HEALTH OUTCOMES PROTOCOL (VEO) (VEO) Analytics) (Medical) (PharmArchitecture)

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1 HEALTH OUTCOMES PROTOCOL UNIQUE IDENTIFIER ABBREVIATED TITLE FINAL PROTOCOL APPROVED FULL TITLE SPONSORSHIP DIVISION/BUSINESS UNIT DEPARTMENT HO STUDY ACCOUNTABLE PERSON(S) CONTRIBUTING AUTHORS RETENTION CATEGORY INFORMATION TYPE KEY WORDS / MESH HEADINGS / META DATA HO (TrackHO) and (etrack) Mepolizumab ITC in Severe Asthma 08-DEC-2014 Indirect treatment comparison (ITC) of mepolizumab versus omalizumab in the treatment of adults and adolescents (aged 12 years) with severe asthma Sponsored Pharma/Research & Development Value Evidence& Outcomes (VEO), R&D Analytics) (VEO) (VEO) (Medical) (PharmArchitecture) (Value Evidence (Clinical Statistics) GRS029 Research Reports / Technical Documents (30 years) Health Outcomes Observational (Non-Interventional) Protocol Efficacy Evidence synthesis Indirect treatment comparison Mepolizumab Meta-analysis Network meta-analysis Omalizumab Severe asthma Safety ASSET ID GSK ASSET INDICATION 16761/SB Mepolizumab Asthma

2 SPONSOR SIGNATORY Upload to isign, enter names of signatories (must have BioSafe Digital Credential), submit for electronic signature. Once signatures are complete, store in IMMS & archive to PIER. HO Study Accountable Person Date Group HO VP/Director Date Medical (GML/MDL/PPL/PMAL/RMD/Equivalent) Date Intellectual Property Date Trademarks Date Global Clinical Safety & Pharmacovigilence Date Statistics Date Enter other signatory Name/Role as needed Date HO PROTOCOL REVIEW COMMITTEE APPROVAL HO PRC CHAIR/SECRETARY Date Approved 2

3 TABLE OF CONTENTS PROTOCOL SYNOPSIS... 5 ABBREVIATIONS INTRODUCTION BACKGROUND STUDY RATIONALE ITC FEASIBILITY ASSESSMENT OBJECTIVES PRIMARY SECONDARY EXPLORATORY RESEARCH METHODOLOGY STUDY DESIGN STUDY POPULATION ELIGIBILITY CRITERIA SAMPLING... Error! Bookmark not defined DATA SOURCE / DATA COLLECTION ELIGIBILITY CRITERIA Included Treatments Excluded Treatments Study Design Inclusion Criteria Study Design Exclusion Criteria ENDPOINTS Primary Endpoint(s) Secondary Endpoint(s) Exploratory Endpoint(s) SAMPLE SIZE/POWER CALCULATIONS HYPOTHESES Heterogeneity DATA ANALYSIS CONSIDERATIONS OUTLINE STATISTICAL ANALYSIS PLAN Frequentist ITC using PBAC (Australia) Guidelines Software Random-Effects Models Bucher Method, by Outcome Type Multivariate Random-Effects Meta-Analysis (mvmeta)... 24

4 Heterogeneity Reporting the ITC Results Bayesian Network Meta-Analysis using NICE (UK) Guidelines Software Fixed-Effects Models Random-Effects Models, by Outcome Type Heterogeneity Evaluation of Baseline Risk Choice of Priors/Convergence Handling Multi-Arm Trials When the Bayesian Model Fails to Converge Reporting the ITC Results ITC Data/Model Considerations (Frequentist and Bayesian Frameworks) Inconsistency Imputation of Missing Standard Deviations Sensitivity Analysis LIMITATIONS STUDY CONDUCT, MANAGEMENT & ETHICS ETHICS/IRB APPROVAL INFORMED CONSENT DATA PRIVACY PERSONALLY IDENTIFIABLE INFORMATION (PII) AE REPORTING DATA STORAGE/ARCHIVAL EXTERNAL INVOLVEMENT THIRD PARTY SUPPLIER (COMPANY NAME, ADDRESS & STAFF NAMES/ /PHONE) EXTERNAL EXPERT/HEALTH CARE PROFESSIONALS (CONSULTANTS & RESEARCH PIS) MILESTONES DISCLOSURE PLAN REFERENCES APPENDIX I

5 PROTOCOL SYNOPSIS UNIQUE IDENTIFIER FULL TITLE ABBREVIATED TITLE GSK ASSET RATIONALE HO (TrackHO) and (etrack) Exploratory indirect treatment comparison (ITC) of the efficacy and safety of mepolizumab versus omalizumab in the treatment of adults and adolescents (aged 12 years) with severe asthma Mepolizumab versus Omalizumab Exploratory ITC in Severe Asthma Mepolizumab Mepolizumab (MEPO) is an anti-il5 monoclonal body (mab), developed as an add-on treatment for patients with severe eosinophilic asthma. It is delivered in a 100mg dose via subcutaneous (SC) injection every 4 weeks. Currently, no other treatments are licensed specifically for severe eosinophilic asthma; however, omalizumab (OMA; anti-ige mab, Xolair TM ) is licensed in a number of countries, as an add-on treatment for patients with moderate-to-severe or severe persistent allergic asthma (exact indication varies by country). While severe eosinophilic asthma and severe allergic asthma are recognized as different phenotypes, it is estimated that approximately 30% of MEPO patients in the DREAM and MENSA trials would also be eligible for OMA. This estimate will be further informed by the ongoing IDEAL study (etrack study ). In this overlap patient population, OMA is a relevant comparator for MEPO. Therefore, in the absence of any head-to-head randomised controlled clinical trials (RCTs) directly comparing MEPO versus OMA, this network meta-analysis will compare the two treatments indirectly, by synthesising available RCT evidence via a common comparator. The ITC will provide key evidence of the relative effectiveness and safety of MEPO versus OMA in severe asthma to support reimbursement dossiers in a number of countries. OBJECTIVES (PRIMARY, SECONDARY & EXPLORATORY) Primary objective: To assess the relative efficacy and safety of MEPO 100mg SC versus OMA, in addition to standard of care (SoC), in the treatment of adults and adolescents (aged 12 years) with severe asthma, in terms of exacerbations, lung function, health-related quality of life (HRQoL), asthma control and adverse events (AE). Secondary objectives: None. Exploratory objectives: None.

