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Statistical Analysis Plan Evobrutinib Phase IIb in Rheumatoid Arthritis MS200527-0060 14 October 2019 / Version 2.0 Integrated Analysis Plan Clinical Trial Protocol MS200527-0060 Identification No. Title: A Phase IIb, Randomized, Double-blind Study in Subjects with Rheumatoid Arthritis Evaluating the Safety and Efficacy of Evobrutinib Compared with Placebo in Subjects with an Inadequate Response to Methotrexate Trial Phase IIb Investigational Medicinal Evobrutinib Product(s) Clinical Trial Protocol 12 July 2018/Version 3.0 Version 16 November 2017/Version 2.1 (for US only) Coordinating Author Integrated Analysis Plan PPD , Merck KGaA / EMD Serono Research & Development Authors Institute, Inc. Function Author(s) / Data Analyst(s) PPD PPD PPD PPD PPD , EMD Serono PPD Research & Development Institute, Inc. Integrated Analysis Plan 14 October 2019 / Version 2.0 Date and Version 'RFXPHQW1RCCI 1/130 2EMHFW1RCCI Evobrutinib Phase IIb in Rheumatoid Arthritis MS200527-0060 14 October 2019 / Version 2.0 Integrated Analysis Plan Merck KGaA / EMD Serono Research & Development Institute, Reviewers Inc. Reviewers: Function Name PPD PPD PPD PPD PPD PPD PPD PPD PPD PPD PPD PPD PPD PPD PPD PPD PPD PPD PPD PPD PPD PPD PPD PPD PPD PPD PPD PPD PPD Reviewers: Function Name PPD PPD PPD PPD PPD PPD PPD PPD PPD PPD PPD PPD This document is the property of Merck KGaA, Darmstadt, Germany, or one of its affiliated companies. 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 © 2019 by Merck KGaA, Darmstadt, Germany or its affiliate. All rights reserved. 'RFXPHQW1RCCI 2/130 2EMHFW1RCCI Evobrutinib Phase IIb in Rheumatoid Arthritis MS200527-0060 14 October 2019 / Version 2.0 Signature Page Integrated Analysis Plan: MS200527-0060 A Phase IIb, Randomized, Double-blind Study in Subjects with Rheumatoid Arthritis Evaluating the Safety and Efficacy of Evobrutinib Compared with Placebo in Subjects with an Inadequate Response to Methotrexate Approval of the IAP by Merck KGaA / EMD Serono Research & Development Institute, Inc. Responsible is documented within CARA. Wet ink signature outside CARA – for PPD use only. Merck KGaA / EMD Serono Research & Date Signature Development Institute, Inc. responsible PPD PPD responsible Date Signature PPD 'RFXPHQW1RCCI 3/130 2EMHFW1RCCI Evobrutinib Phase IIb in Rheumatoid Arthritis MS200527-0060 14 October 2019 / Version 2.0 1 Table of Contents Integrated Analysis Plan ......................................................................................................1 Signature Page ..............................................................................................................3 1 Table of Contents..................................................................................4 2 List of Abbreviations and Definition of Terms ....................................9 3 Modification History ..........................................................................13 4 Purpose of the Integrated Analysis Plan.............................................14 5 Objectives and Endpoints ...................................................................15 6 Overview of Planned Analyses...........................................................19 6.1 Independent Data Monitoring Committee review ..............................19 6.2 Final Analysis .....................................................................................19 7 Changes to the Planned Analyses in the Clinical Trial Protocol........20 8 Protocol Deviations and Analysis Sets...............................................21 8.1 Definition of Protocol Deviations and Analysis Sets .........................21 8.2 Definition of Analysis Sets and Subgroups ........................................21 8.2.1 Sample Size ........................................................................................21 8.2.2 Analysis Sets.......................................................................................21 8.2.3 Subgroup Analysis..............................................................................23 9 General Specifications for Data Analyses ..........................................24 9.1 Actual Treatment Assignment ............................................................24 9.2 Presentation of Tables/Listings/Figures (TLFs) .................................24 9.3 Data handling for the planned analyses ..............................................24 9.4 Presentation of continuous and qualitative variables..........................25 9.5 Definition of baseline .........................................................................26 9.6 Other Specifications............................................................................26 10 Trial Subjects......................................................................................29 10.1 Disposition of Subjects and Discontinuations ....................................29 10.2 Protocol Deviations ............................................................................30 10.2.1 Important Protocol Deviations............................................................31 10.2.2 Clinically Important Protocol Deviations...........................................31 11 Demographics and Other Baseline Characteristics.............................32 11.1 Demographics.....................................................................................32 'RFXPHQW1RCCI 4/130 2EMHFW1RCCI Evobrutinib Phase IIb in Rheumatoid Arthritis MS200527-0060 14 October 2019 / Version 2.0 11.2 Medical History ..................................................................................33 11.3 Other Baseline Characteristics............................................................33 11.3.1 Disease History...................................................................................33 11.3.2 Other ...................................................................................................35 12 Previous or Concomitant Medications/Procedures.............................36 13 Treatment Compliance and Exposure.................................................39 13.1 Exposure .............................................................................................39 13.2 Compliance.........................................................................................42 14 Endpoint Evaluation ...........................................................................44 14.1 Primary Endpoint: ACR20 Response Rate at Week 12......................44 14.2 Secondary Endpoints ..........................................................................53 14.2.1 Key Secondary Endpoints at Week 12 ...............................................53 14.2.2 Other Secondary Endpoints at Week 12.............................................54 14.2.3 Imaging Endpoints at Week 4 and Week 12 ......................................56 14.2.4 HRQoL Endpoints at Week 12...........................................................60 14.2.5 Exploratory Efficacy Endpoints at Week 12 ......................................62 14.3 Subgroup Analysis..............................................................................63 14.4 Open-label Extension..........................................................................65 15 Safety Evaluation................................................................................66 15.1 Adverse Events ...................................................................................66 15.1.1 All Adverse Events.............................................................................67 15.2 Deaths, Other Serious Adverse Events, and Other Significant Adverse Events ...................................................................................70 15.2.1 Deaths .................................................................................................70 15.2.2 Serious Adverse Events ......................................................................70 15.3 Clinical Laboratory Evaluation...........................................................71 15.4 Vital Signs ..........................................................................................73 15.5 12-Lead Electrocardiogram (ECG).....................................................74 15.6 Physical Examination .........................................................................75 15.7 Pregnancy Test....................................................................................75 15.8 Serum IgG, IgA, IgM Levels..............................................................75 15.9 B (CD19+) Cell Count........................................................................76 'RFXPHQW1RCCI 5/130 2EMHFW1RCCI Evobrutinib Phase IIb in Rheumatoid Arthritis MS200527-0060 14 October 2019 / Version 2.0 15.10 Urinalysis Microscopic Evaluation.....................................................76 15.11 HBV DNA ..........................................................................................76 CCI 16 Analyses of Other Endpoints..............................................................77 CCI 17 References...........................................................................................81 18 Appendices .........................................................................................84 18.1 Definitions of Efficacy Endpoints ......................................................84 18.2 HAQ-DI Scoring.................................................................................88
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