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Ponesimod / ACT-128800 Chronic Graft Versus Host Disease Protocol AC-058C202

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Ponesimod / ACT-128800 Chronic Graft Versus Host Disease Protocol AC-058C202 Ponesimod / ACT-128800 Chronic Graft versus Host Disease Protocol AC-058C202 A Phase 2, open-label, single-arm, intra-subject dose-escalation study to investigate the biological activity, safety, tolerability, and pharmacokinetics of ponesimod in subjects with symptomatic moderate or severe chronic GVHD inadequately responding to first or second line therapy Study Phase: 2 NCT Number: NCT02461134 Date: 5 July 2016 Version and History: Final Version 4 Amendment 2, Final Version 3, 21 May 2015 Amendment 1, Final Version 2, 28 January 2015 Final Version 1, 16 December 2014 Confidentiality statement Property of Actelion Pharmaceuticals Ltd. May not be used, divulged, published or otherwise disclosed without the consent of Actelion Pharmaceuticals Ltd. Ponesimod / ACT-128800 Doc No D-16.301 Chronic GVHD Protocol AC-058C202 Confidential Version 4 5 July 2016, page 2/217 SPONSOR CONTACT DETAILS SPONSOR ACTELION Pharmaceuticals Ltd Gewerbestrasse 16 CH-4123 Allschwil Switzerland Clinical Trial Physician Daniele D’Ambrosio, MD, PhD Fax e-mail MEDICAL HOTLINE 1 (800) 540-5687 (USA) Toll phone number: + 41 61 227 05 63 (Switzerland) Site-specific toll telephone numbers and toll-free numbers for the Medical Hotline can be found in the Investigator Site File. ACTELION CONTRIBUTORS TO THE PROTOCOL Clinical Trial Scientist Clinical Science Program Head Daniele D’Ambrosio, MD, PhD Clinical Trial Statistician Clinical Project Statistician Drug Safety Physician NATIONAL PRIMARY INVESTIGATORS National Institutes of Health Ponesimod / ACT-128800 Doc No D-16.301 Chronic GVHD Protocol AC-058C202 Confidential Version 4 5 July 2016, page 3/217 CONTRACT RESEARCH ORGANIZATIONS INFORMATION CENTRAL LABORATORY CENTRAL ENROLLMENT A list of site-specific contact details for CROs can be found in the Investigator Site File. Ponesimod / ACT-128800 Doc No D-16.301 Chronic GVHD Protocol AC-058C202 Confidential Version 4 5 July 2016, page 4/217 SIGNATURE PAGE FOR ACTELION PHARMACEUTICALS LTD Hereinafter called Actelion Treatment name / number Ponesimod / ACT-128800 Indication Chronic graft versus host disease Protocol number, study title AC-058C202, A Phase 2, open-label, single-arm, intra-subject dose-escalation study to investigate the biological activity, safety, tolerability, and pharmacokinetics of ponesimod in subjects with symptomatic moderate or severe chronic GVHD inadequately responding to first or second line therapy I approve the design of this study. Ponesimod / ACT-128800 Doc No D-16.301 Chronic GVHD Protocol AC-058C202 Confidential Version 4 5 July 2016, page 5/217 INVESTIGATOR SIGNATURE PAGE Treatment name / number Ponesimod / ACT-128800 Indication Chronic graft versus host disease Protocol number, study title AC-058C202, A Phase 2, open-label, single-arm, intra-subject dose-escalation study to investigate the biological activity, safety, tolerability, and pharmacokinetics of ponesimod in subjects with symptomatic moderate or severe chronic GVHD inadequately responding to first or second line therapy 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 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 Site Principal Investigator Ponesimod / ACT-128800 Doc No D-16.301 Chronic GVHD Protocol AC-058C202 Confidential Version 4 5 July 2016, page 6/217 TABLE OF CONTENTS SPONSOR CONTACT DETAILS ......................................................................................2 ACTELION CONTRIBUTORS TO THE PROTOCOL .....................................................2 CONTRACT RESEARCH ORGANIZATIONS INFORMATION ...................................3 LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................16 SUBSTANTIAL GLOBAL AMENDMENT 3 .................................................................20 PROTOCOL SYNOPSIS AC-058C202 ............................................................................26 1 BACKGROUND .........................................................................................................54 1.1 Chronic graft versus host disease .................................................................54 1.1.1 Epidemiology ....................................................................................54 1.1.2 Pathogenesis ......................................................................................54 1.1.3 Current treatments .............................................................................55 1.1.4 Unmet medical need .........................................................................56 1.2 Sphingosine 1-phosphate receptors ..............................................................60 1.2.1 S1P and GVHD: preclinical evidence ..............................................60 1.3 Ponesimod, selective modulator of S1P1 ......................................................61 1.3.1 Nonclinical studies ............................................................................61 1.3.2 Clinical studies ..................................................................................62 1.3.2.1 Clinical pharmacology .................................................. 62 1.3.2.2 Pharmacodynamics in humans ...................................... 62 1.3.2.3 Efficacy in humans ........................................................ 63 1.3.2.4 Safety and tolerability ................................................... 64 1.4 Rationale and purpose of the study ...............................................................65 2 STUDY OBJECTIVES ...............................................................................................65 2.1 Main objectives .............................................................................................65 2.2 Exploratory objectives ..................................................................................66 3 OVERALL STUDY DESIGN AND PLAN ...............................................................66 3.1 Study design .................................................................................................66 3.2 Study periods ................................................................................................66 3.2.1 Screening Period ...............................................................................66 Ponesimod / ACT-128800 Doc No D-16.301 Chronic GVHD Protocol AC-058C202 Confidential Version 4 5 July 2016, page 7/217 3.2.2 Core Treatment Period ......................................................................66 3.2.3 Core Safety Follow-up Period / Follow-up Period 1 ........................67 3.2.4 Extension Treatment Period ..............................................................67 3.2.5 Extension Safety Follow-up Period (Follow-up Period 2) ...............68 3.3 Study design rationale ..................................................................................68 3.4 Site personnel and their roles ........................................................................71 3.4.1 Principal investigator and sub-investigator .......................................71 3.4.2 Cardiac safety assessor .....................................................................71 3.4.3 Clinical coordinator / study nurse .....................................................72 3.4.4 Ophthalmologist ................................................................................72 3.4.5 Pulmonary function laboratory technician or expert ........................72 3.4.6 Pulmonologist ...................................................................................72 3.5 Study Committees .........................................................................................73 3.5.1 Study Monitoring Committee ...........................................................73 3.5.2 Ophthalmology Safety Board ...........................................................73 4 SUBJECT POPULATION ..........................................................................................73 4.1 Subject population description .....................................................................73
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