6 STUDY DESIGN Study design: Network meta-analysis with ITC. In order to satisfy ITC methodological requirements in different settings, two approaches to network meta-analysis will be conducted: a. Frequentist framework: Anchored (adjusted) random-effects metaanalysis within a frequentist framework (Bucher et al., 1997) and multivariate random-effects meta-analysis, using multiple-treatments meta-regression; if heterogeneity justifies covariate adjustment and data are sufficient (White 2009; Mavridis and Salanti 2011) b. Bayesian framework: random-effects meta-analysis, with metaregression and bias adjustment in the presence of heterogeneity (Dias et al., 2013); a constant interaction effect will be assumed for all treatments Study period: There are no date or language restrictions on the literature search. Study conduct: Ethics/institutional review board approval is not required. The study will be subject to TrackHO and E-Track monitoring. The protocol and clinical study report summaries will follow posting requirements to Veritas Clinical Trial Register (VCTR). 6

7 STUDY POPULATION AND SAMPLING METHODS As MEPO and OMA are targeted to treat different phenotypes of severe asthma, the most relevant comparison between MEPO and OMA would include only those patients eligible for both treatments. However, whilst it is possible to identify patients within the MEPO trial dataset who meet the weight, immunoglobulin E (IgE) and positive RAST test criteria (based on 4 allergens) for OMA eligibility, the equivalent MEPO-eligible cut of the OMA dataset is not possible to identify, as only aggregate RCT data are available at this time. Exacerbation history was shown to be associated with treatment response in the DREAM study (MEA112997), but not as consistently in the MENSA study (MEA115588). The results of the SLR indicate that no OMA studies use exacerbation inclusion criteria that match exactly those employed in the MEPO RCTs, therefore 3 different populations, which vary the enrolment exacerbation frequency history and the MEPO dataset, will be examined in order to assess the impact of changes to the inclusion criteria. Data from OMA and MEPO RCTs, which enrolled severe asthma patients aged 12 years, receiving 1,000 mcg/day BDP equivalent plus 1 additional controller and with a documented history of exacerbations, will be included in the ITC. In addition to these criteria, the 3 population criteria are further defined: #1: Overlap population: Best approximates the patient population eligible for both MEPO and OMA 2 OCS-treated exacerbation OR 1 severe exacerbation resulting in hospitalisation in previous 12 months MEPO: OMA-eligible patients from the MEPO included trials, as defined by weight, IgE levels and positive RAST test (4 allergens) OMA: RCTs including patients meeting 1 OMA country/regional license #2: Expanded overlap population: Studies enrolling patients with any documented exacerbation history criteria in the past 12 months: 1 exacerbation in the previous 12 months (defined as treatment with OCS or asthma hospitalisation or asthma ED visit) [change from #1] MEPO: OMA-eligible patients from the MEPO included trials, as defined by weight, IgE levels and positive RAST test (4 allergens) OMA: RCTs including patients meeting 1 OMA license #3: Licensed population: It is likely that payers will wish to see the impact of the entire MEPO-eligible dataset and therefore this analysis will include: 1 exacerbation in the previous 12 months (defined as treatment with OCS or asthma hospitalisation or asthma) MEPO: All patients eligible to receive MEPO (regardless of OMA eligibility) [change from #2] OMA: RCTs including patients meeting 1 OMA license 7

8 DATA SOURCE The SLR (HO ) will identify published RCTs of MEPO and OMA in severe asthma, following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Please refer to the SLR protocol for detailed exposition of the study conduct, the RCT inclusion/exclusion criteria and quality assessment. MEPO trials will also be identified internally in GSK. MEPO data will be extracted from publications (preferred) and GSK clinical study reports (CSRs). If required, additional MEPO data tables will be generated for the ITC. All RCT data potentially relevant for meta-analysis will be double-extracted by two SLR reviewers and entered into a single data workbook. The expected evidence network is shown in Figure 1. Figure 1. Evidence network for MEPO 100 SC versus OMA SC DATA ANALYSIS METHODS This study seeks to assess the following endpoints. The feasibility of conducting each analysis, in terms of the availability and comparability of these endpoints in studies meeting the ITC eligibility criteria, will be assessed. Endpoints will only be eligible if they are included in the studies meeting the criteria for the primary population (#1: Overlap population). Primary endpoints: Exacerbations Annualised rate of clinically significant exacerbations, defined as requiring oral/systemic corticosteroids (or at least a doubling of existing dose for maintenance OCS patients) and/or hospitalisation and/or emergency room (ER) treatment Annualised rate of exacerbations, defined as requiring ER treatment and/or hospitalisation Annualised rate of exacerbations, defined as requiring hospitalisation Secondary endpoints: Health-related quality of life (HRQoL) Change from baseline in HRQoL, measured with the St. George s Respiratory Questionnaire (SGRQ) (total score) 1 ; or, if not feasible, 1 The SGRQ, which is validated in patients with chronic airflow limitation (including asthma and chronic obstructive pulmonary disease), was the HRQoL instrument used in the pivotal Phase III studies, MENSA (MEA115588) and SIRIUS (MEA115575). The SGRQ was chosen for these studies as it appears to have greater face validity with regards to aspects of asthma important to patients with 8

