Confidential Clinical Trial Protocol A Drug Interaction Study to Assess the Pharmacokinetics of Narlaprevir and Antiretroviral Drugs Product / formulation: Narlaprevir (J05013, Arlansa ), 100 mg tablets Indication: Treatment of HCV Sponsor: R-Pharm JSC, Russia Legal address: 19 build. 1, Berzarina str., 123154, Moscow, Russia Mailing address: 111 Б, Leninsky prosp. 119421, Moscow, Russia Protocol Number: CJ05013019 Phase: Phase I Version of protocol: Version 8.0 (Incorporated Amendment #5) Date: 20 February 2017 Confidentiality Statement This document is a confidential communication of R-Pharm JSC. Acceptance of this document constitutes the agreement by the recipient that no unpublished information contained within will be published or disclosed without prior written approval, except that this document may be disclosed to the appropriate ethics committee and regulatory authority under the condition that they are requested to keep it confidential. Protocol CJ05013019, Version 8.0 dated 20 Feb 2017 Page 1 of 83 Confidential 1 ADMINISTRATIVE INFORMATION 1.1 Protocol approval and signatures Hereby I confirm that the Protocol CJ05013019: “A Drug Interaction Study to Assess the Pharmacokinetics of Narlaprevir and Antiretroviral Drugs” is created in accordance with the following: • The ethical principles that have their origin in the Declaration of Helsinki. • International Conference on Harmonisation E6 Good Clinical Practice Consolidated Guideline. • All applicable laws and regulations, including, without limitation, data privacy laws, clinical trial disclosure laws, and regulations. Mikhail Samsonov, MD, PhD Chief Medical Officer, “R-Pharm” JSC _________________________ Date / Signature Emilia Krasavina, MD Scientific Advisor “R-Pharm” JSC _________________________ Date / Signature Protocol CJ05013019, Version 8.0 dated 20 Feb 2017 Page 2 of 83 Confidential 1.2 Investigator Agreement This protocol СJ05013019 “A Drug Interaction Study to Assess the Pharmacokinetics of Narlaprevir and Antiretroviral Drugs” is a confidential communication of R Pharm. I confirm that I have read this protocol, I understand it, and I will work according to this protocol. I will also work consistently with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with GCPs and the applicable laws and regulations. Acceptance of this document constitutes my agreement that no unpublished information contained herein will be published or disclosed without prior written approval from R Pharm. I have read this protocol in its entirety and agree to conduct the study accordingly: Investigator name: _________________________________ Date / Signature Center name and address Protocol CJ05013019, Version 8.0 dated 20 Feb 2017 Page 3 of 83 Confidential 1.3 Trial contact list 1) Sponsor: R-Pharm JSC Legal address: 19/1, Berzarina str., 123154, Moscow, Russia Mailing address: 111 Б, Leninsky prosp. 119421, Moscow, Russia Office phone: +7 (495) 956-79-37 Office fax: +7 (495) 956-79-38 2) Scientific Advisor (R-Pharm JSC) Name: Emilia Krasavina Address: 111 Б, Leninsky prosp. 119421, Moscow, Russia Office phone: +7 (495) 956-79-37 Office fax: +7 (495) 956-79-38 Email: [email protected] 3) Almedis LLC Address: 5, Malaya Pirogovskaya str., office 22 119435 Moscow, Russia Office phone: +7 495 937 43 18 Office fax: +7 495 937 43 19 Email: [email protected] 4) Central PK laboratory (ChromSystemsLab ) Name: LLC Chromatography Systems Laboratory Address: 117485 Russia, Moscow, Butlerova St,, 12 Office phone: +7-495-510-43-51 Office fax: Email: www.chromsystemslab.com, [email protected] Protocol CJ05013019, Version 8.0 dated 20 Feb 2017 Page 4 of 83 Confidential In case of emergency For urgent medical advice Emilia Krasavina, Scientific Advisor on duty is available 24 h per day under the following: Emergency number Phone: +7 (916) 210-35-76 For reporting of serious adverse events, please follow the procedures described in Section 7.7.2.2 . The occurrence of SAEs will be notified by the Investigator to “Almedis” by fax or e-mail within 24 hours after becoming aware of their occurrence. The completed SAE form must be sent to the following number or address: 24 h SAE reporting Fax: Number: +7 495 937 43 19 [email protected] Protocol CJ05013019, Version 8.0 dated 20 Feb 2017 Page 5 of 83 Confidential 2 TABLE OF CONTENTS Page 1 ADMINISTRATIVE INFORMATION .............................................................................. 2 1.1 Protocol approval and signatures .......................................................................... 2 1.2 Investigator Agreement ........................................................................................... 3 1.3 Trial contact list ....................................................................................................... 4 2 TABLE OF CONTENTS ................................................................................................ 6 3 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................... 10 4 SYNOPSIS .................................................................................................................. 13 4.1 Study Design Diagram ........................................................................................... 23 4.1.1 Part 1 ................................................................................................................... 23 4.1.2 Part 2 ................................................................................................................... 24 4.2 Study Flow Chart ................................................................................................... 25 4.2.1 Part 1 ................................................................................................................... 25 4.2.2 Part 2 ................................................................................................................... 27 Amendment #4 ................................................................................................................. 29 5 INTRODUCTION ......................................................................................................... 30 5.1 Background ............................................................................................................ 30 5.2 Class or Type of Drug Being Studied/Description of Drug ................................. 31 5.3 Preclinical Profile ................................................................................................... 32 5.4 Clinical Profile ........................................................................................................ 33 5.4.1 Pharmacokinetics .............................................................................................. 33 5.4.2 Safety and Tolerance ......................................................................................... 35 5.5 Rationale ................................................................................................................ 37 5.5.1 Study Conduct Rationale ................................................................................... 37 5.5.2 Study Design Rationale ..................................................................................... 37 5.5.3 Dose Rationale ................................................................................................... 40 6 STUDY OBJECTIVES ................................................................................................ 40 6.1 Primary Objectives ................................................................................................ 40 6.2 Secondary Objectives ........................................................................................... 40 7 INVESTIGATIONAL AND ANALYSIS PLAN .............................................................. 40 Protocol CJ05013019, Version 8.0 dated 20 Feb 2017 Page 6 of 83 Confidential 7.1 Design of the Study/Methodology ........................................................................ 40 7.2 Participation in and Completion of the Study ...................................................... 43 7.3 Study Population ................................................................................................... 43 7.3.1 Subject Inclusion Criteria .................................................................................. 43 7.3.2 Subject Exclusion Criteria ................................................................................. 44 7.3.3 Subject Discontinuation Criteria ....................................................................... 46 7.3.4 Replacement of Subjects ................................................................................... 47 7.4 Treatments ............................................................................................................. 47 7.4.1 Study Treatments ............................................................................................... 47 7.4.2 Non-Study Treatments ....................................................................................... 54 7.4.3 Dietary, Tobacco, Alcohol, Caffeine, and Other Restrictions .......................... 55 7.4.4 Procedures for Monitoring Subject Compliance .............................................. 56 7.5 Blood Sampling ..................................................................................................... 56 7.6 Study Procedures .................................................................................................