Introduction ................................ ............................................................................................. 1 2. Objectives ................................ ............................................................................................... 1 2.1. Primary Objective ................................................................................................................ 1 2.2. Secondary Objective ............................................................................................................ 1 2.3. Exploratory Objectives ........................................................................................................ 1 3. Investigational Plan ................................ ................................................................................. 2 3.1. Overall Study Design and Plan ............................................................................................ 2 3.2. Study Endpoints ................................................................................................................... 2 3.2.1. Primary Endpoint ...................................................................................................... 2 3.2.2. Secondary Endpoint .................................................................................................. 3 3.2.3. Exploratory Endpoint ................................................................................................ 3 3.3. Study Treatment ................................................................................................................... 4 3.4. Dose Adjustment .................................................................................................................. 4 4. General Statistical Considerations ................................ .......................................................... 4 4.1. Sample Size .......................................................................................................................... 5 4.1.1. Arm P Reference Data .............................................................................................. 5 4.1.2. Delay of Vaccine Effect ............................................................................................ 5 4.1.3. Effect Size for Survival ............................................................................................. 6 4.1.4. Power and Significance Level .................................................................................. 6 4.1.5. Number of Subjects and Required Number of Deaths .............................................. 6 4.2. Randomization, Stratification, and Blinding ....................................................................... 8 4.3. Analysis Sets ........................................................................................................................ 8 4.4. Changes in Planned Analysis ............................................................................................... 8 5. Subject Disposition ................................ .................................................................................