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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: 3
Date: 02Nov2020
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TMF Doc ID: 98.03TABLE OF CONTENTS
LIST OF TABLES ................................ ................................ ................................ ..................... 5
APPENDI CES................................ ................................ ................................ ........................... 5
1. VERSI ON HISTORY ................................ ................................ ................................ ............6
2. INTRODUCTION ................................ ................................ ................................ ................. 6
2.1. Study Objectives, Endpoints, and Estimands ................................ ............................ 6
2.2. Study Design................................ ................................ ................................ ...........11
2.2.1. Overall Design ................................ ................................ ............................ 11
2.2.2. Phase1................................ ................................ ................................ ........11
2.2.3. Phase 2/3................................ ................................ ................................ .....12
3. ENDPOINTS AND BASELINE VARIABLES: DEF INITIONS AND
CONVENTIONS ................................ ................................ ................................ ................ 14
3.1. Primary Endpoints ................................ ................................ ................................ ...14
3.1.1. Safet y Endpoints ................................ ................................ ......................... 14
3.1.1.1. L ocal Reactions ................................ ................................ .........14
3.1.1.2. Sy stemic Events (Sy stemic Event S ymptoms and Fever) .........17
3.1.1.3. Use of Antip yretic Medication ................................ .................. 18
3.1.1.4. Adverse Events ................................ ................................ ..........18
3.1.1.5. Serious Adverse Events ................................ ............................. 19
3.1.1.6. Hematology and Chemistry Laboratory Parameters (for
Phase 1 Only )................................ ................................ .................... 19
3.1.2. Vaccine Efficacy Endpoints (for Phase 2/3 Only )................................ ......21
3.2. Secondary Endpoints ................................ ................................ ............................... 21
3.2.1. Immunogenicit y Endpoints ................................ ................................ .........21
3.2.1.1. Neutralizing Titers................................ ................................ .....22
3.2.1.2. IgG Concentrations................................ ................................ ...22
3.2.2. Vaccine Efficacy Endpoints (for Phase 2/3 Only )................................ ......22
3.3. Exploratory Endpoints ................................ ................................ ............................. 23
3.3.1. Immunogenicit y Endpoints (for Phase 2/3 Only )................................ .......23
3.3.2. Additional Endpoints (for Phase 2/3 Onl y)................................ ................ 23
3.4. Baseline and Other Variables ................................ ................................ .................. 23
3.4.1. Demographics, Medical History , and Physical Examination ..................... 24
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TMF Doc ID: 98.033.4.2. E-Diary Completion ................................ ................................ .................... 24
3.4.3. Prior/Concomitant Vaccines and Concomitant Medications...................... 24
3.5. Safet y Endpoints ................................ ................................ ................................ .....25
4. ANALYSIS SETS (PO PULATIONS FOR ANALYS IS)................................ ................... 25
5. GENERAL METHODOLOGY AND CONVENTIONS ................................ .................... 26
5.1. Hypotheses and Decision Rules ................................ ................................ ..............26
5.1.1. Vaccine Efficacy Hypothesis................................ ................................ ......26
5.1.2. Immunogenicit y Hypothesis ................................ ................................ .......27
5.1.3. Sample Size ................................ ................................ ................................ 27
5.1.4. Multiplicity Considerations................................ ................................ ........29
5.2. General Methods ................................ ................................ ................................ .....29
5.2.1. Analy ses for Binary Data................................ ................................ ............29
5.2.2. Analy ses for Continuous Data ................................ ................................ ....29
5.2.2.1. Geometric Means ................................ ................................ ......29
5.2.2.2. Geometric Mean Fold Rises................................ ...................... 30
5.2.2.3.Geometric Mean Ratios ................................ ............................. 30
5.2.2.4. Geometric Mean Fold Rise Ratios ................................ ............30
5.2.2.5. Reverse Cumulative Distribution Curves ................................ ..30
5.3. Methods to Manage Missing Data ................................ ................................ ..........31
6. ANALYSES AND SUMM ARIES................................ ................................ ...................... 31
6.1. Primary Endpoint(s) ................................ ................................ ................................ 31
6.1.1. Safety Endpoints ................................ ................................ ......................... 31
6.1.1.1. L ocal Reactions ................................ ................................ .........31
6.1.1.2. Sy stemic Events ................................ ................................ ........32
6.1.1.3. Adverse Events ................................ ................................ ..........33
6.1.1.4. S erious Adverse Events ................................ ............................. 34
6.1.1.5. Hematology and Chemistry Parameters (for Phase 1 Onl y).....34
6.1.2. Vaccine Efficacy Endpoints (for Phase 2/3 Only )................................ ......35
6.1.2.1. COVID -19 Incidence per 1000 Person -Years of Follow -
up................................ ................................ ................................ .......35
6.2. Secondary Endpoints ................................ ................................ ............................... 36
6.2.1. Immunogenicit y Endpoints ................................ ................................ .........36
6.2.1.1. SARS -CoV-2 Neutralizing Titers (Phase 1) ............................. 37
