ABCD TITLE PAGE Protocol for observational studies based on existing data Document Number: c02330001-03 BI Study Number: 1222.54 BI Investigational Olodaterol Product(s): Title: Cohort study of cardiovascular events in patients with chronic obstructive pulmonary disease initiating olodaterol or other long- acting beta2-agonists Protocol version 3.0 identifier: Date of last version of 14 Oct 2014 protocol: PASS: Yes EU PASS register Study not registered number: Active substance: Olodaterol Medicinal product: Striverdi, Respimat Product reference: BI 1744 Procedure number: Not applicable Marketing authorisation holder(s): Joint PASS: No Date: 28 October 2016 Page 1 of 69 Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission Boehringer Ingelheim Page 2 of 69 Protocol for observational studies based on existing data BI Study Number 1222.54 c02330001-03 Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies Additional Information Research question and Examine the risk of selected cardiac arrhythmias in patients objectives: with chronic obstructive pulmonary disease (COPD) exposed to olodaterol compared with the risk in patients exposed to other long-acting beta2-agonists (LABAs) Examine the risk of acute myocardial infarction (AMI) and other serious ischaemic heart disease events, including unstable angina, in patients with COPD exposed to olodaterol compared with the risk in patients exposed to other LABAs Secondarily, examine the mortality risk in patients with COPD exposed to olodaterol compared with the risk in patients initiating other LABAs Country(-ies) of study: Denmark Author: Marketing authorisation holder(s): MAH contact person: EU-QPPV: Signature of EU-QPPV: The signature of the EU-QPPV is provided electronically Boehringer Ingelheim Page 3 of 69 Protocol for observational studies based on existing data BI Study Number 1222.54 c02330001-03 Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 1. TABLE OF CONTENT TITLE PAGE .................................................................................................................. 1 1. TABLE OF CONTENT......................................................................................... 3 2. LIST OF ABBREVIATIONS................................................................................ 5 3. RESPONSIBLE PARTIES.................................................................................... 7 4. ABSTRACT........................................................................................................... 8 5. AMENDMENTS AND UPDATES..................................................................... 12 6. MILESTONES..................................................................................................... 15 7. RATIONALE AND BACKGROUND................................................................ 16 8. RESEARCH QUESTION AND OBJECTIVES ................................................. 17 9. RESEARCH METHODS .................................................................................... 18 9.1 STUDY DESIGN............................................................................................ 18 9.2 SETTING ........................................................................................................ 18 9.3 VARIABLES .................................................................................................. 20 9.3.1 Exposures ................................................................................................ 20 9.3.1.1 Definition of new use...........................................................................20 9.3.1.2 Follow-up.............................................................................................20 9.3.1.2.1 Exposure definition................................................................................. 21 9.3.2 Outcomes................................................................................................. 22 9.3.2.1 Primary outcomes ................................................................................22 9.3.2.1.1 Case ascertainment ................................................................................. 22 9.3.2.1.2 Review of automated longitudinal health profiles.................................. 23 9.3.2.2 Secondary outcomes ............................................................................23 9.3.3 Covariates................................................................................................ 23 9.3.3.1 Medical characteristics at baseline.......................................................24 9.3.3.1.1 Severity of COPD ................................................................................... 24 9.3.3.1.2 Definition of COPD Severity.................................................................. 25 9.3.3.2 Other Characteristics............................................................................28 9.4 DATA SOURCE............................................................................................. 28 9.4.1 Denmark .................................................................................................. 29 9.4.2 Planned data source summary................................................................. 29 9.5 STUDY SIZE.................................................................................................. 30 9.6 DATA MANAGEMENT................................................................................ 32 Boehringer Ingelheim Page 4 of 69 Protocol for observational studies based on existing data BI Study Number 1222.54 c02330001-03 Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 9.7 DATA ANALYSIS......................................................................................... 33 9.7.1 Main analysis........................................................................................... 33 9.7.1.1 Description of cohort characteristics ...................................................33 9.7.1.2 Characteristics of follow-up.................................................................34 9.7.1.3 Safety endpoints...................................................................................34 9.8 QUALITY CONTROL................................................................................... 36 9.9 LIMITATIONS OF THE RESEARCH METHODS...................................... 36 9.10 OTHER ASPECTS ......................................................................................... 37 9.10.1 Study size limitations .............................................................................. 37 9.10.2 Study standards ....................................................................................... 37 9.10.3 Bias and confounding.............................................................................. 38 9.11 SUBJECTS...................................................................................................... 38 9.11.1 Identification of COPD ........................................................................... 38 9.11.2 Study cohorts........................................................................................... 39 9.11.3 Inclusion criteria...................................................................................... 40 10. PROTECTION OF HUMAN SUBJECTS .......................................................... 41 11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS....................................................................................................... 42 12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS ............................................................................................................................. 43 13. REFERENCES .................................................................................................... 44 13.1 PUBLISHED REFERENCES......................................................................... 44 13.2 UNPUBLISHED REFERENCES................................................................... 49 Annex 1. List of stand-alone documents ................................................................ 50 Annex 2. ENCePP checklist for study protocols.................................................... 51 Annex 3. Evaluation of COPD severity in automated health databases................. 59 Annex 4. ATC codes for selected respiratory medications .................................... 61 Annex 5. Codes for comorbidities and other medications ..................................... 63 Annex 6. Data source descriptions from feasibility report, 1 November 2013...... 67 Boehringer Ingelheim Page 5 of 69 Protocol for observational studies based on existing data BI Study Number 1222.54 c02330001-03 Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 2. LIST OF ABBREVIATIONS AMI Acute Myocardial Infarction ATC Anatomical Therapeutic Chemical BI Boehringer Ingelheim CAT COPD Assessment Test CI Confidence Interval COPD Chronic Obstructive Pulmonary Disease CPRD Clinical Practice Research Datalink DAMD Danish General