Global Clinical Epidemiology Non-interventional study protocol QVA149A2402 Title Multinational database cohort study to assess RMP specified safety outcomes in association with indacaterol/glycopyrronium bromide in Europe Protocol version v02 identifier Date of last version 02 June 2014 of protocol EU PAS register Study not registered number Active substance Indacaterol/glycopyrronium bromide (QVA149) (R03AL04) Medicinal product Ultibro® Breezhaler® Product reference QVA149 Procedure number EMEA/H/C/002679 Marketing Novartis Europharm Limited authorization Wimblehurst Road holder(s) Horsham West Sussex RH12 5AB United Kingdom Joint PASS No Novartis Confidential Page 2 Non-interventional study protocol QVA149/Ultibro®/ QVA149A2402 Research questions and objectives ...[redacted] Country (-ies) of The Netherlands, Spain, Denmark, Italy, United Kingdom study (UK) Author ...[redacted] 02 June 2014 QPPV or delegate Signature Date Property of Novartis Confidential May not be used, divulged, published or otherwise disclosed without the consent of Novartis NI Protocol Template Version 31-Jan-2013 Novartis Confidential Page 3 Non-interventional study protocol QVA149/Ultibro®/ QVA149A2402 1 Table of contents 1 Table of contents ............................................................................................................. 3 List of tables ................................................................................................................... 4 List of figures .................................................................................................................. 5 2 List of abbreviations ........................................................................................................ 6 3 Responsible parties ......................................................................................................... 8 4 Abstract ........................................................................................................................ 10 5 Amendments and updates .............................................................................................. 13 6 Milestones ..................................................................................................................... 14 7 Rationale and background ............................................................................................. 15 8 Research question and objectives .................................................................................. 16 8.1 Primary objectives ............................................................................................. 16 8.2 Secondary objectives ......................................................................................... 16 9 Research methods ......................................................................................................... 17 9.1 Study design ...................................................................................................... 17 9.2 Setting ............................................................................................................... 18 9.2.1 Study population and study cohorts .................................................... 18 9.2.2 Study period ...................................................................................... 19 9.2.3 In- and exclusion criteria .................................................................... 19 9.2.4 Follow-up .......................................................................................... 20 9.3 Variables ........................................................................................................... 22 9.3.1 Endpoints of interest .......................................................................... 22 9.3.2 Exposure of interest ........................................................................... 23 9.3.3 COPD and COPD severity ................................................................. 25 9.3.4 Past use of drugs and concomitant drug use ....................................... 26 9.3.5 Demography, life style factors and comorbidity ................................. 27 9.4 Data sources ...................................................................................................... 28 9.4.1 IPCI database ..................................................................................... 29 9.4.2 HSD database .................................................................................... 30 9.4.3 THIN database ................................................................................... 31 9.4.4 Aarhus database ................................................................................. 31 9.4.5 SIDIAP database ................................................................................ 32 9.5 Study size .......................................................................................................... 32 9.6 Data management .............................................................................................. 35 9.6.1 Identification of Unified Medical Language System® (UMLS®) concepts ............................................................................................. 35 Novartis Confidential Page 4 Non-interventional study protocol QVA149/Ultibro®/ QVA149A2402 9.6.2 Definition of data extraction algorithm ............................................... 35 9.6.3 Event data extraction.......................................................................... 36 9.6.4 Benchmarking of incidence rates of events......................................... 36 9.7 Data analysis...................................................................................................... 37 9.7.1 Yearly analysis for study progress reports .......................................... 37 9.7.2 Final analysis ..................................................................................... 37 9.8 Quality control ................................................................................................... 42 9.9 Limitations of the research methods ................................................................... 43 10 Protection of human subjects ......................................................................................... 44 11 Management and reporting of adverse events/adverse reactions..................................... 45 12 Plans for disseminating and communicating study results .............................................. 45 13 References (available upon request) .............................................................................. 45 Annex 1 - List of stand-alone documents.............................................................................. 49 Annex 2 - ENCePP checklist for study protocols .................................................................. 50 Annex 3 - Additional information ........................................................................................ 56 Annex 3.1 - Event definition ......................................................................................... 56 Annex 3.2 - Validation algorithm .................................................................................. 75 Annex 3.3 - Exposure definition .................................................................................. 101 Annex 3.4 - COPD definition ...................................................................................... 102 Annex 3.5 - Concomitant medication definition .......................................................... 105 Annex 3.6 - Comorbidity definition ............................................................................. 137 List of tables Table 3-1 Main responsible parties ...................................................................... 8 Table 5-1 Study protocol amendments and updates ............................................ 13 Table 6-1 Study milestones ................................................................................ 14 Table 9-1 Launch dates for QVA149 in the five participating countries ............. 19 Table 9-2 Overview of databases ....................................................................... 28 Table 9-3 Sample size and power calculation ..................................................... 33 Table 9-4 Population coverage (≥40 years of age) by individual database .......... 34 Table 9-5 Individual database estimates of QVA149 treated patients for the year 2017 ........................................................................................... 35 Novartis Confidential Page 5 Non-interventional study protocol QVA149/Ultibro®/ QVA149A2402 List of figures Figure 9-1 In- or exclusion in the study based on previous exposure of study drugs .................................................................................................. 20 Figure 9-2 Switching and add-on therapy ............................................................ 21 Figure 9-3 Eligibility to different exposure cohorts ............................................. 21 Figure 9-4 Creation of treatment episode for inhaled COPD therapies ................. 24 Figure 9-5 Identification of period of follow-up .................................................. 25 Figure 9-6 Model for data sharing and elaboration .............................................. 36 Figure 9-7 Different scenarios of follow-up for first episode of exposure ............ 41 Figure 9-8 Sensitivity analysis where complete follow-up of patients is used for the respective analysis .................................................................