Arrhythmogenic potential of drugs FP7-HEALTH-241679 http://www.aritmo-project.org/ Common Study Protocol for Observational Database Studies WP5 – Analytic Database Studies V 1.3 Draft Lead beneficiary: EMC Date: 03/01/2010 Nature: Report Dissemination level: D5.2 Report on Common Study Protocol for Observational Database Studies WP5: Conduct of Additional Observational Security: Studies. Author(s): Gianluca Trifiro’ (EMC), Giampiero Version: v1.1– 2/85 Mazzaglia (F-SIMG) Draft TABLE OF CONTENTS DOCUMENT INFOOMATION AND HISTORY ...........................................................................4 DEFINITIONS .................................................... ERRORE. IL SEGNALIBRO NON È DEFINITO. ABBREVIATIONS ......................................................................................................................6 1. BACKGROUND .................................................................................................................7 2. STUDY OBJECTIVES................................ ERRORE. IL SEGNALIBRO NON È DEFINITO. 3. METHODS ..........................................................................................................................8 3.1.STUDY DESIGN ....................................................................................................................8 3.2.DATA SOURCES ..................................................................................................................9 3.2.1. IPCI Database .....................................................................................................9 3.2.2. PHARMO Database ......................................................................................... 170 3.2.3. Aarhus University Database ...............................................................................11 3.2.4. GePaRD Database ............................................................................................13 3.2.5. THIN Database ..................................................................................................16 3.2.6. Health Search Database ....................................................................................16 3.2.7. Emilia Romagna regional Database ...................................................................16 3.3.STUDY PERIOD ..................................................................................................................19 3.4.COHORT DEFINITION .........................................................................................................20 3.4.1. Inclusion Criteria ................................................................................................20 3.4.2. Cohort Entry .......................................................................................................20 3.4.3. Cohort Exit .........................................................................................................20 3.5.CASE DEFINITION ..............................................................................................................21 3.5.1. Symptomatic QT prolongation ............................................................................21 3.5.2. Torsade de Pointes (TdP) ..................................................................................21 3.5.3. Ventricular arrhytmia (VA) ..................................................................................21 3.5.4. Sudden Unexpected Death (SUD)/ Sudden cardiac death (SCD) ......................22 3.6.SELECTION OF CONTROLS .................................................................................................22 3.7.EXPOSURE DEFINITION ......................................................................................................22 3.7.1. Duration of Continuous Use ...............................................................................25 3.7.2. Dose ..................................................................................................................26 3.7.3. Route of administration ......................................................................................28 3.8.COVARIATES .....................................................................................................................28 4. PRIMARY STATISTICAL ANALYSES .............................................................................29 4.1.MAIN ANALYSIS .................................................................................................................29 4.2.SUB-ANALYSES.................................................................................................................30 4.2.1. Effect of Dosage ................................................................................................30 4.2.2. Effect of Duration of Use ....................................................................................30 4.2.3. Effect of Prior Use ..............................................................................................31 4.2.4. Effect of Co-Medication ......................................................................................31 4.2.5. Effect of Co-Morbidity ........................................................................................31 D5.2 Report on Common Study Protocol for Observational Database Studies WP5: Conduct of Additional Observational Security: Studies. Author(s): Gianluca Trifiro’ (EMC), Giampiero Version: v1.1– 3/85 Mazzaglia (F-SIMG) Draft 4.2.6. Effect of Indication for use ..................................................................................32 4.2.7. Examination of Subgroup Effects .......................................................................32 4.2.8. Examination of Age and Sex Effects ..................................................................32 4.3.CONFOUNDER SELECTION .................................................................................................32 4.4.SENSITIVITY ANALYSES .....................................................................................................32 5. QUALITY ASSURANCE ...................................................................................................33 6. ETHICAL, DATA PRIVACY, AND LEGAL ISSUES ..........................................................33 REFERENCES .........................................................................................................................36 ANNEXES ................................................................................................................................37 ANNEX I –PROTOCOL FOR DRUG UTILIZATION STUDIES ..............................................................36 ANNEX II – FREQUENCY OF OUTCOMES IN DIFFERENT DATABASES – PRELIMINARY ANALYSES ......45 ANNEX III – LIST OF DRUGS THAT WILL BE INVESTIGATED IN THE ARITMO PROJECT ....................46 ANNEX IV – COVARIATES OF INTEREST .....................................................................................63 ANNEX V – LIST OF MEDICATIONS THAT MAY POTENTIALLY INTERACT WITH THE STUDY DRUGS .....67 ANNEX VI – LIST OF MEDICATIONS THAWITH TDP LIABILITY .........................................................70 ANNEX VII – DESCRIPTION OF THE SOFTWARE JERBOA AS DEVELOPED IN EU-ADR PROJECT ......74 D5.2 Report on Common Study Protocol for Observational Database Studies WP5: Conduct of Additional Observational Security: Studies. Author(s): Gianluca Trifiro’ (EMC), Giampiero Version: v1.1– 4/85 Mazzaglia (F-SIMG) Draft Document Information Grant Agreement FP7-HEALTH-241679 Acronym ARITMO Number Full title Arrhythmogenic potential of drugs Project URL http://www.aritmo-project.org/ EU Project Fergal Donnelly ([email protected] ) officer Deliverable Internal Report: Common Study Protocol for Observational Database Studies Work package Numbe 5 Title WP5 – Analytic Database Studies r Delivery date Contractual Month Actual Status Version 1.1 final Nature Report Prototype Other Dissemination Public Confidential Level Authors Gianluca Trifiro’ (EMC), Giampiero Mazzaglia (F-SIMG) (Partner) Responsible Gianluca Trifiro’ Email [email protected] Author Partner EMC Phone +31 (0)10 7044128 Document History Name Date Version Description 19/09/10 v1.1 First draft for internal review Giampiero Mazzaglia (F- 19/09/10 v1.1 Integration of protocol for drug SIMG) utilization studies Alessandro Oteri (EMC) 19/09/10 v1.1 Preparation of the lists of drugs with arrhytmogenic potential and inhibitors of metabolism of the study drugs Tania Schink (Uni-HB) 11/10/2010 v1.2 External revision of the first draft Igor Diemberger (UNIBO) 11/10/2010 v1.2 External revision of the first draft Gianluca Trifiro’ (EMC) 11/10/2010 v1.3 Creation of the revised draft D5.2 Report on Common Study Protocol for Observational Database Studies WP5: Conduct of Additional Observational Security: Studies. Author(s): Gianluca Trifiro’ (EMC), Giampiero Version: v1.1– 5/85 Mazzaglia (F-SIMG) Draft Definitions Partners of the Artimo Consortium are referred to herein according to the following codes: - EMC: Erasmus Universitair Medisch Centrum Rotterdam - FIMIM: Fundació IMIM - LSHTM: London School of Hygiene and Tropical Medicine - UNIBO: Alma Mater Studiorum-Università di Bologna - UNI-HB: Universitaet Bremen - UoNEW: University of Newcastle - UB2: Université Victor Segalen Bordeaux2 - FSM-MCL: Fondazione Salvatore Maugeri Clinica del Lavoro e Della Riabilitazione - CHARITE: Charite - Universitaetsmedizin Berlin - UNIVR: Universita Degli Studi di Verona - SGHMS: St. George’s Hospital Medical School - AZ: AstraZeneca