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Protocol C4591001 (PF-07302048 ) Statistical Analysis Plan
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TMF Doc ID: 98.03Protocol C4591001
A PHASE 1/2/3, PLACEBO -CONTROLLED, RANDOMIZED, OBSERVER -BLIND ,
DOSE -FINDING STUDY T O EVALUATE THE SAFETY, TOLERAB ILITY,
IMMUNOGENICITY, AND EFFICACY OF SARS -COV -
2RNA VACCINE
CANDIDATES AGAINST C OVID -19 IN HEALTHY INDIVIDUALS
Statistical Analysis Plan
(SAP)
Version: 8
Date: 11 Nov 2021
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TMF Doc ID: 98.03TABLE OF CONTENTS
LIST OF TABLES ................................ ................................ ................................ ..................... 7
LIST OF FIGURES ................................ ................................ ................................ ................... 8
APPENDI CES ................................ ................................ ................................ ........................... 8
1. VERSI ON HISTORY ................................ ................................ ................................ ............ 9
2. INTRODUCTION ................................ ................................ ................................ ................. 9
2.1. Study Objectives, Endpoints, and Estimands ................................ ............................ 9
2.2. Study Design ................................ ................................ ................................ ........... 18
2.2.1. Overall D esign ................................ ................................ ............................ 18
2.2.2. Phase 1 ................................ ................................ ................................ ........ 19
2.2.3. Phase 2/3................................ ................................ ................................ .....21
3. ENDPOINTS AND BASELINE VARIABLES: DEF INIT IONS AND
CONVENTIONS ................................ ................................ ................................ ................ 24
3.1. Primary Endpoints ................................ ................................ ................................ ...24
3.1.1. S afety Endpoints ................................ ................................ ......................... 24
3.1.1.1. L ocal Reactions ................................ ................................ ......... 25
3.1.1.2. Sy stemic Events (Sy stemic Event S ymptoms and Fever) ......... 27
3.1.1.3. Use of Antip yretic Medication ................................ .................. 29
3.1.1.4. Adverse Events ................................ ................................ .......... 29
3.1.1.5. Serious Adverse Events ................................ ............................. 30
3.1.1.6. Hematology and Chemistry Laboratory Parameters (for
Phase 1 Only ) ................................ ................................ .................... 30
3.1.2. I mmunogenicit y Endpoints (for the Phase 2/3 Subset for Evaluation
of Boostability and Protection Against Emerging VOCs Only )...................... 32
3.1.3. Vaccine Efficacy Endpoints (for Phase 2/3 Only )................................ ......32
3.2. Secondary Endpoints ................................ ................................ ............................... 33
3.2.1. I mmunogenicit y Endpoints ................................ ................................ ......... 33
3.2.2. Vaccine Efficacy Endpoints (for Phase 2/3 Only )................................ ......33
3.3. Exploratory Endpoints ................................ ................................ ............................. 34
3.3.1. Safet y Endpoints (for Phase 1 Boostability Assessment Only) .................. 34
3.3.2. Vaccine Efficacy Endpoints (for Phase 2/3 Only )................................ ......34
3.3.3. I mmunogenicit y Endpoints ................................ ................................ ......... 35
3.3.4. Additional Endpoints (for Phase 2/3 Onl y)................................ ................ 35
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TMF Doc ID: 98.033.4. Baseline and Other Variables ................................ ................................ .................. 36
3.4.1. Demographics, Medical History , and Phy sical Examination ..................... 36
3.4.2. E- Diary Completion ................................ ................................ .................... 36
3.4.3. Prior/Concomitant Vaccines and Concomitant Medications...................... 37
3.5. Safet y Endpoints ................................ ................................ ................................ .....37
4. ANALYSIS SETS (PO PUL ATIONS FOR ANALYS IS)................................ ................... 37
5. GENERAL METHODOLOGY AND CONVENTIONS ................................ .................... 40
5.1. Hy potheses and Decision Rules ................................ ................................ .............. 40
5.1.1. Vaccine Efficacy Hypothesis ................................ ................................ ......40
5.1.2. I mmunogenicit y Hypothesis ................................ ................................ .......41
5.1.2.1. Hy pothesis for Immunogenicit y Bridging of 12 to 15
Years to 16 to 25 Years ................................ ................................ .....41
5.1.2.2. Hy pothesis for Boostability and Protection Against
Emerging SARS -CoV -2 VOCs ................................ ......................... 41
5.1.3. Sample Size ................................ ................................ ................................ 41
5.1.3.1. Phase 1................................ ................................ ....................... 41
5.1.3.2. Efficacy Against COVID -19................................ ..................... 42
5.1.3.3. Efficacy Against Asy mptomatic Infection ................................ 42
5.1.3.4. I mmunogenicit y Bridging of 12 to 15 Years to 16 to 25
Years ................................ ................................ ................................ ..42
5.1.3.5. Boostability and Protection Against Emerging SARS -
CoV -2 VOCs ................................ ................................ ..................... 43
5.1.3.6. Safet y................................ ................................ ......................... 44
5.1.4. Multiplicity Considerations ................................ ................................ ........ 45
5.1.4.1. Phase 1 ................................ ................................ ....................... 45
5.1.4.2. Phase 2/3 Vaccine Efficacy ................................ ....................... 45
5.1.4.3. Phase 2/3 I mmunogenicity ................................ ........................ 45
5.2. General Methods ................................ ................................ ................................ .....46
5.2.1. Analy ses for Binary Data ................................ ................................ ............ 46
5.2.2. Analy ses for Count Data ................................ ................................ ............. 47
5.2.3. Analy ses for Continuous Data ................................ ................................ ....48
5.2.3.1. Geometric Means ................................ ................................ ......48
5.2.3.2. Geometric Mean Fold Rises................................ ...................... 48
5.2.3.3. Geometric Mean Ratios ................................ ............................. 48
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TMF Doc ID: 98.035.2.3.4. Geometric Mean Fold Rise Ratios ................................ ............ 49
5.2.3.5. Reverse Cumulative Distribution Curves ................................ ..49
5.3. Methods to Manage Missing Data ................................ ................................ .......... 49
6. ANALYSES AND SUMM ARIES................................ ................................ ...................... 49
6.1. Primary Endpoint(s) ................................ ................................ ................................ 49
6.1.1. S afety Endpoints ................................ ................................ ......................... 49
6.1.1.1. L ocal Reactions ................................ ................................ ......... 50
6.1.1.2. Sy stemic Events ................................ ................................ ........ 51
6.1.1.3. Adverse Events ................................ ................................ .......... 52
6.1.1.4. S erious Adverse Events ................................ ............................. 53
6.1.1.5. Hematology and Chemistry Parameters (for Phase 1 Onl y).....53
6.1.2. I mmunogenicit y Endpoints (for the Phase 3 Subset for Evaluation of
Boostability and Protection Against Emerging VOCs Only ) .......................... 54
6.1.2.1. SARS -CoV -2 Reference Strain NT and SA NT at 1
Month After Dose 3 vs Reference Strain NT at 1 Month After
Dose 2 in BNT162b2 -Experienced Participants................................ 54
6.1.2.2. Seroresponse to the Reference Strain and SA Strain at 1
Month After Dose 3 vs Seroresponse to the Reference Strain at
1 Month After Dose 2 in BNT162b2 -Experienced Participants .......55
6.1.2.3. SARS -CoV -2 SA NT at 1 Month After Dose 2 vs
Reference Strain NT a t 1 Month After Dose 2 in BNT162b2-
Naïve Participants ................................ ................................ .............. 55
6.1.2.4. Seroresponse to the SA Strain at 1 Month After Dose 2 vs
Serorespon se to the Reference Strain at 1 Month After Dose 2
in BNT162b2- Naïve Participants ................................ ...................... 56
6.1.3. Vaccine Efficacy Endpoints (for Phase 2/3 Only )................................ ......57
6.1.3.1. COVID -19 Incidence per 1000 Person -Years of Follow -
up ................................ ................................ ................................ .......57
6.2. Secondary Endpoints ................................ ................................ ............................... 58
6.2.1. I mmunogenicit y Endpoints ................................ ................................ ......... 58
6.2.1.1. SARS -CoV -2 Neutralizing Titers (Phase 1) ............................. 59
6.2.1.2. S1- Binding IgG Levels and RBD -Binding IgG Levels
(Phase 1) ................................ ................................ ............................ 60
6.2.1.3. SARS -CoV -2 Neutralizing Titers vs SARS -CoV -2 S1-
Binding IgG Levels and RBD -Binding IgG Levels (Phase 1) .......... 61
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TMF Doc ID: 98.036.2.1.4. SARS -CoV -2 Neutralizing Titers in Participants 12 to 15
Years of Age vs Those 16 to 25 Years of Age (Phase 2/3) ............... 61
6.2.1.5. SARS -CoV -2 SA NT and Reference Strain NT at 1
Month After Dose 3 vs Reference Strain NT at 1 Month After
Dose 2 in BNT162b2 -Experienced Participants................................ 62
6.2.1.6. Seroresponse to the SA Strain and Reference Strain at 1
Month After Dose 3 vs Seroresponse to the Reference Strain at
1 Month After Dose 2 in BNT162b2 -Experienced Participants .......63
6.2.1.7. SARS -CoV -2 SA NT After Dose 3 (BNT162b2 -
Experienced Participants)................................ ................................ ..64
6.2.1.8. SARS -CoV -2 SA NT at 1 Month After Dose 4 vs
Reference Strain NT at 1 Month After Dose 2 in BNT162b2 -
Experienced Participants ................................ ................................ ...64
6.2.1.9. SARS -CoV -2 SA NT at 1 Month After Dose 2
(BNT162b2 -Naïve Participants) ................................ ........................ 65
6.2.1.10. Seroresponse to the SA Strain at 1 Month After Dose 2
(BNT162b2 -Naïve Participants) ................................ ........................ 66
6.2.1.11. Reference Strain NT at 1 Month After Dose 2
(BNT162b2 -Naïve Participants) ................................ ........................ 67
6.2.2. Vaccine E fficacy Endpoints (for Phase 2/3 Only )................................ ......67
6.2.2.1. COVID -19 Incidence per 1000 Person -Years of Follow -
up ................................ ................................ ................................ .......67
6.2.2.2. Confirmed Severe COVID -19 Incidence per 1000 Person -
Years of Follow -up................................ ................................ ............ 68
6.2.2.3. Confirmed COVID -19 Incidence per 1000 Person -Years
of Follow -up (According to the CDC -Defined S ymptoms) .............. 69
6.2.2.4. I ncidence of As ymptomatic SARS -CoV -2 Infection per
1000 Person- Years of Follow -up (According to the N -Binding
Antibody Seroconversion) ................................ ................................ .70
6.2.2.5. I ncidence of As ymptomatic SARS -CoV -2 Infection per
1000 Person- Years of Follow -up (According to the Central
Laboratory –Confirmed NAAT) ................................ ......................... 71
6.3. Exploratory Endpoints ................................ ................................ ............................. 71
6.3.1. Safet y Endpoints (for Phase 1 Boostability Assessment Only) .................. 71
6.3.1.1. L ocal Reactions ................................ ................................ ......... 71
6.3.1.2. Sy stemic Events ................................ ................................ ........ 72
6.3.1.3. Adverse Events ................................ ................................ .......... 73
6.3.1.4. Serious Adverse Events ................................ ............................. 74
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TMF Doc ID: 98.036.3.2. Vaccine Efficacy Endpoints (for Phase 2/3 Only )................................ ......74
6.3.2.1. COVID -19 Incidence per 1000 Person -Years of Blinded
Follow -up ................................ ................................ .......................... 74
6.3.2.2. COVID -19 Incidence per 1000 Person -Years of Follow -
up ................................ ................................ ................................ .......75
6.3.2.3. COVID -19 Incidence per 1000 Person- Years of Follow -
up for Participants Receiving BNT162b2 as a Third Dose as
Part of Protocol Amendment 18 ................................ ........................ 76
6.3.2.4. I ncidence of As ymptomatic SARS -CoV -2 Infection per
1000 Person- Years of Follow -up (According to the N -Binding
Antibody Seroconversion) ................................ ................................ .77
6.3.2.5. I ncidence of As ymptomatic SARS -CoV -2 Infection per
1000 Person- Years of Follow -up (According to the Central
Laboratory –Confirmed NAAT) ................................ ......................... 77
6.3.3. I mmunogenicit y Endpoints ................................ ................................ ......... 78
6.3.3.1. SARS -CoV -2 Reference -Strain Neutralizing Tite rs,
SARS -CoV -2 SA -Variant Neutralizing Titers, and Full -Length
S-Binding or S1 -Binding IgG Levels (Phase 1) ................................ 78
6.3.3.2. SARS -CoV -2 Reference -Strain Neutralizing Titers and
SARS -CoV -2 SA -Variant Neutralizing Titers at 1 Month After
Dose 3 vs SARS- CoV -2 Reference -Strain Neutralizing Titers
at 1 Month After Dose 2 (Phase 1) ................................ .................... 79
6.3.3.3. SARS -CoV -2 Neutralizing Titers, and Full- length S -
Binding or S1 -Binding IgG Levels (Phase 2/3) ................................ 79
6.3.3.4. SARS -CoV -2 Neutralizing Titers in Participants
Receiving Booster Doses (Phase 3) ................................ ................... 80
6.3.3.5. Serological Responses in Participants With Confirmed
COVID -19, Confirmed Severe COVID -19, and SARS -CoV -2
Infection Without Confirmed COVID-19 ................................ ......... 81
6.3.3.6. SARS -CoV -2 NTs for An y VOCs (Phase 3, Boostability
and Protection Against Emerging VOCs) ................................ ......... 81
6.3.4. Additional Analy sis................................ ................................ .................... 81
6.4. Subgroup Analy sis................................ ................................ ................................ ..82
6.5. Baseline and Other Summaries and Anal yses................................ ......................... 82
6.5.1. Baseline Summaries ................................ ................................ .................... 82
6.5.1.1. Demographic Characteristics ................................ .................... 82
6.5.1.2. Medical History ................................ ................................ ......... 82
6.5.2. Study Conduct and Participant Disposition ................................ ................ 82
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TMF Doc ID: 98.036.5.2.1. Participant Disposition ................................ .............................. 82
6.5.2.2. Blood Samples for Assay ................................ .......................... 82
6.5.2.3. E- Diaries ................................ ................................ .................... 83
6.5.3. Study Vaccination Exposure ................................ ................................ .......83
6.5.3.1. Vaccination Timing and Administration ................................ ...83
6.5.4. Prior/Concomitant Vaccination and Concomitant Medications ................. 83
6.6. Safet y Summaries and Analyses ................................ ................................ ............. 83
7. ANALYSES TIMING ................................ ................................ ................................ ......... 83
7.1. I ntroduction of Interim Analy sis................................ ................................ ............. 83
7.2. I nterim Anal yses and Summaries ................................ ................................ ............ 86
7.2.1. Data Monitoring Committee ................................ ................................ .......87
8. REFERENCES ................................ ................................ ................................ .................... 88
9. APPENDI CES ................................ ................................ ................................ ..................... 89
LIST OF TABLES
Table 1. Summary of Changes ................................ ................................ .................. 9
Table 2. List of Primary and Secondary Objectives, Estimands, and
Endpoints for Phase 1 ................................ ................................ ............... 10
Table 3. List of Primary , Secondary, and Tertiary /Exploratory Objectives,
Estimands, and Endpoints for Phase 2/3................................ ................... 12
Table 4. Derived Variables for Presence of Each and An y Local Reaction
Within 7 Days for Each Dose ................................ ................................ ...26
Table 5. Local Reaction Grading Scale ................................ ................................ ..26
Table 6. Systemic Event Grading Scale ................................ ................................ ..28
Table 7. Scale for Fever ................................ ................................ .......................... 29
Table 8. Laboratory Abnormality Grading Scale ................................ ................... 31
Table 9. Power Anal ysis for Noninferiorit y Assessment ................................ .......43
Table 10. Probability of Observing at Least 1 AE by Assumed True Event
Rates With Different Sample Sizes ................................ .......................... 44
Table 11. Interim Anal ysis Plan and Boundaries for Efficacy and Futility .............. 84
Table 12. Statistical Design Operating Characteristics: Probability of Success
or Failure for Interim Analy ses................................ ................................ .85
Table 13. Statistical Design Operating Characteristics: Probability of Success
for Final Anal ysis and Overall ................................ ................................ ..85
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TMF Doc ID: 98.03LIST OF FIGURES
Figure 1. Multiplicity Schema ................................ ................................ .................. 46
APPENDICES
Appendix 1. List of Abbreviations ................................ ................................ ........................... 89
Appendix 2. Details for Bayesian Design ................................ ................................ ................ 91
Appendix 3. IRR and VE Derivation ................................ ................................ ....................... 93
Appendix 4. Asy mptomatic Case Based on N -Binding Antibod y Seroconversion ................. 98
Appendix 5. Asy mptomatic Case Based on Central L aboratory –Confirmed NAAT.............. 99
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TMF Doc ID: 98.031.VERSION HISTORY
Table 1.Summary of C hanges
Version /
DateAssociated Protocol
AmendmentSummary and Rationale for Changes
1/
20 May 2020Protocol amendment 1 ,
13May 2020N/A
2/
30Jul2020Protocol amendment 5,
24July 2020Implem ented the changes made in p rotocol amendment s 2through
5.
3/
02Nov 2020Protocol amendment 9,
29Oct 2020Implem ented the changes made in protocol amendments 6 through
9.
4/
08Jan2021Protocol amendment 11 ,
04Jan2021Implem ented the changes made in protocol amendments 10 and11.
5/
17Mar 2021Protocol amendment 14,
02 Mar 2021Implem ented the changes made in protocol amendments 12 through
14.
6/
14Jun2021Protocol amendment 16,
28May 2021Implem ented the changes made in protocol amendments 1 5and16.
7/
26Jul 2021Protocol amendment 17,
20Jul 2021Implem ented the changes made in protocol amendment 17.
8/
11Nov 2021Protocol amendment 18,
07 Sep 2021Implem ented the changes made in protocol amendment 18.
2.INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analy ses of the data
collected in Study C4591001 . This document may modify the plans outlined in the protocol;
however, an y major modifications of the primary endpoint definition or its anal ysis will also
be reflected in a protocol amendment.
2.1. Study Objectives , Endpoints ,and Estimands
The estimands corresponding to each primary , secondary , and tertiary /exploratory objective
are described in Table 2and Table 3below.
In the primary safet y objective evaluations, missing e -diary data will not be imputed.
Missing AE dates will be imputed according to Pfizer safet y rules. No other missing
information will be imputed in the safet y anal ysis.
The estimands to evaluate the immunogenicity objectives are based on evaluable populations
for immunogenicity (seeSection 4for definition). These estimands estimate vaccine effect
in the hy pothetical setting where participants follow the study schedules and protocol
requirements as directed. Missing antibody results will not be imputed. Immunogenicit y
results that are below the LLOQ will be set to 0.5 × LLOQ in the anal ysis; this may be
adjusted once additional data on the assay characteristics become available.
The estimands to evaluate the efficacy objectives are based on evaluable pop ulations for
efficacy (seeSection 4for definition). These estimands estimate vaccine effect in the
hypothetical setting where participants follow the study schedules and protocol requirements
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TMF Doc ID: 98.03as directed. In addition, VE will be anal yzed by the all -available efficacy population s.
Missing laboratory results will not be imputed for the primary analy sis, but missing data
imputation forthe efficacy endpoint may be performed as a sensitivity analy sis.
Table 2.List of Primary andSecondary Objectives, Estimands, and Endpoints for
Phase 1
Objectives Estimands Endpoints
Prim ary: Prim ary: Prim ary:
To describe the safety and tolerability
profiles of prophylactic BNT162
vaccines in healthy adults after 1 or
2dosesIn participants receiving at least 1 dose
of study intervention, the percentage of
participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
Adverse events (AEs) from
Dose 1 to 1 month after the last
dose
Serious AEs (SAEs) from Dose 1
to 6 months after the last dose Local reactions (pain at the
injection site, redness, and
swelling)
Systemic events (fever, fatigue,
headache, chills, vomiting,
diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)
AEs
SAEs
In addition, the percentage of
participants with:
Abnormal hematology and
chemistry laboratory values 1 and
7 days after Dose 1; and 7 days
after Dose 2
Grading shifts in hematology and
chemistry laboratory assessments
between baseline and 1 and 7 days
after Dose 1; and before Dose 2
and 7 days after Dose 2Hematology and chemistry laboratory
parameters detailed in th e protocol,
Section 10.2 .
