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SOP Cl01b V1.2 CLINICAL TRIAL PROTOCOL A Phase 1, Single-Blind, Randomized, Placebo Controlled, Parallel-Group, Multiple-Dose-Escalation Study to Investigate Safety, Tolerability, and Pharmacokinetics of Emodepside (BAY 44-4400) After Oral Dosing in Healthy Male Subjects Short title Safety, tolerability and PK of multiple-ascending doses of emodepside Name of product(s) Emodepside (BAY 44-4400) Drug Class Anthelmintic cyclooctadepsipeptide Phase 1 Indication Treatment of onchocerciasis (river blindness) and potentially other filarial diseases including lymphatic filariasis Clinical Trial Protocol DNDI-EMO-02 Number EudraCT 2017-003020-75 Sponsor DNDi, Chemin Louis Dunant, 15, 1202 Geneva, Switzerland Phone : +41 22 906 9230 Global/National Dr Jeremy Dennison, Hammersmith Medicines Research, Coordinating Cumberland Avenue, London, NW10 7EW, Investigator/Principal United Kingdom Investigator Phone : +4420 8961 4130 Clinical Trial Protocol Version 5, 25 July 2018 Version / Date Protocol Amendment Amendment 4 Number / Date The information contained in this document is confidential. It is to be used by Investigators, potential Investigators, consultants, or applicable independent ethics committees. It is understood that this information will not be disclosed to others without written authorisation from DNDi, except where required by applicable local laws Confidential Page 1 of 84 Protocol template_Version 1.2_24 April 2014 Protocol number (DNDI-EMO-02) Emodepside (BAY 44-4400) Protocol Version/Date: Version 5, 25 July 2018 CONTACT DETAILS Principal Investigator: Dr Jeremy Dennison, Senior Research Physician and Principal Investigator Hammersmith Medicines Research Limited Cumberland Avenue, London, NW10 7EW, United Kingdom Investigator Site 24-Hour Medical Contact: On-call physician tel: +44 7930 323 244 Co-Investigators: (See Study Procedures Manual) Name and address of Monitor (if other than the Sponsor) Karen Chalk Niche Science & Technology Unit 26, Falstaff House, Bardolph Road, Richmond TW9 2LH, United Kingdom Tel.: +44 20 8332 2588 Mobile: +44 (0)7872 970103 Name, title, address, and telephone number(s) of the Sponsor's medical expert for the trial (24 hours) Nathalie Strub-Wourgaft MD, Medical Director, 15 Chemin Louis Dunant, 1202 Geneva, Switzerland Switchboard: +41 22 906 92 30 Mobile: +41 79 874 05 39 Name, Title, Address, and Telephone Number(s) of the Sponsor's Clinical Project Manager for the Trial Sophie Delhomme, Translation Manager, 15 Chemin Louis Dunant, 1202 Geneva, Switzerland Switchboard: +41 22 906 92 30 Direct: +41 22 9026 92 79 Name, Title, Address, and Telephone Number(s) of other Sponsor Representatives Frédéric Monnot PharmD, Acting Head of Filariasis, 15 Chemin Louis Dunant, 1202 Geneva, Switzerland Switchboard: +41 22 906 92 30 Confidential Page 2 of 84 Clinical Trial Protocol template_Version 1.2_02 June 2014 Protocol number (DNDI-EMO-02) Emodepside (BAY 44-4400) Protocol Version/Date: Version 5, 25 July 2018 Jean-Yves Gillon PharmD, PhD, Head of Translational Sciences, 15 Chemin Louis Dunant, 1202 Geneva, Switzerland Switchboard: +41 22 906 92 30 Name(s) and address(es) of the clinical laboratory(ies) and other medical and/or technical department(s) and/or Institutions involved in the trial (See Study Procedures Manual) Phase 1 Unit Hammersmith Medicines Research Limited Cumberland Avenue, London, NW10 7EW, United Kingdom Switchboard: +44 20 8961 4130 Clinical Laboratory The HMR Analytical Laboratory Cumberland Avenue, London, NW10 7EW, United Kingdom Switchboard: +44 20 8961 4130 Bioanalytic Laboratory Analytical Services International Ltd St. George’s, University of London, Cranmer Terrace, London, SW17 0RE, United Kingdom Switchboard: +44 20 8725 2845 Ophthalmology Clinic (See Study Procedures Manual) Metabolite Analysis Swiss BioQuant AG Rägenstrasse 18, 4153 Reinach, Switzerland Switchboard: +41 61 716 98 16 or 12 Confidential Page 3 of 84 Clinical Trial Protocol template_Version 1.2_02 June 2014 Protocol number (DNDI-EMO-02) Emodepside (BAY 44-4400) Protocol Version/Date: Version 5, 25 July 2018 TABLE OF CONTENTS TABLE OF CONTENTS ............................................................................................. 7 ABBREVIATIONS – GLOSSARY OF TERMS ........................................................ 11 PROTOCOL SUMMARY .......................................................................................... 14 1. BACKGROUND AND STUDY RATIONALE ................................................. 22 1.1. BACKGROUND INFORMATION .................................................................. 22 1.2. RATIONALE FOR THE DEVELOPMENT OF EMODEPSIDE ...................... 24 1.3. SUMMARY OF NON-CLINICAL INFORMATION ......................................... 