Quantitative Safety & Epidemiology Non-Interventional Study Protocol NVA237A2401T Title Multinational, multi-database drug utilization study of inhaled NVA237 in Europe Protocol version v02 identifier Date of last version 05 September 2014 of protocol EU PAS register ENCEPP/SDPP/4845 number Active substance Glycopyrronium bromide (NVA237) (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 Novartis Confidential Page 2 Non-interventional study protocol NVA237/Seebri®/NVA237A2401T Marketing Novartis Europharm Limited authorization Wimblehurst Road holder(s) Horsham West Sussex RH12 5AB United Kingdom Joint PASS No Research questions In the context of the NVA237 marketing authorization and objectives application (and it’s multiple marketing authorization applications), the Committee for Medicinal Products for human use (CHMP) recommended conditions for marketing authorization and product information and suggested to conduct a post-authorization drug utilization study. The objectives of this study are to estimate the subpopulation with cardiovascular co-morbidity and to identify patients groups with missing information in the Risk Management Plan. Country (-ies) of UK, Denmark, Italy, The Netherlands, Spain study Author , MD, PhD The Netherlands Tel: 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 NVA237/Seebri®/NVA237A2401T Marketing authorization holder(s) Novartis Europharm Ltd Marketing authorization holder(s) , MSc, PhD MAH contact person Novartis Pharma AG Quantitative Safety & Epidemiology – DS&E Novartis Campus CH-4002 Basel Switzerland Novartis Confidential Page 4 Non-interventional study protocol NVA237/Seebri®/NVA237A2401T 1 Table of contents 1 Table of contents ............................................................................................................. 4 List of tables ................................................................................................................... 5 List of figures .................................................................................................................. 6 2 List of abbreviations ........................................................................................................7 3 Responsible parties ......................................................................................................... 9 4 Abstract ........................................................................................................................ 12 5 Amendments and updates .............................................................................................. 14 6 Milestones ..................................................................................................................... 17 7 Rationale and background ............................................................................................. 17 8 Research question and objectives .................................................................................. 18 8.1 Main objectives ................................................................................................. 18 8.2 Secondary objectives ......................................................................................... 19 9 Research methods ......................................................................................................... 19 9.1 Study design ...................................................................................................... 19 9.2 Setting ............................................................................................................... 20 9.2.1 Study population and study cohorts ....................................................2 0 9.2.2 Study period ...................................................................................... 20 9.2.3 In- and exclusion criteria ....................................................................2 0 9.2.4 Follow-up .......................................................................................... 21 9.3 Variables ........................................................................................................... 21 9.3.1 NVA exposure and duration of use..................................................... 21 9.3.2 Demography, life style factors and COPD characteristics at time of first prescription .................................................................................2 2 9.3.3 Indication of use for inhaled NVA237 ................................................2 3 9.3.4 Prescribed dosage/posology ............................................................... 23 9.3.5 Concomitant use of other respiratory drugs ........................................ 24 9.3.6 Concomitant use of other anticholinergic drugs ..................................2 4 9.3.7 Underlying co-morbidities ................................................................. 25 9.3.8 Pregnancy or breast-feeding at initiation of NVA237 ......................... 25 9.4 Data sources ...................................................................................................... 25 9.4.1 IPCI Database .................................................................................... 27 9.4.2 HSD - CSD Longitudinal Patient Database ........................................ 27 9.4.3 THIN Database .................................................................................. 28 9.4.4 Aarhus Database ................................................................................ 29 Novartis Confidential Page 5 Non-interventional study protocol NVA237/Seebri®/NVA237A2401T 9.4.5 SIDIAP Database ...............................................................................2 9 9.5 Study size .......................................................................................................... 30 9.6 Data management .............................................................................................. 32 9.7 Data analysis...................................................................................................... 33 9.8 Quality control ...................................................................................................3 4 9.9 Limitations of the research methods ...................................................................3 4 10 Protection of human subjects .........................................................................................3 5 11 Management and reporting of adverse events/adverse reactions..................................... 36 12 Plans of disseminating and communicating study results ...............................................3 6 13 References (available upon request) .............................................................................. 36 Annex 1 – List of stand-alone documents .............................................................................4 0 Annex 2 – ENCePP checklist for study protocols ................................................................. 41 Annex 3 – Exposure and concomitant medication definition ................................................ 48 Annex 4 – Indication of use and co-morbidity definition ...................................................... 73 Annex 4.1 Definition of COPD ..................................................................................... 73 Annex 4.2 Definition of Asthma ....................................................................................7 7 Annex 4.3 Definition of lower respiratory tract infection (eventname=LRTI) ................8 2 Annex 4.4 Ischemic heart disease .................................................................................. 82 Annex 4.5 Cardiac arrhythmia .......................................................................................8 9 Annex 4.6 Definition of Heart Failure ........................................................................... 94 Annex 4.7 Cerebrovascular events ................................................................................ 97 Annex 4.8 Definition of chronic kidney disease(Levey and Coresh 2012) ................... 100 Annex 4.9 Definition of bladder outlow obstruction/urinary retention ......................... 104 Annex 4.10 Definition of BPH (eventtype=BPH) ........................................................ 105 Annex 4.11 Definition of narrow angle glaucoma........................................................ 105 Annex 4.12 Definition of hepatic impairment ..............................................................1 06 Annex 5 Pregnancy and breastfeeding ......................................................................... 109 List of tables Table 3-1 Main responsible parties ...................................................................... 9 Table 5-1 Study protocol amendments and updates ............................................ 14 Table 6-1 Study milestones ................................................................................1 7 Table 9-1 Launch dates for NVA237 in the five participating countries ............. 20 Table 9-2 Overview of databases ....................................................................... 26 Novartis Confidential