Secondary: Secondary: Secondary:
To describe the immune responses
elicited by prophylactic BNT162
vaccines in healthy adults after 1 or
2dosesIn participants complying with the key
protocol criteria (evaluable
participants) at the following time
points after receipt of study
intervention :7 and 21 days after
Dose 1; 7and 14 days and1, 6, 12 ,and
24months after Dose 2
Geometric mean titers (GMTs) at
each time point
Geometric mean fold rise (GMFR)
from before vaccination to each
subsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccinationSARS -CoV -2 neutralizing titers
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TMF Doc ID: 98.03Table 2.List of Primary andSecondary Objectives, Estimands, and Endpoints for
Phase 1
Objectives Estimands Endpoints
Geometric mean concentrations
(GMCs) at each time point
GMFR from prior to first dose of
study intervention to each
subsequent time point
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccinationS1-binding IgGlevels and
RBD -binding IgGlevels
Geometric mean ratio (GMR),
estimated by the ratio of the
geometric mean of SARS -CoV -2
neutralizing titers to the geometric
mean of binding IgGlevels at each
time point SARS -CoV -2 neutralizing titers
S1-binding IgGlevels
RBD -binding IgGlevels
Exploratory: Exploratory: Exploratory:
To describe the immune responses
elicited by a third dose of prophylactic
BNT162 b2administered to healthy
adults 6 to 12 months after the second
dose of either BNT162 b1 or
BNT162 b2 GMC s/GMTsat the time of
Dose 3 and 7days and 1 month
after Dose 3
GMFR sfrom before Dose 3 to
7days and 1 month after Dose 3 SARS -CoV -2 reference -strain
neutralizing titers
SARS -CoV -2 SA-variant
neutralizing titers
Full-length S -binding or
S1-binding IgGlevels
GMR of SARS-CoV -2reference -
strain neutralizing titers 1 month
after Dose 3 to 1 month after
Dose 2 SARS -CoV -2 reference -strain
neutralizing titers
GMR of SARS-CoV -2SA-variant
neutralizing titers 1 month after
Dose 3 to SARS -CoV -2reference -
strain neutralizing titers 1 month
after Dose 2 SARS -CoV -2 reference -strain
neutralizing titers
SARS -CoV -2 SA-variant
neutralizing titers
To de scribe the safety profile of a third
dose of prophylactic BNT162 b2
administered to healthy adults 6 to
12months after the second dose of
either BNT162 b1 or BNT162 b2In participants receiving a third dose of
BNT162b2 , the percentage of
participants reporting:
Local reactions for up to 7 days
after Dose 3
Systemic events for up to 7 days
after Dose 3
AEs and SAEs from Dose 3to
1month after Dose 3 Local reactions (pain at the
injection site, redness, and
swelling)
Systemic events (fever, fatigue,
headache, chills, vomiting,
diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)
AEs
SAEs
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TMF Doc ID: 98.03Table 3. List of Primary, Secondary, and Tertiary/Exploratory Objectives,
Estimands, and Endpoints for Phase 2/3
ObjectivesaEstimands Endpoints
Prim ary Efficacy
To evaluate the efficacy of prophylactic
BNT162b2 against confirmed
COVID -19 occurring from 7 days after
the second dose in participants without
evidence of infection before vaccinationIn participants complying with the key
protocol criteria (evaluable participants)
at least 7 days after receip t of the second
dose of study intervention:
100 × (1 –IRR) [ratio of active vaccine
to placebo]COVID -19 incidence per 1000
person -years of follow -up based on
central laboratory or locally confirmed
NAAT in participants with no
serological or virological evidence
(up to 7 days after receipt of the second
dose) of past SARS-CoV -2 infection
To evaluate the efficacy of prophylactic
BNT162b2 against confirmed
COVID -19 occurring from 7 days after
the second dose in participants with and
without evidence of infection before
vaccinationIn participants complying with the key
protocol criteria (evaluable participants)
at least 7 days after receipt of the second
dose of study intervention:
100 × (1 –IRR) [ratio of active vaccine
to placebo]COVID -19 incidence p er 1000
person -years of follow -up based on
central laboratory or locally confirmed
NAAT
Prim ary Safety
To define the safety profile of
prophylactic BNT162b2 in the first 360
participants randomized (Phase 2)In participants receiving at least 1 dose
of study intervention, the percentage of
participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 7 days after
the second dose
SAEs from Dose 1 to 7 days after
the seconddose Local reactions (pain at the
injection site, redness, and
swelling)
Systemic events (fever, fatigue,
headache, chills, vomiting,
diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)
AEs
SAEs
To define the safety profile of
prophylactic BNT162b2 in all
participants randomized in Phase 2/3In participants receiving at least 1 dose
of study intervention, the percentage of
participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 month after
the second dose
SAEs from Dose 1 to 6 months
after the second dose AEs
SAEs
In a subset of at least 6000
participants:
o Local reactions (pain at the
injection site, redness, and
swelling)
o Systemic ev ents (fever,
fatigue, headache, chills,
vomiting, diarrhea, new or
worsened muscle pain, and
new or worsened joint pain)
To define the safety profile of
prophylactic BNT162b2 in participants
12 to 15 years of age in Phase 3In participants receiving at least 1 dose
of study intervention, the percentage of
participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 month after
the second dose
SAEs from Dose 1 to 6 m onths
after the second dose Local reactions (pain at the
injection site, redness, and
swelling)
Systemic events (fever, fatigue,
headache, chills, vomiting,
diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)
AEs
SAEs
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TMF Doc ID: 98.03Table 3. List of Primary, Secondary, and Tertiary/Exploratory Objectives,
Estimands, and Endpoints for Phase 2/3
ObjectivesaEstimands Endpoints
To describe the sa fety and tolerability
profile of BNT162b2 SAgiven as 1 or 2
doses to BNT162b2 -experienced
participants, or as 2 doses to
BNT162b2 -naïve participants
To describe the safety and tolerability
profile of BNT162b2 given as a third
dose to BNT162b2 -experienced
participants in the subset for evaluation
of boostability and protection against
emerging VOCsIn participants receiving at least 1 dose
of study intervention, the percentage of
participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 month after
the last dose
SAEs from Dose 1 to 5 or 6 months
after the last doseLocal reactions (pain at the injection
site, redness, and swelling)
Systemic events (fever, fatigue,
headache, chills, vomiting, diarrhea,
new or worsened muscle pain, and
new or worsened joint pain)
AEs
SAEs
To describe the safety and tolerability
profile of BNT162b2 given as a third
dose at least 6 months after the second
dose of BNT162b2 (or BNT162b2 SA)
for participants who received a third
dose as part of protocol amendment 18In participants receiving at least 1 dose
of study intervention , the percentage of
participants reporting:
AEs from Dose 3 to 1 month after
Dose 3
SAEs from Dose 3 to 6 months after
Dose 3AEs
SAEs
Prim ary Immunogenicity
BNT162b2 -experienced participants
To demonstrate the noninferiority of the
anti–reference strain immune response
after a third dose of BNT162b2 at 30 μg
compared to after 2 doses of
BNT162b2, in the same individualsGMR of reference strain NT 1 month
after the third dose of BNT162b2 at
30 µg to 1month after the second dose
of BNT162b2
The difference in percentages of
participants with seroresponse to the
reference strain at 1 month after the
third dose of BNT162b2 at 30 μg and
1month after the second dose of
BNT162b2SARS -CoV -2 reference strain NTs in
participants with no serological or
virological evidence (up to 1 month
after receipt of the third dose of
BNT162b2 at 30 µg ) of past
SARS -CoV -2 infection
To demonstrate the noninferiority of the
anti-SA immune response after 1 dose
of BNT162b2 SAcompared to the
anti–reference strain immune response
after 2 doses of BNT162b2, in the same
individualsGMR of SA NT 1 month after 1 dose of
BNT162b2 SAto the reference strain NT
1 month after the second dose of
BNT162b2
The difference in percentages of
participants with seroresponse to the SA
strain at 1 month after 1 dose of
BNT162b2 SAand seroresponse to the
reference strain at 1 month after the
second dose of BNT162b2SARS -CoV -2 SA and reference strain
NTs in participants with no serological
or virological evidence (up to 1 month
after re ceipt of 1 dose of BNT162b2 SA)
of past SARS -CoV -2 infection
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TMF Doc ID: 98.03Table 3. List of Primary, Secondary, and Tertiary/Exploratory Objectives,
Estimands, and Endpoints for Phase 2/3
ObjectivesaEstimands Endpoints
BNT162b2 -naïve participants
To demonstrate the noninferiority of the
anti-SA immune response after 2 doses
of BNT162b2 SAcompared to the
anti–reference strain immune response
after 2 doses of BNT162b2 GMR of SA NT 1 month after the
second dose of BNT162b2 SAto the
reference strain NT 1 month after the
second dose of BNT162b2
The difference in percentages of
participants with seroresponse to the SA
strain at 1 month after the second dose
of BNT162b2 SAand seroresponse to the
reference strain at 1 month after the
second dose of BNT162b2SARS -CoV -2 SA and reference strain
NTs in participants with no serological
or virological evidence (up to 1 m onth
after receipt of the second dose of
BNT162b2 SAor BNT162b2 as
appropriate) of past SARS-CoV -2
infection
Secondary Efficacy
To evaluate the efficacy of prophylactic
BNT162b2 against confirmed
COVID -19 occurring from 14days after
the second dose in participants without
evidence of infection before vaccinationIn participants complying with the key
protocol criteria (evaluable participants)
at least 14days after receipt of the
second dose of study intervention:
100 × (1 –IRR) [ratio of active vaccine
to placebo]COVID -19 incidence per
1000 person -years of follow -up based
on central laboratory or locally
confirmed NAAT in participants with
no serological or virological evidence
(up to 14days after receipt of the second
dose) of past SARS-CoV -2 infection
To evaluate the efficacy of prophylactic
BNT162b2 against confirmed
COVID -19 occurring from 14days after
the second dose in participants with and
without evidence of infection before
vaccinationIn participants complying with the key
protocol criteria (evaluable participants)
at least 14days after receipt of the
second dose of study intervention:
100 × (1 –IRR) [ratio of active vaccine
to placebo]COVID -19 incidence per
1000 person -years of foll ow-up based
on central laboratory or locally
confirmed NAAT
To evaluate the efficacy of prophylactic
BNT162b2 against confirmed severe
COVID -19 occurring from 7 days and
from 14 days after the second dose in
participants without evidence of
infection before vaccinationIn participants complying with the key
protocol criteria (evaluable participants)
at least 7 days
and
at least 14 days
after receipt of the second dose of study
intervention:
100 × (1 –IRR) [ratio of active vaccine
to placebo]Confi rmed severe COVID -19 incidence
per 1000 person -years of follow -up in
participants with no serological or
virological evidence (up to 7 days and
up to 14 days after receipt of the second
dose) of past SARS -CoV -2 infection
To evaluate the efficacy of prophylactic
BNT162b2 against confirmed severe
COVID -19 occurring from 7 days and
from 14 days after the second dose in
participants with and without evidence
of infection before vaccinationIn participants complying with the ke y
protocol criteria (evaluable participants)
at least 7 days
and
at least 14 days
after receipt of the second dose of study
intervention:
100 × (1 –IRR) [ratio of active vaccine
to placebo]Confirmed severe COVID -19 incidence
per 1000 person -years of fo llow-up
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TMF Doc ID: 98.03Table 3. List of Primary, Secondary, and Tertiary/Exploratory Objectives,
Estimands, and Endpoints for Phase 2/3
ObjectivesaEstimands Endpoints
To describe the efficacy of prophylactic
BNT162b2 against confirmed
COVID -19 (according to the
CDC -defined symptoms) occurring
from 7 days and from 14 days after the
second dose in participants without
evidence of infection before vaccinationIn participants complying with the key
protocol criteria (evaluable participants)
at least 7 days
and
at least 14 days
after receipt of the second dose of study
intervention:
100 × (1 –IRR) [ratio of active vaccine
to placebo]COVID -19 incidence per 1000
person -years of follow -up based on
central laboratory or locally confirmed
NAAT in participants with no
serological or virological evidence
(up to 7 days and up to 14 days after
receipt of the second dose) of past
SARS -CoV -2 infection
To describe the efficacy of prophylactic
BNT162b2 against confirmed
COVID -19 (according to the
CDC -defined symptoms) occurring
from 7 days and from 14 days after the
second dose in participants with and
without evidence of infection before
vaccinationIn participants complying with the key
protocol criteria (evaluable participants)
at least 7 days
and
at least 14 days
after receipt of the second dose of study
intervention:
100 × (1 –IRR) [ratio of active vaccine
to placebo]COVID -19 incid ence per 1000
person -years of follow -up based on
central laboratory or locally confirmed
NAAT
To evaluate the efficacy of prophylactic
BNT162b2 against non -S
seroconversion to SARS -CoV -2 in
participants without evidence of
infection or confirmed COVID-19 In participants complying with the key
protocol criteria (evaluable
participants):
100 × (1 –IRR) [ratio of active vaccine
to placebo]Incidence of asymptomatic
SARS -CoV -2 infection p er 1000
person -years of follow -up based on
N-binding antibody seroconversion in
participants with no serological or
virological evidence of past
SARS -CoV -2 infection or confirmed
COVID -19
To evaluate the efficacy of prophylactic
BNT162b2 against asymptomatic
SARS -CoV -2 infection in participants
without evidence of infection up to the
start of the asymptomatic surveillance
periodIn participants complying with the key
protocol criteria (evaluable
participants):
100 × (1 –IRR) [ratio of active vaccine
to placebo]Incidence of asymptomatic
SARS -CoV -2 infection per 1000
person -years of follow -up based on
central laboratory –confirmed NAAT in
participants with no serological or
virological evidence (up to the start of
the asymptomatic surveillance period)
of past SARS -CoV -2 infection
Secondary Immunogenicity
To demonstrate the noninferiority of the
immune response to prophylactic
BNT162b2 in participants 12 to 15
years of age compared to participants
16 to 25 years of ageGMR, estimated by the ratio of the
geometric mean of SARS -CoV -2
neutralizing titers in the 2 age groups
(12-15 years of age to 16 -25 years of
age) 1 month after completion of
vaccinationSARS -CoV -2 neutralizing titers in
participants with no serological or
virological evidence (up to 1 month
after receipt of the second dose) of past
SARS -CoV -2 infection
BNT162b2 -experienced participants
To demonstrate the noninferiority of the
anti-SA immune response after a third
dose of BNT162b2 at 30 μg compared
to the anti –reference strain immune
response after 2 doses of BNT162b2, in
the same individuals GMR of SA NT 1 month after the third
dose of BNT162b2 at 30 µg to the
reference strain NT 1 month after the
second dose of BNT162b2
The difference i n percentages of
participants with seroresponse to the SA
strain at 1 month after the third dose of
BNT162b2 at 30 μg and seroresponse to
the reference strain at 1 month after the
second dose of BNT162b2SARS -CoV -2 SA and reference strain
NTs in participan ts with no serological
or virological evidence (up to 1 month
after receipt of the third dose of
BNT162b2 at 30 µg) of past
SARS -CoV -2 infection
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TMF Doc ID: 98.03Table 3. List of Primary, Secondary, and Tertiary/Exploratory Objectives,
Estimands, and Endpoints for Phase 2/3
ObjectivesaEstimands Endpoints
To demonstrate the noninferiority of the
anti–reference strain immune response
after 1 dose of BNT162b2 SAcompared
to after 2 doses of BNT162b2, in the
same individuals GMR of reference strain NT 1 month
after 1 dose of BNT162b2 SAto 1month
after the second dose of BNT162b2
The difference in percentages of
participants with seroresponse to the
reference st rain at 1 month after 1 dose
of BNT162b2 SAand 1 month after the
second dose of BNT162b2SARS -CoV -2 reference strain NTs in
participants with no serological or
virological evidence (up to 1 month
after receipt of 1 dose of BNT162b2 SA)
of past SARS -CoV -2 infection
To descriptively compare the anti-SA
immune response after 1 dose of
BNT162b2 SAand a third dose of
BNT162b2 at 30 µgGMR of SA NT 1 month after 1 dose of
BNT162b2 SAto 1month after the third
dose of BNT162b2 at 30 μg
The difference in percentages of
participants with seroresponse to the SA
strain at 1 month after 1 dose of
BNT162b2 SAand 1 month after the third
dose of BNT162b2 at 30 µgSARS -CoV -2 SA NT in participants
with no serological or virological
evidence (up to 1 month after rec eipt of
1 dose of BNT162b2 SAor the third dose
of BNT162b2 at 30 µg) of past
SARS -CoV -2 infection
To descriptively compare the anti-SA
immune response after 2 doses of
BNT162b2 SAand the anti –reference
strain immune response after 2 doses of
BNT162b2, in the same individuals GMR of SA NT 1 month after the
second dose of BNT162b2 SAto the
reference strain NT 1 month after the
second dose of BNT162b2
The difference in percentages of
participants with seroresponse to the SA
strain at 1 month after the second dose
of BNT162b2 SAand seroresponse to the
reference strain at 1 month after the
second dose of BNT162b2SARS -CoV -2 SA and reference strain
NTs in participants with no serologic al
or virological evidence (up to 1 month
after receipt of the second dose of
BNT162b2 SA) of past SARS -CoV -2
infection
BNT162b2 -naïve participants
To demonstrate a statistically greater
anti-SA immune response after 2 doses
of BNT162b2 SAcompared to after 2
doses of BNT162b2 GMR of SA NT 1 month after the
second dose of BNT162b2 SAto 1month
after the second dose of BNT162b2
The difference in percentages of
participants with seroresponse to the SA
strain at 1 month after the second dose
of BNT162b2 SAand 1 month after the
second dose of BNT162b2SARS -CoV -2 SA NTs in participants
with no serological or virological
evidence (up to 1 month after receipt of
the second dose of BNT162b2 SAor
BNT162b2 as appropriate) of past
SARS -CoV -2 infectio n
To descriptively compare the
anti–reference strain immune response
after 2 doses of BNT162b2 SAand after 2
doses of BNT162b2 GMR of reference strain NT 1 month
after the second dose of BNT162b2 SAto
1month after the second dose of
BNT162b2
The difference in percentages of
participants with seroresponse to the
reference strain at 1 month after the
second dose of BNT162b2 SAand
1month after the second dose of
BNT162b2SARS -CoV -2 reference strain NTs in
participants with no serological or
virologi cal evidence (up to 1 month
after receipt of the second dose of
BNT162b2 SAor BNT162b2 as
appropriate) of past SARS-CoV -2
infection
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TMF Doc ID: 98.03Table 3. List of Primary, Secondary, and Tertiary/Exploratory Objectives,
Estimands, and Endpoints for Phase 2/3
ObjectivesaEstimands Endpoints
Exploratory
To describe the efficacy of prophylactic
BNT162b2 against confirmed
COVID -19 occurring from 7 days after
the second dose through the blinded
follow -up period in participants without,
and with and without, evidence of
infection before vaccinationIn participants complying with the key
protocol criteria (evaluable participants)
after receipt of the second dose of s tudy
intervention:
100 × (1 –IRR) [ratio of active vaccine
to placebo] COVID -19 incidence per 1000
person -years of blinded follow -up
based on central laboratory or
locally confirmed NAAT
To describe the incidence of confirmed
COVID -19 through the entire study
follow -up period prior to receiving the
third dose of BNT162b2 in participants
who received BNT162b2 at initial
randomization or subsequentlyIn participants who received BNT162b2
(atinitial randomization or
subsequently):
Incidence per 1000 person-ye ars of
follow -up COVID -19 incidence per 1000
person -years of follow -up based on
central laboratory or locally
confirmed NAAT
To describe the incidence of confirmed
COVID -19 after receiving the third dose
of BNT162b2In participants who received the third
dose of BNT162b2:
Incidence per 1000 person-ye ars of
follow -up COVID -19 incidence per 1000
person -years of follow -up based on
central lab oratory or locally
confirmed NAAT
To evaluate the immune response over
time to prophylactic BNT162b2 and
persistence of immune response in
participants with and without
serological or virological evidence of
SARS -CoV -2 infection before
vaccinationGMC/GMT andGMFR at baseline and
1, 6, 12, an d 24 months after completion
of vaccination Full-length S -binding or
S1-binding IgG levels
SARS -CoV -2 neutralizing titers
To describe the incidence of non -S
seroconversion to SARS -CoV -2 through
the entire study follow -up period in
participants who received BNT162b2 at
initial randomizationIn participants who received BNT162b2
at initial randomization:
Incidence per 1000 pers on-years of
follow -upIncidence of asymptomatic
SARS -CoV -2 infection per 1000
person -years of follow -up based on
N-binding antibody seroconversion in
participants with no serological or
virological evidence of past
SARS -CoV -2 infection or confirmed
COVID -19
To describe the efficacy of prophylactic
BNT162b2 against asymptomatic
SARS -CoV -2 infection in participants
with evidence of infection up to the start
of the asymptomatic surveillance periodIn participants complying with the key
protocol criteria (evaluable
participants):
100 × (1 –IRR) [ratio of active vaccine
to placebo]Incidence of asymptomatic
SARS -CoV -2 infection per 1000
person -years of follow -up based on
central laboratory –confirmed NAAT in
participants with serological or
virological evidence (up to the start of
the asymptomatic surveillance period)
of past SARS -CoV -2 infection
To describe the serological responses to
the BNT vaccine candidate and
characterize the SARS -CoV -2 isolate in
cases of:
Confirmed COVID -19
Confirmed severe COVID -19
SARS -CoV -2 infection without
confirmed COVID -19 Full-length S -binding or
S1-binding IgG levels
SARS -CoV -2 neutralizing titers
Identification of SARS -CoV -2
variant(s)
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TMF Doc ID: 98.03Table 3. List of Primary, Secondary, and Tertiary/Exploratory Objectives,
Estimands, and Endpoints for Phase 2/3
ObjectivesaEstimands Endpoints
To describe the safety, immunogenicity,
and efficacy of prophylactic BNT162b2
in individuals with confirmed stable
HIV disease All safety, immunogenicity, and
efficacy endpoints described above
To describe the safety and
immunogenicity of prophylactic
BNT162b2 in individuals 16 to 55 years
of age vaccinated with study
intervention produced by manufacturing
“Process 1” or “Process 2”b AEs
SAEs
SARS -CoV -2 neutralizing titers
To describe the immune response to any
VOCs not already specifiedGeometric mean NT for any VOCs not
already specified, after any dose of
BNT162b2 SAor BNT162b2 SARS -CoV -2 NTs for any VOCs
not already specified
To describe the immune response to a
third dose of BNT162b2 (at 30 µg or a
lower dose of 5 or 10 µg) or a third or
fourth dose of BNT162b2 SAGMTs at Dose 3 and subsequent time
points
GMFRs from Dose 3 to subsequent time
points SARS -CoV -2 reference strain NTs
To describe the cell -mediated immune
response, and additional humoral
immune response parameters, to the
reference strain and SA in a subset of
participants:
7 Days and 1 and 6 months after
BNT162b2 SAgiven as 1 or 2 doses
to BNT162b2 -experienced
participants
7 Days and 1 and 6 months after
BNT162b2 SAgiven as 2 doses to
BNT162b2 -naïve participants
7 Days and 1 and 6 months after
BNT162b2 given as a third dose to
BNT162b2 -experienced participants
a.HIV-positive participants in Phase 3 will not be included in analyses of the objectives, with the exception
of the specific exploratory objective.
b.See the protocol, Section 6.1.1, for description of the manufacturing process.