24 1.4. SUMMARY OF CLINICAL HUMAN DATA ................................................... 28 1.5. ASSESSMENT AND MANAGEMENT OF RISK ........................................... 31 2. STUDY OBJECTIVES AND ENDPOINTS .................................................... 31 2.1. Objectives ............................................................................................................................... 31 2.1.1. Primary Objective ................................................................................................................... 31 2.1.2. Secondary Objectives ............................................................................................................ 32 2.2. Study Endpoints ..................................................................................................................... 32 2.2.1. Primary Safety Endpoint(s) ................................................................................................... 32 2.2.2. Other Safety Endpoint(s) ...................................................................................................... 32 2.2.3. Secondary Endpoint(s) .......................................................................................................... 33 2.3. Exploratory PK variables ....................................................................................................... 33 3. STUDY DESIGN AND STUDY DESIGN RATIONALE .................................. 33 3.1. Study design ........................................................................................................................... 33 3.2. Study duration and duration of subject participation ........................................................ 34 3.3. Definition of the end of trial ................................................................................................... 34 3.4. Rationale of study design ...................................................................................................... 34 4. SELECTION OF SUBJECTS ........................................................................ 35 4.1. Inclusion criteria ..................................................................................................................... 35 4.2. Exclusion criteria .................................................................................................................... 36 4.3. Dietary and lifestyle guidance ............................................................................................... 38 5. SCHEDULE OF EVENTS .............................................................................. 40 5.1. TABLE 2: SCHEDULE OF EVENTS OVERVIEW........................................ 40 5.2. Table 3: Schedule of events expanded view: pre-dosing period .................................... 44 5.3. Table 4: Schedule of events expanded view: first dosing day ........................................ 44 5.4. Table 5: Schedule of events expanded view: last dosing day ......................................... 45 6. ENROLMENT PROCEDURES ...................................................................... 46 7. STUDY TREATMENTS ................................................................................. 46 7.1. Doses and treatment regimens ............................................................................................. 46 7.2. Emodepside study treatment ................................................................................................ 47 7.3. Placebo study treatment ........................................................................................................ 47 Confidential Page 7 of 84 Clinical Trial Protocol template_Version 1.2_02 June 2014 Protocol number (DNDI-EMO-02) Emodepside (BAY 44-4400) Protocol Version/Date: Version 5, 25 July 2018 7.4. IMP supply and handling ....................................................................................................... 48 7.5. Dose escalation ...................................................................................................................... 48 7.6. Study stopping criteria .......................................................................................................... 48 7.6.1. Dose escalation stopping criteria ......................................................................................... 48 7.6.2. Trial stopping criteria ............................................................................................................. 49 7.7. Study treatment labelling, packaging ................................................................................... 49 7.8. Accountability ......................................................................................................................... 49 7.9. Storage
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