9 Lung function Asthma Quality of Life Questionnaire (AQLQ, including MiniAQLQ) (total score) Change from baseline in lung function, defined as pre-bronchodilator FEV 1 (L) [preferred] or if not feasible, change from baseline postbronchodilator FEV 1, FEV 1 % predicted, or morning PEF (L/min) Asthma control Safety Change from baseline in asthma control, measured with the Asthma Control Questionnaire (ACQ) (all versions; ACQ-5 preferred) (total score) Any AEs: comparison of the proportion of patients with any adverse event, as reported by the ITC-eligible clinical trials for OMA and MEPO Serious AEs (SAEs): comparison of the proportion of patients with any Serious Adverse Events, as defined and reported by the ITC-eligible clinical trials for OMA and MEPO Withdrawal due to AEs: comparison of the proportion of subjects who withdrew from the study intervention due to adverse events, as reported by the ITC-eligible trials for OMA and MEPO Fatal AEs: comparison of the proportion of subject deaths during the study, as reported by the ITC-eligible trials for OMA and MEPO As per Study Design above, outcomes will be synthesised in the ITC according to both frequentist and Bayesian approaches. An outline Statistical Analysis Plan is provided in Section 4. Due to the small number of studies identified as eligible for the ITC, it may not be possible to conduct meta-regression to adjust for bias from study-level covariates; however the following covariates will be examined where possible: Population characteristics Mean age at baseline Percentage of males Mean BMI at baseline Mean blood eosinophil cells/μl at baseline Mean serum total IgE IU/mL at baseline Percentage of patients treated with stable OCS at baseline Mean number of exacerbations, requiring oral/systemic corticosteroids (or at least a doubling of existing dose for maintenance OCS patients) or resulting in hospitalisation or ER treatment), during the 12 months prior to randomisation Study characteristics severe asthma and frequent exacerbations, compared with the AQLQ (included in the DREAM (MEA112997) study). Ongoing work is seeking to establish the relative validity and responsiveness of these two measures in the target population; however it is possible that the two instruments may perform differently across different asthma populations. 9

10 Year of randomisation (preferred), or of publication (proxy), reflecting underlying changes in healthcare systems/standards over time Duration of follow-up In addition to the 3 population scenarios outlined in the Study population section, sensitivity analyses (SA) will be used to determine the impact of selected ITC assumptions and/or extreme influential or outlying observations. ITC assumptions to be tested in sensitivity analyses may include, but are not limited to: Addition of the bioequivalent MEPO 75mg IV data Open-label studies Country-specific OMA-eligibility (if required by individual LOCs) Modelling assumptions such as missing data imputation methods (if applicable) The removal of individual studies with obvious between-group baseline imbalance on statistical stability and heterogeneity. SAMPLE SIZE AND POWER We will use information available on all subjects included in the eligible studies as described above. There are no specific requirements for power calculations or sample size for a meta-analysis. 10

11 LIMITATIONS One of the limitations of this ITC is the ability to fully identify the overlap population, i.e. those patients who are eligible for both MEPO and OMA, and in particular, the lack of information on eosinophil levels and the different exacerbation histories within the OMA trial populations (exacerbation history was shown to be associated with treatment response in the DREAM (MEA112997) but not consistently in the MENSA study (MEA115588)). This analysis is also limited by the small number of patients eligible for both MEPO and OMA in the MEPO 100mg SC dataset and by the small number of OMA studies meeting the ITC inclusion criteria. In order to minimise and/or explore these limitations, different population definitions will be applied and sensitivity analyses conducted. In terms of the population, as individual patient level data are available from MEPO trials, the OMA-eligible patients (based on weight, IgE levels and positive RAST test (4 allergens)) can be identified and will be included in the base case. In addition, the strictest exacerbation history definition available in the OMA trials will also be employed. The impact of these criteria will be explored in scenario populations, via inclusion of the full MEPO-eligible dataset and adjustments to the exacerbation frequency history criteria. In terms of sensitivity analyses, the bioequivalent MEPO 75 mg IV data will be included and the study design criteria will be relaxed to allow the inclusion of open-label studies. It should be noted that due to the small number of studies meeting the ITC criteria, it may not be possible to conduct meta-regression to adjust for bias from study-level covariates. Therefore, should heterogeneity be found, this will be explored through further sensitivity analyses focusing on the study inclusion and exclusion criteria. Other sensitivity analyses will be conducted, if required. Finally, as this ITC will be conducted on published OMA data, it is possible that it could also be subject to publication bias. PROTOCOL METHODOLOGY This protocol was developed with reference to guidelines on ITC conduct and reporting published by academics, industry associations and HTA bodies, including: Cochrane, ISPOR, EUnetHTA, CADTH, IQWiG, NICE, PBAC, and SMC. 11

12 ABBREVIATIONS ACQ ACT AE AQLQ BDP BMI CADTH CSR ER ERR EQ-5D EUnetHTA FEV 1 HR HRQoL HTA ICS IgE IQWiG ISPOR ITC IV LABA LABD mab MEPO NICE OCS OMA OR PBAC PEF PICOS PLA PRISMA QA RCT RR SA SAE SAP SC SGRQ SLR SMC SoC VCTR Asthma Control Questionnaire Asthma Control Test Adverse Event Asthma Quality of Life Questionnaire Beclometasone dipropionate Body Mass Index Canadian Agency for Drugs and Technologies in Health (Canada) Clinical study report Emergency room Exacerbation rate ratio EuroQol 5 Dimensions Questionnaire European Network for Health Technology Assessment Forced expiratory volume in 1 second Hazard ratio Health-related quality of life Health technology assessment Inhaled corticosteroid Immunoglobulin E Institute for Quality and Efficiency in Health Care (Germany) International Society for Pharmacoeconomics and Outcomes Research Indirect treatment comparison Intravenous Long-acting beta 2 agonist Long-acting bronchodilator Monoclonal antibody Mepolizumab National Institute for Health and Care Excellence (UK) Oral corticosteroid Omalizumab Odds ratio Pharmaceutical Benefits Advisory Committee (Australia) Peak expiratory flow Population, intervention, comparator, outcomes and study design Placebo Preferred Reporting Items for Systematic reviews and Meta-Analyses Quality assurance Randomised controlled clinical trial Relative risk Sensitivity analysis Serious Adverse Event Statistical Analysis Plan Subcutaneous St. George s Respiratory Questionnaire Systematic literature review Scottish Medicines Consortium (UK) Standard of care Veritas Clinical Trial Register