2.2.Study Design
2.2.1. Overall Design
This is a multicenter, multinational, Phase 1/2/3, randomized, placebo -controlled,
observer -blind, dose -finding, vaccine candidate –selection, and efficacy study in healthy
individuals.
The study consists of 2 parts. Phase 1: to identify preferred vaccine candidate(s) and dose
level(s); Phase 2/3: an expanded cohort and efficacy part. These parts, and the progression
between them, are detailed in the schema ( see p rotocol, Section 1.2).
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TMF Doc ID: 98.03The study will evaluate the safet y, tolerability , and immunogenicit y of 2 different
SARS -CoV-2 R NAvaccine candidate s against C OVID -19and the efficacy of 1 candidate:
As a 2 -dose (separated by 21 day s) schedule ;
At various different dose levels in Phase 1;
As a booster;
In 3 age groups ( Phase 1: 18 to 55 y ears of age, 65 to 85 y ears of age ;
Phase 2/3: ≥12years of age [stratified as 12 -15, 16 -55, or >55 years of age] ).
Dependent upon safet y and/or immunogenicit y data generated during the course of this
study , or the BioNTech study conducted in Germany (BNT162 -01), it is possible that groups
in Phase 1 may be started at the next highest dose , groups may not be started, groups may be
terminated early , and/or groups may be added with dose levels below the lowest stated dose
or intermediate between the lowest and highest stated doses.
The study is observer -blinded, as the ph ysical appearance of the investigational vaccine
candidates and the placebo may differ. The participant, investigator, study coordinator, and
other site staff will be blinded. At the study site, only the dispenser(s)/administrator(s) are
unblinded.
To facilitate rapid review of data in real time, sponsor staff will be unblinded to vaccine
allocation for the participants in Phase 1.
In order to describe the boostability of BNT162, an additional dose of BNT162b2 at 30 µg
will be given to Phase 1 participants approximately 6 to 12 months after their second dose of
BNT162b1 or BNT162b2. This will provide an early assessment of the safet y of a third dose
of BNT162, as well as its immunogenicit y.The assessment of boostability will be further
expanded in a subset of Phase 3 participants at selected sites in the US who will receive a
third dose of BNT162b2 at 30 μg or a third and potential ly a fourth dose of prototy pe
BNT162b2 VOCat 30 µg (based upon the South African variant and hereafter referred to as
BNT162b2 SA). A further subset of Phase 3 participants will receive a third, lower, dose of
BNT162b2 at 5 or 10 μg.
To further describe po tential homologous and heterologous protection against emerging
SARS -CoV -2 VOCs, a new cohort of participants will be enrolled who are COVID -19
vaccine –naïve (ie, BNT162b2-naïve) and have not experienced COVID-19. They will
receive BNT162b2 SAgiven as a 2- dose series, separated by 21 day s.
2.2.2. Phase 1
Each group (vaccine candidate/dose level/age group) will comprise 15 participant s;
12participants will be randomized to receive active vaccine and 3 to receive placebo.
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TMF Doc ID: 98.03For each vaccine candidate/dose level/age group, the following apply :
Additional safet yassessments (see protocol, Section 8.2) .
Controlled enrollment (required only for the first candidate and/or dose level studied):
No more than 5 participants (4 active, 1 placebo) can be vaccinated on the first
day.
Thefirst 5 participants must be observed by blinded site staff for at least 4 hours
after vaccination for an y acute reactions.
Vaccination of the remaining participants will commence no sooner than 24hours
after the fifth participant received his or her vaccination.
Application of stopping rules .
IRC review of safet y data to determine escalation to the next dose level in the 18 -to
55-year age cohort:
Escalation between dose levels will be based on IRC review of at least 7 -day
post–Dose 1 safet y data in this study and/or the BioNTech study conducted in
German y (BNT162 -01).
Note that, since both candidates are based upon the same RNA platform, dose
escalation for the second candidate studied may be based upon the safet y profile
of the first candidat e studied being deemed acceptable at the same, or a higher,
dose level b y the IRC .
Groups of participants 65 to 85 y ears of age will not be started until safet y data for the RNA
platform have been deemed acceptable at the same, or a higher, dose level in t he 18 -to
55-year age cohort by the I RC.
In this phase , 13groups will be studied, corresponding to a total of 195participants.
The I RC will select 1 vaccine candidate that, in Phase 1, has an established dose level per age
group based on induction of a post–Dose 2 immune response, including neutralizing
antibodies, which is expected to be associated with protection against COVID -19, for
progress ion into Phase 2/ 3.
Participants who originally received placebo and become eligible for receipt of BNT162b2 or
another COVID -19 vaccine according to recommendations detailed separately , and available
in the electronic stud y reference portal ,will have the opportunity to receive BNT162b2 in a
phased manner as part of the study . The investigator will ensure the par ticipant meets at least
1 of the recommendation criteria.
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TMF Doc ID: 98.03Any Phase 1 placebo recipient who has not already been offered the opportunity to receive
BNT162b2 will be given this opportunity no later than at the approximate time participants in
Phase 2/3 rea ch Visit 4.
Any participant who originally received placebo but then goes on to receive BNT162b2 will
move to a new visit schedule (p rotocol ,Section 1.3.3).
In order to describe the boostability of BNT162, and potential heterologous protection
against eme rging SARS -CoV -2 VOCs, an additional dose of BNT162b2 at 30 µg will be
given to Phase 1 participants approximately 6to 12 months after their second dose of
BNT162 b1 or BNT162b2.
Phase 1 participants who originall y received BNT162b1 or BNT162b2 at dose lev els of 10,
20, or 30 µg at Doses 1 and 2 will be offered an additional dose of BNT162b2 at 30 µg
approximately 6to 12 months after their second dose of BNT162.
Participants are expected to participate for up to a maximum of approximately 26 months.
2.2.3. Phase 2/3
On the basis of safet y and/or immunogenicit y data generated during the course of this study,
and/or the BioNTech study conducted in Germany (BNT162 -01), 1 vaccine candidate was
selected to proceed into Phase 2/3. Participants in this phase will be ≥12years of age,
stratified as follows: 12 to 15 years, 16 to 55 years, or >55 years. The 12- to 15 -year stratum
will comprise up to approximately 2000 participants enrolled at selected investigational sites.
It is intended that a minimum of 40% of particip ants will be in the >55 -year stratum.
Commencement of each age stratum will be based upon satisfactory post –Dose 2 safety and
immunogenicit y data from the 18 -to 55 -year and 65 -to 85 -year age groups in Phase 1,
respectivel y. The vaccine candidate select ed for Phase 2/3 evaluation is BNT162b2 at a dose
of 30 µg.
Phase 2/ 3 is event -driven. Under the assumption of a true VE rate of ≥60%, after the second
dose of study intervention , a target of 164 primary -endpoint cases of confirmed COVID -19
due to SARS -CoV -2 occurring at least 7days following the second dose of the primary series
of the candidate vaccine will be sufficient to provide 90% power to conclude true VE >30%
with high probability .The t otal number of participants enrolled in Phase 2/ 3 may vary
depending on the incidence of COVID -19 at the time of the enrollment, the true underl ying
VE, and a potential earl y stop for efficacy or futility .
Assuming a COVID -19 attack rate of 1.3% per y ear in the placebo group, accrual of 164 first
primary -endpoint cases within 6 months, an estimated 20% nonevaluable rate, and 1:1
randomization, the BNT162b2 vaccine candidate selected for Phase 2/3 is expected to
comprise approximately 21,999 vaccine recipien ts. This is the number of participants
initially targeted for Phase 2/3 and may be adjusted based on advice from DMC analy ses of
case accumulation and the percentage of participants who are seropositive at baseline.
Dependent upon the evolution of the pandemic, it is possible that the COVID- 19 attack rate
may be much higher, in which case accrual would be expected to be more rapid, enabling the
study ’s primary endpoint to be evaluated much sooner.
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TMF Doc ID: 98.03The first 360 participants enrolled (180 to active vaccine and 180 to placebo, stratified
equally between 18 to 55 years and >55 to 85 years) will comprise the “Phase 2” portion.
Safety data through 7 day s after Dose 2 and immunogenicity data through 1 month after
Dose 2 from these 360 participants will be anal yzed by the unblinded statistical team,
reviewed b y the DMC, and submitted to appropriate regulatory authorities for review.
Enrollment may continue during this period and these participants would be included in the
efficacy evaluation in the “Phase 3” por tion of the study .
In Phase 3, up to approximately 2000 participants, enrolled at selected sites, are anticipated
to be 12 to 15 y ears of age. Noninferiority of immune response to proph ylactic BNT162b2
in participants 12to 15 years of age to response inparticipants 16 to 25 years of age will be
assessed based on the GM Rof SARS -CoV -2 neutralizing titers using a 1.5 -fold margin. A
sample size of 225 evaluable participants (or 280vaccine recipients) per age group will
provide a power of 90.4 % to declare the noninferiority in terms of GM R(lower limit of 95%
CI forGMR>0.67) . A random sample of 280 participant s from each of the 2 age groups
(12to 15 y ears and 16 to 25 y ears) will be selected as an immunogenicity subset for the
noninferiority assessment.
The initial BNT162b2 was manufactured using “Process 1”; however, “Process 2” was
developed to support an increased scale of manufacture. In the stud y, each lot of “Process
2”-manufactured BNT162b2 will be administered to approximately 250 participants 16 to
55 years of age. The safety and immunogenicity of prophy lactic BNT162b2 in individuals
16 to 55 y ears of age vaccinated with “Process 1” and each lot of “Process 2” study
intervention will be described. A random sample of 250 participants from thos e vaccinated
with study intervention produced b y manufacturing “Process 1” will be selected for this
descriptive analy sis.
For evaluation of boostability and protection against emerging VOCs, 600 existing Phase 3
participants 18 to 55 y ears of age will be rerandomized in a 1:1 ratio to receive either a third
dose of BNT162b2 at 30 µg or a third dose of BNT162b2 SA.
A further group of approximately 144 existing Phase 3 participants 18 y ears of age and older
will be enrolled to receive a third, lower, dose of BNT162b2 of either 5 or 10 μg.
Approximately 24 participants 18 to 55 y ears of age and 48 participants > 55 years of age will
be enrolled in each dose group.
An additional group of 30 existing Phase 3 participants 18 to 55 y ears of age will be enrolled
to receive a third and fourth dose of BNT162b2 SA. For these 30 participants, through 1
month after their first dose of BNT162b2 SAthe participant swill be blinded to their vaccine
allocation ,but the investigator and sponsor will not be. Serum samples from these
participants may be used for assay development purposes and, except for objectives relating
to response to a fourth dose, their results will be analy zed separately from the main
immunogenicit y anal yses.
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TMF Doc ID: 98.03Three hundred participants 18 to 55 y ears of age who are COVID -19 vaccine –naïve
(ie, BNT162b2 -naïve) and have not experienced COVID- 19 will be enrolled as a new cohort
of participants to receive BNT162b2 SAgiven as a 2- dose series.
Participants are expected to participate for up to a maximum of approx imately 26 months.
The duration of stud y follow -up may be shorter among participants enrolled in Phase 1
dosing arms that are not evaluated in Phase 2/3.
Participants who originally received placebo and become eligible for receipt of BNT162b2
according to recommendations detailed separatel y, and available in the electronic study
reference portal ,will have the opportunity to receive BNT162b2 in a phased manner as part
of the study . The investigator will ensure the participant meets at least 1 of the
recommendation criteria.
Any Phase 2/3 placebo recipient who has not already been offered the opportunity to receive
BNT162b2 will be given this opportunity no later than 6 months after Vaccination 2 (at the
time of the originally planned Visit 4).
Any partic ipant who originally received placebo but then goes on to receive BNT162b2 will
move to a new visit schedule (p rotocol ,Section 1.3.3).
The changes to the protocol as part of protocol amendment 14 to assess boostability and
homologous/heterologous protecti on against emerging VOCs allow the evaluation of safet y
and immunogenicit y of BNT162b2 SA:
When given as a third dose to C4591001 Phase 3 participants who received a second dose
of BNT162b2 approximately 6 months previousl y (ie, BNT162b2 -experienced) and ha ve
not experienced COVID -19.
In a small separate group of individuals who previously received 2 doses of BNT162b2
followed b y 1 dose of BNT162b2 SA, a second BNT162b2 SAdose will also be given 1
month after Dose 1 of BNT162b2 SA.
When given as a 2 -dose seri es, separated b y 21 days, in newl y recruited participants who
are COVID -19 vaccine– naïve (ie, BNT162b2 -naïve) and have not experienced
COVID -19.
In addition, a group of C4591001 Phase 3 participants who received a second dose of
BNT162b2 approximately 6 mo nths previousl y will receive a third dose of BNT162b2.
This approach will allow an evaluation of immunogenicity against the reference ancestral
SARS -CoV -2 strain (Wuhan -Hu-1/USA -WA1) and the selected South African VOC, using a
noninferiority approach based on neutralizing antibody titers in prior BNT162b2 vaccinees
who receive either a homologous boost (with BNT162b2) or a heterologous boost (with
BNT162b2 SA), as well as new vaccinees receiving 2 doses of BNT162b2 SA.
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TMF Doc ID: 98.03As part of protocol amendment 18, to ref lect current and anticipated recommendations for
COVID -19 vaccine boosters, participants in Study C4591001 who meet specified
recommendations (detailed separatel y and available in the electronic stud y portal) and have
not alread y received one will be offer ed a third dose of BNT162b2 after their second dose of
BNT162. The opportunity to receive a third dose of BNT162b2 will be offered as part of the
study , according to recommendations detailed separatel y, and available in the electronic
study reference port al. This opportunity is onl y for those participants who received their first
2 doses of BNT162 (including BNT162b1, BNT162b2, or BNT162b2 SA) as part of the stud y.
An intensive period of surveillance to evaluate the efficacy of BNT162b2 against
asymptomatic SARS -CoV -2 infection may be conducted at selected sites among Phase 2/3
participants following approval of protocol amendment 11. After an initial in -person visit
where a blood sample will be collected and a nasal (midturbinate) swab obtained , nasal
(midturbinate) swabs will be obtained from consented participants every 2 weeks until
Visit 4, or a sufficient number of cases of SARS -CoV -2 infection have accrued to evaluate
this objective, whichever is sooner, per the SoA in the protocol , Section 1.3. 6. The swabs
will be tested at a central laboratory using NAAT to detect SARS -CoV -2. Participants who
are unblinded because they become potentially eligible for receipt of BNT162b2 according to
recommendations detailed separately , and availab le in the electronic study reference portal,
will not participate in surveillance for as ymptomatic SARS -CoV -2 infection. However,
participants who provided additional consent to conduct biweekl y swabbing for surveillance
of as ymptomatic infection should c ontinue to swab even after unblinding if they originall y
received BNT162b2.
Surveillance for as ymptomatic SARS -CoV -2 infection (swabbing) should cease in
participants enrolled into the subset of participants who will receive an additional dose of
BNT162b2 or BNT162b2 SA.
3.ENDPOINTS AND BASELINE VARIAB LES: DEFINITIONS AND
CONVENTIONS
3.1.Primary Endpoints
3.1.1. Safety Endpoints
For all participants in Phase 1, a subset of at least 6000 participants randomized in Phase 2/3,
receiving at least 1 dose of study intervention, BNT162b2- experienced participants receiving
1 or 2 doses of BNT162b2 SA, BNT162b2 -naïve participants receiving 2 doses of
BNT162b2 SA, and BNT162b2 -experienced participants receiving the third dose of
BNT162b2 in the subset for evaluation of boostability and protection against emerging VOCs
in Phase 3, below are the primary safety endpoints for local reactions andsystemic events:
Local reactions (pain at the injection site , redness ,and swelling ) within 7 day s after
each dose in each vaccine group .
Systemic events ( fever, fatigue, headache, chills, vomiting, diarrhea, new or worsened
muscle pain, and new or worsened joint pain ) within 7 day s after each dose in each
vaccine group .
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TMF Doc ID: 98.03For all particip ants randomized in Phase 1 and Phase 2/3, receiving at least 1 dose of study
intervention, below are the primary safet y endpoints for AEs and SAEs (the last dose in
Phase 1 is the second dose):
AEs from Dose 1 to 1 month after the second dose.
SAEs from Dose 1 to 6 months after the second dose.
In addition, f or the first 360 participants randomized in Phase 2/3 (Phase 2 portion) , receiving
at least 1 dose of stud y intervention, below are the primary safety endpoints for AEs and
SAEs:
AEs from Dose 1 to 7 day safter the second dose.
SAEs from Dose 1 to 7 day safter the second dose.
For BNT162b2 -experienced participants receiving 1 or 2 doses of BNT162b2 SA,
BNT162b2 -naïve participants receiving 2 doses of BNT162b2 SA, and
BNT162b2 -experienced participa nts receiving the third dose of BNT162b2 in the subset for
evaluation of boostability and protection against emerging VOCs in Phase 3, below are the
primary safety endpoints for AEs and SAEs:
AEs from Dose 1 to 1 month after the last dose.
SAEs from Dose 1 to 5 or 6 months after the last dose.
For the participants receiving BNT162b2 as a third dose at least 6 months after the second
dose of BNT162b2 (or BNT162b2 SA) as part of protocol amendment 18 , below are the
primary safety endpoints for AEs and SAEs:
AEs from Dose 3to 1 month after Dose 3 .
SAEs from Dose 3 to 6 months after Dose 3 .
3.1.1.1. Local Reactions
The local reactions assessed and reported in the e -diary are redness, swelling, and pain at the
injection site, from Day 1 through Day 7 after each dose, where Day 1 is the day of each
dose. This section describes derivations with details for the assessment of local reactions:
presence, severity level, duration, and onset day .
Presence or Absence
For the data summary of the presence (y esor no) of a local reaction during the interval from
Day 1 through Day 7 for each dose , where Day 1 is the day of each dose , the following
variables are required in order to compute the proportions:
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TMF Doc ID: 98.03Presence (y es or no) of each severe/ Grade 4 local reaction on each day and any day
(Day 1 through Day 7);
Presence (y es or no) of each local reaction by maximum se verity on an y day (Day 1
through Day 7).
For each local reaction and any local reaction on any day,Table 4explains the algorithm to
derive the presence of a reaction (y es or no) during the interval from Day 1 through Day 7,
where Day 1 is the day of each dose .
Table 4. D erived Vari ables for Presence o f Each and Any Local Reaction Within
7Days for Each Dose
VariableaYes (1) No (0) Missing (.)
Presence of each local
reaction .Participant reports the
reaction as “yes” onany
day ( Day 1 through Day 7).Participant reports the
reaction as “no” on all
7 days ( Day 1 t hrough
Day 7) or as a
combination of “no” and
missing on all 7 days
(Day 1 through Day 7).Participant does not report
anydata on all 7 days (Day 1
through Day 7) for the reaction.
Presence of any local
reaction .Participant reports any
local reaction as “yes” on
any day (Day 1 t hrough
Day 7).For all 3 local reactions,
participant reports “no”
on all 7 days(Day 1
through Day 7) or as a
combination of “no” and
missing on all 7 days
(Day 1 through Da y7).Participant does not report any
data for all 3 local reactions on
all 7 days ( Day 1 t hrough
Day 7).
a.The variables will be derived for each and any of the local reactions (redness, swelling, and pain at the
injection site) and for each and any of the severe local reactions within the interval from Day 1 through
Day 7 after each dose .
Severity and Maximum Severity
Redness and swelling will be measured and recorded in measuring device units
(range: 1to21) and then categorized during anal ysis as absent, mild, moderate, or severe
based on the grading scale in Table 5. Measuring device units can be converted to
centimeters according to the following formula: 1 measuring device unit = 0.5 cm. Pain at
the injection site will be assessed b y the partici pant as absent, mild, moderate, or severe
according the grading scale in Table 5.
Table 5.Local Reaction Grading Scale
Mild
(Grade 1)Moderate
(Grade 2)Severe
(Grade 3)Potentially Life
Threatening
(Grade 4)
Pain at the injection
siteDoes not interfere
with activity .Interferes with
activity .Prevents daily
activity .Emergency room
visit or
hospitalization for
severe pain .
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TMF Doc ID: 98.03Table 5.Local Reaction Grading Scale
Mild
(Grade 1)Moderate
(Grade 2)Severe
(Grade 3)Potentially Life
Threatening
(Grade 4)
Redness >2.0cm to 5.0 cm
(5 to 10 measuring
device units) .>5.0 cm to 10.0 cm
(11 to 20 measuring
device units) .>10cm
(≥21measuring
device units) .Necrosis or
exfoliative
dermatitis .
Swelling >2.0cm to 5.0 cm
(5 to 10 measuring
device units) .>5.0 cm to 10.0 cm
(11 to 20 measuring
device units) .>10cm
(≥21measuring
device units) .Necrosis .
