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Protocol for Non-Interventional Studies Based on Existing Data TITLE PAGE Document Number: C30445781-01 ABCD Protocol for non-interventional studies based on existing data TITLE PAGE Document Number: c30445781-01 BI Study Number: 1237-0090 BI Investigational Stiolto® Respimat® Product(s): The Role of Inhaler Device in the Treatment Persistence with Dual Title: Bronchodilators in Patients with COPD Protocol version 1.0 identifier: Date of last version of N/A protocol: PASS: No EU PAS register Study not registered number: Olodaterol and Tiotropium Bromide (ATC R03AL06) Active substance: Umeclidinium and Vilanterol (ATC R03AL03) Medicinal product: Stiolto® Respimat®; Anoro® Ellipta® Product reference: N/A Procedure number: N/A Joint PASS: No The primary objective of the study is to use US data to determine relative persistence between Olodaterol/Tiotropium Bromide delivered with the Respimat soft mist inhaler and Umeclidinium/Vilanterol delivered with the Ellipta dry powder inhaler using a 1:2 propensity score matched analysis. The secondary objectives of the study are as follows: Research question and - Characterize new users of Olodaterol/Tiotropium Bromide objectives: and Umeclidinium/Vilanterol in terms of demographics, medication use, comorbidities, and other variables, before and after propensity score matching. - Determine the incidence rate and proportion of patients discontinuing or switching among new users of Olodaterol/Tiotropium Bromide and Umeclidinium/ Vilanterol. - Determine the relative rate and proportion of patients discontinuing between Olodaterol/ Tiotropium Bromide and 001-MCG-102_RD-02 (1.0) / Saved on: 22 Oct 2015 Boehringer Ingelheim Page 2 of 69 Protocol for non-interventional studies based on existing data BI Study Number 1237-0090 c30445781-01 Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies Umeclidinium/Vilanterol. using a standard multivariate analysis (If feasible). Country(-ies) of study: United States T: Email: Author: T: Email: BI contact person: Marketing authorisation holder(s): MAH contact person: In case of PASS, add: N/A In case of PASS, add: N/A Date: 22 November 2019 Page 1 of 69 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-MCG-102_RD-02 (1.0) / Saved on: 22 Oct 2015 Boehringer Ingelheim Page 3 of 69 Protocol for non-interventional studies based on existing data BI Study Number 1237-0090 c30445781-01 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........................................................................................5 3. RESPONSIBLE PARTIES ............................................................................................6 4. ABSTRACT...................................................................................................................7 5. AMENDMENTS AND UPDATES.............................................................................15 6. MILESTONES.............................................................................................................15 7. RATIONALE AND BACKGROUND........................................................................15 8. RESEARCH QUESTION AND OBJECTIVES..........................................................16 9. RESEARCH METHODS ............................................................................................17 9.1 STUDY DESIGN..........................................................................................17 9.2 SETTING ......................................................................................................17 9.2.1 Definitions.....................................................................................................17 9.2.2 Study population............................................................................................19 9.3 VARIABLES.................................................................................................20 9.3.1 Exposures ......................................................................................................20 9.3.2 Outcomes.......................................................................................................20 9.3.2.1 Primary outcome..........................................................................................20 9.3.2.2 Secondary outcomes ....................................................................................21 9.3.3 Covariates......................................................................................................21 9.4 DATA SOURCES.........................................................................................23 9.5 STUDY SIZE ................................................................................................23 9.6 DATA MANAGEMENT..............................................................................23 9.7 DATA ANALYSIS .......................................................................................24 9.7.1 Main analysis.................................................................................................24 9.7.1.1 Descriptive Analysis ....................................................................................24 9.7.1.2 Rates and Risks............................................................................................24 9.7.1.3 Comparative Persistence..............................................................................25 9.7.2 Sensitivity Analysis.......................................................................................26 9.8 QUALITY CONTROL .................................................................................27 9.9 LIMITATIONS OF THE RESEARCH METHODS ....................................28 001-MCG-102_RD-02 (1.0) / Saved on: 22 Oct 2015 Boehringer Ingelheim Page 4 of 69 Protocol for non-interventional studies based on existing data BI Study Number 1237-0090 c30445781-01 Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 9.10 OTHER ASPECTS........................................................................................28 9.11 SUBJECTS....................................................................................................28 9.11.1 Cases..............................................................................................................28 9.11.2 Controls .........................................................................................................29 9.12 BIAS..............................................................................................................29 10. PROTECTION OF HUMAN SUBJECTS ..................................................................29 11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS ...............................................................................................................30 12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS..30 13. REFERENCES.............................................................................................................31 13.1 PUBLISHED REFERENCES.......................................................................31 13.2 UNPUBLISHED REFERENCES .................................................................32 ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.........................................................33 ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .........................................34 ANNEX 3: LIST OF MEDICATION MEASURE DEFINITIONS........................................35 ANNEX 4. LIST OF COMORBIDITY, SYMPTOMS AND OTHER MEASURE DEFINITIONS.............................................................................................................38 ANNEX 5. TABLE SHELLS AND PROPOSED FIGURES .................................................60 001-MCG-102_RD-02 (1.0) / Saved on: 22 Oct 2015 Boehringer Ingelheim Page 5 of 69 Protocol for non-interventional studies based on existing data BI Study Number 1237-0090 c30445781-01 Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 2. LIST OF ABBREVIATIONS ACE Angiotensin Converting Enzyme AIDS Acquired Immune Deficiency Syndrome CCAE Commercial Claims and Encounters CDCI Charlson Deyo Comorbidity Index CI Confidence Interval COB Coordination of Benefits COBRA Consolidated Omnibus Budget Reconciliation Act COPD Chronic Obstructive Pulmonary Disease CT Computed Tomography DPI Dry Powder Inhaler ENCEPP European Network of Centres for Pharmacoepidemiology and Pharmacovigilance ESRD End Stage Renal Disease FDC Fixed Dose Combination GLP-1 Glucagon-like Peptide-1 GOLD Global Initiative for Chronic Obstructive Lung Disease HIV Human Immunodeficiency Virus ICD International Classification of Diseases ICS Inhaled Corticosteroid IP Inpatient IQR Interquartile Range IRB Institutional Review Board LABA Long-Acting Beta-Agonists LAMA Long-Acting Muscarinic Antagonists NDC National Drug Code NSAID Nonsteroidal Anti-inflammatory Drug
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