13 1. INTRODUCTION 1.1. BACKGROUND Mepolizumab (MEPO; GSK 16761/SB ) is an anti-il5 monoclonal body (mab), developed as an add-on treatment for patients with severe eosinophilic asthma. It is delivered in a 100mg dose via subcutaneous (SC) injection every 4 weeks. Two pivotal phase III studies were conducted in severe asthma patients with a blood eosinophil count 150 cells/μl at initiation of treatment or 300 cells/μl in the prior 12 months. In MENSA (MEA115588, Ortega et al., 2014), MEPO 100 mg SC significantly reduced clinically significant exacerbations by 53% versus placebo on top of standard of care (SoC) in patients with 2 exacerbations in the previous 12 months, despite treatment with high-dose inhaled corticosteroids and another controller (with or without oral corticosteroids). In the SIRIUS study, MEPO 100mg SC was shown to significantly reduce the OCS dose required, reduce exacerbations, and improve asthma control versus placebo on top of SoC in patients requiring daily OCS therapy. Further supportive exacerbation reduction data were obtained for MEPO (IV formulation only) from the dose-ranging phase IIb/IIIa DREAM trial (MEA112997, Pavord et al., 2012). Currently, no other treatments are licensed specifically for severe eosinophilic asthma; however, omalizumab (anti-ige mab, Xolair TM ) is licensed in a number of countries, as an add-on treatment for patients with moderate-to-severe or severe persistent allergic asthma (exact license varies by country). While severe eosinophilic asthma and severe allergic asthma represent different phenotypes, it is estimated from the DREAM and MENSA trials that approximately 30% of MEPO patients would also be eligible for OMA. This estimate will be further informed by the ongoing IDEAL study (etrack study ). In this overlap patient population, omalizumab (OMA) is a relevant comparator for mepolizumab (MEPO) STUDY RATIONALE There are no head-to-head randomised controlled clinical trials (RCTs) directly comparing MEPO and OMA. In order to address this evidence gap, it is proposed to conduct a network meta-analysis that will compare the two treatments indirectly, by synthesising available RCT evidence via a common comparator. The ITC will provide key evidence of the relative effectiveness of MEPO versus OMA in severe asthma and will support reimbursement dossiers in a number of countries ITC FEASIBILITY ASSESSMENT A systematic literature review (SLR; HO ) will identify the RCT evidence for MEPO and OMA. Those studies meeting the ITC criteria (see section 3.1) will be further assessed for endpoint comparability and data availability. An analysis will be conducted if the PICOS criteria are met by 1 OMA study, the endpoints are deemed to be comparable, and the data required to facilitate the analysis are reported.

14 Only RCTs in which OMA was compared with SoC, with or without placebo, will be considered, such that these common comparators form a link between OMA trials and those of MEPO (Figure 1). Figure 1. RCT evidence network for MEPO 100mg SC versus OMA If there are very few studies available for meta-analysis, inference algorithms may not converge at all. If the network links consist of only one to two studies for each therapy, the adjusted ITC method will be used. Analyses may be stratified by key factors, such as duration of follow-up. However, if limited data are available and duration of follow-up is markedly different across trials, meta-analysis may not be performed. Deviations from this expectation will be noted during data extraction, and alternative reporting times of each relevant outcome will be used for stratification. Specific model details will be determined based on the type of data (and reporting timepoints) available for each relevant endpoint, and are outlined in the following section. If meta-analysis of specific endpoints is possible, a more detailed analysis plan will list the trials to be included, identify those endpoints that were assessed in a similar manner at similar times from the trials to be included. The statistical models will be refined and implemented using frequentist and Bayesian approaches. The analysis plan will describe the planned subgroup and sensitivity analyses, when the heterogeneity warrants such analyses. This ITC protocol seeks to accommodate a wide variety of local requirements, including: differences in treatment eligibility; preferences for alternative ITC methods; requirements to present different subgroup/sensitivity analyses. In order to manage complexity and timely delivery of key analyses, we prioritise those analyses commonly considered of primary interest. However, we recognise that other ITC specifications are potentially valid and may be requested by particular payers. Potential additional analyses are outlined in Appendix I. 2. OBJECTIVES The aim of this exploratory study is to quantitatively assess how the reported clinical efficacy and safety of MEPO compares to that of OMA among patients with severe asthma who could be eligible to receive either therapy. 14

