NCT02907177 Ponesimod / ACT-128800 Relapsing Multiple Sclerosis Protocol AC-058B302 POINT: POnesImod aNd Tecfidera Multicenter, randomized, double-blind, parallel-group, add-on, superiority study to compare the efficacy and safety of ponesimod to placebo in subjects with active relapsing multiple sclerosis who are treated with dimethyl fumarate (Tecfidera®) Study Phase: 3 EudraCT Number: 2012-000541-12 Status and version: Final Version 6 Date: 21 December 2017 Actelion document number D-17.622 (Doc No.): Confidentiality statement The information contained in this document, especially unpublished data, is the property of the sponsor of this study, Actelion Pharmaceuticals Ltd. It is therefore provided to you in confidence as an investigator, potential investigator, or consultant, for review by you, your staff, and an Ethics Committee or Institutional Review Board. It is understood that this information will not be disclosed to others without written authorization from Actelion Pharmaceuticals Ltd, except to the extent necessary to obtain informed consent from those persons to whom the study treatment may be administered. TPL-000052_v10 Ponesimod / ACT-128800 EudraCT 2012-000541-12 Relapsing multiple sclerosis Doc No D-17.622 Protocol AC-058B302, POINT Confidential Version 6 21 December 2017, page 2/330 SPONSOR CONTACT DETAILS SPONSOR ACTELION Pharmaceuticals Ltd Gewerbestrasse 16 CH-4123 Allschwil Switzerland +41 61 565 65 65 Clinical Trial Physician Contact details of the Clinical Trial Physician can be found in the Investigator Site File MEDICAL HOTLINE Site-specific toll telephone numbers and toll-free Toll phone number: [number] numbers for the Medical Hotline can be found in the Investigator Site File ACTELION CONTRIBUTORS TO THE PROTOCOL Clinical Trial Scientist PPD , MSc Clinical Project Scientist PPD PhD Clinical Science Program Head PPD , MD, PhD Clinical Trial Statistician PPD . (FH) Clinical Project Statistician PPD , MSc Clinical Trial Physician Ewa Lindenstrøm, MD, PhD Clinical Trial Pharmacologist PPD Drug Safety Physician PPD , MD Ponesimod / ACT-128800 EudraCT 2012-000541-12 Relapsing multiple sclerosis Doc No D-17.622 Protocol AC-058B302, POINT Confidential Version 6 21 December 2017, page 3/330 CONTRACT RESEARCH ORGANIZATIONS INFORMATION CENTRAL LABORATORY Covance, Inc. 8211 SciCor Drive Indianapolis, IN USA 46214 Covance, Inc. 7 rue Marcinhes Geneva Meyrin Switzerland 1217 Covance, Inc. 1 International Business Park #01-01 The Synergy Singapore 609917 CENTRAL PK ANALYSIS PRA Health Sciences - Early Development Services LABORATORY Bioanalytical Laboratory Amerikaweg 18 9407 TK Assen, The Netherlands CENTRAL Almac Clinical Technologies RANDOMIZATION 25 Fretz Road Souderton PA 18964 USA CENTRAL MRI READING MIAC Corporation c/o University Hospital Basel Mittlere-Strasse 83 CH 4031 Basel, Switzerland CENTRAL ECGs READING eResearch Technology GmbH Sieboldstr. 3 97230 Estenfeld, Germany ELECTRONIC DIARY eResearch technology GmBH Sieboldstr. 3 97230 Estenfeld, Germany A list of site-specific contact details for Contract Research Organizations (CROs) can be found in the Investigator Site File. Ponesimod / ACT-128800 EudraCT 2012-000541-12 Relapsing multiple sclerosis Doc No D-17.622 Protocol AC-058B302, POINT Confidential Version 6 21 December 2017, page 4/330 SIGNATURE PAGE FOR ACTELION PHARMACEUTICALS LTD Hereinafter called Actelion Treatment name / number Ponesimod / ACT-128800 Indication Relapsing multiple sclerosis Protocol number, study acronym, study title AC-058B302, POINT, Multicenter, randomized, double-blind, parallel-group, add-on, superiority study to compare the efficacy and safety of ponesimod to placebo in subjects with active relapsing multiple sclerosis who are treated with dimethyl fumarate (Tecfidera®) I approve the design of this study. TITLE NAME DATE SIGNATURE PPD Clinical Trial Ewa Lindenstrøm, Physician MD, PhD P Clinica P PPD PPD Project D Statistician PPD ,PPD PPD Ponesimod / ACT-128800 EudraCT 2012-000541-12 Relapsing multiple sclerosis Doc No D-17.622 Protocol AC-058B302, POINT Confidential Version 6 21 December 2017, page 5/330 INVESTIGATOR SIGNATURE PAGE Treatment name / number Ponesimod / ACT-128800 Indication Relapsing multiple sclerosis Protocol number, study acronym, study title AC-058B302, POINT, Multicenter, randomized, double-blind, parallel-group, add-on, superiority study to compare the efficacy and safety of ponesimod to placebo in subjects with active relapsing multiple sclerosis who are treated with dimethyl fumarate (Tecfidera®) I agree to the terms and conditions relating to this study as defined in this protocol, the electronic Case Report Form (CRF), and any other protocol-related documents. I fully understand that any changes instituted by the investigator(s) without