DESLORATADINE PAGE 1 EPIDEMIOLOGY NO.: EP07044.002 PROTOCOL NO/AMENDMENT NO.: MK-4117-203 EU PAS REGISTER NO./EUDRACT NO.: 15038 Association between use of desloratadine and risk of seizures, supraventricular tachycardia, and atrial fibrillation or flutter: A Nordic register-based study (EU GUIDANCE: 23 JANUARY 2013 EMA/738724/2012) 05822K DESLORATADINE P A G E 2 EPI DE MI OL O G Y N O.: EP 07044.002 PROTOCOL NO/A MEND MEN T N O.: M K -4117 -2 0 3 E U P AS RE GISTE R N O./ EUDRACT NO .: 15038 PASS INF OR MATI ON Titl e Ass o ci ati o n b et w een use of desloratadine and risk of seizures, s u pr a v e ntri c ul ar t a c h y c ar di a, a n d atri al fi brill ati o n or fl utt er: A N or di c r e gist er -based study V e rsi o n i d e ntifi e r of t h e 1 fi nal st u dy re port Date of last versio n of t he 1 0 May 2019 fi nal st u dy re port E U P AS register nu mber E UP AS15038 Active s u bsta nce Desloratadine, A T C code R06 A X27; Phar macotherapeutic group: A nti hist a mi n es – H 1 a nt a g o nist Medicinal product A E RI US, AZ O M YR, and NE OCL ARIT Y N Product reference E U/ 1/ 0 0/ 1 6 0, A E RI U S E U/ 1/ 0 0/ 1 5 7, A Z O M Y R E U/1/00/161, NE OCL ARIT Y N Procedure nu mber E ME A/ H/ C/000313/ ME A/065, AE RI US E ME A/ H/C/000310/ ME A/065, AZ O M YR E ME A/ H/C/000314/ ME A/065, NE OCL ARIT Y N Marketing authorisation Merck Sharp & Doh me B. V. hol der(s) Waarder w e g 3 9 2031 B N Haarle m The Netherlands Joint P ASS N o Research question and T o d es cri b e t h e us e of d esl or at a di n e i n t h e g e n er al p o p ul ati o n; t o o bjectives describe the incidence rates of first seizure, supraventricular t a c h y c ar di a, atri al fi brill ati o n or fl utt er , a n d first r e c urr e nt s ei z ur e; and to exa mine the associations bet ween desloratadine exposure a n d ris k of first s ei z ur e, s u pr a v e ntri c ul ar t a c h y c ar di a, atri al fi brill ati o n or fl utt er, a n d first r e c urr e nt s ei z ur e. Co u ntry( -ies) of st u dy D e n m ar k, Fi nl a n d, and S weden A ut hor A n n ett e Kj ær Ers b øll P P D of S o ut h er n D en mark St u di estr æ d e 6 D K -1 4 5 5 Copenhagen K Den mark P h o n e: P P D E -ma il: P P D Merck Final Repository 1 0 -J U N -2019 ( R C A M) Date (E U G UI D A NCE: 23 J A N U AR Y 2013 E M A/738724/2012) 05822 K DESLORATADINE P A G E 3 EPI DE MI OL O G Y N O.: EP 07044.002 PROTOCOL NO/A MEND MEN T N O.: M K -4117 -2 0 3 E U P AS RE GISTE R N O./ EUDRACT NO .: 15038 MAR KETIN G AUTHORISATION HOLDER ( S) M ar k eti n g a ut h oris ati o n Merck Sharp & Doh me B. V. h ol der(s) Waarder w e g 3 9 2031 B N Haarle m The Netherlands M A H contact person P P D Gl o b al R e g ul at or y Aff airs – R AI E M E A R e gi o n al Center Merck Sharp & Doh me ( Europe), I n c. Lynx Binnenhof 5 1200 Brussels, Belgiu m P h o n e: P P D F a x: P P D E -ma il: P P D (E U G UI D A NCE: 23 J A N U AR Y 2013 E M A/738724/2012) 05822 K DESLORATADINE PAGE 4 EPIDEMIOLOGY NO.: EP07044.002 PROTOCOL NO/AMENDMENT NO.: 4117-203 EU PAS REGISTER NO./EUDRACT NO.: 15038 text TABLE OF CONTENTS TABLE OF CONTENTS .............................................................................................. 4 LIST OF TABLES ......................................................................................................... 7 LIST OF FIGURES ....................................................................................................... 8 LIST OF ANNEXES...................................................................................................... 9 1 ABSTRACT................................................................................................................. 10 2 LIST OF ABBREVIATIONS .................................................................................... 14 3 INVESTIGATORS ..................................................................................................... 15 4 OTHER RESPONSIBLE PARTIES......................................................................... 15 5 MILESTONES ............................................................................................................ 16 6 RATIONALE AND BACKGROUND ...................................................................... 17 7 RESEARCH QUESTION AND OBJECTIVES ...................................................... 17 8 AMENDMENTS AND UPDATES............................................................................ 18 9 RESEARCH METHODS........................................................................................... 18 9.1 Study design.............................................................................................................. 18 9.2 Setting........................................................................................................................ 