DMID 01-650 PROTOCOL TITLE: A Multicenter, Randomized Dose Response Study of the Safety, Clinical and Immune Responses of Dryvax® Administered to Children 2 to 5 Years of Age INVESTIGATORS: UCLA Center for Vaccine Research (CVR) Principal Investigator: Joel Ward, M.D. Thuan Le, M.D. S. Michael Marcy, M.D. Susan Partridge R.N., M.B.A. Martin Lee, Ph.D. Cincinnati Children’s Hospital Medical Center Principal Investigator: David Bernstein, M.D. Michael Gerber, M.D. Amy Hoeper, R.N. SPONSOR: Division of Microbiology and Infectious Diseases (DMID) National Institute of Allergy and Infectious Diseases (NIAID) National Institutes of Health (NIH) DMID Program Officers Holli Hamilton, M.D., M.P.H. Steven Heyse, M.D., M.P.H. Mamodikoe Makhene, M.D., M.P.H. 27 Sept 2002 Version 2.0 Table of Contents 1.0 STUDY OBJECTIVES........................................................................................................... 5 1.1 Overall objectives ....................................................................................................... 5 1.2 Specific objectives ..................................................................................................... 5 1.2.1 Primary Objective........................................................................................... 5 1.2.2 Secondary Objectives .................................................................................... 5 2.0 BACKGROUND / STUDY RATIONALE................................................................................. 5 2.1 Background .................................................................................................................. 5 2.2 Vaccinia vaccine trials.................................................................................................. 7 2.2.1 Adult studies..................................................................................................... 8 2.2.1.1 Pilot Study in Vaccinia-naïve Adults. ……………………………. .. 8 2.2.1.2 Multicenter Study in Vaccinia-naïve Adults ................................. 10 2.2.2 Pediatric studies............................................................................................. 12 2.2.2.1 NIAID Studies .............................................................................. 12 2.2.2.2 Dryvax Jet Injection Study………….…………………...………… 14 2.3 Rationale for the current study .................................................................................. 15 3.0 STUDY DESIGN.................................................................................................................... 15 3.1 Overview .................................................................................................................... 15 3.2 Dryvax Vaccine .......................................................................................................... 16 3.3 Study population ........................................................................................................ 16 3.4 Inclusion and exclusion criteria.................................................................................. 17 3.5 Study groups .............................................................................................................. 18 3.5.1 Initial Study ………………………………………………………………………. 19 3.5.2 Potential second phase follow up study…………………..……………………19 3.5.3 Diagram of potential study groups and stages ...............................................21 3.6 Study procedures ....................................................................................................... 21 3.6.1 Subject recruitment and education ................................................................ 21 3.6.2 Informed consent ........................................................................................... 22 3.6.3 Randomization/Blinding ................................................................................. 22 3.6.4 Study visits and procedures........................................................................... 23 3.6.4.1 Overview (flowchart) .................................................................... 23 3.6.5 Vaccine and study drug handling and administration ................................... 27 3.6.5.1 Dryvax ………………………………………………………….. 27 3.6.5.2 VIG .................................................................................... 28 3.6.5.3 Cidofovir ................................................................................... 29 3.6.6 Limiting transmission to contacts................................................................... 29 3.6.6.1 Semi-occlusive dressings and dressing changes ....................... 29 3.6.6.2 Nurses / physicians...................................................................... 29 3.6.6.3 Contacts ....................................................................................... 30 3.6.7 Revaccination................................................................................................. 30 3.6.8 Study or Subject Termination ........................................................................ 30 4.0 ASCERTAINMENT OF ADVERSE EVENTS ....................................................................... 31 4.1 Adverse events .......................................................................................................... 31 4.2 Serious adverse events ............................................................................................. 35 27 Sept 2002 2 Version 2.0 4.3 Assessment and reporting of adverse events ...........................................................35 4.4 Secondary transmission: surveillance and isolation procedures ..............................38 4.5 Safety monitoring oversight .......................................................................................38 4.6 Treatments for adverse events ..................................................................................38 4.6.1 Pruritis ............................................................................................................39 4.6.2 Fever or pain ..................................................................................................39 4.6.3 Vaccinia Immune Globulin (VIG) ...................................................................39 4.6.4 Cidofovir .........................................................................................................39 5.0 LABORATORY EVALUATIONS ..........................................................................................42 5.1 Schedule of specimen collections .............................................................................42 5.2 Materials for specimen collection .............................................................................42 5.3 Specimen labeling......................................................................................................42 5.4 Specimen collection and processing procedures......................................................42 5.5 Serologic responses ..................................................................................................43 5.6 Cell mediated responses ...........................................................................................43 5.7 Viral cultures and viral titers.......................................................................................43 5.8 Laboratory safety precautions ...................................................................................44 6.0 DATA MANAGEMENT..........................................................................................................44 7.0 SAFETY MONITORING COMMITTEE .................................................................................44 8.0 SAMPLE SIZE, STATISTICAL METHODS AND ANALYSES............................................44 8.1 Sample size justification ............................................................................................44 8.2 Safety and efficacy analyses .....................................................................................45 8.2.1 Effectiveness..................................................................................................45 8.2.1.1 Primary endpoint ........................................................................45 8.2.1.2 Secondary endpoints ...................................................................46 8.2.2 Safety .........................................................................................................46 9.0 ADMINISTRATIVE AND REGULATORY ISSUES ..............................................................46 9.1 Compliance with the protocol.....................................................................................46 9.2 Informed consents .....................................................................................................47 9.3 Patient confidentiality.................................................................................................47 9.4 IRB approval ..............................................................................................................47 9.5 Study monitoring ........................................................................................................48 9.6 Retention of records...................................................................................................48 10.0 REFERENCES.......................................................................................................................49 11.0 APPENDICES ........................................................................................................................51