in asthma requiring emergency hospital treatment Exacerbations were defined as any deterioration in asthma that required an increase in rescue medication use (beta-agonist) over that used during the run-in period of46 puffs/day for X2 consecutive days, or an increase of X2 doses/day in regular inhaled medication (study medication or additional ICS) for X2 days by the patient s own decision, or X2 days when asthma symptoms prevented the patient s work or normal activities. If rescue medication was insufficient, exacerbations were treated with oral prednisolone (25 mg) for 5 days. hospitalisaton MILD: increase reliever MODERATE: OC/antibiotics SEVERE: Hospitalisation MODERATE: ICS, systemic Corticosteroids Mild / moderate

41 Dahl 2006 Mild Morning PEF420% below baseline (mean of last 7 days of run-in) for X2 consecutive days, or More than 3 additional reliever occasions/24-h period with respect to baseline for X2 consecutive days, or Awakening at night due to asthma for X2 consecutive nights Moderate Deterioration in asthma requiring treatment with oral prednisolone mg per day for 7 10 days. This may be either: Morning PEF430% below baseline (mean of last 7 days of run-in) for X2 consecutive days, or A clinical deterioration assessed by the investigating physician as requiring oral steroid treatment Severe Deterioration in asthma requiring hospital admission Bousquet 2007 first severe exacerbation, defined as deterioration in asthma leading to hospitalisation/ emergency room (ER) treatment and/or oral corticosteroid treatment for at least 3 days. emergency treatment, hospitalisation, OC MILD: nightime awakening + SABA; PEF<=80% of baseline MODERATE: Ocs SHARE study An exacerbation was defined as deterioration in asthma resulting in a hospitalisation/emergency room visit or the use of oral corticosteroids due to asthma. emergency treatment, hospitalisation, OC Koenig 2008 Godard 2008 Huchon 2009 Reddel weeks; An exacerbation was defined as worsening asthma for which treatment with medication other than the double-blind study drugs or study-provided albuterol was necessary, and was treated with oral prednisone burst of 1 mg/kg per day for 4 days followed by half that dose for 3 days; Calculated from 24% of 154 patients 24 weeks; Severe exacerbation was defined as worsening of asthma leading to hospitalisation; Evaluable N=156; 24 weeks; AM; Moderate exacerbation was defined as worsening of asthma leading to a prescription for a short use of oral corticosteroids; Calculated from 7.7% of 156 The occurrence of asthma exacerbations was recorded, according to pre-defined criteria, as follows: Mild-to-moderate exacerbation: diurnal PEF variability >20% and 30%; SABA use between four and eight puffs per day; or nocturnal awakening due to asthma e all during at least two consecutive days. Severe exacerbation: need for oral corticosteroid; asthma-related unscheduled medical visit or visit to an emergency department; hospital admission for asthma; diurnal PEF variability >30% or SABA inhalation of more than eight puffs per day during at least two consecutive days; or nocturnal awakening due to asthma during at least three consecutive 24-hour periods. Moderate exacerbations were defined by an increase in rescue b2-agonist use by 2 occasions and/or a fall in PEF by 2 standard deviations (SD) from baseline mean on 2 of 3 consecutive days. Study medication was doubled for 2 weeks; if necessary, FP 250 mg bd could be added for two weeks. Severe exacerbations were defined as increase in rescue b2-agonist by 2 occasions in a day compared with baseline and a fall in PEF by 3 SD from baseline mean on 2 of 3 consecutive days worsening asthma + Any treatment other than study treatment hospitalisation emergency treatment, hospitalisation, OC; FEV <=80% of baseline; nightime awakenings SABA; PEF<= 3*SD of baseline MODERATE: Ocs MILD / MODERATE: nightime awakening + SABA; PEF<=80% of baseline MILD / MODERATE: nightime awakening + SABA; PEF<= 2*SD of baseline