15 2.1. PRIMARY To assess the relative efficacy and safety of MEPO 100mg SC versus OMA, in addition to SoC, in the treatment of adults and adolescents (aged 12 years) with severe asthma, in terms of exacerbations, lung function, health-related quality of life (HRQoL) and asthma control. None SECONDARY 2.3. EXPLORATORY None. 3. RESEARCH METHODOLOGY 3.1. STUDY DESIGN This ITC will be conducted as a network meta-analysis of pre-specified efficacy and safety endpoints, using available RCT data for MEPO and OMA. In order to satisfy varying ITC methodological requirements in different settings, two different modelling approaches will be presented. First, within a frequentist framework, an anchored (adjusted) random-effects meta-analysis (Bucher et al. 1997) will be conducted. Multivariate random-effects meta-analysis, using multipletreatments meta-regression, will be conducted if heterogeneity justifies covariate adjustment and data are sufficient (White, 2009; Mavridis and Salanti, 2011). Second, a Bayesian random-effects meta-analysis, with meta-regression and bias adjustment in the presence of heterogeneity, will be conducted (Dias et al., 2013). A constant interaction effect will be assumed for all treatments. The PICOS for this ITC are: Population: Severe asthma patients aged 12 years of age receiving 1,000 mcg/day BDP equivalent plus 1 additional controller, with a documented history of exacerbations AND the additional population criteria outlined in the table in Section 3.2 below. Intervention: MEPO 100mg SC plus SoC (primary analysis); with MEPO 75mg IV included in sensitivity analyses only. Comparator: OMA plus SoC. Outcomes: Efficacy endpoints: exacerbations; lung function; health-related quality of life (HRQoL); asthma control. Safety endpoints: any Adverse Events (AEs); Serious AEs (SAEs); withdrawal due to AEs; fatal AEs. Study design: Double-blind (primary analysis) and open-label (sensitivity analyses only) RCTs of 12 weeks duration STUDY POPULATION Asthma and severe asthma represent a heterogeneous mix of phenotypes which reflect the biological pathophysiology impacting disease expression and course. The clinical expression of 15

16 asthma may vary between the different severities and also between phenotypes within severe asthma. As MEPO and OMA are targeted to treat different phenotypes of severe asthma, the most relevant comparison between MEPO and OMA would include only those patients eligible for both treatments. However, whilst it is possible to identify patients within the MEPO trial dataset who meet the weight, immunoglobulin E (IgE) and positive RAST test criteria (based on 4 allergens) for OMA eligibility, the equivalent MEPO-eligible cut of the OMA dataset is not possible to identify, as only aggregate RCT data are available at this time. Exacerbation history was shown to be associated with treatment response in the DREAM study (MEA112997), but not as consistently in the MENSA study (MEA115588). The results of the SLR indicate that no OMA studies use exacerbation inclusion criteria that match exactly those employed in the MEPO RCTs, therefore 3 different populations, which vary the enrolment exacerbation frequency history and the MEPO dataset, will be examined in order to assess the impact of changes to the inclusion criteria. Severe asthma patients aged 12 years receiving 1,000 µg/day BDP equivalent plus 1 additional controller and with a documented history of exacerbations, are eligible for inclusion in the ITC. In addition to these criteria, the 3 population criteria are further defined: Population & rationale Exacerbation history MEPO criteria (IPD data) OMA criteria (aggregate RCT data) #1: Overlap Best approximation of the patient population eligible for both MEPO and OMA. 2 OCS-treated exacerbation OR 1 severe exacerbation resulting in hospitalisation in previous 12 months MEPO- and OMAeligible patients from the MEPO trials OMA-eligibility defined by weight, IgE levels and positive RAST test (4 allergens) RCTs including patients meeting 1 OMA country/regional license #2: Expanded overlap Indication statement for OMA does not specify the exact number of exacerbations required. 1 exacerbation in the previous 12 months (defined as treatment with OCS or asthma hospitalisation or asthma ED visit) As above As above #3: Licensed It is expected that payers will wish to see the impact of the entire MEPO-eligible dataset. As above All patients eligible to receive MEPO (regardless of OMA eligibility) As above IPD: Individual patient level data 16

17 ELIGIBILITY CRITERIA The ITC study criteria are described in Section 3.2 above. The respective eligibility criteria for MEPO and OMA are listed below: Mepolizumab MEPO is currently under regulatory review (at November 2014), and furthermore, there are likely to be country/regional variations in the exact indication statements. For the purposes of this ITC, the patient population eligible for MEPO is defined as those with severe eosinophilic asthma identified by either a blood eosinophil count 150 cells/μl at initiation of treatment or a blood eosinophil count 300 cells/μl in the prior 12 months and with a history of exacerbations. Omalizumab The patient population eligible for OMA are those with allergic asthma, who demonstrate a positive skin test for any of four specified aeroallergens and with a pre-treatment serum IgE versus body weight combination that meets local licensed OMA prescribing criteria: Country/Region EU Australia Canada Key additional OMA eligibility criteria Severe persistent allergic asthma Eligible baseline IgE levels 30 IU/mL to 1,500 IU/mL Weight 20 kg to <150 kg Maximum dosage of 600mg SC every 2 weeks Moderate-to-severe asthma Eligible baseline IgE levels 30 IU/mL to 1,300 IU/mL Weight > 30 kg to 150 kg Maximum dosage of 375mg SC every 2 weeks Moderate-to-severe persistent asthma Eligible baseline IgE levels 30 IU/mL to 700 IU/mL Weight 20 kg to 150 kg Maximum dosage of 375mg SC every 2 weeks 17

18 Sample size and power calculation for network meta-analysis Currently there are no guidelines or requirements from HTA bodies (i.e. NICE, PBAC, etc.) to assess the power of a NMA a-priori. Nevertheless, once a set of studies is selected an effective sample size for the ITC can be performed to inform the precision of the estimates. The effective sample size of an indirect comparison is defined as the number of samples required in order to produce a matching degree of power and precision from a single headto-head trial. Once the effective sample size is determined, the formula for a power calculation for meta-analysis can be used. We will use the method proposed by Thorlund and Mills (2012) to calculate sample size and statistical power for network meta-analysis: The general formula for the heterogeneity-corrected effective sample size is: n AC (1 I 2 AC ) n BC (1 I 2 BC ) n AC (1 I 2 AC ) + n BC (1 I 2 BC ) where n AC and n BC are the actual sample sizes in the meta-analyses of A vs. C and B vs. C, 2 2 respectively, and I AC and I BC are measures of heterogeneity. We can also calculate the retrospective power of the available evidence for meta-analysis by inserting the effective sample size as n in the formula below. Power = 1 β = Φ 1 z 1 α 2 + (n d 2 )/(C V 2 ) Here, β is the type-2 error and Φ is the cumulative standard normal distribution function; d is the treatment effect (equal to the difference of the log (Rate Ratio) between MEPO and OMA) from the primary endpoint (exacerbation rate), and V 2 is the variance around that treatment effect. C is a constant depending on the randomization ratio and the number of treatment arms (C = 4 with a randomization ratio of 1:1 and two treatment arms). Since the primary objective is to assess the relative efficacy and safety of MEPO 100mg SC versus OMA in addition to SoC, in the treatment of adults and adolescents (aged 12 years) with severe asthma, in terms of clinically severe exacerbations, we could estimate the sample size and power calculation based on this primary endpoint, using the eligible studies (See appendix II for details on power simulations) DATA SOURCE / DATA COLLECTION The SLR (HO ) will identify published RCTs of MEPO and OMA in severe asthma, following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Please refer to the SLR protocol for detailed exposition of the study conduct, and RCT inclusion/exclusion criteria and quality assessment. There are no date or language restrictions on the literature search. MEPO trials will also be identified internally in GSK. MEPO data will be extracted from publications (preferred) and GSK clinical study reports (CSRs). If required, additional MEPO data tables will be generated for the ITC. 18