For each local reaction reported for each dose , the maximum severity grade will be derived
for the e -diary collection period (Day 1 through Day 7, where Day 1 is the day of each dose )
as follows:
maximum severity grade = highest grade (maximum severity ) within 7days after
vaccination (Day 1 through Day 7) among severity grades where the answers are
neither “no” nor missing for at least 1 day durin g the interval from Day 1 through
Day 7.
Duration (First to Last Day Reported)
For participants experiencing any local reactions (or those with a derived reaction as
described in Table 5), the maximum duration (last day of reaction –first day of reaction + 1)
will be derived for each study vaccination. Resolution of the reaction is the last day on
which the reaction is recorded in the e -diary or the date the reaction ends if it is unresolved
during the participant e-diary recording period (end date collected on the CRF), unless
chronicity is established. If there is no known end date, the duration will be considered
unknown and set to missing. However, if a reaction isongoing atthe time of a subsequent
vaccination, the end date/day for the ongoing reaction would be the date/day that the next
vaccine is administered ,which will be used for the duration computation. Participants with
no reported reaction have no duration.
Onset Day
The onset day of each local reaction will be derived. Onset day is defined as the first day of
reporting an y severit y.
For the onset day of each local reaction, if participant s report change in severi ty of the local
reaction, onl y the first day of reporting that specific local reaction will be counted.
3.1.1.2. Systemic Events ( Systemic Event Symptoms and Fever)
The sy stemic events assessed and recorded in the e-diary are vomiting, diarrhea, headache,
fatigue, chills, new or worsened muscle pain, and new or worsened joint pain from Day 1
through Day 7, where Day 1 is the day of each dose . The derivations for s ystemic events will
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TMF Doc ID: 98.03be handled in a way similar to the way local reactions are handled for presence of event,
severit y level, duration, and onset day .
The variables associated with the sy stemic events will be computed in a way similar to the
way local reactions are computed ( seeSection 3.1.1.1 ). Maximum temperature range over
the period from Day 1 through Day 7 will be mapped into the ranges described in Table 7for
summary of maximum temperature.
The symptoms will be assessed by the participant as absent, mild, moderate, or severe
according to the grading scale in Table 6.
Table 6.Systemic Event Grading Scale
Mild
(Grade 1)Moderate
(Grade 2)Severe
(Grade 3)Potentially Life
Threatening
(Grade 4)
Vom iting 1-2 times in
24hours .>2 times in
24hours .Requires IV
hydration .Emergency room visit or
hospitalization for
hypotensive shock .
Diarrhea 2 to 3 loose stools
in24 hours .4 to 5 loose stools
in 24 hours .6 or more loose
stools in 24 hours .Emergency room visit or
hospitalization for
severe diarrhea .
Headache Does not interfere
with activity .Some interference
with activity .Prevents daily
routine activity .Emergency room visit or
hospitalization for
severe headache .
Fatigue Does not interfere
with activity .Some interference
with activity .Prevents daily
routine activity .Emergency room visit or
hospitalization for
severe fatigue .
Chills Does not interfere
with activity .Some interference
with activity .Prevents daily
routine activity .Emergency room visit or
hospitalization for
severe chills .
New or worsened
muscle painDoes not interfere
with activity .Some interference
with activity .Prevents daily
routine activity .Emergency room visit or
hospitalization for
severe ne w or worsened
muscle pain .
New or worsened
joint painDoes not interfere
with activity .Some interference
with activity .Prevents daily
routine activity .Emergency room visit or
hospitalization for
severe ne w or worsened
joint pain .
Abbreviation: IV = intravenous.
Oral temperature will be collected in the evening ,daily ,for 7 day s following each dose
(Day s 1 through 7, where Day 1 is the day of each dose ) and at an y time during the 7 days
that fever is suspected. Fever is defined as an oral temperature of ≥38.0°C (100.4 °F). The
highest temperature for ea ch day will be recorded in the e -diary .
Temperature will be measured and recorded to 1 decimal place. Temperatures recorded in
degrees Fahrenheit will be programmatically converted to degrees Celsius for reporting.
Temperatures <35.0 °C and >42.0°C will b e excluded from the anal ysis. Fever will be
grouped into ranges for the anal ysis according to Table 7below.
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TMF Doc ID: 98.03Table 7.Scale for Fever
≥38.0°C to 38.4 °C(100.4 °F to 101.1 °F)
>38.4°C to 38.9 °C(101.2 °F to 102.0 °F)
>38.9 °C to 40.0 °C(102.1 °F to 104.0 °F)
>40.0 °C(>104.0 °F)
Note: Fever is defined as temperature ≥38.0 °C (≥100.4° F).
3.1.1.3. Use of Antipyretic Medication
The use of antip yretic medication is also recorded in the e -diary from Day 1 through Day 7,
where Day 1 is the day ofeach dose . For the use of antipy retic medication from Day 1
through Day 7after each dose , the following endpoints and variables will be derived for
analysis following the sa me rules as for local reactions ( see Section 3.1.1.1 ),where
applicable.
Presence (y es or no) of use of antipy retic medication on each day (Day 1 through Day 7);
Presence (y es or no) of use of antipy retic medication on any day (Day 1 through Day 7);
Duration (first to last day reported) of use of antipyretic medication;
Onset day of use of antipy retic medication.
The u se of antip yreticmedication will be summarized and included in the sy stemic event
summary tables but will not be considered a s ystemic event.
3.1.1.4. Adverse Events
AEs will be assessed from the time of informed consent through 1 month after the second
dose or 1 month after the last dose for thesubset for evaluation ofboostability andprotection
against emerging VOCs .
The primary endpoint s “AEs from Dose 1 to 1 month after the second dose”and“AEs from
Dose 1 to 1 month after the last dose,” forevaluation of boostability and protection against
emerging VOCs ,and other AE endpoints will be summarized by SOC and PT at the
participant level. For the subset for
evaluation ofboostability andprotection against
emerging VOCs, Dose 1 refers to the first dose of BNT162b2 SAor first dose of BNT162b2
booster .
Theseprimary endpoint swill be supported by summaries and listings of related AEs, severe
AEs, and immediate AEs (within the first 30 minutes after each dose ).
AE reporting will be based on the specific report ing period. Standard algorithms for
handling missing AE dates will be applied as described in the Pfizer Vaccine data standard
rules.
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TMF Doc ID: 98.03For Phase 2/3 only, a 3-tier approach will be used to summarize AEs. Under this approach,
AEs are classified into 1 of 3 tiers. Different analy ses will be performed for different tiers :
Tier 1 events: These are prespecified events of clinical importance and are identified
in a list in the product’s Safety Review Plan .
Tier 2 events: These are events that are not Tier 1 but are considered “relatively
common .”A MedDRA PTis defined as a Tier 2 event if there are at least 1%
participant s with the AE term in at least 1vaccine group.
Tier 3 events: These are events that are neither Tier 1 nor Tier 2.
3.1.1.5. Serious Adverse Events
SAEs will be collected from the time the participant provides informed consent to
approximately 6 months after the second dose of study intervention (Visit 8 for Phase 1
participants and Visit 4 for Phase 2/3 participants).
For BNT162b2 -experienced participants in the subset for evaluation of boostability and
protection against emerging VOCs, SAEs will be collected from the time the participant
provides informed consent (for participation in the subset) through and including Visit 306
(5or 6 months after t he last dose, depending upon group).
For BNT162b2 -naïve participants inthe subset for evaluation of protection against emerging
VOCs, SAEs will be collected from the time the participant provides informed consent
through and including Visit 405 (6 months after the second dose).
The safet y endpoint s“SAEs from Dose 1 to 6 months after the second dose” and“SAEs from
Dose 1 to 5 or 6 months after the last dose” for evaluation of boostability and protection
against emerging VOCs will be summarized by SOC and PT at the participant level. For the
subset for evaluation of boostability and protection against emerging VOCs, Dose 1 refers to
the first dose of BNT162b2 SAor first dose of BNT162b2 booster.
3.1.1.6. Hematology and Chemistry Laboratory Param eters(for Phase 1 O nly)
For participants in Phase 1, below are the additional primary safet y endpoints:
Abnormal hematology and chemistry laboratory values 1 and 7 day s after Dose 1; and
7 day s after Dose 2.
Grading shifts in hematology and chem istry laboratory assessments between baseline
and 1 and 7 days after Dose 1; and before Dose 2 and 7 day s after Dose 2.
The following safet y laboratory tests will be performed at the times defined in the protocol,
Section 1.3 (S chedule of Activities) . Additional laboratory results may be reported on these
samples as a result of the method of anal ysis or the ty pe of analy zer used by the clinical
laboratory , or as derived from calculated values. These additional tests would not require
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TMF Doc ID: 98.03additional collection of blood. Unscheduled clinical laboratory measurements may be
obtained at an y time during the stud y to assess any perceived safety issues.
Hem atology Chemistry
Hem oglobin
Hem atocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)BUN and creatinine
AST, ALT
Total bilirubin
Alkaline phosphatase
Clinically significant abnormal laboratory findings should be recorded in the AE CRF in
accordance with the following grading scale ( Table 8).Additionally , the primary criterion
for abnormalit y will follow the Pfizer safet y rule book.
Table 8. Laboratory Abnormality Grading Scale
Hem atology Mild
(Grade 1) Moderate
(Grade 2) Severe
(Grade 3) Potentially Life
Threatening
(Grade 4)
Hem oglobin
(Fem ale) -g/dL 11.0 –12.0 9.5 –10.9 8.0 –9.4 <8.0
Hem oglobin
(Male) -g/dL 12.5 –13.5 10.5 –12.4 8.5 –10.4 <8.5
WBC increase -
cells/mm310,800 –15,000 15,001 – 20,000 20,001 – 25,000 >25,000
WBC decrease -
cells/mm32500 –3500 1500 –2499 1000 –1499 <1000
Lymphocytes
decrease -cells/mm3750 –1000 500 –749 250 –499 <250
Neutrophils decrease
-cells/mm31500 –2000 1000 –1499 500 –999 <500
Eosinophils -
cells/mm3650 –1500 1501 –5000 >5000 Hypereosinophilic
Platelets decreased -
cells/mm3125,000 –140,000 100,000 –124,000 25,000 –99,000 <25,000
Chemistry Mild (Grade 1) Moderate
(Grade 2) Severe
(Grade 3) Potentially Life
Threatening
(Grade 4)
BUN - mg/dL 23 –26 27 –31 >31 Requires dialysis
Creatinine -mg/dL 1.5 –1.7 1.8 –2.0 2.1 –2.5 >2.5 or requires
dialysis
Alkaline phosphate -
increase by factor 1.1 –2.0 ×ULN 2.1 –3.0 ×ULN 3.1 –10 ×ULN >10 ×ULN
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TMF Doc ID: 98.03Table 8. Laboratory Abnormality Grading Scale
Liver function tests -
ALT, AST
increase by factor 1.1 –2.5 ×ULN 2.6 –5.0 ×ULN 5.1 –10 ×ULN >10 ×ULN
Bilirubin -when
accompanied
by any increase in
liver function test -
increase by factor 1.1 –1.25 ×ULN 1.26 –1.5 ×ULN 1.51 –1.75 ×ULN >1.75 ×ULN
Bilirubin -when liver
function test is
norm al -increase by
factor 1.1 –1.5 ×ULN 1.6 –2.0 ×ULN 2.0 –3.0 ×ULN >3.0 ×ULN
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea
nitrogen; ULN = upper limit of normal; WBC = white blood cell.
3.1.2. Immunogenicity Endpoints (for the Phase 2/3 Subset for E valuation of
Boostability and P rotection Against E merging VOCs Only)
SARS -CoV -2 reference strain NTs.
SARS -CoV -2 SA NTs.
In order to allow direct comparability with the reference strain, the anti -SA NTs may be
adjusted to account for intrinsic variant or assay characte ristics.
Titers (and IgG concentrations , secondary and exploratory endpoints) above the LLOQ are
considered accurate and their quantitated values will be reported. Values below the LLOQ,
denoted as BLQ, will be set to 0.5 × LLOQ for analy sis. However, th is calculation may be
adjusted based upon additional data from the assay . LLOQ results will be included in the
analysis specification once they are available.
3.1.3. Vaccine Efficacy Endpoints (for Phase 2/ 3 Only)
COVID -19 incidence per 1000 person- years of follow -up based on central laboratory
or locally confirmed NAAT in participants with no serological or virological
evidence ( prior to 7 day s after receipt of the second dose)of past SARS -CoV -2
infection (counting cases from 7 day s after the second dose ).
COVID -19 incidence per 1000 person- years of follow -up based on central laboratory
or locally confirmed NAAT (counting cases from 7 day s after the second dose ).
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TMF Doc ID: 98.033.2. Secondary Endpoints
3.2.1. Immunogenicity Endpoints
Phase 1
In participants compl ying with the key protocol criteria (evaluable participants) at the
following time points after receipt of stud y intervention:
7 and 21 day s after Dose 1; 7 and 14 day s and 1, 6, 12, and 24 months after Dose 2.
Below are the secondar y immunogenicit y endpoints for Phase 1:
SARS -CoV -2 neutralizing titers .
S1-binding IgG levels .
RBD- binding IgG levels .
Phase 2/3
Participants 12 to 15 y ears of age and 16 to 25 years of age:
SARS -CoV -2 neutralizing titers.
Participants in the subset for evaluation of boostability and protection against emerging
VOCs :
SARS -CoV -2 reference strain NTs.
SARS -CoV -2 SA NTs.
In order to allow direct comparability with the reference strain, the anti -SA NTs may be
adjusted to account for intrinsic variant or assay characteristics.
3.2.2. Vaccine Efficacy Endpoints (for Phase 2/3 Only)
COVID -19 incidence per 1000 person- years of follow -up based on central laboratory
or locally confirmed NAAT in participants with no serological or virological
evidence ( prior to 14days after receipt of the second dose) of past SARS -CoV -2
infection (counting cases from 14 day s after the second dose) .
COVID -19 incidence per 1000 person- years of follow -up based on central laboratory
or locally confirmed NAAT (counting cases from 14 day s after the second dose) .
Confirmed severe COVID- 19 incidence per 1000 person -years of follow -up in
participants with no serological or virological evidence (prior to 7 day s and prior to
14 day s after receipt of the second dose) of past SARS -CoV -2 infection (counting
cases from 7 day s and 14 day s after the second dose ).
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TMF Doc ID: 98.03Confirmed severe COVID- 19 incidence per 1000 person -years of follow -up(counting
cases from 7 day s and 14 day s after the second dose) .
According to the CDC -defined s ymptoms, COVID -19 incidence p er 1000
person -years of follow -up based on central laboratory or locall y confirmed NAAT in
participants with no serological or virological evidence ( prior to 7 day s and prior to
14 day s after receipt of the second dose) of past SARS -CoV -2 infection (counting
cases from 7 day s and 14 day s after the second dose) .
According to the CDC -defined s ymptoms, COVID -19 incidence per 1000
person -years of follow -up based on central laboratory or locall y confirmed NAAT
(counting cases from 7 day s and 14 day s after the second dose) .
Incidence of as ymptomatic SARS -CoV -2 infection per 1000 person -years of
follow -up based on N -binding antibod y seroconversion in participants with no
serological or virological evidence of pa st SARS -CoV -2 infection or confirmed
COVID -19.
Incidence of as ymptomatic SARS -CoV -2 infection per 1000 person -years of
follow -up based on central laboratory –confirmed NAAT in participants with no
serological or virological evidence (up to the start of theasymptomatic surveillance
period) of past SARS -CoV -2 infection.
3.3.Exploratory Endpoints
3.3.1. Safety Endpoints (for Phase 1 Boostability Assessment Only)
Local reactions (pain at the injection site, redness, and swelling) for up to 7 day s after
Dose 3.
Systemic events (fever, fatigue, headache, chills, vomiting, diarrhea, new or worsened
muscle pain, and new or worsened joint pain) for up to 7 day s after Dose 3 .
AEs from Dose 3 to 1 month after Dose 3.
SAEs from Dose 3 to 1 month after Dose 3 .
3.3.2. Vaccine Efficacy Endpoints (for Phase 2/3 Only)
COVID -19 incidence per 1000 person- years of blinded follow -up based on central
laboratory or locally confirmed NAAT in participants without, and with and without,
evidence of infection (counting cases from 7 day s after the second dose) .
COVID -19 incidence per 1000 person- years of follow -up based on central laboratory
or locally confirmed NAAT in participants who received BNT162b2 at initial
randomization or subsequently (counting cases from 7 day s after the second
BNT162b2 v accination ).
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TMF Doc ID: 98.03Incidence of as ymptomatic SARS -CoV -2 infection per 1000 person -years of
follow -upbased on N -binding antibod y seroconversion in participants who received
BNT162b2 and who have no serological or virological evidence of past SARS -CoV -2
infection or confirmed COVID-19.
Incidence of as ymptomatic SARS -CoV -2 infection per 1000 person -years of
follow -up based on central laboratory –confirmed NAAT in participants with
serological or virological evidence (up to the start of theasymptomatic surveillanc e
period) of past SARS- CoV -2 infection.
3.3.3. Immunogenicity En dpoints
InPhase 1 participants participat inginboostability assessment at the following time points
after receipt of a third dose of BNT162b2:
At the time of Dose 3 and 7 day s and 1 month after Dose 3.
Below are the exploratory immunogenicit y endpoints for Phase 1:
SARS -CoV -2 reference -strain neutralizing titers .
SARS -CoV -2 SA -variant neutralizing titers .
Full-length S- binding or S1-binding IgGlevels .
InPhase 2 /3participants at the following time points after receipt of study intervention:
Baseline and1, 6, 12, and 24 months after completion of vaccination.
Below are the exploratory immunogenicit y endpoints for P hase 2/3:
SARS -CoV -2 neutralizing titers .
Full-length S- binding or S1-binding IgGlevels .
3.3.4. Additional Endpoints (for Phase 2/3 Only)
All safet y, immunogenicity ,and efficacy endpoints described above will be
summarized separatel y for participants with confirmed stable HIV .
AEs, SAEs , and SARS -CoV -2 neutralizing titers will be summarized separatel y for
participants 16 to 55 of age vaccinated with study intervention produced b y
manufacturing “Process 1” and each lot of “Process 2 .”All participants who receive d
“Process 2” vaccine and a ran dom sample of 250 participants 16 to 55 y ears of age
selected from those who received “ Process 1” vaccine will be included for the
side-by-side descriptive summary of “Process 1” and each lot of “Process 2.”
Identification of SARS -CoV -2 variant(s) .
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TMF Doc ID: 98.03SARS -CoV -2 NTs for any VOCs not alread y specified.
SARS -CoV -2 NTs for a third dose of BNT162b2 (at 30 µg or a lower dose of 5 or
10µg) or a third or fourth dose of BNT162b2 SA.
Cell-mediated immune response endpoints.
3.4.Baseline and Other Variables
Measurem ents or samples collected prior to Dose 1 are considered the baseline data for the
assessments.
3.4.1. Demographics, Medical History, and Physical Examination
The demographic variables are age at Dose 1 (in years ), sex (male or female), race
(black/African American, American Indian or Alaskan native, Asian, Native Hawaiian or
other Pacific Islander, white), and ethnicit y (Hispanic/Latino, non -Hispanic/non -Latino, not
reported). In cases where more than 1 category is selected for race, the participant would be
counted under the category “multiracial” for analysis. For Phase 2/3, BM I will also be
included in the demographic variables .
Age at the time of vaccination (in y ears) will be derived based on the participan t’s birthday .
For example, if the vaccination day is 1 day before the participant ’s 19th birthday , the
participant is considered to be 18 y ears old. For participant s who were randomized but not
vaccinated, the randomization date will be used in place of the date of vaccination at Dose 1
for the age calculation. If the randomization date is also missing, then the informed consent
date will be used for the age calculation.
Medical history will be categorized according to MedDRA. Comorbidities that increas ethe
risk for severe COVID -19 illness will be categorized based on medical history terms .
For Phase 1, a physical examination will be performed. It will evaluate an y clinically
significant abnormalities within the following body s ystems: general appearance; skin; head,
eyes, ears, nose, and throat; heart; lungs; abdomen; musculoskeletal; extremities;
neurological; and l ymph nodes. Clinically signi ficant abnormal results will be recorded in
the CRF .
For Phase 2/3, If the clinical assessment indicates that a ph ysical examination is necessary to
comprehensivel y evaluate the participant, ph ysical examination will be performed and
recorded an y findings in the source documents and, if clinically significant, it will be
recorded on the medical history CRF.
3.4.2. E- Diary Completion
For all participants in Phase 1, a subset of at least 6000 in Phase 2/3, and participants in the
subset for evaluation of boostabili ty and protection against emerging VOCs, an e-diary will
be considered transmitted if any data for local reactions, sy stemic events, or use of
antipy retic medication are present for any day. If all data are missing for all items on the
e-diary for all 7 day s after vaccination, then the e -diary will be considered not transmitted.
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TMF Doc ID: 98.03An e -diary will be considered completed if all expected data for all 7 day s are available
(ie,not missing). Otherwise, the e -diary will be considered incomplete. For an y given day ,
an e-diary will be considered complete if all expected data are available.
3.4.3. Prior/Concomitant Vaccines and Concomitant Medications
The following concomitant medications and vaccinations will be recorded in the CRF:
All vaccinations received from 28 days prior to study enrollment until the 6- month
follow -up visit (Visit 8 for Phase 1 participants, and Visit 4 for Phase 2/3 participants).