42 Renzi 2010 Severe exacerbations were defined as deterioration in asthma requiring emergency hospital treatment/admission or according to investigator opinion. A patient was withdrawn if he or she required hospitalization or more than 3 exacerbations requiring treatment with oral corticosteroids. hospitalisation; emergency Djukanovic 2010 Bodzenta- Lukaszyk 2011 Atienza 2012 defined as worsening asthma requiring treatment beyond study drug and needing supplemental salbutamol use) severe asthma exacerbation requiring treatment (i.e. emergency treatment, hospitalization, use of oral or parenteral corticosteroids); severe asthma exacerbation, defined as deterioration in asthma leading to oral corticosteroid treatment for at least 3 days, or hospitalisation or ER treatment due to asthma. Mild exacerbations were defined using diary data as morning PEF Accepted Article additional asthma medication not per protocol (including OC + salbutamol ) OC+hosp & emergency + urgent care + Ocs / parenteral CS Deterioration + OC + hospitalisation / ER MILD: PEF <=20% baseline; 2+ rescue puffs / 24h; nightime awakening Bergmann 2004 Weinstein 2010 Katial 2011 GOAL study GOAL study Kerwin 2011 that was below baseline by 20%, daily as-needed mediation use 2 inhalations above baseline or a night-time awakening due to asthma symptoms. not specified asthma deteriorations (i.e., severe asthma exacerbations). Asthma deteriorations were defined by any one of the three following criteria: (1) a decrease below 80% of baseline FEV1; (2) a decrease below 70% of baseline PEF for at least 2 consecutive days; or (3) a clinically judged deterioration (i.e., asthma attack) resulting in emergency treatment, hospitalization, or treatment with additional asthma medication such as systemic glucocorticosteroids defined as the requirement for treatment with an oral or parenteral corticosteroid, or an unscheduled urgent care visit (e.g., unscheduled clinic visit, physician office visit, emergency room visit, or hospitalization) for acute asthma symptoms requiring intervention (requiring oral corticosteroids, hospitalizations or emergency visits) Severe exacerbations requiring hospitalisation or emergency visit asthma exacerbation defined by the requirement for treatment with an oral or parenteral corticosteroid, or an unscheduled urgent care (e.g. unscheduled clinic visit, physician office visit, emergency room visit, hospitalization) for acute asthma symptoms requiring intervention per subject per year OC+hosp & emergency + urgent care + oral / systemic Cs OC+hosp & emergency + urgent care OC/syst Cs +hosp & emergency + urgent care defined as asthma deteriorations; FEV1 <-80% of baseline; PEF <- 30% of baseline; 2+ consecutive days; ER, Hospital or Ocs Hosp & emergency + urgent care

43 HZA study HZA study HZA study FFA study HZA study B2C study severe asthma exacerbation was defined as deterioration of asthma requiring the use of systemic corticosteroids (tablets, suspensions, or injection) for at least 3 days or an inpatient hospitalization or emergency department visit due to asthma that required systemic corticosteroids. withdrawn >3 exac severe exacerbation was defined as deterioration of asthma requiring the use of systemic corticosteroids (tablets, suspensions or injection) for at least 3 days or an in-patient hospitalisation or emergency department visit due to asthma that required systemic corticosteroids. Subjects were withdrawn due to lack of efficacy if they experienced a severe asthma exacerbation or worsening asthma, or at the investigator s discretion. A severe exacerbation was defined as deterioration of asthma requiring the use of systemic or oral corticosteroids (tablets, suspension or injection) for at least 3 days, or an in-patient hospitalisation or emergency department visit due to asthma that required systemic corticosteroids. Subjects were also withdrawn due to lack of efficacy if they had worsening of asthma that required any additional treatment other than study medication or use of rescue albuterol/salbutamol. The worsening asthma was to be treated as deemed necessary by the investigator. A severe exacerbation was defined as deterioration of asthma requiring the use of systemic or oral corticosteroids (tablets, suspension, or injection) for at least 3 days, or an in-patient hospitalisation or emergency department visit due to asthma that required systemic corticosteroids Subjects were also withdrawn due to lack of efficacy if they had worsening of asthma that required any additional treatment other than study medication or use of rescue albuterol/salbutamol. The worsening asthma was to be treated as deemed necessary by the Investigator. not specified 12 weeks; Severe asthma exacerbation was defined as deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days or an in-patient hospitalisation or emergency department visit due to asthma that required systemic corticosteroids; One patient each was hospitalised due to exacerbation and reported severe exacerbation in the post-treatment period OC/syst Cs +hosp & emergency OC/syst Cs +hosp & emergency OC/syst Cs +hosp & emergency OC/syst Cs +hosp & emergency OC/syst Cs +hosp & emergency

