Protocol No. 01.05.2017 Confidential JULY 4, 2017 MUHAS/ KAROLINSKA INSTITUTET /UPPSALA UNIVERSITY Clinical Research Protocol “Aiming at prolonging the therapeutic life span of artemisinin-based combination therapies in an era of imminent Plasmodium falciparum resistance in Bagamoyo District, Tanzania - new strategies with old tools”. DR. LWIDIKO EDWARD MHAMILAWA- PHD STUDENT MUHAS Muhimbili University of Health and Allied Sciences Version Date: 04th July 2017 Page 1 of 92 Protocol No. 01.05.2017 Confidential MUHAS/ KAROLINSKA INSTITUTET /UPPSALA UNIVERSITY Clinical Research Protocol “Aiming at prolonging the therapeutic life span of artemisinin-based combination therapies in an era of imminent Plasmodium falciparum resistance in Bagamoyo District, Tanzania - new strategies with old tools”. Protocol Number: 01.05.2017 – ALU -PQ Version Date: 04th July 2017 Version 05 Investigational Product: Artemether-Lumefantrine and Primaquine Development Phase: Phase IV Sponsors: Muhimbili University of Health and Allied Sciences; Dept. of Parasitology and Medical Entomology P. O. Box 65001 Upanga, Dar es salaam Tanzania, Karolinska Institutet, Dept of Molecular, Tumor and Cell Biology, Nobelsväg 16 171 77 Stockholm, Sweden Uppsala University, Dept. of Women's and Children's Health, IMCH, Drottninggatan 4, 75310 Uppsala Sweden Funding Organization: Swedish International Development Agency (SIDA) & Swedish Research Council Principal Investigator: Name: Dr. Lwidiko Edward Mhamilawa Telephone: +255712865206 Fax: E-mail: [email protected] Version Date: 04th July 2017 Page 2 of 92 Protocol No. 01.05.2017 Confidential Co-investigators / Name: Dr. Billy Ngasala supervisors: Address: P.O Box 65011 DSM Mobile: 0754316359 Email:[email protected] Name: Prof. Anders Bjorkman Address: Solnavägen 1, 171 77 Solna, Sweden Mobile: +46 (0) 8-524 868 29. Email: [email protected] Name: Prof. Andreas Mårtensson Address: Kapellgränd 6A, 13146 Nacka, Sweden Mobile: +46-737454034 Email: [email protected] Coordinating Center: Muhimbili University of Health and Allied Sciences; Dept. of Parasitology and Medical Entomology P. O. Box 65001 Upanga, Dar es salaam Tanzania, Approval: Sponsor Signature (Name and Title) Date This confidential information about an investigational product is provided for the exclusive use of investigators of this product and is subject to recall at any time. The information in this document may not be disclosed unless state law or regulations require such disclosure. Subject to the foregoing, this information may be disclosed only to those persons involved in the study who have a need to know, with the obligation not to further disseminate this information. Version Date: 04th July 2017 Page 3 of 92 Protocol No. 01.05.2017 Confidential PROTOCOL AGREEMENT I have read the protocol specified below. In my formal capacity as Investigator, my duties include ensuring the safety of the study subjects enrolled under my supervision and providing Muhimbili University of Health and Allied Sciences (MUHAS), Karolinska Institutet (KI) and Uppsala University, with complete and timely information, as outlined in the protocol. It is understood that all information pertaining to the study will be held strictly confidential and that this confidentiality requirement applies to all study staff at this site. Furthermore, on behalf of the study staff and myself, I agree to maintain the procedures