107 2.1 Primary Objective ................................................................................................. 107 2.2 Secondary Objectives ........................................................................................... 108 2.3 Exploratory Objectives ......................................................................................... 108 3 Investigational Plan ........................................................................................................ 110 3.1 Study Design ......................................................................................................... 110 3.1.1. Overall Treatment Investigational Administration Schedule ............................... 110 3.1.2. Rationale of Study Design ............................................................................ 114 4.0. Patient Selection and Withdrawal Criteria ..................................................................... 116 4.1. Selection of Study Population ................................................................................. 116 4.1.1. Inclusion Criteria .................................................................................................. 116 4.1.2. Exclusion Criteria ................................................................................................. 124 4.2. Withdrawal of Patients from the Study ................................................................ 129 4.2.1. Reasons for Withdrawal/Discontinuation .............................................. 129 4.2.2. Handling of Withdrawals ...................................................................... 131 4.2.3. Replacements ......................................................................................... 132 5. Study Treatments ........................................................................................................... 133 5.1. Method of Assigning Patients to Treatment ......................................................... 133 5.2.