44 Appendix 2: Statistical Analysis Plan Details Specific Modeling Strategy, by endpoint FEV (primary endpoint) An MTC model will be designed to estimate the relative treatment effect on FEV1 / FEV AUC for the following comparators: 1. BUD/FOR 400/12 BID (Symbicort 400) 2. SFC 250/50 BID (Seretide 250) 3. BDP/FOR 200/12 BID (Flutiform check) 4. FF/VI 100/25 QD (Relvar) 5. BUD/FOR 160/9 BID (Symbicort 200) 6. BUD 400 BID 7. FF 100 QD 8. Placebo 9. BUD/FOR 160/9 QD 10. BUD/FOR 320/9 QD 11. BUD 320 QD A total of 15 studies are included in this scenario, therefore, a distribution will be assigned to each study, Study = a S for S=1,, 15 With a S ~ N m,s 2 ( ) Scenario 1 (Base case): The model will be estimated assuming the following: 1. Normal model for continuous data (likelihood) 2. Hierarchical additive study effects 5. Random effects for each treatment Treatment t, for t=1, 11 T(x s,t ) N(µ s,t, t 2 ) With µ s,t, N(µ t, t 2 ) With s=study The following model outputs will be generated, based on the posterior distributions: The relative treatment effect (non-inferiority) of Relvar vs. other ICS/LABA combination therapies (primary) The rank of Relvar in comparison with other ICS/LABAs (secondary) The effect of drug class ICS/LABAs compared with LABAs (secondary) The role of heterogeneity in study design (sample size, use of surrogate endpoints, trial duration, population characteristics) in the observed variability of trial results (secondary)

45 Evidence networks for lung function Table XX below shows the evidence network as identified based on the results for the original systematic review. The network links via SFC 250/50 and via placebo. In addition, despite the network is broken for FF/VI 200 and FF 200, it is possible to attempt a closure it the population of studies identified (n=15) shows very little study-to-study variation. The link is executed by assuming a common comparator (i.e. for example via the steroid in the studies where one is used). The "model" provides a link. This procedure is possible if and only if the of study-to-study variation is low. An example can clarify the procedure. Suppose studies are available within the same population with the following comparisons: A vs. B, A vs. C, B vs. D, and then a study with E vs. F. A, B, C, and D can be linked through the trials. E and F have no overlap with A, B, C, and D, so the link is broken. Now suppose the variation in study results is very small (the A results are similar in each study, the B results are similar etc.. ) Then it is possible to assume that there is little variation and thus E can be linked to A, and so on. In the case of large study to study variability then the ability to compare A to E is weak and the comparisons have very large variability. Although the comparison can still be made, it will just bring about large uncertainty. The studyto-study variability is not know up-front but is determined by the data. For this reason, and importantly, it is not possible to establish a priori whether the network can be closed and therefore the assessment of the extent to which a comparison of FF/VI 200 is possible will be known after the analysis is executed. Exacerbations An MTC model will be designed to estimate the relative treatment effect on exacerbation rates for the following comparators: 1. FF/VI 100/25

46 2. FF/VI 200/25 3. FF FF Placebo 6. SFC 100/50 BID 7. SFC 250/50 BID 8. SFC 500/50 BID 9. BUD/FOR 100/4.5 BID 10. BUD/FOR 160/9 BID 11. BUD/FOR 200/4.5 BID 12. BUD/FOR 320/9 BID or BUD/FOR 400/12 BID 13. FP/FOR 100/10 BID 14. FP/FOR 250/10 BID 15. FP/FOR 500/20 BID 16. FP/FOR 500/24 BID 17. BDP/FOR 200/12 BID 18. BDP/FOR 500/12 BID A total of 73 studies are included in this scenario, therefore, a distribution will be assigned to each study, Study = a S for S=1,, 73 With a S ~ N m,s 2 ( ) Scenario 1 (Base case): The model will be estimated assuming the following: 3. Poisson Model for count data (likelihood) 4. Hierarchical additive study effects 6. Random effects for each treatment Treatment t, for t=1, 18 P(x s,t ) Pois ( s,t ) With t N(µ, 2 ) With s=study The following model outputs will be generated, based on the posterior distributions: The relative treatment effect (non-inferiority) of Relvar vs. other ICS/LABA combination therapies (primary) The rank of Relvar in comparison with other ICS/LABAs (secondary) The effect of drug class ICS/LABAs compared with LABAs (secondary) The role of heterogeneity in study design (sample size, definition of exacerbations, trial duration, population characteristics) in the observed variability of trial results (secondary) Evidence networks for exacerbations The embedded Excel file shows the entire evidence network as identified based on the results for the systematic review. An associated Excel file to this protocol illustrates the network. Here below is a summary of the network links between interventions included in the MTC for the exacerbations endpoint:

47 26 studies link via placebo, of which: To SFC 100/50 (n=6, Kerwin 2008 Boonsawat 2008 Chuchalin 2008 Kavuru 2000 Pearlman 2004 Postma 2011 Shapiro 2000) To SFC250/50 (n=1, Shapiro 2000) To BUD/FOR (low, medium, high) (n=4, OPTIMA, Noonan 2006 Berger 2010 Corren 2007) To Flutiform (low dose) (n=1, Nathan 2012) 26 studies of SFC 100/50, of which FP 100 (n=10) and to FP 250 (n=3) SFC 250/50 links to FP 250 (8) and to FP 500(n=1, Bergmann 2004) Flutiform (BDP/FOR) mid dose (n=2, Papi 2007 Papi 2012), high dose BUD/FOR (Aalbers 2004 Busse 2008 Kuna 2007 Dahl 2006) Flutiform mid dose links to flutiform high dose (n=1, Huchon 2009) BUD/FOR high dose (n=1, Papi 2007 ) SFC 500/250 links up with: FP500 (n=1, Reddel 2010 ) FP250 (n=2, Aubier 1999 Van 2001 ); FP 250 links to Foster (FP/FOR, n=1 (500/20), n=1(250/10)) and BUD/FOR n=1, Bodzenta-Lukaszyk 2011 ) Forster low dose and mid dose link to each other (Mansur 2012 ) and to BUD/FOR mod dose (Bodzenta-Lukaszyk 2012) Relvar 100 and 200 link up with placebo (n=1, 827) SFC 500/25 (n=1, 091), FP 500 (n=1) and FP200 (n=1)

48 QOL Quality of life data appear sparse. The measure taken into consideration in this protocol is the AQLQ score. Other measures are collected in a subset of studies and are therefore unsuitable for evidence synthesis based on extensive comparisons AQLQ An MTC model will be designed to estimate the relative treatment effect on the AQLQ for the following comparators: SFC 250/50 BID FF/VI 100/25 FF 100 FP 100 BID Placebo BUD/FOR 320/9 BID (flexible dose) BUD 800 BID A total of 6 studies are included in this scenario, therefore, a distribution will be assigned to each study, Study = a S for S=1,, 6 With a S ~ N m,s 2 ( ) Scenario 1 (Base case): The model will be estimated assuming the following: 5. Normal Model for continuous data (likelihood) 6. Hierarchical additive study effects 7. Random effects for each treatment Treatment t, for t=1, 7 T(x s,t ) N(µ s,t, t 2 ) With µ s,t, N(µ t, t 2 ) Where s=study The following model outputs will be generated, based on the posterior distributions: The relative treatment effect of Relvar vs. other ICS/LABA combination therapies (secondary endpoint) The rank of Relvar in comparison with other ICS/LABAs (secondary) The role of heterogeneity in study design (sample size, trial duration, population characteristics) in the observed variability of trial results (secondary) Evidence networks foraqlq Table XX below shows the evidence network as identified based on the results for the systematic review.

