Cl a d ri bi n e Integrate d A n al ysis P l a n E M R700568 -012 Integrated Analysis Plan Cli ni c al St u dy P r ot o c ol E M R700568-012 I d e ntifi c ati o n N o. Titl e Pr os p e cti v e o bs er v ati o n al long -t er m s af et y r e gistr y of M ulti pl e S cl er osis p ati e nts w h o h a v e p arti ci p at e d i n cl a dri bi n e cli ni c al trials (P R E MI E R E) Eudra CT Nu mber 2009-017978-21 Study Phase N o n -E x p eri m e nt al r e gistr y I n v esti g ati o n al M e di ci n al Cladribine Merck Europe 10 m g t a bl ets Pro d uct(s) Cl a dri bi n e is a n adenosine dea minase -r esist a nt a n al o g u e of deox yadenosine t h at e x erts its eff e ct i n M S vi a pr ol o n g e d suppression of peripheral ly mphocy t e c o u nts Cli ni c al St u dy P r ot o c ol 2 0 J ul y 2 0 1 6 / V ersi o n 4. 0 i n cl u di n g a m e n d m e nt N o. 2 Versio n Integrated Analysis Plan Coordinating Author A ut hor P P D Merck P P D F u ncti o n A ut h or P P D P P P P D D Integrated Analysis Plan 2 1 Nove mber 2018 / V ersi o n 1. 0 Date and Version Integrated Analysis Plan F u ncti o n Na me Revie wers P P D M erck P P D P P D Merck P P D P P D M erck P P D P P D , P P P P D P P D D P P D P P D P P D T his d o c u m e nt is t h e pr o p ert y of M er c k K G a A, D ar mst a dt, G er m a n y, or o n e of its affili at e d co mpanies. It is i nt e n d e d f or r estri ct e d us e o nl y a n d m a y n ot - i n f ull or p art - be passed on, reproduced, published or used without e x pr ess p er missi o n of M er c k K G a A, D ar mst a dt, G er m a n y or its affili at e. C o p y ri g ht © 2018 by Merck K Ga A, Dar mstadt, Ger many o r its affili at e. All ri g hts r es e r v e d. 1/ 1 3 4 1/ 1 3 5 Cl a d ri bi n e Integrate d A n al ysis P l a n E M R700568 -012 Approval Page Integrated Analysis Plan: E MR700568 -012 Prospective o bs er v ati o n al l o n g -ter m safet y r e gistr y of M ulti pl e S cl er osis p ati e nts w h o h a v e p arti ci p at e d i n cl a dri bi n e cli ni c al tri als ( P R E MI E R E) Merck Respons i bl e D ate Sig nat ure P P D Via EL D O R A D O approval process 2/ 1 3 4 2/ 1 3 5 Cladribine Integrated Analysis Plan EMR700568-012 1 Table of Contents Integrated Analysis Plan...................................................................................................... 1 Approval Page 2 1 Table of Contents ................................................................................. 3 2 List of Abbreviations and Definition of Terms.................................... 6 3 Modification History............................................................................ 7 4 Purpose of the Integrated Analysis Plan .............................................. 8 5 Objectives and Endpoints..................................................................... 8 6 Overview of Planned Analyses ............................................................ 9 6.1 Intermediate Analyses.......................................................................... 9 6.2 Final Analysis ...................................................................................... 9 7 Changes to the Planned Analyses in the Clinical Study Protocol...... 10 8 Protocol Deviations and Analysis Populations .................................. 12 8.1 Definition of Protocol Deviations and Analysis Sets......................... 12 8.2 Definition of Analysis Populations and Subgroups ........................... 12 9 General Specifications for Data Analyses.......................................... 13 9.1 Treatment groups ............................................................................... 13 9.2 Analysis Period .................................................................................. 14 9.3 Identification of patients .................................................................... 14 9.4 Dictionary coding............................................................................... 14 9.5 Study Day 1........................................................................................ 15 9.6 Registry Day 1 ................................................................................... 15 9.7 Baseline.............................................................................................. 15 9.8 End of clinical trial............................................................................. 15 9.9 Last date in PREMIERE .................................................................... 15 9.10 Last ALC date with value in PREMIERE ......................................... 15 9.11 Conversion factors ............................................................................. 15 9.12 Handling of missing data ................................................................... 16 9.13 Presentation of continuous and qualitative variables......................... 16 9.14 Significance level............................................................................... 16 9.15 Software(s) ......................................................................................... 16 10 Study Participants .............................................................................. 16 3/134 3/135 Cladribine Integrated Analysis Plan EMR700568-012 10.1 Disposition of Participants and Discontinuations .............................. 16 10.2 Protocol Deviations............................................................................ 18 11 Demographics and Other Baseline Characteristics............................ 18 11.1 Demographics .................................................................................... 18 11.2 Medical History.................................................................................. 19 12 Previous Medications or Medications/Procedures in PREMIERE .... 19 12.1 Previous medications ......................................................................... 19 12.2 Medications in PREMIERE............................................................... 19 12.2.1 Disease Modifying Drugs in PREMIERE.......................................... 20 12.3 Procedures in PREMIERE................................................................. 20 12.4 Handling of Partial dates for Medications ......................................... 20 13 Study intervention Compliance and Exposure................................... 21 14 Efficacy Analyses............................................................................... 21 15 Safety Analyses.................................................................................. 21 15.1 Primary Endpoints.............................................................................. 21 15.1.1 Serious Adverse Events Related to Cladribine .................................. 21 15.1.2 Blood and Lymphatic System Disorders ........................................... 22 15.1.3 Neoplasms Benign, Malignant, and Unspecified............................... 23 15.1.4 Lymphopenia...................................................................................... 23 15.2 Secondary Endpoints: Pregnancy....................................................... 26 15.3 Adverse Events................................................................................... 27 15.3.1 All Adverse Events ............................................................................ 27 15.3.2 Serious Adverse Events...................................................................... 27 15.4 Deaths, Other Serious Adverse Events, and Other Significant Adverse Events................................................................................... 28 15.4.1 Deaths................................................................................................. 28 15.5 Adverse Event of Special Interest...................................................... 28 15.5.1 AESI= Infections................................................................................ 28 15.5.2 AESI = Malignancies ......................................................................... 30 15.6 Handling of Missing or Partial AE Dates (onset, resolution date)..... 30 15.7 Clinical Laboratory Evaluation.......................................................... 30 15.8 Vital Signs.......................................................................................... 30 15.9 Other Safety or Tolerability Evaluations ........................................... 30 4/134 4/135 Cladribine Integrated Analysis Plan EMR700568-012 16 Analyses of Other Endpoints ............................................................. 31 17 References.......................................................................................... 31 18 Appendices......................................................................................... 32 18.1 Pregnancy and neonatal topics (SMQ 20000185).............................. 32 18.2 Adverse Events Related to Pregnancy ................................................. 1 18.3 AESI: Opportunistic Infections............................................................ 1 18.4 AESI Herpes Zoster ............................................................................. 3 18.5 Malignant or Unspecified Tumours (SMQ 20000091)........................ 4 18.6 AESI: Malignancies ............................................................................. 1 Table of Contents of Table Table 1 Changes from the planned analyses in the clinical study protocol .... 10 Table 2 Table header example ........................................................................ 13 Table 3 Identification