previous agreement with the sponsor would constitute a protocol deviation, including any ancillary studies or procedures performed on study subjects (other than those procedures necessary for the wellbeing of the subjects). I agree to conduct this study in accordance with the Declaration of Helsinki principles, International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, and applicable regulations and laws. I will obtain approval by an Institutional Review Board or Independent Ethics Committee (IRB/IEC) prior to study start and signed informed consent from all subjects included in this study. If an amendment to the protocol is necessary, I will obtain approval by an IRB/IEC and ensure approval by regulatory authorities (if applicable) have been obtained before the implementation of changes described in the amendment. I will allow direct access to source documents and study facilities to sponsor representative(s), particularly monitor(s) and auditor(s), and agree to inspection by regulatory authorities or IRB/IEC representative. I will ensure that the study treatment(s) supplied by the sponsor are being used only as described in this protocol. I will ensure that all subjects or legally designated representatives have understood the nature, objectives, benefits, implications, risks and inconveniences for participating in this study. During the conduct of the study, I will constantly monitor the risk/benefit balance for an individual subject. I confirm herewith that the sponsor is allowed to enter and utilize my professional contact details and function in an electronic database for internal purposes and for submission to Health Authorities worldwide. Country Site Town Date Signature number Principal Investigator Ponesimod / ACT-128800 EudraCT 2012-000541-12 Relapsing multiple sclerosis Doc No D-17.622 Protocol AC-058B302, POINT Confidential Version 6 21 December 2017, page 6/330 TABLE OF CONTENTS ACTELION CONTRIBUTORS TO THE PROTOCOL.....................................................2 CONTRACT RESEARCH ORGANIZATIONS INFORMATION ...................................3 LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................17 SUBSTANTIAL GLOBAL AMENDMENT 5.................................................................22 PROTOCOL SYNOPSIS AC-058B302............................................................................32 1 BACKGROUND.........................................................................................................60 1.1 Multiple sclerosis..........................................................................................60 1.1.1 Pathogenesis......................................................................................60 1.1.2 Clinical course ..................................................................................60 1.1.3 Epidemiology....................................................................................62 1.1.4 Treatment of MS...............................................................................62 1.1.4.1 Injectable disease-modifying therapies ...................................63 1.1.4.2 Orally administered disease-modifying therapies ...................63 1.1.4.3 Unmet need in relapsing multiple sclerosis.............................63 1.2 Sphingosine-1-phosphate receptors..............................................................64 1.3 Ponesimod ....................................................................................................65 1.3.1 Nonclinical studies............................................................................65 1.3.1.1 Efficacy of combined dimethyl fumarate and ponesimod in rats .......................................................................................66 1.3.1.2 Combination toxicity study of combined dimethyl fumarate and ponesimod in beagle dogs .................................67 1.3.2 Clinical studies..................................................................................67 1.3.2.1 Clinical pharmacology ............................................................68 1.3.2.2 Pharmacodynamics in humans ................................................68 1.3.2.3 Efficacy in humans..................................................................69 1.3.2.4 Safety and tolerability .............................................................70 1.3.3 Background treatment.......................................................................71 1.4 Purpose and rationale of the study................................................................71 1.5 Summary of known and potential risks and benefits....................................72 2 STUDY OBJECTIVES ...............................................................................................75