49 The network links via SFC 250/50, FF/VI 100/25 and placebo. In addition, despite the network is broken for SFC 500/100, FF/VI 200 and FF 200, it is possible to attempt a closure it the population of studies identified (n=11) shows very little study-tostudy variation. The link is executed by assuming a common comparator (i.e. for example via the steroid in the studies where one is used). The "model" provides a link. This procedure is possible if and only if the of study-to-study variation is low. An example for this method is illustrated in Section above. For this reason, and importantly, it is not possible to establish a priori whether the network can be closed and therefore the assessment of the extent to which a comparison of FF/VI 200 is possible will be known after the analysis is executed. Appendix 3: Asthma Systematic Review of clinical efficacy literature, Final January 2013

50 HO Protocol Template Purpose statement The purpose of this protocol is to provide an overall schematic approach and methodology to be followed for this project. Purpose statement The purpose of this protocol is to provide an overall schematic approach and methodology to be followed for this project. Table of Contents Table of Contents 1 Abbreviations 3 1 Objective and research question Primary objective Sub objectives 4 2 Background Disease background Definition and clinical features of asthma Epidemiology and disease burden Causal factors Severity Current treatment options Scope and decision problem 8 3 Studies to include Population Disease Study designs Interventions Comparators Language 11 4 Data sources Databases Publication timeframe Conference proceedings Other sources 12 5 Information to extract Study information Treatment details Study population Efficacy outcomes Safety outcomes 17 GlaxoSmithKline 1

51 HO Protocol Template <Table of Contents 5.6 Tolerability outcomes Critical appraisal 19 6 Methodology Systematic review Study reporting 20 7 Summary 21 Appendix A Glossary of terms 24 Appendix B Critical appraisal 25 A.1 Descriptive appraisal 25 A.2 CONSORT checklist 26 8 References 28

52 HO Protocol Template Abbreviations Abbreviations ACD Asthma Control Diary ACT Asthma control test ACQ Asthma Control Questionnaire AQLQ Asthma Quality of Life Questionnaire BSC Best Supportive Care CENTRAL Cochrane Central Register of Controlled Trials CONSORT Consolidated Standards of Reporting Trials COPD Chronic obstructive pulmonary disease EMA European Medicines Agency Embase Excerpta Medica Database EQ-5D EuroQol 5D FDA Food and Drug Administration FEV Forced Expiratory Volume FF Fluticasone furoate GINA Global Initiative for Asthma HRQoL Health Related Quality of Life ICS Inhaled Corticosteroids ITT Intention To Treat LABA Long-Acting Beta Agonist LAMA Long-Acting Muscarinic antagonist LWAQ Living With Asthma Questionnaire MAQLQ Marks Asthma Quality of Life Questionnaire MEDLINE Medical Literature Analysis and Retrieval System Online mitt Modified Intention To Treat MS Microsoft NICE National Institute for Health and Clinical Excellence PEF Peak Expiratory Flow PP Per Protocol PRISMA Preferred Reporting Items for Systematic reviews and Meta-Analyses QoL Quality of Life RCT Randomised Controlled Trials SF-36 Short Form 36 SGRQ St. Georges Respiratory Questionnaire STA Single technology appraisal TNF Tumor Necrosis Factor UMEC Umeclidinium UK United Kingdom US United States VI Vilanterol WHO World Health Organisation GlaxoSmithKline 3

53 HO Protocol Template Objective and research question Objective and research question HERON Evidence Development (HERON) was commissioned by GSK to undertake a systematic literature review of all the inhaled therapies in the maintenance treatment for asthma. GSK is evaluating the efficacy and safety of a number of inhaled therapies in the maintenance treatment of asthma and chronic obstructive pulmonary disease (COPD). These include: Relvar, a new once daily combination product of fluticasone furoate (FF), an inhaled corticosteroid (ICS) and vilanterol (VI), a long-acting beta agonist (LABA) Project Zephyr, a once daily dual bronchodilator in COPD (VI + umeclidinium [UMEC]) Project Aura (FF + UMEC) UMEC monotherapy FF monotherapy A closed triple combination containing VI, UMEC, and FF Asthma is a chronic disease characterised by recurrent attacks of breathlessness and wheezing, which vary in severity and frequency from person to person. According to the World Health Organization, nearly 235 million individuals currently suffer from asthma. It is the most common chronic disease among children. Asthma is under-diagnosed and under-treated. It creates considerable burden on individuals and families and often restricts individuals activities for a lifetime. The objective of the review is to provide a comprehensive assessment of efficacy, safety, and tolerability of all classes of inhaled therapies in the maintenance treatment for asthma through a systematic literature review. This review will identify and analyse the up-to-date evidence base relating to asthma. The systematic literature review was also commissioned to help inform knowledge gaps in the currently available evidence base with an aim to support future market access activities. Primary objective To systematically assess the available clinical evidence base on all classes of inhaled therapies in the maintenance treatment for asthma Sub objectives To assess the evidence base on clinical effectiveness of Relvar vs. other ICS/LABAs combination therapies in asthma To assess the evidence base on clinical effectiveness of Relvar vs. ICS monotherapy in asthma To assess the evidence base on clinical effectiveness of Relvar vs. other monotherapies in asthma