In addition, for Phase 1 participants who go on to receive a third dose of BNT162,
concomitant vaccinations will b e collected from the time the participant provides
informed consent (for receipt of Vaccination 3) through and including Visit 8c (1 month
after the third dose). For BNT162 -experienced participants in the subset for evaluation of
boostability and protecti on against emerging VOCs, all vaccinations received will be
recorded from 28 day s prior to the time the participant provides informed consent (for
participation in the subset) through and including Visit 306. For BNT162b2- naïve
participants inthe subset for evaluation of protection against emerging VOCs, all
vaccinations received will be recorded from 28 days prior to stud y enrollment through
and including Visit 405.
Prohibited medications listed in the protocol , Section 6.5.1 ,will be recorded, to includ e
start and stop dates, name of the medication, dose, unit, route, and frequency .
In addition, for participants enrolled in Phase 1, all current medication at baseline will be
recorded, to include start date, name of the medication, dose, unit, route, and frequency .
3.5.Safety Endpoints
Local reactions, s ystemic events, AEs, and SAEs have been described above in the primary
safet y endpoints.
4.ANALYSIS SET S (POPULATIONS FOR ANAL YSIS )
Data for all participants will be assessed to determine if participants meet the criteria for
inclusion in each anal ysis population prior to unblinding and releasing the database and
classifications will be documented per SOPs.
Population Description
Enrolled All participants who have a signed ICD.
Randomized All participants who are assigned a randomization number in the
IWR sy stem.
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TMF Doc ID: 98.03Population Description
Dose 1 evaluable
immunogenicit yFor Phase 1 onl y, all eligible randomized participants who receive
the vaccine to which they are randomly assigned at the first dose,
have at least 1 valid and determin ate immunogenicity result from
theblood collection within an appropriate window after Dose 1
(same as visit window, ie ,within 19-23 day s after Dose 1) , and
have no other important protocol deviations as determined by the
clinician.
Dose 2 evaluable
immu nogenicit yAll eligible randomized participants who receive 2 doses of the
vaccine to which they are randomly assigned ,with Dose 2
received within the predefined window (within 19-42 day s after
Dose 1), have at least 1 valid and determinate immunogenicity
result after Dose 2from the blood collection within an
appropriate window after Dose 2 ( within 6 -8 day s after Dose 2
for Phase 1 and within 28- 42 day s after Dose 2 for P hase 2/3),
and have no other important protocol deviations as determined b y
the clini cian.
Dose 3 booster
evaluable
immunogenicit yAll eligible randomized participants who receive 2 doses of
BNT162b2 (or BNT162b1 for Phase 1) as initially randomized,
with Dose 2 received within the predefined window (within 19-42
days after Dose 1) , receive a third dose of BNT162b2 or
BNT162b2 SAas rerandomized (or receive a third dose of
BNT162b2 for Phase 1) , have at least 1 valid and determinate
immunogenicit y result after Dose 3 from a blood collection
within an appropriate window (within 28 -42 da ys after Dose 3),
and have no other important protocol deviations as determined b y
the clinician.
Dose 4 booster
evaluable
immunogenicit yAll eligible randomized participants who receive 2 doses of
BNT162b2 as initially randomized, with Dose 2 received wi thin
the predefined window (within 19 -42 day s after Dose 1) , receive
2 booster doses of BNT162b2 SAas rerandomized, have at least 1
valid and determinate immunogenicit y result after Dose 4 from a
blood collection within an appropriate window (within 28 -42
days after Dose 4) , and have no other important protocol
deviations as determined by the clinician.
Dose 1 all -available
immunogenicit yFor Phase 1 onl y: all randomized participants who receive at least
1 dose of the stud y intervention with at least 1 val id and
determinate immunogenicity result after Dose 1 but before Dose
2.
Dose 2 all -available
immunogenicit yAll randomized participants who receive at least 1 dose of the
study intervention with at least 1 valid and determinate
immunogenicit y result afte r Dose 2.
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TMF Doc ID: 98.03Population Description
Dose 3 booster
all-available
immunogenicit yAll randomized participants who receive 2 doses of BNT162b2
(or BNT162b1 for Phase 1) at initial randomization, receive a
third dose of BNT162b2 or BNT162b2 SAat rerandomization (or
receive a third dose of BNT162b2 for Phase 1) , and have at least
1 valid and determinate immunogenicit y result after Dose 3.
Dose 4 booster
all-available
immunogenicit yAll randomized participants who receive 2 doses of BNT162b2 at
initial randomiza tion, receive 2 booster doses of BNT162b2 SAat
rerandomization, and have at least 1 valid and determinate
immunogenicit y result after Dose 4.
Evaluable efficacy
(7 day s)All eligible randomized participants who receive all
vaccination(s) as randomized , with Dose 2 received within the
predefined window (within 19 -42 day s after Dose 1) and have no
other important protocol deviations as determined by the clinician
on or before 7 day s after Dose 2.
Evaluable efficacy
(14 day s)All eligible randomized participants who receive all
vaccination(s) as randomized, with Dose 2 received within the
predefined window (within 19 -42 day s after Dose 1) and have no
other important protocol deviations as determined by the clinician
on or befor e 14days after Dose 2.
Evaluable efficacy
(seroconversion)All eligible randomized participants who receive all
vaccination(s) as randomized, with Dose 2 received within the
predefined window (within 19 -42 day s after Dose 1) , have at least
1 N-binding antibody test result available at a post–Dose 2 visit,
and have no other important protocol deviations as determined b y
the clinician prior to the first post –Dose 2 N-binding antibod y
test.
Evaluable efficacy
(asymptomatic
surveillance )All eligible randomized participants who receive all
vaccination(s) as randomized, with Dose 2 received within the
predefined window (within 19 -42 day s after Dose 1) , consented
to participate in the asymptomatic surveillance, and have no other
important protocol deviations as determined b y the clinician on or
before the start of the asymptomatic surveillance period .
All-available efficacy Dose 1 all -available efficacy : All randomized participants who
receive at least 1 vaccination.
Dose 2 all -available efficacy : All ra ndomized participants who
complete 2 vaccination doses.
Safety All randomized participants who receive at least 1 dose of the
study intervention.
Analy ses of reactogenicity endpoints will be based on a subset of
the safet y population that includes participants with any e-diary
data reported after vaccination.
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TMF Doc ID: 98.03Population Description
Booster safety All participants who receive at least 1 booster dose of the stud y
intervention.
The important protocol deviations will be determined by themedical monitor . An important
protocol deviation is a protocol deviation that, in the opinion of the sponsor’s clinician,
would materially affect assessment of immunogenicity /efficacy , eg, participant receipt of a
prohibited vaccine or medication that might affect immune response or a medication error
with suspected decrease in potency of the vaccine. The sponsor’s clinician will identify
those participant s with important protocol deviations that result in exclusion from anal ysis
populations before an y unblinded anal ysis in Phase 2/3 is carried out.
5.GENERAL METHODOLOGY AND CONVENTIONS
To facilitate rapid review of data in real time, sponsor staff will be unblinded to study
intervention allocation for the participants in Phase 1 .The majorit y of sponsor staff will be
blinded to study intervention allocation in Phase 2/3. All laboratory testing personnel
performing serology assay s will remain blinded to study intervention assigned/received
throughout the stud y. Further details can be found in the protocol, Section 6.3. The timing
for statistical anal yses is specified in Section 7.
5.1. Hypotheses and Decision Rules
5.1.1. Vaccine Efficacy Hypoth esis
Phase 2/3 of the study has 2 primary efficacy endpoints evaluating VE, which is defined as
VE= 100 × (1–IRR). IRR is calculated as the ratio of first confirmed COVID- 19 illness
rate in the active vaccine group to the corresponding illness rate in the placebo group
(see Appendix 3fordetails on the calculation of IRR and VE) . The assessment of VE will be
based o n posterior probabilities of VE 1>30% and VE 2>30% using beta-binomial models.
VE 1represents VE for prophy lactic BNT162b 2against confirmed COVID -19 in participants
without evidence of infection before vaccination, and VE 2represents VE for prophy lactic
BNT162b 2against confirmed COVID -19 in all participants after vaccination.
For participants with multiple confirmed cases, only the first case will contribute to the VE
calculation for each h ypothesis. VE 1and VE 2will be evaluated sequentially to control the
overall ty pe I error to the desired level of 2.5%. VE is demonstrated if there is sufficient
evidence ( high posterior probability ) that either VE 1>30% or both VE 1and VE 2are >30%.
The assessment for the pr imary anal ysis will be based on posterior probability using a
beta-binomial model (see Appendix 2for details) .
The secondary objectives regarding VE against asy mptomatic SARS -CoV -2 infection
(determined b y asymptomatic seroconversion of N -binding antibody and/or asymptomatic
SARS -CoV -2 infection based on central laboratory–confirmed NAAT) will be evaluated
based on the lower bound of the 95% CI calcula ted using the Clopper -Pearson method . VE
will be demonstrated if the lower bound of the 2 -sided 95% CI for VE is >20%.
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TMF Doc ID: 98.035.1.2. Immunogenicity Hypothesis
5.1.2.1. Hypothesis for Immunogenicity Bridging of 12 to 15 Years to 16 to 25 Years
One of the secondary objectives in the Phase 3 part of the study is to evaluate noninferiorit y
of the immune response to prophy lactic BNT162b2 in participants 12 to 15 y ears of age
compared to the response in participants 16 to 25 years of age at 1 month a fter Dose 2.
The (Dose 2) evaluable immunogenicit y population will be used for the following h ypothesis
testing:
H0: ln(µ 2) –ln(µ 1) ≤ ln(0.67)
where ln (0.67) corresponds to a 1.5- fold margin for noninferiorit y, ln(µ2) and ln(µ1) are the
natural log of the geometric mean of SARS -CoV -2 neutralizing titers from BNT162b2
recipients 12 to 15 years of age and 16 to 25 y ears of age , respectivel y, measured 1 month
after Dose 2 . If the lower limit of the 95% CI for the GMR (12- 15 years of age to
16-25years of age) is >0.67, the noninferiorit y objective is met.
5.1.2.2. Hypothesis for Boostability and Protection Against Emerging SARS -CoV -2
VOCs
The primary and secondary objectives for boostability and protection against emerging
VOCs for BNT162b2- experienced participants and BNT162b2- naïve participants will be
assessed based on :
GMRs of SARS -CoV -2 SA and/or reference strain neutralizing titers using a 1.5 -fold
noninferiority margin . Noninferiority is met if the lower limit of the alpha -adjusted CI
for the GMR is >0. 67 and the point estimate of the GMR is≥0.8.
The difference in percentages of participants with seroresponse to the SA strain and/or
the reference strain using a 10% noninferiority margin. Noninferiorit y is met if the lower
limit of the alpha -adjusted CI for the difference in percentages of participants with
seroresponse is > -10%.
Seroresponse is defined as achieving ≥4-fold rise from baseline (before Dose 1). If the
baseline measurement is below LLOQ, the postvaccination measure of ≥4 × LLOQ is
considered seroresponse.
5.1.3. Sample Size
5.1.3.1. Phase 1
Phase 1 comprises 15 participants (randomization ratio of 4:1 so that 12 receive active
vaccine and 3 receive placebo) per group; 13 vaccine groups are studied, corresponding to a
total of 195 participants.
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TMF Doc ID: 98.035.1.3.2. Efficacy Again st COVID -19
For Phase 2/3, with assumptions of a true VE of 60% after the second dose of study
intervention , a total of approximately 164 first confirmed COVID -19 illness cases will
provide approximately 90% power. This would be achieved with 1 7,600evaluable
participants per group or 21,999vaccine recipients randomized in a 1:1 ratio with placebo,
for a total sample size of 43,998 , based on the assumption of a 1.3 % illness rate per year in
the placebo group, accrual of 164 first primary -endpoint cases within 6 months, and 20% of
the participants being nonevaluable or having serological evidence of prior infection with
SARS -CoV -2, potentially making them immune to further infection. Dependent upon the
evolution of the pandemic, it is possible that the COVID -19 attack rate may be much higher,
in which case accrual would be expected to be more rapid, enabling the study ’s primary
endpoint to be evaluated much sooner. The total number of participants enrolled in Phase 2/ 3
may vary depending on the incidence of COVID -19 at the time of the enrollment, the true
underly ing VE, and a potential earl y stop for efficacy or futility .
5.1.3.3. Efficacy Against Asymptomatic Infection
The secondary objectives regarding VE against asy mptomatic SARS -CoV -2 infection will be
assessed in Phase 2/3 participants (determined b y asymptomatic seroconversion of N -binding
antibody and/or asymptomatic SARS -CoV -2 infection based on central laboratory –confirmed
NAAT) . Assuming a true VE of 70%, a total of 53 asy mptomatic cases will provide
approximately 90% power to conclude true VE>20%. A total of 206 cases is needed to have
90% power if the true VE is 50%. The h ypothesis forasymptomatic seroconversion of
N-binding antibody will be tested if at least 206 cases are acc rued. The h ypothesis for
asymptomatic infection based on central laboratory –confirmed NAAT in participants who
are consented to participate in the intensive surveillance phase will be tested if at least 53
cases are accrued.
5.1.3.4. Immunogenicity Bridging of 12 to 15 Years to 16 to 25 Years
In Phase 3, approximately 2000 participants are anticipated to be 12 to 15 years of age. A
random sample of 280participant s will be selected foreach of the 2 age groups (12 to 15
years and 16 to 25 y ears) as an immunogenicity subset for the noninferiority assessment.
With the standard deviation and observed GMT difference assumed in the power analysis
below, a sample size of 225 evaluable participants (or 280 vaccine recipients) per age group
will provide a powe r of 90.4% to declare the noninferiorit y of adolescent sto 16-to
25-year-olds in terms of neutralizing antibody GMR , 1 month after the second dose
(see Table 9).
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TMF Doc ID: 98.03Table 9. Power Analysis for Noninferiority Assessment
Criteria Standard Deviation
(Log Value)aAssu med Observed
GMT Difference
(Log Scale)Number of
Evaluable
Participants per
Age GroupPowerb
Lower limit of 95%
CI for GMR
(12-15/16 -25) >0.670.65 -0.2 225 90.4%
Abbreviation: GMR = geometric mean ratio; GMT = geometric mean titer.
a. R eference: 1 month after Dose 2, BNT162b2 (30µg), 18-to 55- year age group (C4591001 Phase 2).
b.At 0.05 alpha level (2 -sided).
5.1.3.5. Boostability and Protection Against Emerging SARS -CoV -2 VOCs
To assess boostability and protection against emerging SARS -CoV -2 VOCs, approximately
300 participants will be enrolled in each of the 3 groups (BNT162b2 -experienced participants
to receive either a third dose of BNT162b2 at 30 µg [Group 1] or a third dose of
BNT162b2 SA[Group 2], BNT162b2-naïve participants to receive 2 doses of BNT162b2 SA
[Group 3]) to provide an acceptable safet y database.
Assuming a 20% nonevaluable rate, approximately 240 evaluable participants in each group
will contr ibute to immunogenicity evaluation. This will provide sufficient power for
noninferiority evaluations with appropriate multiplicity adjustment for t ype I error control.
For comparisons based on GMR, the assay standard deviation in log scale is assumed to be
0.74 based on results from Phase 2 of the study and adjusted for assay variability . A GMR of
1 is assumed for each comparison.
For comparisons based on seroresponse, a 90% response rate is assumed for each
comparative group or at each comparative time p oint.
Within -Group Comparison for BNT162b2- Experienced Participants
For each randomized group of BNT162b2 -experienced participants (Group 1: received a
third dose of BNT162b2 at 30 µg ,and Group 2: received a third dose of BNT162b2 SA), with
240 evaluable participants and the stated assumptions for the GMR and standard deviation,
the study has >99.9% power to demonstrate noninferiorit ybased on GMR for the objectives
in vaccine -experienced individuals using a 1.5-fold margin.
Assuming a true response rate of 90% at each time point and 10% of the participants hav ing
a different response status at 2 comparative time points , the study has 99% power to show
noninferiority based on seroresponse rate for the objectives in vaccine -experienced
individuals using a 10% margin. The study will have 89% power to show noninferiority if
20% of the participants have a different response status at 2comparative time points.
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TMF Doc ID: 98.03Between -Group Comparison of BNT162b2 -Naïve Participants to Selected Existing Phase 3
Participants Who Received 2 Doses of BNT162b2
Approximately 300 participants will be selected from the existing Phase 3 participants who
received 2 doses of BNT162b2 to form the control group for the BNT162b2 -naïve
participants. A propensity score and Mahalanobis- metric matching approach will be used to
select the matching contro l group participants to ensure comparable distribution of age, sex,
and other demographic factors in the control group and BNT162b2 -naïve group. The
propensity score (ie, the probability of being in the BNT162 b2-naïve group rather than in the
control group) based on alogistic regression , including age, sex, and state/region as matching
factors ,will be calculated. For each BNT162b2- naïve participa nt, the 5 existing Phase 3
participant swith the closest propensity score as the preliminary matching participant s will be
identified and then the 1 with the closest Mahalanobis distance will be chosen as the final
match.
With 240 evaluable BNT162b2- naïve participants and 240 evaluable participants in the
control group and the above -stated assumptions for the GMR, standard deviation, and
seroresponse rate , the study has >99.9% power to declare noninferiority based on GMR for
the objectives in vaccine -naïve individuals using a 1.5-fold margin and 89.7% power to
declare noninferiority based on seroresponse rate using a 10% margin.
5.1.3.6. Safety
For safet y outcomes, Table 10shows the probability of observing at least 1 AE for a given
true event rate of a particular AE, for various sample sizes. For example, if the true AE rate
is 10%, with 12 participants in a vaccine group, there is 72% probability of observing at least
1AE.
Table 10. Probability of Observing at Least 1 AE by Assumed True Event Rates With
Different Sample Sizes
Assu med True
Event Rate of an AEN=12 N=45 N=180 N=300 N=3000 N=6000 N=9000 N=15000
0.01% 0. 00 0.00 0.02 0.03 0.26 0.45 0.59 0.78
0.02% 0. 00 0.01 0.04 0.06 0.45 0.70 0.83 0.95
0.04% 0.00 0.02 0.07 0.11 0.70 0.91 0.97 >0.99
0.06% 0.01 0.03 0.10 0.16 0.83 0.97 0.99 >0.99
0.08% 0.01 0.04 0.13 0.21 0.91 0.99 0.99 >0.99
0.10% 0.01 0.04 0.16 0.26 0.95 0.99 0.99 >0.99
0.15% 0.02 0.07 0.24 0.36 0.99 0.99 >0.99 >0.99
0.20% 0.02 0.09 0.30 0.45 >0.99 >0.99 >0.99 >0.99
0.25% 0.03 0.11 0.36 0.53 >0.99 >0.99 >0.99 >0.99
0.30% 0.04 0.13 0.42 0.59 >0.99 >0.99 >0.99 >0.99
0.35% 0.04 0.15 0.47 0.65 >0.99 >0.99 >0.99 >0.99
0.50% 0.06 0.20 0.59 0.78 >0.99 >0.99 >0.99 >0.99
1.00% 0.11 0.36 0.84 0.95 >0.99 >0.99 >0.99 >0.99
2.00% 0.22 0.60 0.97 >0.99 >0.99 >0.99 >0.99 >0.99
3.00% 0.31 0.75 >0.99 >0.99 >0.99 >0.99 >0.99 >0.99
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TMF Doc ID: 98.03Table 10. Probability of Observing at Least 1 AE by Assumed True Event Rates With
Different Sample Sizes
Assu med True
Event Rate of an AEN=12 N=45 N=180 N=300 N=3000 N=6000 N=9000 N=15000
5.00% 0.46 0.90 >0.99 >0.99 >0.99 >0.99 >0.99 >0.99
7.00% 0.58 0.96 >0.99 >0.99 >0.99 >0.99 >0.99 >0.99
10.00% 0.72 0.99 >0.99 >0.99 >0.99 >0.99 >0.99 >0.99
5.1.4. Multiplicity Considerations
5.1.4.1. Phase 1
For Phase 1, there is no hy pothesis testing.
5.1.4.2. Phase 2/3 Vaccine Efficacy
For Phase 2/3, a Bay esian approach will be applied for the firstprimary efficacy endpoint at
the interim and final analy ses. The boundaries for declaring efficacy at interim analy ses and
success criteria for the final anal ysis are adjusted appropriatel y to control the type I error at
0.025 ( Table 13).
5.1.4.3. Phase 2/3 Immunogenicity
Figure 1outlines the t ype I error control strategy for multiple objectives a cross different
populations (BNT162b2 -experienced or BNT162b2 -naïve) and estimands (GMR or
seroresponse).
Theobjectives for BNT162b2 -experienced participants and BNT162b2- naïve participants
will be evaluated independent ly. The vaccine -experienced and vaccine -naïve individuals are
different populations with different objectives. The 2 populations are included in the same
study to improve operational efficiency .Therefore, no t ype I error adjustments will be
applied to the assessments of the 2 population s.
For each population, the objectives will be evaluated separatel y for each estimand . To
control the overall t ype I error, the 1 -sided alpha of 0.025 will be split and allocated equall y
to each estimand. Specifically , for each estimand , the hypotheses w ill be tested in sequential
order (as listed in the objectives in Section 3) using a 1-sided alpha of 0.0125 (Figure 1,
where E and N represent vaccine -experienced and vaccine -naïve, respectively , and a and b
represent GMR and seroresponse estimands, respectively ).
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TMF Doc ID: 98.03Figure 1.Multiplici ty Schema
5.2.General Methods
Time points for local reactions and systemic events refer to data within 7 day s after each
dose. CIs for all endpoints in the statistical analy sis will be presented as 2 -sided at the 95%
level unless specified otherwise.