19 All RCT data potentially relevant for meta-analysis will be double-extracted by two SLR reviewers and entered into a single data workbook. Processes governing data extraction, quality assurance and the quality assessment of RCT evidence are described in the approved SLR protocol ELIGIBILITY CRITERIA Included Treatments MEPO 100mg SC plus SOC. o MEPO 75mg IV plus SOC will be included in sensitivity analyses only (defined as per Section 3.2.1) OMA plus SOC, administered in accordance with local licensed OMA prescribing criteria (defined as per Section 3.2.1) None specified Excluded Treatments Study Design Inclusion Criteria Parallel-group RCTs Double-blind studies. Open-label studies will be included in sensitivity analyses only RCT duration 12 weeks Where a protocol-driven change in ICS/OCS maintenance dosage is implemented, only those data from periods prior to the change may be included in the ITC At least one relevant and comparable efficacy or safety endpoint can be determined, extracted or calculated from the available RCT data Study Design Exclusion Criteria Other study types, such as: single-arm clinical trials; preclinical studies; Phase 1 studies; prognostic studies; retrospective studies; observational studies; case reports; cohort studies; commentaries and letters that do not report RCTs; consensus reports; non-randomised clinical trials; reviews; meta-analyses (RCTs contributing to meta-analyses will be retrieved) Duration of follow-up < 12 weeks (considered an insufficient exposure length to perform valid evaluations of the selected efficacy endpoints) Data from periods following protocol-driven change in ICS/OCS maintenance dosage No relevant and comparable efficacy or safety endpoints can be determined, extracted or calculated from the available RCT data ENDPOINTS This study seeks to include the following endpoints; however, the feasibility of conducting each analysis, in terms of the availability and comparability of these endpoints in studies meeting the other ITC eligibility criteria, will be assessed. 19

20 Primary Endpoint(s) Endpoints will only be eligible if they are included in the studies meeting the criteria for the primary population (#1: Overlap population). Exacerbations Annualised rate of exacerbations, defined as requiring oral/systemic corticosteroids (or at least a doubling of existing dose for maintenance OCS patients) and/or hospitalisation and/or emergency room treatment Annualised rate of exacerbations, defined as requiring emergency room treatment and/or hospitalisation Annualised rate of exacerbations, defined as requiring hospitalisation Secondary Endpoint(s) Health-related quality of life (HRQoL) Change from baseline in HRQoL, measured with the St. George s Respiratory Questionnaire (SGRQ) (total score) 2 ; or, if not feasible; Asthma Quality of Life Questionnaire (AQLQ, including MiniAQLQ) (total score) Lung function Change from baseline in lung function, defined as pre-bronchodilator FEV 1 (L) [preferred] or if not feasible, change from baseline post-bronchodilator FEV 1, FEV 1 % predicted, or morning PEF (L/min) Asthma control Safety Change from baseline in asthma control, measured with the Asthma Control Questionnaire (ACQ) (all versions; ACQ-5 preferred) (total score) Any AE: comparison of the proportion of subjects with any adverse event, as reported by the ITC-eligible clinical trials for OMA and MEPO Serious AEs: comparison of the proportion of subjects with any Serious Adverse Events, as defined and reported by the ITC-eligible clinical trials for OMA and MEPO Withdrawal due to AEs: comparison of the proportion of subjects who withdrew from the study intervention due to adverse events, as reported by the ITC-eligible trials for OMA and MEPO Fatal AEs: comparison of the proportion of subject deaths during the study, as reported by the ITC-eligible trials for OMA and MEPO 2 The SGRQ, which is validated in patients with chronic airflow limitation (including asthma and chronic obstructive pulmonary disease), was the HRQoL instrument used in the pivotal Phase III studies, MENSA (MEA115588) and SIRIUS (MEA115575). The SGRQ was chosen for these studies as it appears to have greater face validity with regards to aspects of asthma important to patients with severe asthma and frequent exacerbations, compared with the AQLQ (included in the DREAM (MEA112997) study). Ongoing work is seeking to establish the relative validity and responsiveness of these two measures in the target population; however it is possible that the two instruments may perform differently across different asthma populations. 20

