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Evobrutinib Phase IIb in Rheumatoid Arthritis MS200527-0060 Clinical Trial Protocol Clinical Trial Protocol Number MS200527-0060 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 Phase IIb IND Number CCI EudraCT Number 2017-000384-32 Coordinating Investigator PPD Sponsor For all countries except the USA and Japan: Merck KGaA, Frankfurter Str. 250 64293 Darmstadt, Germany For Japan only: Merck Serono Co., Ltd. (Affiliate of Merck KGaA, Darmstadt, Germany) Arco Tower, 1-8-1 Shimomeguro Meguro-ku, Tokyo 153-8926, Japan And For the USA EMD Serono Research & Development Institute, Inc. 45A Middlesex Turnpike Billerica, MA 01821 USA Medical Responsible: PPD EMD Serono Research & Development Institute 45A Middlesex Turnpike, Billerica, MA 01821, USA Telephone: PPD 'RFXPHQW1RCCI 1/130 2EMHFW1RCCI Evobrutinib Phase IIb in Rheumatoid Arthritis MS200527-0060 Clinical Trial Protocol Version 12 July 2018/Version 3.0 (Amendment 4) Replaces Version 13 December 2017/Version 2.0 'RFXPHQW1RCCI 2/130 2EMHFW1RCCI Evobrutinib Phase IIb in Rheumatoid Arthritis MS200527-0060 Protocol Amendment Summary of Changes Protocol History Version Number Type Version Date 1.0 Original Protocol 11 May 2017 1.1 Amendment specific for US 03 July 2017 2.0 Global Amendment 13 December 2017 2.1 Amendment specific for US 16 November 2017 3.0 Global Amendment 12 July 2018 Protocol Version [3.0] (12-July-2018) This amendment is nonsubstantial based on the criteria in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European Union because it neither significantly impacts the safety or physical/mental integrity of participants nor the scientific value of the study. After receiving feedback from multiple regulatory agencies, the Sponsor has decided not to initiate the Open-label Extension (OLE) Period. Section # and Description of Change Brief Rationale Name Throughout All mention of OLE and related Implementing Sponsor decision to not initiate the procedures, objectives, and duration OLE Period estimates were removed Synopsis Removed Table 2 and Table 3 No longer required given Sponsor decision to not initiate the OLE Period 8.6. Planned Removed 12-week analysis and moved Without the OLE, there is no need to run an Analysis consistency analysis to be part of the interim analysis before the final analysis final analysis Synopsis Added text to explain removal of OLE Give guidance for subjects who enroll in the OLE Period and provide procedure for Period prior to implementation of Protocol Version subjects already in the OLE Period 3.0. 7.1.3. Open- Added text to explain removal of OLE Give guidance for subjects who enroll in the OLE label Extension Period and provide procedure for Period prior to implementation of Protocol version Period subjects already in the OLE Period 3.0. 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 subsidiary. Copyright © 2018 by Merck KGaA, Darmstadt, Germany, or its subsidiary. All rights reserved. 'RFXPHQW1RCCI 3/130 2EMHFW1RCCI Evobrutinib Phase IIb in Rheumatoid Arthritis MS200527-0060 Protocol Table of Contents Protocol Amendment Summary of Changes........................................................................3 Protocol History ..............................................................................................................3 Protocol Version [3.0] (12-July-2018).................................................................................3 Protocol Table of Contents ..................................................................................................4 Table of In-Text Tables .......................................................................................................8 Table of In-Text Figures ......................................................................................................8 List of Abbreviations .........................................................................................................10 1 Synopsis..............................................................................................14 2 Sponsor, Investigators and Trial Administrative Structure ................30 3 Background Information.....................................................................31 3.1 Rheumatoid Arthritis ..........................................................................31 3.2 Evobrutinib .........................................................................................31 CCI 3.4 Risk/Benefit ........................................................................................34 4 Trial Objectives ..................................................................................35 4.1 Primary Objective...............................................................................35 4.2 Key Secondary Objective ...................................................................35 4.3 Other Secondary Objectives ...............................................................36 CCI 5 Investigational Plan ............................................................................36 5.1 Overall Trial Design and Plan ............................................................36 5.2 Discussion of Trial Design .................................................................40 5.2.1 Scientific Rationale for the Trial ........................................................40 CCI 5.2.3 Rationale for Endpoints ......................................................................45 5.2.4 Inclusion of Special Populations ........................................................52 5.3 Selection of Trial Population..............................................................52 5.3.1 Inclusion Criteria ................................................................................53 5.3.2 Exclusion Criteria ...............................................................................55 5.4 Criteria for Randomization and Initiation of Trial Treatment............60 5.5 Criteria for Subject Withdrawal..........................................................61 'RFXPHQW1RCCI 4/130 2EMHFW1RCCI Evobrutinib Phase IIb in Rheumatoid Arthritis MS200527-0060 5.5.1 Withdrawal from Trial Therapy..........................................................61 5.5.2 Withdrawal from the Trial..................................................................64 5.6 Premature Termination of the Trial ....................................................64 5.7 Definition of End of Trial...................................................................65 6 Investigational Medicinal Product and Other Drugs Used in the Trial.....................................................................................................65 6.1 Description of the Investigational Medicinal Product........................65 6.2 Dosage and Administration ................................................................66 6.3 Assignment to Treatment Groups.......................................................66 6.4 Noninvestigational Medicinal Products to be Used............................67 6.5 Concomitant Medications and Therapies ...........................................67 6.5.1 Permitted Medicines ...........................................................................67 6.5.2 Prohibited Medicines..........................................................................68 6.5.3 Other Interventions .............................................................................70 CCI 6.6 Packaging and Labeling of the Investigational Medicinal Product....71 6.7 Preparation, Handling, and Storage of the Investigational Medicinal Product...............................................................................72 6.8 Investigational Medicinal Product Accountability .............................72 6.9 Assessment of Investigational Medicinal Product Compliance .........73 6.10 Blinding ..............................................................................................73 6.11 Emergency Unblinding.......................................................................74 6.12 Treatment of Overdose .......................................................................74 6.13 Medical Care of Subjects after End of Trial.......................................75 7 Trial Procedures and Assessments......................................................75 7.1 Schedule of Assessments....................................................................75 7.1.1 Screening Period.................................................................................76 7.1.2 Treatment Period ................................................................................76 7.1.3 Open-label Extension Period (Only Applicable Prior to Protocol Version 3.0) ........................................................................................76 7.1.4 Safety Follow-up Visit........................................................................77 'RFXPHQW1RCCI 5/130 2EMHFW1RCCI Evobrutinib Phase IIb in Rheumatoid Arthritis MS200527-0060 7.2 Demographic and Other Baseline Characteristics ..............................77 7.2.1 Demography .......................................................................................77
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