5.2.1. Analyses for Binary Data
Descriptive statistics for categorical variables (eg, proportions) are the percentage (%), the
numerator (n) ,and the denominator (N) used in the percentage calculation, and the 95% CI s
where applicable.
The exact 95% CI for binary endpoints for each group will be computed using the
Fdistribution (Clopper -Pearson ).1The 95% CI for the between- group difference for binary
endpoints will be calculated using the Miettinen and Nurminen method.2
For the within -group comparison of binary endpoints , eg,percentage of partici pants with
seroresponse, the 2-sided 95% CIforthe difference in proportions will be calculated using an
adjusted Wald interval as described by Agresti and Min (2005).3This is done by adding 0.5
to each cell according to Agresti and Min’s method , and thus 2 is added to the total n (see the
table below ). The following table gives a representation of the cells in a 2 ×2 table for
matched proportions of participants achieving seroresponse .
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TMF Doc ID: 98.03Illustration of cells in a 2 ×2 table for matched proportions
Time Point 1 Time Point 2
Participants with
seroresponseParticipants without
seroresponseTotal
Participants with
seroresponsea b a + b (p1)
Participants without
seroresponsec d c + d
Total a + c (p2) b + d n
The interest of comparison, p2 – p1 can be written as (a +c)/n –(a+b)/n= (c–b)/n. The
2-sided 95% CIfor the difference inmatched proportion susing the adjusted Wald method is:
( ∗− ∗)
∗± ⁄ ( ∗+ ∗)−[( ∗− ∗) ∗⁄ ]
∗
with ∗= + 0.5 , ∗= + 0.5 , ∗= + 2 , α= 0.05.
For Phase 2/3 onl y, the 3-tier approach will be used to summarize AEs. For both Tier 1
(ifany are identified during the stud y) and Tier 2 events, a 95% CI for the between- group
difference in proportions will be calculated based on the Miettinen and Nurminen2method.
In addition, for Tier 1 events (if any ), the as ymptotic p -values will also be presented for the
difference in proportions, based on the same test statistic and under the assumption th at the
test statistic is asy mptotically normally distributed. For Tier 3 events, counts and
percentages for each vaccine group will be provided.
A Bayesian beta -binomial model with a minimally informative prior will be also used for VE
primary endpoints ( see Appendix 2).
5.2.2. Analyses for Count Data
The number of occurrences of a certain event is count data and thus could be modeled using
Poisson distribution. The incidence rate is estimated as the number of events observed
divided by the total person -yearsof follow -up.
Assuming an observed event is from Poisson distribution with parameter λT, where λ is the
incidence rate and T is the total person -yearsof follow -up, based on the relationship between
the Poisson and chi-square distribution ,4theexact lower and upper α- percent 2 -sided
confidence limits for λT can be estimated by :
= , ⁄
and = ( ), ⁄
, respectivel y, where Y is the number of events observed.
The exact lower and upper confidence limit for incidence rate λ can then be obtained as
and
, respectivel y.
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TMF Doc ID: 98.035.2.3. Analyses f or Continuous Data
Unless otherwise stated, descriptive statistics for continuous variables are n, mean, median,
standard deviation, minimum, and maximum.
5.2.3.1. Geometric Means
For immunogenicity results of SARS -CoV -2 neutralizing titers, the GMTs will be comput ed
along with associated 95% CIs. The GMTs will be calculated as the mean of the assay
results after making the logarithm transformation and then exponentiating the mean to
express results on the original scale .Two-sided 95% CI s will be obtained by taking log
transforms of titers , calculating the 95% CI with reference to Student’s t- distribution, and
then exponentiating the confidence limits. Similarly , GMCs and 95% CI swill be calculated
for S1-binding IgGlevels and RBD- binding IgG levels .
5.2.3.2. Geometric Mean Fold Rises
GMFRs will be defined as the result after vaccination divided by the result before
vaccination . GMFRs are limited to participant s with nonmissing values at both time points.
GMFRs will be calculated as the mean of the difference of logarit hmicall y transformed
neutralization titers or antibody levels ( later result minus earlier result ) and exponentiating
the mean. The associated 2- sided 95% CIs are obtained by constructing CIs using Student’s
t-distribution for the mean difference on the na tural log scale and exponentiating the
confidence limits.
5.2.3.3. Geometric Mean Ratio s
For SARS -CoV -2 neutralizing titers and S1-binding IgG levels and RBD -binding IgG levels ,
the GMRs will be provided along with associated 95% CI s.GMRs will be limited to
participants with nonmissing values for both SARS- CoV -2 neutralizing titers and S1-binding
IgG level s/RBD -binding IgG levels at each time point. The GMR will be calculated as the
mean of the difference of logarithmicall y transforme d assay results (eg, SARS -CoV -2
neutralizing titers minus S1- binding IgG level for each participant) and exponentiating the
mean. Two- sided CIs will be obtained by calculating CIs using Student’s t -distribution for
the mean difference of the logarithmical ly transformed assay results and exponentiating the
confidence limits.
For SARS -CoV -2 neutralizing titers in participants 12 to 15 y ears of age and 16 to 25 y ears
of age, the GMRs will be provided along with associated 95% CI. The GMR and its 2- sided
95% CI will be derived by calculating differences in means and CIs on the natural log scale
of the titers based on the Student’s t -distribution and then exponentiating the results. The
difference in means on the natural log scale will be 12 to 15 y ears minus 16 to 25 y ears.
Noninferiorit y will be declared if the lower bound of the 2 -sided 95% CI for the GMR is
greater than 0.67.
For assessment of boostability and protection against emerging VOCs, t he comparisons of
different NTs (anti -SA or anti –reference strain) or the same NTs at different time points
within the same group will be limited to participants with nonmissing values at both time
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TMF Doc ID: 98.03points or both NT measurements. GMRs will be calculated a s the mean of the difference of
logarithmicall y transformed titers for each participant (eg, later time point minus earlier time
point) and exponentiating the mean. The associated 2- sided CIs will be obtained by
constructing CIs using Student’s t distribu tion for the mean difference on the logarithm scale
and exponentiating the confidence limits .
For the between -group comparison, GMRs will be calculated as the mean of the difference of
logarithmicall y transformed assay results between 2 groups and exponent iating the mean.
The associated 2 -sided 97.5% CIs will be obtained by calculating CIs using Student’s
t-distribution for the mean difference of the logarithmically transformed titers and
exponentiating the confidence limits.
5.2.3.4. Geometric Mean Fold Rise Ratio s
The ratios of GMFR A to GMFR B and GMFR A to GMFR C may be explored, where
GMFR A is the GMof the ratio of the SARS -CoV -2 neutralizing titer at the time point after
vaccination to the corresponding titer at the time point before vaccination, G MFR B is the
GMof the ratio of the S1-binding IgGlevel at the time point after vaccination to the
corresponding antibody level at the time point before vaccination , and GMFR C is the GMof
the ratio of the RBD -binding IgG level at the time point after vacc ination to the
corresponding antibody level at the time point before vaccination .
5.2.3.5. Reverse Cumulative Distribution Curves
Empirical RCDCs will plot proportions of participant s with values equal to or exceeding a
specified assay value versus the indicated assay value, for all observed assay values. Data
points will be joined by a step function with data points on the left side of the step.
5.3. Methods to Manage Missing Data
For endpoints, the m issing data handling rules are described in the corresponding endpo int
sections.
For the missing dates, the sponsor data standard rules for imputation will be applied
(eg,partial dates for AEs will be imputed according to Pfizer standard algorithms).
Missing COVID -19 test data in Phase 2/3 for computing VEwill be impute d in the
sensitivity anal ysis.Details are included in Section 6.1.3.1.2 .
6.ANALYSES AND SUMMARIES
6.1.Primary Endpoint (s)
6.1.1. Safety Endpoints
The safet y analyses after the first dose and after booster dose(s) are based on the safet y
population and booster safet y population, respectively. Anal yses of reactogenicity endpoints
are based on a subset of the safet y population that includes participants with any e-diary data
reported after vaccination. Participants will be summarized by vaccine group according to
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TMF Doc ID: 98.03the study interventions they actuall y received. Missing e -diary data will not be imputed;
missing AE dates will be handled accord ing to the Pfizer safet y rules.
6.1.1.1. Local Reactions
6.1.1.1.1. Main Analysis
Estimand: The percentage of participants reporting local reactions (redness, swelling ,and
pain at the injection site) within 7 days after each dose (Section 2.1).
Analy sis set:Safety or booster safet y populations ( Section 4).
Analy sis time point: Within 7 day s after each dose .
Analy sis methodology : Descriptive statistics (Section 5.2.1 ).
Intercurrent events and missing data: The participants without any e-diary data
throughout the 7 day s after vaccination will be excluded from the anal ysis at that
particular vaccination ; missing values will not be imputed.
Report ing results: Descriptive statistics for each and any local reaction after each dose in
each vaccine group will be presented b y maxi mum severity and cumulatively across
severit y levels. Confirmed e -diary errors will be excluded from t he anal ysis. Descriptive
summary statistics will include counts and percentages of participants with the indicated
endpoint and the associated 2-sided Clopper -Pearson 95% CI s.
6.1.1.1.2. Supplementary Analyses
To support the assessment of local reactions, the follow ing endpoints (as defined in
Section 3.1.1.1 ) will be summarized with the same anal ysis time point and analysis
population , analy sis me thodology ,and appropriate reporting results. Confirmed e -diary
errors will be excluded from these analyses.
Duration (day s) of each local reaction after each dose .
Onset day of each local reaction after each dose .
These continuous endpoints will be summarized by display ing n, mean, median, standard
deviation, minimum, and maximum for each vaccine group.
Figures:
Bar charts with the proportions of participants for each local reaction throughout 7 day s will
be plotted for each vaccine group. The bars will be divided into severit y categories to
highlight the proportions of participants b y maximum severity .
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TMF Doc ID: 98.036.1.1.2. Systemic Events
6.1.1.2.1. Main Analysis
Estimand: The percentage of participants reporting s ystemic events ( fever, fatigue,
headache, chills, vomiting, diarrhea, new or worsened muscle pain, and new or worsened
jointpain) within 7 day s after each dose (Section 2.1 ).
Analy sis set: S afety or booster safet y populations ( Section 4).
Analy sis time point: Within 7 day s after each dose .
Analy sis methodology : Descriptive statistics (Section 5.2.1 ).
Intercurrent events and missing data: The participants without any e-diary data
throughout the 7 day s after vaccination will be excluded from the anal ysis at that
particular vaccination ; missing values will not be imputed.
Reporting result s: Descriptive statistics for each systemic event after each dose in each
vaccine group will be presented by maximum severity and cumulatively across severity
levels. Descriptive summary statistics will include counts and percentages of participants
with the indicated endpoint and the associated 2-sided Clopper -Pearson 95% C Is.
6.1.1.2.2. Supplementary Analyses
The following endpoints for assessment of s ystemic events will be summarized similarly to
the assessment of local reactions:
Duration of each s ystemic event after each dose .
Onset day of each s ystemic event after each dose .
These continuous endpoints will be summarized by display ing n, mean, median, standard
deviation, minimum, and maximum for each vaccine gr oup.
The use of antip yretic medication (see Section 3.1.1.3 ) will be summarized similarly to
systemic events, except that there is no se verity level associated with the use of antipy retic
medication.
Figures:
Bar charts with the proportions of participant s reporting each s ystemic event throughout
7days after each dose will be plotted for each vaccine group. The bars will be divided into
severit y categories to highlight the proportions of participant s by severity .
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TMF Doc ID: 98.036.1.1.3. Adverse Events
6.1.1.3.1. Main Analysis
Estimand: The percentage of participants reporting AEs from Dose 1 to 1 month after the
second dose for all phases, from Dose 1 to 7 day s after the second dose for the first 360
participants randomized in Phase 2 , from Dose 1 (of booster BNT162b2 or BNT162b2 SA)
to 1 month after the last dose for participants in the Phase 3 subset for evaluation of
boostability and protection against emerging VOCs , and from Dose 3 to 1 month after
Dose 3 for participants receiving BNT162b2 as a third dose as part of protocol
amendment 18 (Section 2.1 ).
Analy sis set: Safety orbooster safet y populations ( Section 4).
Analy sis time point: Dose 1 to 1 month after the second dose for all phases, Dose 1 to 7
days after the second dose for the first 360 participants randomized in Phase 2 , Dose 1
(of boost er BNT162b2 or BNT162b2 SA) to 1 month after the last dose for participants in
the Phase 3 subset for evaluation of boostability and protection against emerging VOCs ,
and from Dose 3 to 1 month after Dose 3 for participants receiving BNT162b2 as a third
dose as part of protocol amendment 18.
Analy sis methodology : Descriptive statistics ( Section 5.2.1 ) for all phases andadditional
3-tiered approach for Phase 2/3 (Section 3.1.1.4 ).
Intercurrent events and missing data: Partial AE dates will be imputed using the Pfizer
standard algorithm.
Reporting result s: AEs will be categorized according to MedDRA terms. A 3-tier
approach will be used to summarize AEs for Phase 2/3 only . Under this approach AEs
are classified into 1 of 3 tiers (Section 3.1.1.4 ). For both Tier 1 and Tier 2 events, 2 -sided
95% CI s for the difference between the active vaccine and placebo groups in the
percentage of participants reporting the events based on the Mi ettinen and Nurminen2
method will be provided. In addition, for Tier 1 events, the as ymptotic p -values will also
be presented for the difference betw een groups in the percentage of participants reporting
the events, based on the same test statistic and under the assumption that the test statistic
is asy mptoticall y normally distributed. AE display s will be sorted in descending order of
point estimates of risk difference within SOC . Descriptive summary statistics (counts,
percentages, and associated Clopper- Pearson 95% CI s) will be provided for any AEs for
each vaccine group.
6.1.1.3.2. Supplementary Analyses
Immediate AEs (within the first 30 minutes after each dose) will also be summarized for each
vaccine group . All AEs after informed consent and prior to the first vaccination will not be
included in the anal yses but will be listed.
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TMF Doc ID: 98.036.1.1.4. Serious Adverse Events
6.1.1.4.1. Main Analyses
Estimand: The percentage of participants reporting SAEs from Dose 1 to 6 month s after
the second dose for all phases, from Dose 1 to 7 day s after the second dose for the first
360 participants randomized in Phase 2 , from Dose 1 (of booster BNT162b2 or
BNT162b2 SA) to 5 or 6 months after the last dose for participants in the Phase 3 subset
for evaluation of boostability and protection against emerging VOCs , and from Dose 3 to
6 months after Dose 3 for participants receiving BNT162b2 as a third dose as part of
protocol amendment 18 (Section 2.1).
Analy sis set: Safety or booster safet y populations ( Section 4).
Analy sis time point: Dose 1 to 6 month safter the second dose for all phases, Dose 1 to 7
days after the second dose for the first 360 participants randomized in Phase 2 , Dose 1
(of booster BNT162b2 or BNT162b2 SA) to 5 or 6 months after the last dose for
participants in the Phase 3 subset for evaluation of boostability and protection against
emerging VOCs , and from Dose 3 to 6 months after Dose 3 for participants receiving
BNT162b 2 as a third dose as part of protocol amendment 18 .
Analy sis methodology : Descriptive s tatistics ( Section 5.2.1 ).
Intercurrent events and missing data: Partial SAE dates will be imputed using the Pfizer
standard algorithm.
Reporting results: SAEs will be categorized according to MedDRA terms. Counts,
percentages, and the associated Clopper -Pearson 95% CI s of SAEs will be provided for
each vaccine group.
6.1.1.5. Hematology and Chemistry Parameters (for Phase 1 Only)
6.1.1.5.1. Main Analyses
Estimand s: The percentage of participants with abnormal hematology and chemistry
laboratory values 1 and 7 day s after Dose 1; and 7 day s after Dose 2 ( Section 2.1).
The percentage of participants with grading shifts in hematology and chemistry
laboratory assessments between baseline and 1 and 7 day s after Dose 1; and before
Dose 2 and 7 day s after Do se 2 ( Section 2.1).
Analy sis set: Safety population ( Section 4).
Analy sis time point: 1 and 7 day s after Dose 1; and 7 day s after Dose 2.
Analy sis methodology : Descriptive statistics including counts and percentage
(Section 5.2.1 ).
Intercurrent events and missing data: Missing values will not be imputed.
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TMF Doc ID: 98.03Reporting results: Descriptive summary statistics will be provided including counts and
percentages of participants with the indicated endpoint and the associated
Clopper -Pearson 2 -sided 95% CI s.
6.1.2. Immunogenicity Endpoints (for the Phase 3 Subset for Evaluation of Boostability
and Protection Against Emerging VOCs Only)
6.1.2.1. SARS -CoV -2 Reference Strain NT and SA NT at 1 Month After Dose 3 vs
Reference Strain NT at 1 Month After Dose 2 in BNT162b2 -Experienced Participants
6.1.2.1.1. Main Analyses
Estimands:
E1a: GMR of reference strain NT 1 month after the third dose of BNT162b2 at 30 μg
to 1 month af ter the second dose of BNT162b2 in the same individuals (Section 2.1).
E2a: GMR of SA NT 1 month after 1 dose of BNT162b2 SAto the reference strain NT
1 month after the second dose of BNT162b2 in the same individuals (Section 2.1).
Analy sis set: Dose 3booster evaluable and all -available immunogenicit ypopulations
(Section 4).
Analy sis time points: 1 month after the second dose of BNT162b2, 1 month after the
third dose of BNT162b2 at 30 µg , and 1 month after 1 dose of BNT162b2 SA.
Analy sis methodology : The compa risons of different NTs (anti -SA or anti –reference
strain) or the same NTs at different time points within the same group will be limited to
participants with nonmissing values at both time points or both NT measurements. GMRs
will be calculated as the mea n of the difference of logarithmically transformed titers for
each participant (eg, later time point minus earlier time point) and exponentiating the
mean (Section 5.2.3.3 ). The associated 2 -sided 9 7.5% CI s will be obtained by
constructing CIs using Student’s t-distribution for the mean difference on the logarithm
scale and exponentiating the confidence limi ts.Noninferiority of E1a and E2a will be
assessed sequentially . Noninferiority will be declared if the lower bound of the 2- sided
97.5% CI for the GMR is >0.67 and the point estimate of the GMR is ≥0.8.
Intercurrent events and missing data: Titers below the LLOQ or denoted as BLQ will be
set to 0.5 × LLOQ for analy sis. However, this calculation may be adjusted based upon
additional data from the assay . Missing data will not be imputed.
Reporting results: The GMTs at each time point, GMRs ,and the associated 2 -sided
97.5% CI s will be provided.
Figures:
Empirical RCDCs will be provided for SARS- CoV -2 SA and reference s train NTs at each
time point.
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TMF Doc ID: 98.036.1.2.2. Seroresponse to the Reference Strain and SA Strain at 1 Month After Dose 3 vs
Seroresponse to t he Reference Strain at 1 Month After Dose 2 in BNT162b2 -
Experienced Participants
6.1.2.2.1. Main Analyses
Estimands:
E1b: The difference in percentages of participants with seroresponse to the reference
strain at 1 month after the third dose of BNT162b2 at 30 µg and 1 month after the
second dose of BNT162b2 in the same individuals (Section 2.1).
E2b: The difference in percentages of participants with seroresponse to the SA strain
at 1 month after 1 dose of BNT162b2 SAand seroresponse to the reference strain at
1month after the s econd dose of BNT162b2 in the same individuals (Section 2.1).
Analy sis set: Dose 3booster evaluable and all -available immunogenicit ypopulations
(Section 4).
Analy sis time points: 1 month after the second dose of BNT162b2, 1 month after the
third dose of BNT162b2 at 30 μg , and 1 month after 1 dose of BNT162b2 SA.
Analy sis methodology : Similar to E1a and E2a, the within -group comparisons of
seroresponse to different NTs (anti- SA or anti –reference strain) or the same NTs at
different time points within the same group w ill be limited to partic ipants with
nonmissing values at both time points or both NT measurements. The percentages of
participants with seroresponse at each time point and the difference in percentages will be
provided. The 2 -sided 97.5% CI s for the diffe rence in percentages of participants with
seroresponse will be calculated using the adjusted Wald interval as described byAgresti
and Min (2005)3for comparing matched proportions ( Section 5.2.1 ). Noninferiorit y of
E1b and E2b will be assessed sequentially . Noninferiorit y will be declared if the lower
bound of the 2- sided 97.5% CI for the difference in percentages of participants with
seroresponse is greater than -10%.
Intercurrent events and missing data: Titers below the LLOQ or denoted as BLQ will be
set to 0.5 × LLOQ for analy sis. However, this calculation may be adjusted based upon
additional data from the assay . Missing data will not be imputed.
Reporting results: The c ounts, percentages of participants with seroresponse at each time
point, the difference in percentages ,and the associated 2 -sided 97.5% CIs will be
provided.
6.1.2.3. SARS -CoV -2 SA NT at 1 Month After Dose 2vsReference Strain NT at 1
Month After Dose 2 in BNT162b2 -Naïve Participants
6.1.2.3.1. Main Analyses
Estimands:
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TMF Doc ID: 98.03N1a: GMR of SA NT 1 month after the second dose of BNT162b2 SAto the reference
strain NT 1 month after the second dose of BNT162b2 ( Section 2.1).
Analy sis set: Dose 2evaluable and all -available immunogenicit ypopulations ( Section 4).
Analy sis time points: 1 month after the second dose of BNT162b2 and1 month after the
second dose of BNT162b2 SA.
