“Novel Strategies to Prevent Malaria and Improve Maternal-Child Health in Africa” (PROMOTE II) A UCSF/ MAKERERE UNIVERSITY COLLABORATION Title: Prevention of Malaria in HIV-uninfected Pregnant Women and Infants Short Title: PROMOTE Birth Cohort 3 NCT02793622 VERSION 5.0 Sponsored by: The National Institute of Child Health and Human Development Bill and Melinda Gates Foundation Principal Investigators: Grant Dorsey, MD, PhD University California San Francisco Moses Kamya, MBChB, MMed, PhD Makerere University College of Health Sciences Protocol Version 5.0, 27 February 2018 1 TABLE OF CONTENTS PROTOCOL TEAM ROSTER .............................................................................................................. 6 GLOSSARY ........................................................................................................................................ 9 SCHEMA ......................................................................................................................................... 10 1. INTRODUCTION ................................................................................................................. 11 1.1. Background ................................................................................................................ 11 1.2. Preliminary studies .................................................................................................... 15 1.3. Rationale ................................................................................................................... 18 2. STUDY OBJECTIVES ............................................................................................................ 20 2.1. Objective 1 ................................................................................................................. 20 2.2. Objective 2 ................................................................................................................. 20 2.3. Objective 3 ................................................................................................................. 21 2.4 Objective 4 ................................................................................................................. 21 3. STUDY DESIGN ................................................................................................................... 21 4. SELECTION AND ENROLLMENT OF SUBJECTS .................................................................. 22 4.1. Inclusion Criteria ........................................................................................................ 22 4.2. Exclusion Criteria ....................................................................................................... 22 4.3. Initial Screening ......................................................................................................... 22 4.4. Study Enrollment Procedures and Baseline Evaluation ............................................... 23 5. STUDY TREATMENT ........................................................................................................... 24 5.1. Treatment Group Assignments ................................................................................... 24 5.2. Treatment Allocation ................................................................................................. 24 5.3. Study Drug Dosing and Formulations ......................................................................... 24 Table 1. Drug formulation and labeling ........................................................................... 25 5.4. Blinding, Study Drug Administration, and Duration .................................................... 25 5.5. Study Drug Accountability .......................................................................................... 26 6. SUBJECT MANAGEMENT ................................................................................................... 26 6.1. Subject Follow-up ...................................................................................................... 26 PROMOTE-II Birth Cohort 3 Protocol version 5.0, 27 Feb 2018 2 6.2. Diagnosis and Management of Malaria ...................................................................... 26 6.3. Management of Non-Malaria Illnesses ....................................................................... 28 6.4. After Hours Visits ....................................................................................................... 28 6.5. Routine Assessments ................................................................................................. 28 6.6. Delivery visit .............................................................................................................. 29 6.7. Postpartum visits. ...................................................................................................... 30 6.8. Medical Care Outside the Study Clinic ........................................................................ 30 6.9. Duration of Follow-up and Criteria for Premature Study Withdrawal ......................... 31 6.10. Diagnostic and Laboratory Testing ............................................................................. 31 6.10.1. Microscopy ......................................................................................................... 32 6.10.2. Clinical Laboratory Studies ................................................................................ 32 6.10.3. Placental Studies ............................................................................................... 33 6.10.4. Molecular and Parasitology Studies ................................................................. 33 6.10.5. Immunology Studies .......................................................................................... 35 6.10.6. Sample Storage for Future Use ......................................................................... 35 6.11. Co-enrollment Guidelines .......................................................................................... 36 6.12. MANAGEMENT OF ADVERSE EVENTS POTENTIALLY RELATED TO STUDY DRUGS ......... 36 6.13. Grade 1 or 2 Adverse Events ...................................................................................... 36 6.14. Grade 3 or 4 Adverse Events ...................................................................................... 36 7. MONITORING OF ADVERSE EVENTS AND MANAGEMENT .............................................. 37 7.1. Monitoring and Reporting of Adverse Events ............................................................. 37 7.1.1. Definitions ............................................................................................................ 37 7.1.2. Identification of Adverse Events ......................................................................... 38 7.1.3. Reporting of Adverse Events ............................................................................... 38 Table 2. Guidelines for reporting adverse events ........................................................... 39 8. STATISTICAL CONSIDERATIONS ........................................................................................ 39 8.1. Hypothesis 1 .............................................................................................................. 39 8.1.1. Primary Outcome ................................................................................................ 40 8.1.2. Secondary Outcomes ........................................................................................... 40 8.1.3. Analyses ............................................................................................................... 40 8.2. Hypothesis 2 .............................................................................................................. 41 8.2.1. Primary Outcome ................................................................................................ 41 8.2.2. Secondary Outcomes ........................................................................................... 42 Table 4. Secondary outcomes .......................................................................................... 42 8.2.3. Analyses ............................................................................................................... 42 PROMOTE-II Birth Cohort 3 Protocol version 5.0, 27 Feb 2018 3 8.3. Hypothesis 3 .............................................................................................................. 43 8.3.1. Primary Outcomes ............................................................................................... 43 8.3.2. Secondary Outcomes .............................................................................................. 43 8.3.3. Analyses .................................................................................................................. 43 8.4. Sample size and power .................................................................................................. 44 8.5. Data and Safety Monitoring Plan ............................................................................... 44 8.5.1. Data and Safety Monitoring Board ..................................................................... 45 8.5.2. Interim safety analysis ........................................................................................ 46 Table 5. Schedule of interim safety analysis and boundaries to monitor study outcome ..........................................................................................................................................