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Protocol for Non-Interventional Studies Based on Existing Data TITLE PAGE Document Number: C26457869-01 hTITLE PAGE Protocol for non-interventional studies based on existing data TITLE PAGE Document Number: c26457869-01 BI Study Number: 1245.195 BI Investigational Jardiance ® (empagliflozin) Product(s): Title: Multi-country non-interventional study on the effectiveness of Empagliflozin in adult patients with type 2 diabetes in Europe and Asia. Protocol version 1.0 identifier: Date of last version of N/A protocol: PASS: No EU PAS register number: Study not yet registered in the EU PAS register. Will be registered prior to data collection start. Active substance: Empagliflozin (A10BK03) Medicinal product: Jardiance ® Product reference: Europe: EMEA/H/C/002677Asia: 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 cardiovascular events, cardiovascular mortality (where available) and all-cause mortality (where available). Secondary objectives are to evaluate health care utilization and cost of care outcomes (where available). Countries of study: Denmark, Finland, Germany, Israel, Japan, Norway, South Korea, Spain, Sweden, Taiwan, United Kingdom Author: StatFinn-EPID Research: Elisabeth Björkqvist, Susanna Flaherty, Katja Hakkarainen, Fabian Hoti, Riho Klement, Juha Mehtälä, Laura Saarelainen, Iveta 001-MCS-90-124_RD-01 (4.0) Boehringer Ingelheim Page 2 of 100 Protocol for non-interventional studies based on existing data BI Study Number 1245.195 c26457869-01 Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies Trojcakova Harvard Medical School: Elisabetta Patorno, MD, PhD Boehringer Ingelheim: Anouk Déruaz Luyet, PhD Kimberly G. Brodovicz, DrPH Moe H. Kyaw, PhD Marketing authorisation Boehringer Ingelheim International GmbH 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: 29 November 2018 Page 2 of 100 Proprietary confidential information © 2018 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 100 Protocol for non-interventional studies based on existing data BI Study Number 1245.195 c26457869-01 Proprietary confidential information © 2018 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 ........................................................................................................... 8 5. AMENDMENTS AND UPDATES ..................................................................... 12 6. MILESTONES ..................................................................................................... 12 7. RATIONALE AND BACKGROUND ................................................................ 12 8. RESEARCH QUESTION AND OBJECTIVES ................................................. 14 8.1 PRIMARY OBJECTIVES: EFFECTIVENESS ............................................. 14 8.2 SECONDARY OBJECTIVES ON EFFECTIVENESS ................................. 14 8.3 SECONDARY OBJECTIVES ON HEALTH CARE RESOURCE UTILIZATION (HCRU) AND COST OF CARE .......................................... 15 9. RESEARCH METHODS .................................................................................... 15 9.1 STUDY DESIGN ............................................................................................ 15 9.1.1 Country-specific studies as components of this multi-country study ..... 16 9.2 SETTING ........................................................................................................ 17 9.2.1 Overview ................................................................................................. 17 9.2.2 Study population ..................................................................................... 19 9.2.3 Study period and follow-up ..................................................................... 20 9.3 VARIABLES .................................................................................................. 21 9.3.1 Exposures: study drugs ............................................................................ 21 9.3.2 Outcomes ................................................................................................. 25 9.3.3 Covariates at baseline (baseline characteristics) ..................................... 27 9.3.4 Other variables required for analyses ...................................................... 28 9.4 DATA SOURCES ........................................................................................... 29 9.5 STUDY SIZE .................................................................................................. 29 9.6 DATA MANAGEMENT ................................................................................ 31 9.6.1 Country-specific studies .......................................................................... 31 9.6.2 Multi-country study combining country-specific results ........................ 32 001-MCS-90-124_RD-01 (4.0) Boehringer Ingelheim Page 4 of 100 Protocol for non-interventional studies based on existing data BI Study Number 1245.195 c26457869-01 Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 9.7 DATA ANALYSIS ......................................................................................... 32 9.7.1 Propensity score methodology ................................................................ 32 9.7.2 Baseline characteristics / descriptive statistics ........................................ 33 9.7.3 Primary effectiveness outcomes .............................................................. 36 9.7.4 Sensitivity analyses for primary effectiveness outcomes ........................ 38 9.7.5 Secondary outcomes: effectiveness, HCRU and costs of care ................ 39 9.7.6 Sensitivity analyses for secondary effectiveness, HCRU and cost of care outcomes ................................................................................................. 41 9.7.7 Combining effectiveness results from countries: meta-analyses ............ 41 9.7.8 Combining HCRU and cost of care results from countries descriptively 42 9.7.9 Adjustment for multiple comparisons ..................................................... 42 9.8 QUALITY CONTROL ................................................................................... 42 9.8.1 Country-specific studies: localized protocols, localized SAPs, country-specific analyses, and country-specific study reports ............... 42 9.8.2 Multi-country study: master protocol, master SAP, analyses with aggregate-level results from the countries, and final report ................... 43 9.9 LIMITATIONS OF THE RESEARCH METHODS ...................................... 44 9.9.1 Data sources and variables ...................................................................... 44 9.9.2 Identifying patients with T2DM .............................................................. 44 9.9.3 Drug exposure ......................................................................................... 44 9.9.4 Bias and confounding .............................................................................. 44 9.9.5 Analyses .................................................................................................. 44 9.10 OTHER ASPECTS ......................................................................................... 45 9.11 SUBJECTS ...................................................................................................... 45 9.11.1 Cases ........................................................................................................ 45 9.11.2 Controls ................................................................................................... 45 9.12 BIAS ................................................................................................................ 45 10. PROTECTION OF HUMAN SUBJECTS .......................................................... 45 10.1 COUNTRY-SPECIFIC STUDIES ................................................................. 46 10.2 MULTI-COUNTRY STUDY ......................................................................... 46 11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS ....................................................................................................... 46 001-MCS-90-124_RD-01 (4.0) Boehringer Ingelheim Page 5 of 100 Protocol for non-interventional studies based on existing data BI Study Number 1245.195 c26457869-01 Proprietary confidential information ©
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