21 9.3 Subjects ..................................................................................................................... 21 9.4 Variables ................................................................................................................... 24 9.4.1 Exposure ................................................................................................................. 24 9.4.2 Outcome.................................................................................................................. 26 9.4.3 Covariates ............................................................................................................... 27 9.4.4 Other variables........................................................................................................ 31 9.5 Data sources and measurement .............................................................................. 31 9.5.1 Study Procedures .................................................................................................... 32 9.6 Bias ............................................................................................................................ 33 9.7 Study size .................................................................................................................. 36 9.7.1 Fixed sample size.................................................................................................... 36 9.7.2 Proportion of current and non-current exposure time among DL users for the purpose of calculation of minimum detectable IRR ................................................. 36 9.7.3 Background event rate ............................................................................................ 37 9.7.4 Number of years in the study.................................................................................. 37 (EU GUIDANCE: 23 JANUARY 2013 EMA/738724/2012) 05822K DESLORATADINE PAGE 5 EPIDEMIOLOGY NO.: EP07044.002 PROTOCOL NO/AMENDMENT NO.: 4117-203 EU PAS REGISTER NO./EUDRACT NO.: 15038 text 9.7.5 Statistical parameters and assumptions................................................................... 38 9.7.6 Example of calculating the minimum detectable IRR ............................................ 38 9.8 Data transformation ................................................................................................ 39 9.8.1 Data management.................................................................................................... 40 9.9 Statistical methods ................................................................................................... 42 9.9.1 Main summary measures ........................................................................................ 42 9.9.2 Main statistical methods ......................................................................................... 42 9.9.2.1 Substudy 1: Descriptive analysis of exposure of DL........................................... 42 9.9.2.2 Substudy 2: First seizure...................................................................................... 43 9.9.2.3 Substudy 3: SVT.................................................................................................. 43 9.9.2.4 Substudy 4: Atrial fibrillation/flutter ................................................................... 44 9.9.2.5 Substudy 5: First recurrent seizure ...................................................................... 45 9.9.2.6 Additional information for Substudies 2A, 3A, 4A, and 5A ............................... 45 9.9.2.7 Additional information for Substudies 2B, 3B, 4B, and 5B ................................ 46 9.9.3 Missing values ........................................................................................................ 46 9.9.4 Sensitivity analyses................................................................................................. 47 9.9.5 Post hoc analyses .................................................................................................... 56 9.9.6 Amendments to the statistical analysis plan ........................................................... 57 9.10 Quality control ....................................................................................................... 58 10 RESULTS .................................................................................................................. 59 10.1 Participants............................................................................................................. 59 10.1.1 Protection of Human Subjects .............................................................................. 59 10.2 Descriptive data.....................................................................................................