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SHUPLVVLRQRI0HUFN.*D$'DUPVWDGW*HUPDQ\RULWVVXEVLGLDU\ &RS\ULJKW E\ 0HUFN .*D$ 'DUPVWDGW *HUPDQ\ RU LWV VXEVLGLDU\ $OOULJKWVUHVHUYHG 1 Table of Contents 1 Table of Contents ..................................................................................3 2 List of Abbreviations ............................................................................6 3 Responsible Parties ...............................................................................9 4 Abstract ...............................................................................................11 5 Amendments and Updates ..................................................................18 6 Milestones ...........................................................................................18 7 Rationale and Background ..................................................................19 8 Research Question and Objectives .....................................................22 8.1 Primary Objective ...............................................................................22 8.2 Secondary Objectives .........................................................................22 9 Research Method ................................................................................23 9.1 Study Design .......................................................................................23 9.1.1 Design Overview ................................................................................23 9.1.2 Outcomes ............................................................................................25 9.2 Setting .................................................................................................29 9.2.1 Study Population .................................................................................29 9.2.2 Definition of Study Cohorts and Description of Treatments ..............30 9.2.3 Study Time Periods .............................................................................31 9.3 Variables .............................................................................................32 9.3.1 Exposure Variables .............................................................................32 9.3.2 Other Variables (Covariates) ..............................................................33 9.4 Data Source .........................................................................................36 9.4.1 Denmark .............................................................................................37 9.4.2 Sweden ................................................................................................39 9.5 Study Size ...........................................................................................40 9.6 Data Management ...............................................................................46 9.7 Data Analysis ......................................................................................46 9.7.1 Analysis Sets .......................................................................................47 9.7.2 Derived and Transformed Data ..........................................................51 9.7.3 Statistical Methods ..............................................................................51 9.7.4 Sequence of Analyses .........................................................................66 3/100 9.8 Quality Control ...................................................................................66 9.9 Limitations of the Research Methods .................................................67 9.9.1 Selection Bias .....................................................................................67 9.9.2 Information Bias .................................................................................67 9.9.3 Confounding by Baseline Characteristics ...........................................69 9.9.4 Unmeasured Confounding ..................................................................69 9.9.5 Study Size and Time Trends ...............................................................70 9.9.6 Generalizability ...................................................................................70 9.10 Other Aspects ......................................................................................70 9.10.1 Independent Ethics Committee or Institutional Review Board ..........70 9.10.2 Quality Assurance ...............................................................................71 9.10.3 Archiving ............................................................................................71 10 Protection of Human Subjects ............................................................71 10.1 Subject Identification and Privacy ......................................................71 11 Management and Reporting of Adverse Events .................................71 12 Plans for Disseminating and Communicating Study Results .............72 12.1 Study Report .......................................................................................72 12.2 Publication ..........................................................................................72 12.3 Cost Results in Health-Economic Studies ..........................................72 13 References ...........................................................................................73 14 Appendices .........................................................................................79 14.1 List of Stand-Alone Documents .........................................................79 14.2 ENCePP Checklist for Study Protocols ..............................................80 14.3 Additional Information .......................................................................86 14.3.1 Outcome variables (Section 9.1.2): Diagnosis and Procedure Codes for Definition and Databases for Identification .......................86 14.3.2 Censoring Criteria (Section 9.2.3): Diagnosis and Procedure Codes for Definition ...........................................................................89 14.3.3 Exposure (Section 9.3.1) and Other Variables (Section 9.3.2): Codes for Definition ...........................................................................90 14.3.4 Summary of the Cost-effectiveness Model .........................................94 14.4 Signature Pages and Responsible Persons for the Study ....................95 Signature Page – Protocol Lead .........................................................................................96 4/100 Signature Page – Principal-in-Charge, Coordinating