Quantitative Safety & Epidemiology NVA237 / Glycopyrronium bromide Non-interventional Study Report NVA237A2402T Multinational, multi-database cohort study to assess adverse cardiovascular and cerebrovascular outcomes and mortality in association with inhaled NVA237 in Europe Final Report Redacted Report Author Document Status Final Date of final version of the study report 17-Nov-2017 EU PAS register number ENCEPP/SDPP/5035 Property of Novartis Confidential May not be used, divulged, published or otherwise disclosed without the consent of Novartis NIS Report Template Version 2.0 August-13-2014 Novartis Confidential Page 2 Non-interventional study report NVA237A/Seebri® Breezhaler®/CNVA237A2402T PASS information Multinational, multi-database cohort study to assess Title adverse cardiovascular and cerebrovascular outcomes and mortality in association with inhaled NVA237 in Europe –Final Report Version identifier of the Version 1.0 (final) Final report Date of last version of 17 November 2017 the final report EU PAS register number ENCEPP/SDPP/5035 Active substance Glycopyrronium bromide (R03BB06) Medicinal product Seebri® Breezhaler®, Tovanor® Breezhaler®, Enurev® Breezhaler® Product reference NVA237 Procedure number Seebri Breezhaler: EMEA/H/C/0002430 Tovanor Breezhaler: EMEA/H/C/0002690 Enurev Breezhaler: EMEA/H/C0002691 Marketing authorization Novartis Europharm Ltd holder Joint PASS No Research question and Use of inhaled anticholinergics has been associated objectives with an increased risk of cardiovascular and cerebrovascular events. In the context of the NVA237 marketing application in Europe, the Committee for Medicinal Products for Human Use (CHMP) required the conduct of a post-authorization safety study (PASS) to assess the association between the use of NVA237 and cardiovascular and cerebrovascular events. The objectives of this study are to assess the incidence rates and relative risks of 1) cardiovascular and cerebrovascular outcomes and 2) mortality among new users of NVA237 with COPD compared to new users of comparator drugs (long-acting antimuscarinic antagonists [LAMAs] excluding NVA237) or long-acting β2 agonists (LABAs) Country(-ies) of study United Kingdom, Denmark, Italy, The Netherlands, Spain Author Novartis Confidential Page 3 Non-interventional study report NVA237A/Seebri® Breezhaler®/CNVA237A2402T Marketing authorization holder Marketing authorization holder(s) MAH contact person Novartis Confidential Page 4 Non-interventional study report NVA237A/Seebri® Breezhaler®/CNVA237A2402T Table of contents Table of contents .................................................................................................................4 List of tables ........................................................................................................................7 List of figures ......................................................................................................................8 1 Abstract..............................................................................................................................11 2 List of abbreviations ..........................................................................................................15 3 Investigators ......................................................................................................................17 4 Other responsible parties ...................................................................................................18 5 Milestones..........................................................................................................................18 6 Rationale and background .................................................................................................19 7 Research question and objectives......................................................................................20 7.1 Main objective .......................................................................................................20 8 Amendments and updates to the protocol .........................................................................20 9 Research methods..............................................................................................................24 9.1 Study design...........................................................................................................24 9.2 Setting....................................................................................................................25 9.3 Subjects..................................................................................................................25 9.3.1 In- and exclusion criteria.......................................................................25 9.3.2 Follow-up ..............................................................................................26 9.4 Variables ................................................................................................................27 9.4.1 Endpoints of interest .............................................................................27 9.4.2 Exposure................................................................................................27 9.4.3 COPD severity ......................................................................................30 9.4.4 Concomitant drug use ...........................................................................30 9.4.5 Demography, life-style factors and comorbidity ..................................31 9.5 Data sources and measurement..............................................................................32 9.6 Bias ........................................................................................................................34 9.7 Study size...............................................................................................................34 9.8 Data transformation ...............................................................................................35 9.9 Statistical methods.................................................................................................36 9.9.1 Main summary measures.......................................................................36 9.9.2 Main statistical methods........................................................................37 9.9.3 Missing values.......................................................................................39 9.9.4 Sensitivity analyses ...............................................................................39 9.9.5 Amendments to the statistical analysis plan..........................................40 9.10 Quality control .......................................................................................................40 Novartis Confidential Page 5 Non-interventional study report NVA237A/Seebri® Breezhaler®/CNVA237A2402T 10 Results ...............................................................................................................................40 10.1 Participants ............................................................................................................40 10.2 Descriptive data .....................................................................................................43 10.2.1 Baseline characteristics by exposure cohort and database....................43 10.2.2 COPD characteristics by exposure cohort and database.......................45 10.2.3 Co-morbidities by exposure cohort and database .................................49 10.2.4 Use of other respiratory medications by exposure cohort and database - assessed during the year prior to index date and on index date ........................................................................................................51 10.2.5 Use of non-respiratory medications by exposure cohort and database.................................................................................................52 10.3 Outcome data.........................................................................................................53 10.3.1 Frequencies of main events in the pooled dataset.................................54 10.3.2 Frequencies of additional events in the pooled database ......................54 10.4 Main results ...........................................................................................................57 10.4.1 Incidence rates of main events across exposure cohorts.......................57 10.4.2 Incidence rates of additional events across exposure cohorts...............57 10.4.3 Kaplan Meier Curves ............................................................................61 10.4.4 Hazard ratios for NVA237 vs. LABA and NVA237 vs. LAMA..........61 10.5 Sensitivity analysis ................................................................................................67 10.5.1 Analysis in complete naïve patients and in patients without missing data with regard to COPD severity and smoking (= complete cases)...67 10.5.2 Sensitivity analysis 2 – No censoring at start of other drug..................69 10.5.3 Sensitivity analysis 3 – Wash-out period of 60 days ............................69 10.5.4 Sensitivity analysis 4 – Analysis of total follow-up time .....................69 10.6 Adverse events/adverse reactions..........................................................................71 11 Discussion..........................................................................................................................71 11.1 Key results .............................................................................................................71