21 None specified Exploratory Endpoint(s) 3.4. SAMPLE SIZE/POWER CALCULATIONS Not applicable; this is a synthesis of existing RCT evidence. Sample size and power can be discussed retrospectively, when analysis is complete. See also Section 1.3 ITC Feasibility Assessment HYPOTHESES We will test for significance, with α = 0.05, any differences between MEPO and OMA in relative risk (i.e. risk/rate/hazard ratio or risk/rate difference) of each feasible efficacy and safety endpoint. In the Bayesian framework, the probability of superiority of each treatment versus its comparators will be obtained and should be interpreted as a continuum; the Bayesian framework does not yield itself to yes/no hypothesis testing using credible intervals, unlike the confidence intervals obtained in the frequentist framework Heterogeneity With a network meta-analysis, the value of randomisation only holds within a trial, and not across trials. As a result, there is the risk that patients assigned to the different trials are not comparable. If the distribution of treatment-effect modifiers (e.g. % of very severe patients) is not similar across trials comparing different interventions in the network of studies, transitivity is violated, the studies are heterogeneous, and the ITC results will be biased. Due to the small number of studies identified as eligible for the ITC, it may not be possible to conduct meta-regression to adjust for bias from study-level covariates; however the following covariates will be examined where possible: Population characteristics Mean age at baseline Percentage of males Mean blood eosinophil cells/μl at baseline Mean serum total IgE IU/mL at baseline Percentage of patients treated with stable OCS at baseline Mean number of exacerbations, requiring oral/systemic corticosteroids (or at least a doubling of existing dose for maintenance OCS patients)or resulting in hospitalisation or emergency room treatment, during the 12 months prior to randomisation 21

22 Study characteristics Year of randomisation (preferred), or year of publication (proxy), reflecting underlying changes in healthcare systems/standards over time Duration of follow-up 4. DATA ANALYSIS CONSIDERATIONS 4.1. OUTLINE STATISTICAL ANALYSIS PLAN This section presents a draft statistical analysis plan (SAP). Further details of model specifications and testing procedures/criteria will be specified in the final SAP Frequentist ITC using PBAC (Australia) Guidelines Indirect treatment comparisons will be conducted using a frequentist approach as required by the Pharmaceutical Benefits Advisory Committee (PBAC) in Australia. This section borrows from the descriptions and specifications published by the PBAC (Guidelines, 2013) Software Frequentist indirect treatment comparisons/multiple treatment comparisons will be conducted with Stata or R Random-Effects Models A set of frequentist ITCs will be developed using a random effects approach. PBAC prefers singlestep indirect comparison [e.g. (B vs. C) and (A vs. C) to compare A vs. B, see Fig. 2-a] to multi-step indirect comparison (comparing A and B involving C and D as common references (Fig. 2-b). This approach may require to have two separate single-step indirect comparisons of A and B involving C and D as separate common references [e.g. (B vs. C) and (A vs. C), (B vs. D) and (C vs. D) to find indirect comparison A vs. B, see Fig. 2-c]. If one single-step indirect comparison is feasible, then the Bucher method (Bucher et al., 1997) will be used as the primary method. However, if multiple single-step indirect comparisons or two (or more) separate single-step or multi-step indirect comparisons are feasible, then we will use a multivariate random-effects meta-analysis (mvmeta). Fig. 2: ITC network (dot line: indirect comparison) Bucher Method, by Outcome Type We will use the Bucher method when a single-step indirect comparison is feasible. There are three methods for different data types, as shown below: a) count data; b) continuous data and c) dichotomous data. 22

23 a) Count data for exacerbation rate Step 1: The log (exacerbation rate=event/person-time) for each treatment of interest relative to a common comparator (i.e. AC and BC) will be estimated. The exacerbation rate ratio 3 (ERR) for each treatment of interest relative to a common comparator (i.e. ERR AC for A vs. C and ERR BC for B vs C) will be estimated using standard random effects meta-analyses, as proposed by DerSimonian and Laird (3). The log (ERR) is assumed to follow a normal distribution, therefore, if not available, the standard error of log (ERR) can be calculated directly from the confidence intervals of ERR estimates. Step 2: The ERR for the indirect comparison of treatments A versus B may be estimated by taking the ratio of the two ERRs from (A vs. C) and (B vs. C) ERR AB (= λ AB ) = ERR AC(= λ AC ) ERR BC (= λ BC ) (1) so that the indirect comparison can be calculated as: log (λ AB ) = log (λ AC ) log (λ BC ) Given that the ERRs are estimated based on different studies and therefore are independent, the variance for this effect is the pooled variance, as it is for the standard error: var(log (λ AB )) = var(log (λ AC )) + var(log (λ BC )) SE(log (λ AB )) = SE(log(λ AC )) 2 + SE(log(λ BC )) 2 After calculating these quantities, the log-transformed ERR will be converted back to raw units using an inverse transformation. b) Continuous data for FEV 1 or QoL scales Step 1: The pooled mean difference in change from baseline for each treatment of interest relative to a common comparator (i.e. AC and BC) will be estimated using standard random effects metaanalyses, as proposed by DerSimonian and Laird (3). Step 2: Let μ AC, SE(μ AC ) andμ BC, SE(μ BC ) be the combined mean difference and corresponding standard error of the A vs C and B vs C meta-analytic comparisons, respectively. The indirect comparison of treatments A versus B may then be estimated as follows: μ AB = μ AC μ BC var(μ AB ) = var(μ AC ) + var(μ BC ) SE(μ AB ) = SE(μ AC ) 2 + SE(μ BC ) 2 (2) 3 We use the terms exacerbation rate and exacerbation rate ratio (ERR) in preference to hazard rate and hazard rate ratio (HR). Hazard terminology usually refers to survival, or time-dependent, analyses (e.g. time to exacerbation), while incident rate terminology is more appropriate for event rate analyses (e.g. exacerbation rate). 23

