Company substance code: 280922 EMR700568-012 Cladribine Observational Study Protocol Study Protocol Number EMR700568-012 Title Prospective observational long-term safety registry of Multiple Sclerosis patients who have participated in cladribine clinical trials (PREMIERE). EudraCT Number 2009-017978-21 Sponsor In USA EMD Serono, Inc. An affiliate of Merck KGaA, Darmstadt, Germany One Technology Place, Rockland, MA02370 Phone: +1 781 982 9000 Fax: +1 781 681 2902 In Rest of The World Merck Serono SA – Geneva An affiliate of Merck KGaA, Darmstadt, Germany 29 quai des Bergues 1201 Geneva / Switzerland Medical Responsible PPD EMD Serono Research & Development Institute, Inc. A subsidiary of Merck KGaA, Darmstadt, Germany 45A Middlesex Turnpike Billerica MA 01821, USA Phone: PPD E-mail: PPD Sponsor’s Legal Representative Merck KGaA, Frankfurter Strasse 250, 64293 (EU) Darmstadt, Germany Study Protocol Version 20 July 2016 /Version 4.0 including amendment No. 2 'RFXPHQW1RCCI 1/51 2EMHFW1RCCI Company substance code: 280922 EMR700568-012 Cladribine Replaces Study Protocol Version Version 3.0; 23 July 2012 Current Protocol Amendment Amendment No. 2 (Global), 20 July 2016 This document is the property of Merck KGaA, Darmstadt, Germany, or one of its subsidiaries. It is intended for restricted use only and may not – in full or part – be passed on, reproduced, published or used without express permission of Merck KGaA, Darmstadt, Germany, or its affiliate. Copyright © 2016 by Merck KGaA, Darmstadt, Germany, or its subsidiary. All rights reserved 'RFXPHQW1RCCI 2/51 2EMHFW1RCCI Company substance code: 280922 EMR700568-012 Cladribine SIGNATURE PAGE Protocol Lead responsible for designing the study: I approve the design of the study. Signature Date of Signature PPD EMD Serono Research & Development Institute, Inc. A subsidiary of Merck KGaA, Darmstadt, Germany 45A Middlesex Turnpike Billerica MA 01821, USA Phone: PPD E-mail: PPD 'RFXPHQW1RCCI 3/51 2EMHFW1RCCI Company substance code: 280922 EMR700568-012 Cladribine PRINCIPAL REGISTRY PHYSICIAN SIGNATURE Study Title: Prospective observational long-term safety registry of Multiple Sclerosis patients who have participated in cladribine clinical trials (PREMIERE). Protocol Version/Date: Version 4.0 including amendment 2 / 20 July 2016 Center Number: Principal Registry Physician’s site number in the registry Principal Registry Physician: Principal Registry Physician’s full name, title and academic degree (e.g., Associate Professor, M.D., M.Sc., Prof. Dr. med., etc.) I, the undersigned, am responsible for the conduct of the registry at this site and affirm that ! I understand and will conduct the registry according to the protocol, any approved protocol amendments, Good Pharmacoepidemiology Practices (GPP) [1], Good Clinical Practice [2] and all applicable Regulatory Authority requirements and national laws. ! I will not deviate from the protocol without prior written permission from the Sponsor and prior review and written approval from the Institutional Review Board or Independent Ethics Committee, except where necessary to prevent immediate danger to a subject. Signature Date of Signature Insert Name, academic qualifications Insert Position (job title) Insert Address of Institution Insert Phone, fax, e-mail Each Principal Registry Physician (PRP) will sign a copy of this page. The original signed signature sheets will be filed in the Registry Master File. 'RFXPHQW1RCCI 4/51 2EMHFW1RCCI Company substance code: 280922 EMR700568-012 Cladribine Further Sponsor Responsible Persons PPD EMD Serono Research & Development Institute, Inc. A subsidiary of Merck KGaA, Darmstadt, Germany 45A Middlesex Turnpike Billerica, MA 01821, USA Phone: PPD Email: PPD PPD EMD Serono Research & Development Institute, Inc. A subsidiary of Merck KGaA, Darmstadt, Germany One Technology Place Rockland, MA02370, USA Phone: PPD E-mail address: PPD 'RFXPHQW1RCCI 5/51 2EMHFW1RCCI Company substance code: 280922 EMR700568-012 Cladribine Table of contents Table of contents ..............................................................................................................6 Table of Figures ..............................................................................................................8 List of Abbreviations ...........................................................................................................9 1 Synopsis..............................................................................................11 2 Sponsor, registry physicians and Study Administrative Structure .....14 3 Background Information.....................................................................15 4 Study Objectives.................................................................................17 5 Study design........................................................................................18 5.1 Study Population.................................................................................18 5.2 Study Enrollment................................................................................18 5.2.1 Physician Enrollment..........................................................................18 5.2.2 Subject Enrollment .............................................................................19 5.3 Inclusion Criteria ................................................................................19 5.4 Exclusion Criteria ...............................................................................19 5.5 Study Region/Location .......................................................................20 5.6 Study Cohort.......................................................................................20 5.7 Follow-up and Study Duration ...........................................................20 5.7.1 Study Termination ..............................................................................21 5.7.2 Lost to Follow-up ...............................................................................21 6 Study Endpoints..................................................................................21 6.1 Primary Endpoints ..............................................................................21 6.2 Secondary Endpoint............................................................................22 6.3 Definitions related to study Endpoints ...............................................22 7 Assessment of Medication Exposure..................................................24 7.1 Prior Exposure to Cladribine ..............................................................24 8 Data sources and Study Procedures....................................................24 8.1 Data Sources .......................................................................................25 8.2 Schedule of Interviews and Subject Questionnaires...........................26 8.3 Baseline Subject Demographic and Other Characteristics .................26 8.3.1 Registry Baseline Data Elements........................................................27 8.3.1.1 Information from registry enrollment interview.................................27 'RFXPHQW1RCCI 6/51 2EMHFW1RCCI Company substance code: 280922 EMR700568-012 Cladribine 8.3.1.2 Information from medical health records review ...............................27 8.3.1.3 Data elements from the clinical trial database....................................27 8.3.1.4 Interviews at pregnancy baseline and offspring baseline ...................28 8.4 Follow-Up Interviews.........................................................................29 8.5 Reporting of Adverse events ..............................................................30 8.5.1 Definitions ..........................................................................................31 8.5.1.1 Adverse Events ...................................................................................31 8.5.1.2 Adverse Drug Reaction.......................................................................31 8.5.1.3 Serious Adverse Events ......................................................................31 8.5.1.4 Serious Adverse Drug Reaction..........................................................32 8.5.1.5 Definition of the Adverse Event Reporting Period.............................33 8.5.2 Recording of Adverse Events in the CRF (Methods of Recording and Assessing Adverse Events)..........................................................33 8.5.3 Procedure for Reporting Serious Adverse Events ..............................34 8.5.3.1 Pregnancy and In Utero Drug Exposure.............................................34 8.5.4 Safety Reporting to Regulatory Authorities, Investigators and Independent Ethics Committees/Institutional Review Boards ...........35 9 Data Analysis and Statistics................................................................36 9.1 Registry size........................................................................................36 9.2 Data analysis.......................................................................................36 9.2.1 General Considerations.......................................................................36 9.2.2 Treatment/Analysis Period .................................................................37 9.3 Study Reporting and Analysis ............................................................37 9.3.1 Missing Data.......................................................................................38 10 Ethical, Scientific and Regulatory Aspects ........................................38