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Protocol C4591001 PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines) Protocol C4591001 A PHASE 1/2/3, PLACEBO-CONTROLLED, RANDOMIZED, OBSERVER-BLIND, DOSE-FINDING STUDY TO EVALUATE THE SAFETY, TOLERABILITY, IMMUNOGENICITY, AND EFFICACY OF SARS-COV-2 RNA VACCINE CANDIDATES AGAINST COVID-19 IN HEALTHY INDIVIDUALS Study Sponsor: BioNTech Study Conducted By: Pfizer Study Intervention Number: PF-07302048 Study Intervention Name: RNA-Based COVID-19 Vaccines US IND Number: 19736 EudraCT Number: 2020-002641-42 Protocol Number: C4591001 Phase: 1/2/3 Short Title: A Phase 1/2/3 Study to Evaluate the Safety, Tolerability, Immunogenicity, and Efficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Individuals Page 1 PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines) Protocol C4591001 TABLE OF CONTENTS LIST OF TABLES .....................................................................................................................8 1. PROTOCOL SUMMARY .....................................................................................................9 1.1. Synopsis ....................................................................................................................9 1.2. Schema ....................................................................................................................17 1.3. Schedule of Activities .............................................................................................18 1.3.1. Phase 1 ........................................................................................................18 1.3.2. Phase 2/3 .....................................................................................................23 2. INTRODUCTION ...............................................................................................................26 2.1. Study Rationale .......................................................................................................26 2.2. Background .............................................................................................................26 2.2.1. Clinical Overview .......................................................................................27 2.3. Benefit/Risk Assessment .........................................................................................27 2.3.1. Risk Assessment .........................................................................................29 2.3.2. Benefit Assessment .....................................................................................31 2.3.3. Overall Benefit/Risk Conclusion ................................................................31 3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................31 3.1. For Phase 1 ..............................................................................................................31 3.2. For Phase 2/3 ...........................................................................................................33 4. STUDY DESIGN.................................................................................................................36 4.1. Overall Design .........................................................................................................36 4.1.1. Phase 1 ........................................................................................................36 4.1.2. Phase 2/3 .....................................................................................................37 4.2. Scientific Rationale for Study Design .....................................................................39 4.3. Justification for Dose ..............................................................................................39 4.4. End of Study Definition ..........................................................................................40 5. STUDY POPULATION ......................................................................................................40 5.1. Inclusion Criteria .....................................................................................................40 5.2. Exclusion Criteria ....................................................................................................41 Page 2 PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines) Protocol C4591001 5.3. Lifestyle Considerations ..........................................................................................44 5.3.1. Contraception ..............................................................................................44 5.4. Screen Failures ........................................................................................................44 5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study Intervention Administration ......................................................................................44 6. STUDY INTERVENTION ..................................................................................................45 6.1. Study Intervention(s) Administered ........................................................................46 6.1.1. Manufacturing Process ...............................................................................46 6.1.2. Administration ............................................................................................46 6.2. Preparation/Handling/Storage/Accountability ........................................................47 6.2.1. Preparation and Dispensing ........................................................................48 6.3. Measures to Minimize Bias: Randomization and Blinding.....................................48 6.3.1. Allocation to Study Intervention ................................................................48 6.3.2. Blinding of Site Personnel ..........................................................................48 6.3.3. Blinding of the Sponsor ..............................................................................49 6.3.4. Breaking the Blind ......................................................................................50 6.4. Study Intervention Compliance ...............................................................................50 6.5. Concomitant Therapy ..............................................................................................50 6.5.1. Prohibited During the Study .......................................................................50 6.5.2. Permitted During the Study ........................................................................51 6.6. Dose Modification ...................................................................................................51 6.7. Intervention After the End of the Study ..................................................................52 7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL ...........................................................................52 7.1. Discontinuation of Study Intervention ....................................................................52 7.2. Participant Discontinuation/Withdrawal From the Study .......................................53 7.2.1. Withdrawal of Consent ...............................................................................53 7.3. Lost to Follow-up ....................................................................................................54 8. STUDY ASSESSMENTS AND PROCEDURES ...............................................................54 8.1. Efficacy and/or Immunogenicity Assessments .......................................................55 8.1.1. Biological Samples .....................................................................................58 8.2. Safety Assessments .................................................................................................58 8.2.1. Clinical Safety Laboratory Assessments (Phase 1 Participants Only) .......59 Page 3 PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines) Protocol C4591001 8.2.2. Electronic Diary ..........................................................................................59 8.2.2.1. Grading Scales ...........................................................................60 8.2.2.2. Local Reactions .........................................................................60 8.2.2.3. Systemic Events ........................................................................61 8.2.2.4. Fever ..........................................................................................62 8.2.2.5. Antipyretic Medication .............................................................62 8.2.3. Phase 1 Stopping Rules ..............................................................................62 8.2.4. Surveillance of Events That Could Represent Enhanced COVID-19 and Phase 2/3 Stopping Rule ...........................................................................64 8.2.5. Randomization and Vaccination After a Stopping Rule Is Met .................64 8.2.6. Pregnancy Testing ......................................................................................65 8.3. Adverse Events and Serious Adverse Events ..........................................................65 8.3.1. Time Period and Frequency for Collecting AE and SAE Information .......65 8.3.1.1. Reporting SAEs to Pfizer Safety ...............................................66 8.3.1.2. Recording Nonserious AEs and SAEs on the CRF ...................66 8.3.2. Method of Detecting AEs and SAEs ..........................................................66 8.3.3. Follow-up of AEs and SAEs
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