54 HO Protocol Template Background Background Disease background Definition and clinical features of asthma Asthma is defined as as a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role" by the Global Initiative for Asthma (GINA) report published in the year The chronic inflammation is associated with airway hyper-responsiveness that results in recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or early morning. These episodes are usually associated with widespread, but variable, airflow obstruction within the lung that is often reversible either spontaneously or with treatment (Global Initiative for Asthma 2011). The main clinical features of asthma correspond to frequent and returning symptoms, airflow obstruction, bronchial hyper-responsiveness, and a principal causal inflammation (Figure 1). Figure 1: The Interplay and Interaction between Airway Inflammation and the Clinical Symptoms and Pathophysiology of Asthma SOURCE: (National Heart 2007) Epidemiology and disease burden The overall global prevalence of asthma corresponded to 300 million individuals of all ages and all ethnicities that were afflicted with asthma as per the WHO 2007 report (Masoli 2004; World Health Organization 2007). McFadden and colleagues reported that the prevalence of severe asthma presuming hospitalisation as an ideal substitute was approximately 4% of all attacks and 21% of all incidents in urgent care centres in the US (McFadden, Jr. 2003). In the US, costs related to the medical management of asthma amounted to US$3300 per person from 2002 until The average yearly cost of scheduled and unscheduled management of asthma in seven European nations (France, Germany, Italy, the Netherlands, Spain, Sweden, and the UK) amounted to 789 for patients aged 0 to 4 yrs, 463 for patients aged 5 to 15 yrs and 566 for adults (Williams 2006). Causal factors The underlying inflammation has a major role in the pathophysiology of asthma. The manifestation of asthma relates to a complex, interactive course that initiates due to an interaction between the two major factors host factors (particularly genetics) and environmental exposures that come about at a critical time in the development of the immune system. The major risk factors that are associated with the advancement and manifestation of asthma are depicted in Figure 2. Figure 2: Host factors and environmental exposures

55 HO Protocol Template Background SOURCE: (National Heart 2007); LRI: Lower Respiratory Illnesses; PIV: Parainfluenza Virus; RSV: Respiratory Syncytial Virus Severity The GINA guidelines reported that asthma severity is based on severity of underlying disease and its responsiveness to treatment. The asthma severity according to the type and frequency of asthma symptoms is presented in Table 1. Table 1: Classification of asthma severity according to type and frequency of asthma symptoms on the basis of Global Initiative for Asthma guidelines Frequency of asthma symptoms Day time Night time Severe episodes in the past 12 months Exercise-induced symptoms in the past 12 months Symptom frequency during a typical week SOURCE: (Global Initiative for Asthma 2011) Severe persistent 3 times per day Every night/most nights Moderate Every day ( 2 times/day) persisten t Mild persistent 2 times/week Intermittent <2 times/week 2 times/week 2 times/month <2 times/month Every day Every day 2 times/week 1 time/week Every day Every day 2 times/week 1 time/week 8-21 times/week 7-20 times/week 3-6 times/week 2 times/week

56 HO Protocol Template Background Current treatment options Despite the publication of National Asthma Education and Prevention Program guidelines, asthma remains poorly controlled (Spangler 2012). Current guidelines recommend long-term treatment with ICS because of their proven effectiveness in managing the chronic airway inflammation that characterises persistent asthma (Figure 3). ICS monotherapy should be explored before alternatives such as leukotriene modifiers and LABAs are attempted, especially after the US Food and Drug Administration s 2010 warning that LABAs should never be used alone to treat asthma due to the increased risk of severe exacerbations leading to hospitalisation in both children and adults, with a possibility of death. Figure 3: Treatment recommendations as per GINA SOURCE: (Bateman 2008); ICS: Inhaled Corticosteroids