required to carry out the study in accordance with accepted GCP principles and to abide by the terms of this protocol. Protocol Number: 01.05.2017 Protocol Title: Aiming at prolonging the therapeutic life span of artemisinin-based combination therapies in an era of imminent Plasmodium falciparum resistance in Bagamoyo District, Tanzania - new strategies with old tools. Protocol Date: 04th July 2017 July 4th 2017 Investigator Signature Date Dr. Lwidiko Edward Mhamilawa Print Name and Title Site # 01 Site Name Yombo Dispensary Address P. O. Box Chasimba Bagamoyo – Pwani Tanzania Phone Number +255712865206 Version Date: 04th July 2017 Page 4 of 92 Protocol No. 01.05.2017 Confidential TABLE OF CONTENTS Table of Contents 1 BACKGROUND 16 1.1 OVERVIEW OF CLINICAL STUDIES 17 2 STUDY RATIONALE 17 2.1 RISK / BENEFIT ASSESSMENT 18 3 STUDY OBJECTIVES 19 3.1 BROAD OBJECTIVE 19 3.2 SPECIFIC OBJECTIVES 19 4 STUDY DESIGN 20 4.1 STUDY AREA 20 4.2 STUDY OVERVIEW 20 5 CRITERIA FOR EVALUATION 20 5.1 PRIMARY EFFICACY ENDPOINT 20 5.2 SECONDARY EFFICACY ENDPOINTS 20 5.3 SAFETY EVALUATIONS 21 6 SUBJECT SELECTION 21 6.1 STUDY POPULATION 21 6.2 INCLUSION CRITERIA 21 6.3 EXCLUSION CRITERIA 21 7 CONCURRENT MEDICATIONS 22 7.1 ALLOWED MEDICATIONS AND TREATMENTS 22 8 STUDY TREATMENTS 23 8.1 METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS 23 8.2 BLINDING 23 8.3 FORMULATION OF TEST AND CONTROL PRODUCTS 23 8.3.1 FORMULATION OF TEST PRODUCT 23 8.3.2 FORMULATION OF CONTROL PRODUCT 24 8.3.3 PACKAGING AND LABELING 24 8.4 SUPPLY OF STUDY DRUG AT THE SITE 24 8.4.1 DOSAGE/DOSAGE REGIMEN 24 8.4.2 DISPENSING 26 8.4.3 STORAGE 26 8.4.4 STUDY DRUG ACCOUNTABILITY 26 8.5 MEASURES OF TREATMENT COMPLIANCE 26 Version Date: 04th July 2017 Page 5 of 92 Protocol No. 01.05.2017 Confidential 9 STUDY PROCEDURES AND GUIDELINES 26 9.1 CLINICAL ASSESSMENTS 27 9.1.1 CONCOMITANT MEDICATIONS 27 9.1.2 DEMOGRAPHICS 27 9.1.3 MEDICAL HISTORY 27 9.1.4 PHYSICAL EXAMINATION 27 9.1.5 VITAL SIGNS 27 9.1.6 ECG 27 9.1.7 PREGNANCY SCREENING 27 9.1.8 ADVERSE EVENTS 27 9.2 CLINICAL LABORATORY MEASUREMENTS 27 9.2.1 BLOOD COLLECTION PROCEDURES: 27 9.2.2 MICROSCOPY 28 9.2.3 LOOP MEDIATED ISOTHERMAL AMPLIFICATION (LAMP) 30 9.2.4 HAEMOGLOBIN 31 9.2.5 URINALYSIS 31 9.2.6 BLOOD CHEMISTRY PROFILE 31 9.3 RESEARCH LABORATORY MEASUREMENTS 31 9.3.1 MOLECULAR GENOTYPING 31 9.3.2 PHARMACOKINETIC MEASUREMENTS 32 10 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 32 10.1 ADVERSE EVENTS 32 10.2 SERIOUS ADVERSE EXPERIENCES (SAE) 33 10.2.1 SERIOUS ADVERSE EXPERIENCE REPORTING 34 10.3 MEDICAL MONITORING 34 11 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 34 11.1 EARLY DISCONTINUATION OF STUDY DRUG 34 11.2 WITHDRAWAL OF SUBJECTS FROM THE STUDY 35 11.3 REPLACEMENT OF SUBJECTS 35 12 PROTOCOL VIOLATIONS 35 13 DATA SAFETY MONITORING 36 14 STATISTICAL METHODS AND CONSIDERATIONS 36 14.1 DATA SETS ANALYZED 36 14.2 PATIENTS FLOW DIAGRAM 36 14.3 PRIMARY ANALYSIS PLAN 37 14.4 ANALYSIS OF SECONDARY ENDPOINTS 37 14.5 INTERIM ANALYSIS 37 14.6 SAMPLE SIZE AND RANDOMIZATION 37 15 DATA COLLECTION, RETENTION AND MONITORING 38 15.1 DATA COLLECTION INSTRUMENTS 38 Version Date: 04th July 2017 Page 6 of 92 Protocol No. 01.05.2017 Confidential 15.2 DATA MANAGEMENT PROCEDURES 38 15.3 DATA QUALITY CONTROL AND REPORTING 38 15.4 ARCHIVAL OF DATA 39 15.5 AVAILABILITY AND RETENTION OF INVESTIGATIONAL RECORDS 39 15.6 MONITORING 39 15.7 SUBJECT CONFIDENTIALITY 