I4V-MC-B011 Non-interventional PASS Protocol Page 1 Post-Authorisation Safety Study (PASS) Information Study I4V-MC-B011: A Retrospective Cohort Study to Assess the Safety of Baricitinib Title Compared with Other Therapies Used in the Treatment of Rheumatoid Arthritis in Nordic Countries Version identifier Version 1.0 Date of last version 23 Jul 2018 EU PAS Register No.: EUPAS25151 Active substance Baricitinib; ATC code L04AA37 Medicinal product(s): Olumiant (baricitinib) 2-mg and 4-mg film-coated tablets Product reference: EU/1/16/1170 Procedure number: EMEA/H/C/004085 Marketing authorisation Eli Lilly Nederland BV, Papendorpseweg 83, 3528BJ Utrecht, The Netherlands holder(s) Joint PASS No Research question and This study aims to evaluate the safety of baricitinib among rheumatoid arthritis (RA) objectives patients treated in routine clinical care. Primary objectives: (1) to compare the incidence rates and profiles of: serious infections overall (including herpes zoster) and opportunistic infections (including tuberculosis, Candida infections, and progressive multifocal leukoencephalopathy); major adverse cardiovascular events; malignancies overall (including lymphoma and typically virus-induced malignancies such as cervical and many oropharyngeal cancers); and venous thromboembolism, among RA patients with long-term exposure to baricitinib compared to similar patients with long-term exposure to other indicated medications; (2) to describe the incidence rates of the following individual outcomes: lymphoma; herpes zoster; opportunistic infections such as tuberculosis, Candida, and progressive multifocal leukoencephalopathy; rhabdomyolysis; agranulocytosis; hyperlipidaemia(hypercholesterolaemia, hypertriglyceridaemia); gastrointestinal perforations; and liver injury. Secondary objectives: (3) to monitor the incidence rates of the aggregate outcomes of serious infections overall, MACE, malignancies overall, and VTE in very elderly patients, that is, those ≥75 years of age; (4) to assess the effectiveness of risk minimisation activities by describing the pattern of use of baricitinib and the occurrence of pregnancy, active tuberculosis or active viral hepatitis, and monitoring and treatment of lipid levels in relation to such use in routine clinical care. Countries of study Denmark, Finland, Norway, and Sweden Author PPD PPD E-mail: PPD Phone: PPD Approval Date: 29-Nov-2018 GMT I4V-MC-B011 Non-interventional PASS Protocol Page 2 Marketing Authorisation Holder Marketing authorisation Eli Lilly Nederland BV, Papendorpseweg 83, 3528BJ Utrecht, The Netherlands holder (MAH) MAH contact person PPD Eli Lilly and Company Lilly Corporate Center Indianapolis, IN 46285 United States Email: PPD Telephone: PPD I4V-MC-B011 Non-interventional PASS Protocol Page 3 1. Table of Contents Section Page 1. Table of Contents................................................................................................................3 2. List of Abbreviations ..........................................................................................................9 3. Responsible Parties ...........................................................................................................11 4. Abstract ............................................................................................................................12 5. Amendments and Updates.................................................................................................14 6. Milestones.........................................................................................................................15 7. Rationale and Background ................................................................................................16 8. Research Question and Objectives.....................................................................................18 9. Research Methods.............................................................................................................19 9.1. Study Design................................................................................................................19 9.2. Setting..........................................................................................................................19 9.2.1. Study Population..................................................................................................20 9.2.2. Eligibility.............................................................................................................20 9.2.3. Patient Subgroups of Special Interest ...................................................................21 9.3. Variables......................................................................................................................21 9.3.1. Drug Exposure.....................................................................................................21 9.3.1.1. Drug Exposure and Cohort Identification for Malignancy Analyses.........................................................................................................23 9.3.1.2. Drug Exposure and Cohort Identification for Nonmalignancy Analyses ...............................................................................23 9.3.1.3. Example of Exposure Classification ...............................................................24 9.3.1.3.1. Medication Restarts ..................................................................................26 9.3.2. Outcomes.............................................................................................................28 9.3.2.1. Malignancy, Excluding Nonmelanoma Skin Cancer .......................................28 9.3.2.2. Nonmelanoma Skin Cancer ............................................................................28 9.3.2.3. Serious Infections ...........................................................................................29 9.3.2.4. Opportunistic Infections .................................................................................29 9.3.2.5. Major Adverse Cardiovascular Events............................................................30 9.3.2.6. Venous Thromboembolism.............................................................................30 9.3.2.7. Gastrointestinal Perforations...........................................................................30 9.3.2.8. Liver Injury ....................................................................................................30 9.3.2.9. Rhabdomyolysis .............................................................................................31 9.3.2.10. Hyperlipidaemia (Including Hypercholesterolaemia and Hypertriglyceridaemia)...................................................................................31 I4V-MC-B011 Non-interventional PASS Protocol Page 4 9.3.2.11. Myelosuppresion (Agranulocytosis) ...............................................................31 9.3.3. Covariates............................................................................................................31 9.4. Data Sources ................................................................................................................32 9.4.1. The Nordic Health System ...................................................................................32 9.4.2. National Clinical Rheumatology Registries ..........................................................33 9.4.3. National Hospital Registries.................................................................................35 9.4.4. Prescription Data..................................................................................................36 9.4.5. The Medical Birth Registers.................................................................................37 9.4.6. Education and Income Data..................................................................................37 9.4.7. Quality Assurance and Quality Control ................................................................37 9.4.8. Data Period ..........................................................................................................38 9.5. Study Size ....................................................................................................................38 9.6. Data Management ........................................................................................................40 9.6.1. Data to Be Collected ............................................................................................40 9.6.1.1. Missing Data ..................................................................................................40 9.7. Data Analysis...............................................................................................................41 9.7.1. Analysis Population .............................................................................................41 9.7.2. Background and Rationale for Propensity Scores .................................................42 9.7.3. Propensity-Score Definition and Estimation .........................................................42 9.7.4. Using the Propensity Score to Address Channelling Bias .....................................42 9.7.5. Evaluation of the Propensity-Score Model and Stratification................................43 9.7.6. Malignancy Analysis............................................................................................43 9.7.6.1. Malignancy Excluding Nonmelanoma Skin Cancer ........................................43 9.7.6.2. Nonmelanoma Skin Cancer