ABCD e title PAGE Protocol for non-interventional studies based on existing data TITLE PAGE Document Number: c26457869-02 BI Study Number: 1245.195 BI Investigational Jardiance ® (empagliflozin) Product(s): Title: Multi-country non-interventional study on the effectiveness and safety of Empagliflozin in adult patients with type 2 diabetes in Europe and Asia Protocol version 2.0 identifier: Date of the last version 29 November 2018 of the protocol: PASS: No EU PAS register EUPAS27606 number: Active substance: A10BK03 empagliflozin Medicinal product: Jardiance Product reference: Europe: EMEA/H/C/002677 Asia: NA Procedure number: N/A Joint PASS: No Research question and The main objective of this study is to compare effectiveness objectives: outcomes between the incident users of empagliflozin or any SGLT-2 inhibitor and the incident users of any DPP-4 inhibitor. The effectiveness outcomes include, where available, cardiovascular events, renal effectiveness outcomes, and cardiovascular and all-cause mortality. Additional analyses include safety outcomes. Health care resources utilization and cost of care outcomes will also be evaluated. Countries of study: Denmark, Finland, Germany, Israel, Japan, Norway, South Korea, Spain, Sweden, Taiwan, United Kingdom. Other countries may be included later. 001-MCS-90-124_RD-01 (4.0) Boehringer Ingelheim Page 2 of 132 Protocol for non-interventional studies based on existing data BI Study Number 1245.195 c26457869-02 Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies Author: StatFinn-EPID Research: Ilkka Tamminen, Katja Hakkarainen, Fabian Hoti, Riho Klement, Juha Mehtälä, Laura Saarelainen, Giorgi Tskhvarashvili Harvard Medical School: Elisabetta Patorno, MD, PhD Boehringer Ingelheim: Anouk Déruaz Luyet, PhD Kimberly G. Brodovicz, DrPH Moe H. Kyaw, PhD Marketing Boehringer Ingelheim International GmbH authorization holder: Binger Strasse 173 55126 Ingelheim am Rhein Germany MAH contact person: Kimberly G Brodovicz, DrPH, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA In case of PASS, add: N/A <EU-QPPV:> In case of PASS, add: N/A <Signature of EU- QPPV:> Date: 11 October 2019 Page 1 of 132 Proprietary confidential information © 2019 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 001-MCS-90-124_RD-01 (4.0) Boehringer Ingelheim Page 3 of 132 Protocol for non-interventional studies based on existing data BI Study Number 1245.195 c26457869-02 Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 1. TABLE OF CONTENTS TITLE PAGE.............................................................................................................................1 1. TABLE OF CONTENTS........................................................................................3 2. LIST OF ABBREVIATIONS.................................................................................6 3. RESPONSIBLE PARTIES.....................................................................................7 4. ABSTRACT..........................................................................................................10 5. AMENDMENTS AND UPDATES......................................................................15 6. MILESTONES......................................................................................................16 7. RATIONALE AND BACKGROUND.................................................................16 8. RESEARCH QUESTION AND OBJECTIVES...................................................19 8.1 PRIMARY OBJECTIVES: EFFECTIVENESS............................................19 8.2 SECONDARY OBJECTIVES ON CARDIOVASCULAR EFFECTIVENESS.........................................................................................20 8.3 SECONDARY OBJECTIVES ON RENAL EFFECTIVENESS..................20 8.4 SECONDARY OBJECTIVES ON SAFETY................................................20 8.5 SECONDARY OBJECTIVES ON HEALTH CARE RESOURCE UTILIZATION (HCRU) AND COST OF CARE.........................................21 9. RESEARCH METHODS .....................................................................................22 9.1 STUDY DESIGN...........................................................................................22 9.1.1 Country-specific studies as components of this multi-country study............23 9.2 SETTING.......................................................................................................24 9.2.1 Overview........................................................................................................24 9.2.2 Study population ............................................................................................26 9.2.3 Study period and follow-up ...........................................................................28 9.3 VARIABLES .................................................................................................28 9.3.1 Exposures: study drugs ..................................................................................29 9.3.2 Outcomes .......................................................................................................35 9.3.3 Covariates at baseline (baseline characteristics)............................................41 9.3.4 Other variables required for analyses ............................................................42 9.4 DATA SOURCES .........................................................................................42 9.5 STUDY SIZE.................................................................................................42 001-MCS-90-124_RD-01 (4.0) Boehringer Ingelheim Page 4 of 132 Protocol for non-interventional studies based on existing data BI Study Number 1245.195 c26457869-02 Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 9.6 DATA MANAGEMENT...............................................................................45 9.6.1 Country-specific studies.................................................................................45 9.6.2 A multi-country study combining country-specific results ...........................45 9.7 DATA ANALYSIS........................................................................................46 9.7.1 Propensity score methodology.......................................................................46 9.7.2 Baseline characteristics / descriptive statistics ..............................................47 9.7.3 Primary effectiveness outcomes ....................................................................51 9.7.4 Sensitivity analyses for primary effectiveness outcomes ..............................53 9.7.5 Secondary outcomes: effectiveness, safety, HCRU and costs of care...........54 9.7.6 Sensitivity analyses for secondary effectiveness, safety, HCRU and cost of care outcomes.................................................................................................61 9.7.7 Combining effectiveness results from countries: meta-analyses...................62 9.7.8 Presenting the HCRU and cost of care results from countries descriptively.63 9.7.9 Adjustment for multiple comparisons............................................................63 9.8 QUALITY CONTROL..................................................................................63 9.8.1 Country-specific studies: localized protocols, localized SAPs, country- specific analyses, and country-specific study reports....................................63 9.8.2 Multi-country study: master protocol, master SAP, analyses with aggregate- level results from the countries, and final report ...........................................63 9.9 LIMITATIONS OF THE RESEARCH METHODS.....................................64 9.9.1 Data sources and variables.............................................................................64 9.9.2 Identifying patients with T2DM ....................................................................65 9.9.3 Drug exposure................................................................................................65 9.9.4 Bias and confounding ....................................................................................65 9.9.5 Analyses.........................................................................................................65 9.10 OTHER ASPECTS ........................................................................................65 9.11 SUBJECTS ....................................................................................................65 9.11.1 Cases ..............................................................................................................65 9.11.2 Controls..........................................................................................................65 9.12 BIAS ..............................................................................................................66 10. PROTECTION OF HUMAN SUBJECTS ...........................................................66 10.1 COUNTRY-SPECIFIC STUDIES ................................................................66 001-MCS-90-124_RD-01 (4.0) Boehringer Ingelheim Page 5 of 132 Protocol for non-interventional studies based on existing data BI Study