Analy sis methodology : For the between -group comparison, GMR swill be calculated as
the mean of the difference of logarithmicall y transformed assay results between 2 groups
and exponentiating the mean ( Section 5.2.3.3 ). The associated 2-sided 97.5% CIs will be
obtained by calculating CIs using Student’s t -distribution for the mean difference of the
logarithmically transformed titers and exponentiating t he confidence limits.
Noninferiorit y will be declared if the lower bound of the 2- sided 97.5% CI for the GMR
is >0.67 and the point estimate of the GMR is ≥0.8.
Intercurrent events and missing data: Titers below the LLOQ or denoted as BLQ will be
set to 0.5 × LLOQ for analysis. However, this calculation may be adjusted based upon
additional data from the assay . Missing data will not be imputed.
Reporting results: The GMTs at each time point, GMRs ,and the associated 2 -sided
97.5% CI s will be provided.
Figures:
Empirical RCDCs will be provided for SARS- CoV -2 SA and reference strain NTs at each
time point for each vaccine group .
6.1.2.4. Seroresponse to the SA Strain at 1 Month After Dose 2 vs Seroresponse to the
Reference Strain at 1 Month After Dose 2 in BNT162b 2-Naïve Pa rticipants
6.1.2.4.1. Main Analyses
Estimands:
N1b: The difference in percentages of participants with seroresponse to the SA strain
at 1 month after the second dose of BNT162b2 SAand seroresponse to the reference
strain at 1 month after the second dose of BNT162b2 (Section 2.1).
Analy sis set: Dose 2evaluable and all -available immunogenicit ypopulations ( Section 4).
Analy sis time points: 1 month after the second dose of BNT162b2 and1 month after the
second dose of BNT162b2 SA.
Analy sis methodology : Thedifference in percentages of participants with seroresponse
and associated 2 -sided 97.5% CI s will be calculated using the Miettinen and Nurminen
method2(Section 5.2.1 ).Noninferiorit y will be declared if the lower bound of the
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TMF Doc ID: 98.032-sided 97.5% CI for the difference in percentages of participants with seroresponse is
greater than -10%.
Intercurrent events and missing data: Titers below the LLOQ or denoted as BLQ will be
set to 0.5 × LLOQ for analy sis. However, this calculation may be adjusted based upon
additional data from the assay . Missing data will not be imputed.
Reporting results: The counts, percentages of participants with seroresponse at each time
point, the difference in percentages ,and the associated 2 -sided 97.5% CIs will be
provided.
6.1.3. Vaccin e Efficacy Endpoints (for Phase 2/3 Only)
6.1.3.1. COVID -19 Incidence per 1000 Person -Years of Follow -up
6.1.3.1.1. Main Analyses
Estimand s:
100 × (1 – IRR) [ratio of confirmed COVID -19 illness from 7 day s after the second
dose per 1000 person -years of follow -up in participants without evidence of inf ection
(prior to 7 day s after receipt of the second dose) for the active vaccine group to the
placebo group ( Section 2.1)].
100 × (1 – IRR) [ ratio of confirmed COVID -19 illness from 7 day s after the second
dose per 1000 person -years of follow -up in participants with and without evidence of
infection (prior to 7 day s after receipt of the second dose) for the active vaccine group
to the placebo group ( Section 2.1)].
Analy sis set: Evaluable efficacy (7 day s) and all -available efficacy populations
(Section 4).
Analy sis time point: At interim anal yses and final analysis when the surveillance period
ends.
Analy sis methodology : Assessment of VE will be performed for confirmed COVID-19
from 7days after the receipt of the second dose of study intervention onwards, and will
be estimated b y 100 × (1 –IRR), where IRR is the calculated ratio of COVID -19 illness
rate per 1000 person -years of follow -up in the active vaccine group to the corresponding
illness rate in the placebo group after the second dose (see Appendix 3for details on the
derivation of IRR and VE). The posterior probability (ie, P[VE >30%|data]) a t each
interim analy sis and final analysis will be computed using a beta -binomial model and a
specified minimally informative beta distribution as prior (details can be found in
Appendix 2).
Intercurrent events and missing data: Missing efficacy data (symptom is present without
laboratory testing data) will not be imputed in the main anal yses.
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TMF Doc ID: 98.03Reporting results: The point estima te of VE, 95% credible intervals using the 2.5 th
percentile and the 97.5 thpercentile, and Bay esian posterior probability of VE greater
than 30% will be provided (details can be found in Appendix 2).
6.1.3.1.2. Sensitivity and Supplemental Analyses
With MAR assumption, a missing efficacy endpoint (laboratory -confirmed COVID -19
results ) may be imputed based on predicted probability using the full y conditional
specification method.5 The imputation will run multiple times (up to 1000) and summary
statistics similar to those used in the main anal ysiswill be tabulated across the imputations.
Other imputation methods witho utthe MAR assumption may be explored, eg , a tipping point
analysis.
All COVI D-19 cases after Dose 1 may be anal yzed using the Dose 1 all- available efficacy
population. COVI D-19 disease -related information may be summarized or listed.
After the final efficacy analy ses at 164 first primary cases , updated efficacy analy ses will be
performed with additional data accrued. The point estimate of VE in the blinded follow -up
period and associated 2 -sided 95% CI will be derived using the Clopper Pearson method
adjusted for surveillance time , and t he posterior probability (ie, P[VE >30%|data]) will be
provided. VE at different follow -uptime interval sand against different variant strains may
be assessed.
Efficacy could also be assessed over a longer time period using time- to-event data anal ysis
methods to account for censoring ( participants censored when they receive other vaccines or
withdraw ) as well as potentially confounding factors. A Kaplan -Meier curve showing the
cumulative incidence of COVID-19 cases ov er time may also be informative to understand
the sustainability of VE.
For the assessment of efficacy in the presence of potential crossover, the established
adjusting methods may be considered . For example, a rank-preserving structural failure time
mode l may be appropriate to attempt to reconstruct data for the control arm as if crossover
had not occurred, with the aim of reducing bias an d allowing the vaccine effect to be
assessed more accuratel y.
6.2. Secondary Endpoints
6.2.1. Immunogenicity Endpoints
Phase 1
The statistical anal ysis of immunogenicit y results for Phase 1 will be primarily based on the
Dose 1 and Dose 2 evaluable immunogenicity populations. Serology data after a
postbaseline positive SARS -CoV -2 test result will not be included in the analy sis based on
the evaluable immunogenicity populations. An additional analy sis will be performed based
on the all -available populations if there is a large enough difference in sample size between
the all -available immunogenicity population and the evaluable immunogenicity population.
Participants will be summarized according to the vaccine group to which they were
randomized. Missing serology data will not be imputed.
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TMF Doc ID: 98.03Phase 2/3
The statistical anal ysis of immunogenicit y results for Phase 2/3 will be based on Dose 2
evaluable immunogenicity population. Serology data after a postbaseline positive
SARS -CoV -2 test result will not be included in the anal ysis based on the evaluable
immunogenicit y population . An additional anal ysis may be performed based on the Do se 2
all-available immunogenicity population if needed. Participants will be summarized
according to the vaccine group to which they were randomized. Missing serology data will
not be imputed .
6.2.1.1. SARS -CoV -2 Neutralizing Titers (Phase 1 )
6.2.1.1.1. Main Analyses
Estimand s:
GMTs (Section 2.1).
GMFR from before vaccination to each subsequent time point after vaccination
(Section 2.1).
Proportion of participants achieving ≥4-fold rise from before vaccination to each
subsequent time point after vaccination ( Section 2.1).
Analy sis set: Dose 1 and Dose 2 evaluable and all -available immunogenicity population s
(Section 4).
Analy sis time point s: 7 and 21 day s after Dose 1; 7 and 14 days and 1, 6, 12 and
24months after Dose 2 .
Analy sis methodology : GMs and the associated 2 -sided CI s will be derived by
calcul ating means and CIs on the natural log scale based on Student’s t- distribution, and
then exponentiating the results (Section 5.2.3.1 ).GMFRs will be limited to participants
with nonmissing values prior to the first dose and at the postvaccination time point. The
GMFR will be calculated as the mean of the difference of logarithmically transformed
assay results (later time point – earlie r time point) and exponentiated to transform results
back to the original scale. Two- sided CIs will be obtained by calculating CI s using
Student’s t -distribution for the mean difference of the logarithmically transformed assay
results and exponentiating the confidence limits ( Section 5.2.3.2 ).Percent ages of
partic ipants with ≥4 -fold rise will be calculated with the associated 2- sided 95% C Is
(Clopper -Pearson method ).
Intercurrent events and missing data: Titers below the LLOQ or denoted as BLQ will be
set to 0.5 × LLOQ for analy sis.However, this calculation may be adjusted based upon
additional data from the assay . Missing data wil l not be imputed.
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TMF Doc ID: 98.03Reporting results: The GMTs at each time point , GMFRs from before vaccination to each
subsequent time point after vaccination , and the percent ages of partic ipants achieving
≥4-fold rise and the associated 2-sided 95% CIs from before vacc ination toeach time
point after vaccination .
Figures:
Empirical RCDCs will be provided for SARS -CoV -2 neutralizing titers after Dose 1 and
after Dose 2 (Section 5.2.3.5 ).
6.2.1.2. S1-Binding IgG Levels and RBD -Binding IgG L evels (Phase 1)
6.2.1.2.1. Main Analyses
Estimand s:
GMCs (Section 2.1).
GMFR from before vaccination to each subsequent time point after vaccination
(Section 2.1 ).
Proportion of participants achieving ≥4-fold r ise from before vaccination to each
subsequent time point after vaccination ( Section 2.1).
Analy sis set: Dose 1 and Dose 2 evaluable and all -available immunogenicity population s
(Section 4).
Analy sis time point s: 7 and 21 day s after Dose 1; 7 and 14 days and 1, 6, 12, and
24months after Dose 2 .
Analy sis methodology : GMs and the associated 2 -sided CI s will be derived by
calculating means and CIs on the natural log scale based on Student’s t- distribution, and
then exponentiating the results ( Section 5.2.3.1 ). GMFRs will be limited to participants
with nonmissing values prior to the first dose and at the postvaccination time point. The
GMFR will be calculated by exponentiating the mean of the difference of logarithmically
transformed assay results (later time point – earlier time point). Two -sided CI s will be
obtained by calculating CI s using Student’s t -distribution for the mean difference of the
logarithmicall y transformed assay results and exponentiating the confidence limits
(Section 5.2.3.2 ). Percenta ges of partic ipants with ≥4-fold rise will be calculated with the
associated 2- sided 95% CI s (Clopper -Pearson method).
Intercurrent events and missing data: Concentrations below the LLOQ or denoted as BLQ
will be set to 0.5 × LLOQ for analy sis.However, this calculation may be adjusted based
upon additional data from the assay .Missing data will not be imputed.
Reporting results: The GMC s, GMFRs, and percent ages of partic ipants with ≥4-fold rise
and the associated 2 -sided 95% CI s will be provided for eac h study intervention
(active/placebo) within each group before vaccination and at each time point.
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TMF Doc ID: 98.03Figures:
Empirical RCDCs will be provided for S1-binding IgGlevels and RBD -binding IgG levels
after Dose 1 and after Dose 2 (Section 5.2.3.5 ).
6.2.1.3. SARS -CoV -2 Neutralizing Titers vsSARS -CoV -2S1-Binding IgG Levels and
RBD -Binding IgG L evels (Phase 1)
6.2.1.3.1. Main Analyses
Estimand s:
GMRof SARS -CoV -2 neutralizing titer sto S1-binding IgGlevels (Section 2.1).
GMR of SARS -CoV -2 neutralizing titer sto RBD- binding IgG levels (Section 2.1).
Analy sis set: Dose 1 and Dose 2 evaluable and all -available immunogenicity population s
(Section 4).
Analy sis time point s: 7 and 21 day s after Dose 1; 7 and 14 days and 1, 6, 12, and
24months after Dose 2 .
Analy sis methodology : GMRs will be limited to participants with nonmissing values fo r
both SARS -CoV -2 neutralizing titers and S1-binding IgGlevel or RBD -binding IgG
level at each time point. The GMR will be calculated as the mean of the difference of
logarithmicall y transformed assay results (eg, SARS -CoV -2 neutralizing titers minus
S1-binding IgGlevels for each participant) and exponentiat ing the mean
(Section 5.2.3.3 ).Two-sided CI s will be obtained by calculati ng CIs using Student’s
t-distribution for the mean difference of the logarithmically transformed assay results and
exponentiating the confidence limits (Section 5.2.3.3 ).
Intercurrent events and missing data: Concentrations below the LLOQ or denoted as BLQ
will be set to 0.5 × LLOQ for analy sis.However, this calculation may be adjusted based
upon additional data from the assay .Missing data will not be imputed.
Reporting results: The GMRs and the associated 2 -sided 95% CIs will be provided for
each study intervention within each group before vaccination and at each time point.
6.2.1.4. SARS -CoV -2 Neutralizing Titer sin Participants 12 to 15 Years of Age vs Those
16 to 25 Years of Age (Phase 2/3 )
6.2.1.4.1. Main Analyses
Estimands: GMR ,estimated by the ratio of the geometric mean of SARS -CoV -2
neutralizing titers in the 2 age groups (12 -15 years of age to 16- 25 years of age) 1 m onth
after completion of vaccination (Section 2.1).
Analy sis set: Dose 2 evaluable and all -available immunogenicit y populations ( Section 4).
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TMF Doc ID: 98.03Analy sis time points: 1 month after Dose 2 .
Analy sis methodology : The GMR and its 2- sided 95% CI will be derived by calculating
differences in means and CI s on the natural log scale of the titers based on the Student’s
t-distribution and then exponentiating the results. The difference in means on the natural
log scale will be 12 to 15 y ears minus 16 to 25 y ears. Noninferiorit y will be declared if
the lower bound of the 2 -sided 95% CI for the GMR is greater than 0.67
(Section 5.2.3.3 ).
Intercurrent events and missing data: Concentrations below the LLOQ or denoted as BLQ
will be set to 0.5 × LLOQ for analy sis. However, this calculation may be adjusted based
upon additional data from the assay . Missing data will not be imputed.
Reporting results: The GMRs and the associated 2 -sided 95% CIs will be provided.
6.2.1.4.2. Supplemental Analyses
The counts, percentages of participants with seroresponse (achieving ≥4-fold rise from
baseline ,as defined in Section 5.1.2.2 ), the difference in percentages between the 2 age
groups (12- 15 years of age minus 16-25 years of age) ,and the associated 2 -sided 95% CIs
will be provided .
6.2.1.5. SARS -CoV -2 SANT and Reference Strain NT at 1 Month After Dose 3 vs
Reference Strain NT at 1 Month After Dose 2 in BNT162b2 -Experienced Participants
6.2.1.5.1. Main Analyses
Estimands:
E3a: GMR of SA NT 1 month a fter the third dose of BNT162b2 at 30 μg to the
reference strain NT 1 month after the second dose of BNT162b2 in the same
individuals (Section 2.1).
E4a: GMR of reference strain NT 1 month after 1 dose of BNT162b2 SAto 1 month
after the second dose of BNT162b2 in the same individuals ( Section 2.1).
Analy sis set: Dose 3booster evaluable and all -available immunogenicit ypopulations
(Section 4).
Analy sis time points: 1 month after the second dose of BNT162b2, 1 month after the
third dose of BNT162b2 at 30 µg , and 1 month after 1 dose of BNT162b2 SA.
Analy sis methodology : GMRs and t he associated 2 -sided 97.5% CIs will be calculated in
the same way as for the primary endpoints E1a and E2a ( Section 6.1.2.1.1 ). If
noninferiority is established for both E1a and E2a, E3a and E4a will be assessed
sequentially using the same criterion ( lower bound of the 2- sided 97.5% CI for the GMR
is >0.67 and the point estimate of the GMR is ≥0.8).
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TMF Doc ID: 98.03Intercurrent events and missing data: Titers below the LLOQ or denoted as BLQ will be
set to 0.5 × LLOQ for analy sis. However, this calculation may be adjusted based upon
additional data from the assay . Missing data will not be imputed.
Reporting results: The GMTs at each time point, GMRs ,and the associated 2 -sided
97.5% CI swill be provided.
Figures:
Empirical RCDCs will be provided for SARS- CoV -2 SA and reference strain NTs at each
time point.
6.2.1.6. Seroresponse to the SA Strain and Reference Strain at 1 Month After Dose 3 vs
Seroresponse to the Reference Strain at 1 Month After Dose 2 in BNT162b2-
Experienced Participants
6.2.1.6.1. Main Analyses
Estimands:
E3b: The difference in percentages of participants with seroresponse to the SA strain
at 1 month after the third dose of BNT162b2 at 30 μg and serore sponse to the
reference strain at 1 month after the second dose of BNT162b2 in the same
individuals (Section 2.1).
E4b: The difference in percentages of participants with seroresponse to the reference
strain at 1 month after 1 dose of BNT162b2 SAand 1 month after the second dose of
BNT162b2 in the same i ndividuals (Section 2.1).
Analy sis set: Dose 3booster evaluable and all -available immunogenicit ypopulations
(Section 4).
Analy sis time points: 1 month after the second dose of BNT162b2, 1 month after the
third dose of BNT162b2 at 30 µg , and 1 month after 1 dose of BNT162b2 SA.
Analy sis methodology : The differen ce in percentages of participants with seroresponse
and the associated 2 -sided 97.5% CI s will be calculated in the same way as for the
primary endpoints E1b and E2b ( Section 6.1.2.2.1 ). If noninferiority is established for
both E1b and E2b, E3b and E4b will be assessed sequentially using the same criterion
(lower bound of the 2- sided 9 7.5% CI for the difference in percentages is greater
than -10% ).
Intercurrent events and missing data: Titers below the LLOQ or denoted as BLQ will be
set to 0.5 × LLOQ for analy sis. However, this calculation may be adjusted based upon
additional data from the assay . Missing data will not be imputed.
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TMF Doc ID: 98.03Reporting results: The counts, percentages of participants with seroresponse at each time
point, the difference in percentages ,and the associated 2 -sided 97.5% CIs will be
provided.
6.2.1.7. SARS -CoV -2 SA NT After Dose 3(BNT162b2- Experienced Participants)
6.2.1.7.1. Main Analyses
Estimands:
GMR of SA NT 1 month after 1dose of BNT162b2 SAto 1 month after the third dose
of BNT162b2 at 30 μg ( Section 2.1).
The difference in percentages of participants with seroresponse to the SA strain at
1month after 1 dose of BNT162b2 SAand 1 month after the third dose of BNT162b2
at 30 µg ( Section 2.1).
Analy sis set: Dose 3booster evaluable and all -available immunogenicit ypopulations
(Section 4).
Analy sis time points: 1 month after the third dose of BNT162b2 at 30 μg and 1 month
after 1 dose of BNT162b2 SA.
Analy sis methodology : GMR and the associated 2 -sided 95% CI will be calculated in the
same way as for the primary endpoint N1a ( Section 6.1.2.3.1 ).The difference in
percentages of participants with se roresponse and the associated 2 -sided 95% CI s will be
calculated in the same way as for the primary endpoints N1b ( Section 6.1.2.4.1 ).
Intercurrent events and missing data: Titers below the LLOQ or denoted as BLQ will be
set to 0.5 × LLOQ for analy sis. However, this calculation may be adjusted based upon
additional data from the assay . Missing data will not be imputed.
Reporting results: The GMTs at each time point, GMRs ,and the associated 2 -sided 95%
CIs will be provided. The counts, percentages of participants with seroresponse at each
time point, the difference in percentages ,and the associated 2 -sided 95% CIs will be
provided.
Figures:
Empirical RCDCs will be provided for SARS- CoV -2 SA NTs at each time point for each
vaccine group.
6.2.1.8. SARS -CoV -2 SA NT at 1 Month After Dose 4 vs Reference Strain NT at 1
Month After Dose 2 in BNT162b2 -Experienced Participants
6.2.1.8.1. Main Analyses
Estimands:
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TMF Doc ID: 98.03GMR of SA NT 1 month after the second dose of BNT162b2 SAto the reference strain
NT 1 month after the second dose of BNT162b2 in the same individuals
(Section 2.1 ).
The difference in percentages of participants with seroresponse to the SA strain at
1 month after the second dose of BNT162b2 SAand seroresponse to the reference
strain at 1 month after the second dose of BNT162b2 in the same individuals
(Section 2.1).
Analy sis set: Dose 4booster evaluable and all -available immunogenicit ypopulations
(Section 4).
Analy sis time points: 1 month after the second dose of BNT162b2 and 1 month after the
second dose of BNT162b2 SA.
Analy sis methodology : GMR and the associated 2 -sided 95% CI will be calculated in the
same way as for the primary endpoint s E1a and E2a (Section 6.1.2.1 ).The difference in
percentages of participants with seroresponse and the associated 2 -sided 95% CI s will be
calculated in the same way as for the primary endpoints E1b and E2b ( Section 6.1.2.2.1 ).
Intercurrent events and missing data: Titers below the LLOQ or denoted as BLQ will be
set to 0.5 × LLOQ for analy sis. However , this calculation may be adjusted based upon
additional data from the assay . Missing data will not be imputed.
Reporting results: The GMTs at each time point, GMRs ,and the associated 2 -sided 95%
CIs will be provided. The counts, percentages of participants with seroresponse at each
time point, the difference in percentages ,and the associated 2 -sided 95% CIs will be
provided.
Figures:
Empirical RCDCs will be provided for SARS- CoV -2 SA and reference strain NTs at each
time point.
