Quantitative Safety & Epidemiology QVA149 / Indacaterol /Glycopyrronium bromide Non-interventional Final Study Report CQVA149A2401 Multinational, multi-database drug utilization study of indacaterol/glycopyrronium bromide in Europe Redacted Report Author Document Status Final Date of final version 05-Nov-2017 of the study report EU PAS register ENCePP/SDPP/7795 number 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 QVA149A/Ultibro® Breezhaler®/QVA149A2401 PASS information Title Multinational, multi-database drug utilization study of indacaterol/glycopyrronium bromide in Europe Version identifier of the Version 1.0 final study report Date of last version of 05 November 2017 the final study report EU PAS register number ENCePP/SDPP/7795 Active substance Indacaterol/glycopyrronium bromide (QVA149) (R03AL04) Medicinal product Ultibro® Breezhaler® Xoterna® Breezhaler® Ulunar® Breezhaler® Product reference QVA149 Procedure number EMEA/H/C/002679 EMEA/H/C/003755 EMEA/H/C/003875 Marketing authorization holder Joint PASS No Research question and To estimate the use of QVA149 off-label and in the objectives subpopulations with missing information mentioned in the risk management plan (RMP) Country(-ies) of study United Kingdom, Denmark, Italy, The Netherlands, Spain Author Novartis Confidential Page 3 Non-interventional study report QVA149A/Ultibro® Breezhaler®/QVA149A2401 Marketing authorization holder Marketing authorization holder(s) MAH contact person Novartis Confidential Page 4 Non-interventional study report QVA149A/Ultibro® Breezhaler®/QVA149A2401 Table of contents Table of contents .................................................................................................................4 List of tables ........................................................................................................................7 List of figures ......................................................................................................................8 1 Abstract..............................................................................................................................10 2 List of abbreviations ..........................................................................................................15 3 Investigators ......................................................................................................................17 4 Other responsible parties ...................................................................................................19 5 Milestones..........................................................................................................................19 6 Rationale and background .................................................................................................20 7 Research question and objectives......................................................................................21 7.1 Primary objectives .................................................................................................21 7.2 Secondary objectives .............................................................................................21 8 Amendments and updates to the protocol .........................................................................22 9 Research methods..............................................................................................................23 9.1 Study design...........................................................................................................23 9.2 Setting....................................................................................................................23 9.3 Subjects..................................................................................................................24 9.3.1 In- and exclusion criteria.......................................................................24 9.3.2 Follow-up ..............................................................................................24 9.4 Variables ................................................................................................................24 9.4.1 QVA149 exposure and duration of use.................................................24 9.4.2 Demography, life style factors and COPD characteristics prior to time of first prescription........................................................................25 9.4.3 Indication of use of inhaled QVA149 ...................................................26 9.4.4 Prescribed dosage/posology..................................................................27 9.4.5 Switching patterns (switching to and from other treatments) ...............27 9.4.6 Concomitant use of other respiratory drugs ..........................................29 9.4.7 Concomitant use of systemic anticholinergic drugs..............................29 9.4.8 Underlying comorbidities......................................................................30 9.4.9 Pregnancy or breast-feeding at initiation of QVA149 ..........................31 9.5 Data sources and measurement..............................................................................31 9.6 Bias ........................................................................................................................32 9.7 Study size...............................................................................................................33 9.7.1 Statistical procedure characteristics for off-label use ...........................33 9.7.2 Estimation of two-sided confidence intervals for comorbidities ..........34 Novartis Confidential Page 5 Non-interventional study report QVA149A/Ultibro® Breezhaler®/QVA149A2401 9.8 Data transformation ...............................................................................................34 9.9 Statistical methods.................................................................................................36 9.9.1 Main summary measures.......................................................................36 9.9.2 Main statistical methods........................................................................37 9.9.3 Missing values.......................................................................................37 9.9.4 Sensitivity analyses ...............................................................................38 9.9.5 Amendments to the statistical analysis plan..........................................38 9.10 Quality control .......................................................................................................38 10 Results ...............................................................................................................................38 10.1 Participants ............................................................................................................38 10.2 Descriptive data .....................................................................................................39 10.2.1 Baseline characteristics of QVA149 users............................................39 10.2.2 COPD characteristics of patients initiating QVA149 ...........................43 10.2.3 Prescribed dosage and treatment duration of QVA149.........................43 10.2.4 Switching patterns (switching to and from other treatments) ...............44 10.2.5 Comorbidity in patients initiating QVA149..........................................44 10.2.6 Use of other drugs in patients initiating QVA149 ................................45 10.3 Outcome data.........................................................................................................45 10.4 Main results ...........................................................................................................46 10.4.1 Off-label use of QVA149......................................................................46 10.4.2 Cardiovascular and cerebrovascular comorbidities ..............................50 10.4.3 Missing information in the RMP and high-risk treatment conditions...53 10.4.4 Uninterrupted use of QVA149 for more than one year.........................56 10.5 Other analyses........................................................................................................56 10.6 Adverse events/adverse reactions ..........................................................................56 11 Discussion..........................................................................................................................56 11.1 Key results .............................................................................................................56 11.2 Limitations.............................................................................................................57 11.3 Interpretation..........................................................................................................60 11.4 Generalizability......................................................................................................62 12 Other information ..............................................................................................................62 13 Conclusion.........................................................................................................................63 14 References (available upon request)..................................................................................64