39 16 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 39 16.1 PROTOCOL AMENDMENTS 40 16.2 INSTITUTIONAL REVIEW BOARDS AND INDEPENDENT ETHICS COMMITTEES 40 16.3 INFORMED CONSENT FORM 40 16.4 PUBLICATIONS 41 17 BUDGET 41 17.1 BUDGET JUSTIFICATION 43 17.2 WORK PLAN 44 17.3 INVESTIGATOR RESPONSIBILITIES 46 18 BIBLIOGRAPHY 47 19 APPENDIX I. SCHEDULE OF EVENTS DURING STUDY VISITS 49 53 20 APPENDIX II: INFORMED CONSENT 53 20.1 ENGLISH VERSION 53 20.2 SWAHILI VERSION 59 21 APPENDIX III: INFORMED ASSENT FORM 65 21.1 ENGLISH VERSION 65 21.2 SWAHILI 69 22 APPENDIX IV: CASE RECORD FORM (CRF): 73 23 APENDIX IV: SERIOUS ADVERSE EVENT REPORT FORM: 79 24 APENDIX V: ADVERSE EVENT FORM 81 24.1.1 APPENDIX VB 82 24.1.3 APPENDIX VB 88 24.1.4 PROCEDURE FOR INVESTIGATION OF SUSPECTED HEMOLYSIS 92 24.1.5 PROCEDURE FOR MANAGEMENT OF HEMOLYSIS 92 Version Date: 04th July 2017 Page 7 of 92 Protocol No. 01.05.2017 Confidential LIST OF ABBREVIATIONS AE adverse event ACT Artemisinin-Based Combination Therapy AL Artemether-Lumefantrine ALT Alanine aminotransferase CRF Case report form DAPI (4',6-diamidino-2-phenylindole) DBS Dried Blood Spot DMC Data Monitoring Committee DSMB Data Safety Monitoring Board ECG Electro- Cardiogram FDA Food and Drug Authority GCP Good Clinical Practice GCT Gametocyte Clearance Time Hb Hemoglobin HIPAA Health Insurance Portability and Accountability Act of 1996 ICF informed consent form ICH International Conference on Harmonization IEC Independent Ethics Committee IRB Institutional Review Board KI Karolinska Institutet LAMP Loop-mediated isothermal Amplification LLIN Long Lasting Insecticide Treated Nets MoMic Mobile Microscopy mRDT Malaria Rapid Diagnostic Test MUHAS Muhimbili University of Health and Allied Sciences mRNA Messenger Ribonucleic Acid NMCP National Malaria Control Program PCR Polymerase Chain Reaction PCR- RFLP PCR-Restriction Fragment Length Polymorphism PI Principal Investigator PK Pharmacokinetics PQ Primaquine QT-NASBA Quantitative Nucleic Acid Sequence Based Assay SAE serious adverse experience RNA Ribonucleic Acid SIDA Swedish International Development Agency Version Date: 04th July 2017 Page 8 of 92 Protocol No. 01.05.2017 Confidential SPSS Statistical Package for Social Science SNP Single Nucleotide Polymorphism WBC White Blood Cells WHO World Health Organization Version Date: 04th July 2017 Page 9 of 92 Protocol No. 01.05.2017 Confidential PROTOCOL SYNOPSIS TITLE Aiming at prolonging the therapeutic life span of artemisinin-based combination therapies in an era of imminent Plasmodium falciparum resistance in Bagamoyo District, Tanzania - new strategies with old tools. SPONSOR Muhimbili University of Health and Allied Sciences; Dept. of Parasitology and Medical Entomology P. O. Box 65001 Upanga, Dar es salaam Tanzania, Karolinska Institutet, Dept of Molecular, Tumor and Cell Biology, Nobelsväg 16 171 77 Stockholm, Sweden Uppsala University, Dept. of Women's and Children's Health, IMCH, Drottninggatan 4, 75310 Uppsala, Sweden FUNDING Swedish International Development Agency (SIDA) & Swedish ORGANIZATION Research Council NUMBER OF SITES ONE RATIONALE Despite documented high cure rates of ACT in Tanzania, and Africa elsewhere, clinical trials conducted in Tanzania with SIDA and Swedish Research Council support, provide evidence for in vivo selection of lumefantrine tolerant/resistant parasites among recurrent infections[1], [2].