24 c) Dichotomous outcomes (yes/no) Step 1: The pooled relative risks (RR) for each treatment of interest relative to a common comparator (i.e. RR AC for A vs. C and RR BC for B vs. C) will be estimated using standard fixed effects or random effects meta-analyses, as proposed by DerSimonian and Laird (3). Step 2: The relative risks for the indirect comparison of treatments A versus B may be estimated by taking the ratio of the two relative risk ratios: RR AB = RR AC RR BC (3) Such that the indirect comparison can be calculated as: log (RR AB ) = log (RR AC ) log (RR BC ) Given that the RRs are estimated based on different studies and therefore are independent, the variance for this effect is the pooled variance, as it is for the standard error: var(log (RR AB )) = var(log (RR AC )) + var(log (RR BC )) SE(log (RR AB )) = SE(log (RR AC )) 2 + SE(log (RR BC )) 2 After calculating these quantities, the log-transformed RR will be converted back to raw units using an inverse transformation. For studies with zero-cell counts for a particular endpoint, computational problems can occur in one or both groups in an individual study. Inverse variance meta-analytical methods (both the inversevariance fixed-effects methods and the DerSimonian and Laird random-effects methods) involve computing an intervention effect estimate and its standard error for each study. For studies where no events were observed in one or both arms, these computations often involve dividing by a zero count, which yields a computational error. A fixed value (= 0.5) will be added to all cells of study results tables where the problems occur Multivariate Random-Effects Meta-Analysis (mvmeta) We will conduct a multivariate random-effects meta analysis (mvmeta) when two (or more) separate single-step or multi-step indirect comparison is feasible. STATA or R will used for conducting this analysis. The data for mvmeta comprise the point estimate, y i, and the within-study variance-covariance matrix, S i, for each study i = 1 to n. We assume: y i ~ N μ i, S i μ i ~ N(μ, Σ ) 24

25 2 τ 1 κ 12 τ 1 τ 2. Σ = κ 12 τ 1 τ 2 2 τ (4) where y i, μ i are p x 1 vectors, and Σ are p x p matrices. The within-study variance, S i, is assumed to be known. Our aim is to estimate μ and Σ. μ = ( i w i ) 1 ( i w i y i ) (5) where w i = (Σ + S i ) 1 Multivariate random-effects meta-regression was developed as an extension of mvmeta. y i ~ N μ i, S i μ i ~ N( βx i, Σ ) 2 τ 1 κ 12 τ 1 τ 2. Σ = κ 12 τ 1 τ 2 2 τ (6) Here y i is a vector of estimates from the i-th study, S i is their variance-covariance matrix, μ i is the study-specific mean vector, and X i is a matrix of study-specific covariates. In this model, the data are y i, S i, and X i, and we aim to estimate the regression coefficients β and the between-studies variancecovariance matrix Σ. β = i X i w i X í 1 i y i w i X í (7) where w i = (Σ + S i ) Heterogeneity The statistical heterogeneity of A vs. C or B vs. C in the meta-analysis will be assessed using the Cochran Q, chi-square test and the I 2 statistic with 95% Confidence Interval (CI). PBAC requires that the random effects model is always used, even when fixed effects is appropriate. If we suspect that confounders (treatment-effect modifiers) are present in an indirect comparison while conducting mvmeta, we adjust for study-level covariates via network meta-regression. This can be done using Eq. (7) to estimate the comparative treatment effects between two drugs, by using STATA or R, as long as we have a sufficient number of studies to perform adjustment via metaregression (more studies are required for meta-regression than meta-analysis) Reporting the ITC Results Results of the individual trials (rates: point estimates and 95% confidence intervals; continuous: point estimates and 95% confidence intervals; dichotomous: number with the event, number in the group, RR) together with the pooled results (point estimates and 95% confidence intervals), the Cochran Q, the I2, and chi-square test results will be presented on a forest plot. 25

26 The results of the ITC will be presented as ERR/RR//mean difference with 95% CI and a p-value. The random effects pairwise meta-analyses will be conducted with STATA using mvmeta (StataCorp Stata Statistical Software: Release 13.1) or R (R Development Core Team, using the packages mvmeta, meta and metafor. Table 1 demonstrates an example of the summary presentation of ITC results (PBAC guidelines, 2013). Table 1. Table shell for ITC relative effect results (frequentist models) Trial ID Trial 1 Trial 2 Etc Trial(s) proposed treatment Treatment Effect RR (95%CI) Proposed treatment N with Event/ N(%) Common reference N with Event/ N(%) Trials of main comparator Common reference N with Event/ N(%) Pooled N/A N/A N/A N/A Comparator N with Event/ N(%) Treatment Effect RR (95%CI) Indirect estimate of effect indirect ERR/RR (95% CI) N/A N/A N/A N/A N/A Bayesian Network Meta-Analysis using NICE (UK) Guidelines Indirect treatment comparisons will be conducted using a frequentist approach as required by the National Institute for Health and Care Excellence (NICE) in the UK. This section borrows from the descriptions and specifications published by NICE (DSU Technical Support Document 2, 2011). Bayesian methods for network meta-analysis are analogous to frequentist methods with the primary distinction being the use of prior distributions for the mean of the overall estimate, the means of the individual estimates of each study, and the between-study variance for random effects models. Priors provide an expectation of the distributions that parameters will take. Priors can be defined as non-informative or informative distributions. The former are used to make inferences that are not greatly affected by external information. The latter are based on some prior knowledge and have a stronger influence on the posterior distribution and hence on the estimate of relative effectiveness. The use of non-informative priors will generally result in effect estimates that are comparable to those in a frequentist approach. While model flexibility is a strength of Bayesian methods, it is also a potential weakness, as additional information may be incorporated in a biased or non-transparent manner. The use of informative priors must be accompanied by a justification and a clear description of how they were generated to maintain transparency. For the ITCs, the common Generalised Linear Model (GLM) framework can be applied in Bayesian contexts. Bayesian Markov Chain Monte Carlo (MCMC) has been the mainstay of comprehensive decision analysis, because simulation from a Bayesian posterior distribution supplies both statistical estimation and inference, and a platform for probabilistic decision making under uncertainty. An advantage of Bayesian MCMC is that appropriate distributions, and therefore credible intervals, are automatically generated for all these quantities. Nonetheless, particular care must be taken in checking convergence. Users should also ensure that, after convergence, each chain is sampling from the same posterior. Posteriors will be examined visually for spikes and unwanted peculiarities, and 26