6.2.1.9. SARS -CoV -2 SA NT at 1 Month After Dose 2 (BNT162b2 -Naïve Participants)
6.2.1.9.1. Main Analyses
Estimands:
N2a: GMR of SA NT 1 month after the second dose of BNT162b2 SAto 1 month after
the second dose of BNT162b2 ( Section 2.1).
Analy sis set: Dose 2evaluable and all -available immunogenicit ypopulations ( Section 4).
Analy sis time points: 1 month after the second dose of BNT162b2 and 1 month after the
second dose of BNT162b2 SA.
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TMF Doc ID: 98.03Analy sis methodology : GMR and the associated 2 -sided 97.5% CI will be calculated in
the same way as for the primary endpoint N1a ( Section 6.1.2.3.1 ). Statistical superiority
of N2a will be assessed if noninferiorit y of N1a is established. Superiority of N2 a will be
declared if the lower bound of the 2- sided 97.5% CI for the GMR is greater than 1.
Intercurrent events and missing data: Titers below the LLOQ or denoted as BLQ will be
set to 0.5 × LLOQ for analy sis. However, this calculation may be adjusted ba sed upon
additional data from the assay . Missing data will not be imputed.
Reporting results: The GMTs at each time point, GMRs ,and the associated 2 -sided
97.5% CI s will be provided.
Figures:
Empirical RCDCs will be provided for SARS- CoV -2 SA at each time point for each vaccine
group .
6.2.1.10. Seroresponse to the SA Strain at 1 Month After Dose 2 (BNT162b2- Naïve
Participants)
6.2.1.10.1. Main Analyses
Estimands:
N2b: The difference in percentages of participants with seroresponse to the SA strain
at 1 month after the secon d dose of BNT162b2 SAand 1 month after the second dose
of BNT162b2 (Section 2.1).
Analy sis set: Dose 2evaluable and all -available immunogenicit ypopulations ( Section 4).
Analy sis time points: 1 month after the second dose of BNT162b2 and 1 month after the
second dose of BNT162b2 SA.
Analy sis methodology : The difference in percentages of participants with seroresponse
and the associated 2 -sided 97.5% CI s will be calculated in the same way as for the
primary endpoint N1b (Section 6.1.2.4.1 ). Statistical superiorit y of N2b will be assessed
if noninferiorit y of N1b is established. Superiority of N2b will be declared if the lower
bound of the 2- sided 97.5% CI for the difference in percentages of participants with
seroresponse is greater than 0%.
Intercurrent events and missing data: Titers below the LLOQ or denoted as BLQ will be
set to 0.5 × LLOQ for analy sis. However, this calculation may be adjusted based upon
additional data from the assay . Missing data will not be imputed.
Reporting results: The counts, percentages of participants with seroresponse at each time
point, the diff erence in percentages ,and the associated 2 -sided 97.5% CIs will be
provided.
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TMF Doc ID: 98.036.2.1.11. Reference Strain NT at 1 Month After Dose 2 (BNT162b2 -Naïve Participants)
6.2.1.11.1. Main Analyses
Estimands:
GMR of reference strain NT 1 month after the second dose of BNT162b2 SAto
1month after the second dose of BNT162b2 (Section 2.1).
The difference in percentages of participants with seroresponse to the reference strain
at 1 month after the second dose of BNT162b2 SAand 1 month after the second dose
of BNT162b2 ( Section 2.1).
Analy sis set: Dose 2evaluable and all -available immunogenicit ypopulations ( Section 4).
Analy sis time points: 1 month after the second dose of BNT162b2 and 1 month after the
second dose of BNT162b2 SA.
Analy sis methodology : GMR and the associated 2 -sided 95% CI will be calculated in the
same way as for the primary endpoint N1a ( Section 6.1.2.3.1 ). The difference in
percentages of participants with seroresponse and the associated 2 -sided 95% CI s will be
calculated in the same way as for the primary endpoints N1b ( Section 6.1.2.4.1 ).
Intercurrent events and missing data: Titers below the LLOQ or denoted as BLQ will be
set to 0.5 × LLOQ for analy sis. However, this calculation may be adjusted based upon
additional data from the assay . Missing data will not be imputed.
Reporting results: The GMTs at each time point, GMRs ,and the associated 2 -sided 95%
CIs will be provided. The counts, percentages of participants with seroresponse at each
time point, the difference in percentages ,and the associated 2 -sided 95% CIs will be
provided.
Figures:
Empirical RCDCs will be provid ed for SARS -CoV -2 reference strain NTs at each time point
for each vaccine group.
6.2.2. Vaccine Efficacy Endpoints (for Phase 2/3 Only)
6.2.2.1. COVID -19 Incidence per 1000 Person -Years of Follow -up
6.2.2.1.1. Main Analyses
Estimands:
100 × (1 – IRR) [ratio of confirmed COVID -19 illness from 14 day s after the second
dose per 1000 person -years of follow -up in participants without evidence of infection
(prior to 14 day s after receipt of the second dose) for the active vaccine group to the
placebo group ( Section 2.1)].
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TMF Doc ID: 98.03100 × (1 – IRR) [ratio of confirmed COVID -19 illness from 14 day s after the second
dose per 1000 person -years of follow -up in participants with and without evidence of
infection (prior to 14 days after receipt of the second dose) for the active vaccine
group to the placebo group ( Section 2.1)].
Analy sis set: Evaluable efficacy (14 day s) and all -available efficacy populations
(Section 4).
Analy sis time point: End of the surveillance period or at IAs if requested.
Analy sis methodology : The same method used for primary VE endpoints will be applied
(Section 6.1.3.1.1 ).
Intercurrent events and missing data: Missing efficacy data will not be imputed in the
main anal yses.
Reporting results: The same output generated for primary VE endpoints will be provided
(Section 6.1.3.1.1 ).
6.2.2.2. Confirmed Severe COVID -19 Incidence per 1000 Person -Years of Follow -up
6.2.2.2.1. Main Analyses
Estimand s:
100 × (1 – IRR) [ ratio of confirmed severe COVID -19 illness from 7 day s and from
14 day s after the second dose per 1000 person -years of follow -up in participants
without evidence of infection (prior to 7 day s and14 day s after receipt of the second
dose) for the active vac cine group to the placebo group ( Section 2.1)].
100 × (1 – IRR) [ ratio of confirmed severe COVID -19 illness from 7 da ys and from
14 day s after the second dose per 1000 person -years of follow -up in participants with
and without evidence of infection (prior to 7 day s and 14 day s after receipt of the
second dose) for the active vaccine group to the placebo group ( Section 2.1)].
Analy sis set: Evaluable efficacy (7 day s and 14 day s) and all -available efficacy
populations ( Section 4).
Analy sis time point: End of the surveillance period or at IAs if requested .
Analy sis methodology : The same method used for primary VE endpoints will be applie d
(Section 6.1.3.1.1 ).
Intercurrent events and missing data: Missing efficacy data will not be imputed in the
main anal yses.
Reporting results: The same output generated for primary VE endpoints will be provided
(Section 6.1.3.1.1 ).
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TMF Doc ID: 98.036.2.2.2.2. Supplemental Analyses
All severe COVID -19 cases occurring after Dose 1 will be summarized descriptively .
After the final efficacy analy ses at 164 first primary cases, updated efficacy analyses will be
performed for severe COVID -19 incidence from 7 day s after the second dose with additional
data accrued. The point estimate of VE in the blinded follow- up period and associated
2-sided 95% CI will be derived using the Clopper Pearson method adjusted for surveillance
time, and the posterior probability (ie, P[VE >30%|data]) will be provided.
In addition to the protocol defin ition of severe COVID -19, supportive analy ses using the
CDC definition of severe COVID -19 will be performed .
6.2.2.3. Confirmed COVID -19 Incidence per 1000 Person -Years of Follow -up
(According to the CDC -Defined Symptoms)
6.2.2.3.1. Main Analyses
Estimand s:
100 × (1 – IRR) [ratio of confirmed COVID -19 illness according to the CDC -defined
symptoms from 7 day s and from 14 day s after the second dose per 1000 person- years
of follow -up in participants without evidence of infection (prior to 7 day s and 14 day s
after receipt of the second dose) for the active vaccine group to the placebo group
(Section 2.1)].
100 × (1 – IRR) [ratio of confirmed COVID -19 illness according to the CDC- defined
symptoms from 7 day s and from 14 day s after the second dose per 1000 person- years
of follow -up in participants with and without evidence of infection (prior to 7 days
and 14 day s after receipt of the second dose) for the active vaccine group to the
placebo group ( Section 2.1)].
Analy sis set: Evaluable efficacy (7 day s and 14 day s)and all -available efficacy
populations ( Section 4).
Analy sis time point: End of the surveillance period.
Analy sis methodology : Assessment of VE will be performed for centrally confirmed
COVID -19 according to the CDC -defined s ymptoms from 7 day s and from 14 day s after
the receipt of the second dose of study intervention onwards, and will be estimated by
100 × (1 – IRR), where IRR is the calculated ratio of COVID -19 illness rate according to
the CDC -defined s ymptoms per 1000 person -years of follow -up in the active vaccine
group to the corresponding illness rate in the placebo group after the second dose.
The 2 -sided 95% CI for VE will be derived using the Clopper -Pearson method adjusted
for surveillance time.
Intercurrent events and missing data: Missing efficacy data will not be imputed in the
main anal yses.
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TMF Doc ID: 98.03Reporting results: VE and the associated 2 -sided 95% CI s derived using the
Clopper -Pearson method adjusted for surveillance time will be provided.
6.2.2.4. Incidence of Asymptomatic SARS -CoV -2 Infection per 1000 Person -Years of
Follow -up (According to the N-B inding Antibody S eroconversion )
6.2.2.4.1. Main Analyses
Estimands:
100 × (1 – IRR) [ratio of asymptomatic SARS -CoV -2 infection per 1000
person -years of follow -up based on N -binding antibody seroconversion in
participants with no serological or virological evidence of past SARS -CoV -2
infection or confirmed COVID -19for the active vaccine group to the placebo group
(Section 2.1)].
Analy sis set: Evaluable efficacy (seroconversion) and all -available efficacy populations
(Section 4).
Analy sis time point: End of the surveillance period .
Analy sis methodology : An as ymptomatic case ( Appendix 4) is defined as positive
N-binding antibody at a post–Dose 2 visit in participants without serological evidence of
infection (determined b y negative N -binding antibody ) at Visit 1 or virological evidence
of infection ( determined by negative NAAT at Visit 1 and Visit 2 and at the time of a
potential COVID -19 illness ). A secondary definition will be applied without the
requirement for a negative NAAT at Visit 2. VE will be estimated by 100 × (1 -IRR),
where IRR is the calculated ratio of as ymptomatic infection per 1000 person- years of
follow -up in the active vaccine group to the corresponding infection in the placebo group.
The 2 -sided 95% CI for VE will be derived using the Clopper -Pearson method adjusted
for surveillance time. The VEis demonstrated if the lower bound of the 2-sided 95% CI
for VE is greater than 20%. The analy sis of the primary definition of as ymptomatic cases
will be based on the evaluable efficacy (seroconversion) population and the Dose 2
all-available efficacy population. The anal ysis of the secondary definition of
asymptomatic cases will be based on the Dose 1 all -available efficacy population .
Intercurrent events and missing data: Missing efficacy data will not be imputed in the
main anal yses.
Reporting results: VE and the associated 2-sided 95% CI s derived using the
Clopper -Pearson method adjusted for surveillance time will be provided.
6.2.2.4.2. Supplemental Analyses
Descriptive summary of VE against as ymptomatic infection over different time intervals
(ie,prior to 1 month after Dose 2, from 1 month after Dose 2 onward), along with the
associated 2- sided 95% CI , will be calculated using the same method as above .
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TMF Doc ID: 98.036.2.2.5. Incidence of Asymptomatic SARS -CoV -2 Infection per 1000 Person -Years of
Follow -up (According to the C entral Laboratory–Confirmed NAAT)
6.2.2.5.1. Main Analyses
Estimands:
100 × (1 – IRR) [ratio of asymptomatic SARS -CoV -2 infection per 1000
person -years of follow -up based on central laboratory –confirmed NAAT in
participants without serological or virological evidence of infection ( up to the start of
the asy mptomatic surveillance period ) for the active vaccine group to the placebo
group ( Section 2.1)].
Analy sis set: Evaluable efficacy (asymptomatic surveillance ) and all -available efficacy
populations ( Section 4)and only participants who consented to participate in the
asymptomatic surveillance .
Analy sis time point: End of the surveillance period.
Analy sis methodology : An as ymptomatic case definition based on central laboratory –
confirmed NAAT can be found in Appendix 5.VE will be estimated by 100 × (1 - IRR),
where IRR is the calculated ratio of as ymptomatic infection per 1000 person -years of
follow -up in the active vaccine group to the corresponding infection in the placebo group.
The 2 -sided 95% CI for VE will be derived using the Clopper -Pearson method adjusted
for surveillance time. The success criterion is met if lower bound of the 2- sided 95% CI
for VE is greater than 20%.
Intercurrent events and missing data: Missing efficacy data will not be imputed in the
main anal yses.
Reporting results: VE and the associated 2 -sided 95% CI s derived using the
Clopper -Pearson method adjusted for surveillance time will be provided.
6.3.Exploratory Endpoints
6.3.1. Safety Endpoints (for Phase 1 Boostability Assessment Only)
6.3.1.1. Local Reactions
6.3.1.1.1. Main Analysis
Estimand: The percentage of participants reporting local reactions (redness, swelling, and
pain at the injection site) within 7 day s after Dose 3 (Section 2.1).
Analy sis set: Phase 1 participants who received a third dose of BNT162b2 6 to 12 months
after the second dose of either BNT162b1 or BNT162b2.
Analy sis time point: Within 7 day s after Dose 3 .
Analy sis methodology : Descriptive statistics (Section 5.2.1 ).
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TMF Doc ID: 98.03Intercurrent events and missing data: The participants without any e-diary data
throughout the 7 day s after vaccination will be excluded from the anal ysis at that
particular vaccination; missing values will not be imputed.
Reporting results: Descriptive statistics for each and any local reaction after Dose 3 by
initial vaccine and age group will be presented b y maximum severity and cumulatively
across severit y levels. Confirmed e -diary errors will be excluded from the anal ysis.
Descriptive summary statistics will include counts and percentages of participants with
the indicated endpoint and the as sociated 2- sided Clopper -Pearson 95% CIs.
6.3.1.1.2. Supplementary Analyses
To support the assessment of local reactions, the following endpoints (as defined in
Section 3.1.1.1 ) will be summarized with the same anal ysis time point andanalysis
population , analy sis methodology , and appropriate reporting results. Confirmed e- diary
errors will be excluded from these an alyses.
Duration (day s) of each local reaction after each dose.
Onset day of each local reaction after each dose.
These continuous endpoints will be summarized by display ing n, mean, median, standard
deviation, minimum, and maximum for each initial vaccine and age group .
Figures:
Bar charts with the proportions of participants for each local reaction throughout 7 day s will
be plotted for each initial vaccine and age group. The bars will be divided into severity
categories to highlight the proportions of pa rticipants by maximum severity.
6.3.1.2. Systemic Events
6.3.1.2.1. Main Analysis
Estimand: The percentage of participants reporting s ystemic events (fever, fatigue,
headache, chills, vomiting, diarrhea, new or worsened muscle pain, and new or worsened
joint pain) within 7 da ys after Dose 3 (Section 2.1).
Analy sis set: Phase 1 participants who received a third dose of BNT162b2 6 to 12 months
after the second dose of either BNT162b1 or BNT162b2.
Analy sis time point: Within 7 day s after Dose 3 .
Analy sis methodology : Descriptive statistics ( Section 5.2.1 ).
Intercurrent events and missing data: The participants without any e-diary data
throughout the 7 day s after vaccination will be excluded from the anal ysis at that
particular vaccination; missing values will not be imputed.
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TMF Doc ID: 98.03Reporting r esults: Descriptive statistics for each sy stemic event after Dose 3 in each
initial vaccine and age group will be presented b y maximum severity and cumulatively
across severit y levels. Descriptive summary statistics will include counts and
percentages of participants with the indicated endpoint and the associated 2 -sided
Clopper -Pearson 95% CIs.
6.3.1.2.2. Supplementary Analyses
The following endpoints for assessment of s ystemic events will be summarized similarly to
the assessment of local reactions:
Duration of each s ystemic event after each dose.
Onset day of each s ystemic event after each dose.
These continuous endpoints will be summarized by display ing n, mean, median, standard
deviation, minimum, and maximum for each initial vaccine and age group.
The use of antip yretic medication (see Section 3.1.1.3 ) will be summarized similarly to
systemic events, except that there is no severit y level associated with the use of antipy retic
medication.
Figures:
Bar charts with the proportions of participant s reporting each s ystemic event throughout
7days after Dose 3 will be plotted for each initial vaccine and age group. The bars will be
divided into severity categories to highlight the proportions of participant s by severit y.
6.3.1.3. Adverse Events
6.3.1.3.1. Main Analysis
Estimand: The percentage of participants reporting AEs from Dose 3to 1 month after
Dose 3 (Section 2.1).
Analy sis set: Phase 1 participants who received a third dose of BNT162b2 6 to 12 months
after the second dose of either BNT162b1 or BNT162b2.
Analy sis time poin t: Dose 3 to 1 month after Dose 3 .
Analy sis methodology : Descriptive statistics ( Section 5.2.1 ).
Intercurrent events and missing data: Partial AE dates will be imputed using the Pfizer
standard algorithm.
Reporting results: AEs will be categorized according to MedDRA terms. Descriptive
summary statistics (counts, percentages, and associated Clopper -Pearson 95% CI s) will
be provided fo r any AEs for each initial vaccine and age group.
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TMF Doc ID: 98.036.3.1.3.2. Supplementary Analyses
Immediate AEs (within the first 30 minutes after Dose 3 ) will also be summarized for each
initial vaccine and age group.
6.3.1.4. Serious Adverse Events
6.3.1.4.1. Main Analyses
Estimand: The percentage of participants reporting SAEs from Dose 3to 1month after
Dose 3 (Section 2.1).
Analy sis set: Phase 1 part icipants who received a third dose of BNT162b2 6 to 12 months
after the second dose of either BNT162b1 or BNT162b2.
Analy sis time point: Dose 3 to 1 month after Dose 3.
Analy sis methodology : Descriptive statistics ( Section 5.2.1 ).
Intercurrent events and missing data: Partial SAE dates will be imputed using the Pfizer
standard algorithm.
Reporting results: SAEs will be categorized according to MedDRA terms. Counts,
percentages, and the associated Clopper -Pearson 95% CI s of SAEs from Dose 3to
1month after Dose 3 will be provided for each initial vaccine and age group.
6.3.2. Vaccine Efficacy En dpoints (for Phase 2/3 Only)
6.3.2.1. COVID -19 Incidence per 1000 Person -Years of Blinded Follow -up
6.3.2.1.1. Main Analyses
Estimands:
100 × (1 – IRR) [ratio of confirmed COVID -19 illness based on central laboratory or
locally confirmed NAAT from 7 days after the second dose through the blinded
follow -up period per 1000 person -years of follow -up in participants without evidence
of infection (prior to 7days after receipt of the second dose) for the active vaccine
group to the placebo group ( Section 2.1)].
100 × (1 – IRR) [ratio of confirmed COVID -19 illness based on central laboratory or
locally confirmed NAAT from 7 days after the second dose through the blinded
follow -up period per 1000 person -years of follow -up in participants with and without
evidence of infection for the active vaccine group to the placebo group ( Section 2.1)].
Analy sis set: Evaluable efficacy (7days) and all -available efficacy populations
(Section 4).
Analy sis time point: End of the surveillance period (blinded follow -up).
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TMF Doc ID: 98.03Analy sis methodology :After the primary objectives are met at the final analy sis of at
least 164 first primary cases, the study will continue with blinded follow -up until the
participant is unblinded at the time of being eligible for receipt of BNT162b2 according
to recommendat ions detailed separately , and available in the electronic study reference
portal, or no later than at approximately Visit 4. A descriptive update of VE will be
provided with additional follow- up data. VE=100 × (1 – IRR) will be estimated with
confirmed COVID -19 illness from 7 day s after the second dose through the blinded
follow -up period. The 2 -sided 95% CI for VE will be derived using the Clopper -Pearson
method adjusted for surveillance time.
Intercurrent events and missing data: Missing efficacy data will not be imputed in the
main anal yses.
Reporting results: VE and the associated 2 -sided 95% CI s derived using the
Clopper -Pearson method adjusted for surveillance time .
6.3.2.1.2. Supportive Analyses
Supportive analy sis of time to confirmed COVID- 19 illness will be performed using
Kaplan -Meier cumulative incidence curves. Participants who were randomized to placebo
will be censored at the time of receipt of BNT162b2. An RPSFT model may be explored to
reconstruct data for the control arm.
VE at different follow -up time intervals and against different variant strains may be assessed.
6.3.2.2. COVID -19 Incidence per 1000 Person -Years of Follow -up
6.3.2.2.1. Main Analyses
Estimands:
COVID -19 incidence based on central laboratory or locally confirmed NAAT from
7 day s after the second dose through the entire study follow -up period prior to
receiving the third dose of BNT162b2 per 1000 person- years of follow -up in
participants without evidence of infection (prior to 7 day s after receipt of the second
BNT162b2 vacc ination) who received BNT162b2 at initial randomization or
subsequently (Section 2.1).
COVID -19 incidence based on ce ntral laboratory or locally confirmed NAAT from
7 day s after the second dose through the entire study follow -up period prior to
receiving the third dose of BNT162b2 per 1000 person- years of follow -up in
participants with and without evidence of infection who received BNT162b2 at initial
rand
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