PASS Information Title Aclidinium Bromide Post-Authorisation Safety Study to Evaluate the Risk of Cardiovascular Endpoints: Common Study Protocol Protocol version Version 3.0 (18 May 2017) identifier Date of last version 02 June 2015, version 2.2 of protocol (Version 2.1, 29 July 2014, Version 2.0, 14 April 2014; Version 1.1, 19 April 2013) EU PAS register ENCEPP/SDPP/13616; 23 May 2014 number Active substance Aclidinium bromide (ATC code: R03BB05) Aclidinium bromide/formoterol fumarate dihydrate (ATC code: R03AL05) Medicinal product Eklira® Genuair®/Bretaris® Genuair® Duaklir® Genuair®/Brimica® Genuair® Product reference Eklira® Genuair®: H0002211 Bretaris® Genuair®: H0002706 Duaklir® Genuair®: H0003745 Brimica® Genuair®: H0003969 Procedure number Eklira® Genuair®: EMEA/H/C/002211 Bretaris® Genuair®: EMEA/H/C/002706 Duaklir® Genuair®: EMEA/H/C/003745 Brimica® Genuair®: EMEA/H/C/003969 Marketing AstraZeneca AB authorisation holder(s) Joint PASS No Research question The overall objective of this PASS is to evaluate the potential and objectives cardiovascular safety concerns and all-cause mortality described in the risk management plan for aclidinium bromide, through sequential, nested case-control studies for each endpoint of interest. Specific objectives are as follows: . To compare the risk of congestive heart failure (CHF); acute myocardial infarction (AMI), including community coronary heart disease (CHD) death; stroke; and all-cause mortality in patients with COPD initiating treatment with aclidinium bromide (monotherapy; concomitant with formoterol not in fixed-dose combination; and fixed- dose combination with formoterol, when available) and other inhaled COPD medications with the risk in patients with COPD initiating treatment with LABAs. To compare the risk of congestive heart failure, acute myocardial infarction, stroke, and all-cause mortality in patients with COPD initiating treatment with aclidinium bromide (monotherapy; concomitant with formoterol not in fixed-dose combination; and fixed- dose combination with formoterol, when available) with the risk in patients with COPD initiating other inhaled treatments for COPD. To evaluate the effect of dose and duration of each of the study medications on the risk of each individual endpoint. When the fixed-dose combination of aclidinium/formoterol becomes available, new users will be included in the cohort for evaluation. A new additional endpoint of cardiac arrhythmias is planned to be evaluated for CONFIDENTIAL 1 of 82 this cohort. Country(-ies) of United Kingdom; other country(ies) to be determined study Author Cristina Rebordosa, MD, PhD Cristina Varas-Lorenzo, MD, PhD RTI Health Solutions Av. Diagonal 605, 9-1 08028 Barcelona, Spain Telephone: +34.93.362 2807 Fax: +34.93.760.8507 E-mail: [email protected] Marketing Authorisation Holder(s) Marketing AstraZeneca AB authorisation SE-151 85 Södertälje holder(s) Sweden MAH contact person Magnus Ysander AstraZeneca EU QPPVEU AstraZeneca AB SE-151 85 Södertälje Sweden CONFIDENTIAL 2 of 82 The protocol Aclidinium Bromide Post-Authorisation Safety Study to Evaluate the Risk of Cardiovascular Endpoints: Common Study Protocol, Version 2.1, was approved as part of the granted marketing authorisation of fixed-dose combination Duaklir Genuair as a new medicinal product for human use by the European Medicines Agency in November 2014. Version 2.2, clarified AstraZeneca as the new MAH. The current amendment, Version 3.0, updates the study timelines. CONFIDENTIAL 5 of 82 Aclidinium Bromide Post-Authorisation Safety Study to Evaluate the Risk of Cardiovascular Endpoints: Common Study Protocol, Version 3.0, 18 May 2017 1 Table of Contents 1 Table of Contents....................................................................................... 6 List of Tables..................................................................................................... 7 List of Figures ................................................................................................... 7 2 List of Abbreviations.................................................................................. 8 3 Responsible Parties ................................................................................. 10 4 Abstract ................................................................................................... 10 5 Amendments and Updates ....................................................................... 15 6 Milestones and Timeline .......................................................................... 16 7 Rationale and Background ....................................................................... 18 8 Research Question and Objectives........................................................... 20 9 Research Methods ................................................................................... 20 9.1 Study Design ...................................................................................... 21 9.1.1 Definition of New Users.......................................................... 23 9.1.2 Choice of Comparator Drugs ................................................... 24 9.1.3 Definition of Index Prescription ............................................... 25 9.2 Setting............................................................................................... 26 9.2.1 Study Cohort ........................................................................ 26 9.2.2 Nested Case-Control Studies .................................................. 29 9.2.3 Health Care Databases........................................................... 30 9.3 Variables............................................................................................ 32 9.3.1 Study Endpoints.................................................................... 32 9.3.2 Exposure Assessment ............................................................ 37 9.3.3 Risk Factors and Confounding ................................................. 38 9.4 Data Sources ...................................................................................... 41 9.5 Study Size.......................................................................................... 41 9.6 Data Collection and Management .......................................................... 43 9.7 Data Analysis...................................................................................... 43 9.7.1 Cohort Description................................................................. 43 9.7.2 Cohort Analysis..................................................................... 44 9.7.3 Nested Case-Control Analysis ................................................. 44 9.7.4 Subgroup Analyses................................................................ 48 9.7.5 Effect of Dose and Duration .................................................... 49 9.7.6 Errors, Inconsistent Values, and Missing Data ........................... 49 9.8 Quality Control.................................................................................... 50 9.9 Limitations of the Research Methods...................................................... 50 9.10 Other Aspects ..................................................................................... 52 10 Protection of Human Subjects and Other Good Research Practice ........... 52 10.1 Informed Consent ............................................................................... 52 10.2 Participant Confidentiality..................................................................... 53 10.3 Compensation..................................................................................... 53 11 Management and Reporting of Adverse Events/Adverse Reactions ......... 53 CONFIDENTIAL 6 of 82 Aclidinium Bromide Post-Authorisation Safety Study to Evaluate the Risk of Cardiovascular Endpoints: Common Study Protocol, Version 3.0, 18 May 2017 12 Plans for Disseminating and Communicating Study Results..................... 53 13 References............................................................................................... 54 Annex 1. List of Stand-Alone Documents......................................................... 60 Annex 2. ENCePP Checklist for Study Protocols............................................... 61 Annex 3. Codes for Medications and Diagnoses............................................... 68 Annex 4. Proposed European Databases ......................................................... 74 Annex 5. Potential Confounding and Risk Factors ........................................... 77 List of Tables Table 1. First-Choice Medications in the Initial Management of COPD According to European Clinical Guidelines ...............................................................25 Table 2. Diagnosis Codes to Identify Patients With COPD ....................................27 Table 3. Exclusion Conditions ..........................................................................28 Table 4. Estimated Number of Aclidinium Bromide Users Captured in Each Prescription Database by Year .............................................................31 Table 5. Summary of Information and Codes Used for Case-Finding for Heart Failure, Acute Myocardial Infarction, and Stroke ...............................................36 Table 6. Classification of Time at Risk of Current Use of Aclidinium Bromide According to the Use of the Rest of Study Medications ..........................................38 Table 7. Assessment of COPD Severity .............................................................40