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TMF Doc ID: 98.036.2.1.2. S1- Binding IgG Levels and RBD -Binding IgG Levels
(Phase 1) ................................ ................................ ............................ 38
6.2.1.3. GMR of SARS -CoV-2 Neutralizing Titer to SARS -CoV-2
S1-Binding IgG Levels and RBD -Binding IgG Levels (Phase
1)................................ ................................ ................................ ........39
6.2.1.4. GMR of SARS -CoV-2 Neutralizing Titers in Participants
12 to 15 Years of Age to Those 16 to 25 Years of Age (Phase
2/3)................................ ................................ ................................ .....39
6.2.2. Vaccine Efficacy Endpoints (for Phase 2/3 Only )................................ ......40
6.2.2.1. COVID -19 Incidence per 1000 Person -Years of Follow -
up................................ ................................ ................................ .......40
6.2.2.2. Confirmed Severe COVID -19 Incidence per 1000 Person -
Years of Follow -up................................ ................................ ............41
6.2.2.3. Confirmed COVID -19 Incidence per 1000 Person -Years
of Follow -up (According to the CDC -Defined S ymptoms) ..............41
6.3. Exploratory Endpoints ................................ ................................ ............................. 42
6.3.1. Immunogenicit y Endpoints (for Phase 2/3 Only )................................ .......42
6.3.1.1. SARS -CoV-2 Neutralizing Titers, and S1 -Binding IgG
Levels and RBD -Binding IgG Levels ................................ ...............42
6.3.1.2. N- Binding Antibody ................................ ................................ ..43
6.3.1.3. Serological Responses in Participants With Confirmed
COVID-19, Confirmed Severe COVID -19, and SARS -CoV-2
Infection Without Confirmed COVID-19................................ .........44
6.3.2. Additional Analy sis................................ ................................ .................... 44
6.4. Subgroup Analy sis................................ ................................ ................................ ..44
6.5. Baseline and Other Summaries and Anal yses................................ ......................... 44
6.5.1. Baseline Summaries ................................ ................................ .................... 44
6.5.1.1.Demographic Characteristics ................................ .................... 44
6.5.1.2. Medical History ................................ ................................ .........44
6.5.2. Study Conduct and Participant Disposition ................................ ................ 45
6.5.2.1. Participant Disposition ................................ .............................. 45
6.5.2.2. Blood Samples for Assay ................................ .......................... 45
6.5.2.3. E- Diaries................................ ................................ .................... 45
6.5.3. Study Vaccination Exposure ................................ ................................ .......45
6.5.3.1. Vaccination Timing and Administration ................................ ...45
6.5.4. Prior/Concomitant Vaccination and Concomitant Medications ................. 46
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TMF Doc ID: 98.036.6. Safet y Summaries and Analyses ................................ ................................ .............46
7. ANALYSES TIMING ................................ ................................ ................................ .........46
7.1. Introduction of Interim Analy sis................................ ................................ .............46
7.2. Interim Anal yses and Summaries ................................ ................................ ............49
7.2.1. Data Monitoring Committee ................................ ................................ .......49
8. REFERENCES ................................ ................................ ................................ .................... 50
9. APPENDI CES................................ ................................ ................................ ..................... 51
LIST OF TABLES
Table1. Summary of Changes ................................ ................................ .................. 6
Table2. List of Primary and Secondary Objectives, Estimands, and
Endpoints for Phase 1 ................................ ................................ ................. 7
Table3. List of Primary , Secondary, and Tertiary /Exploratory Objectives,
Estimands, and Endpoints for Phase 2/3 ................................ ..................... 8
Table4. Derived Variables for Presence of Each and An y Local Reaction
Within 7 Days for Each Dose ................................ ................................ ...15
Table5. Local Reaction Grading Scale................................ ................................ ..16
Table6. Systemic Event Grading Scale ................................ ................................ ..17
Table7. Scale for Fever ................................ ................................ .......................... 18
Table8. Laboratory Abnormality Grading Scale ................................ ................... 20
Table9. Power Anal ysis for Noninferiorit y Assessment ................................ .......28
Table10. Probability of Observing at Least 1 AE by Assumed True Event
Rates With Different Sample Sizes ................................ .......................... 28
Table11. Interim Anal ysis Plan and Boundaries for Efficacy and Futility ..............47
Table12. Statistical Design Operating Characteristics: Probability of Success
or Failure for Interim Analy ses................................ ................................ .48
Table13. Statistical Design Operating Characteristics: Probability of Success
for Final Anal ysis and Overall ................................ ................................ ..48
APPENDICES
Appendix 1. List of Abbreviations ................................ ................................ ........................... 51
Appendix 2. Details for Bayesian Design ................................ ................................ ................ 53
Appendix 3. IRR and VE Derivation ................................ ................................ ....................... 55
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TMF Doc ID: 98.031.VERSION HISTORY
Table1.Summary of C hanges
Version/
DateAssociated Protocol
AmendmentSummary and Rationale for Changes
1/
20 May2020Protocol amendment 1 ,
13May 2020N/A
2/
30Jul2020Protocol amendment 5,
24July 2020Implemented the changes made in p rotocol amendment s2through 5.
3/
02Nov2020Protocol amendment 9,
29Oct 2020Implemented the changes made in protocol amendments 6 through 9.
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 it s analysis 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 Table2and Table3below.
In the primary safety 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 analysis.
The estimands to evaluate the immunogenicity objectives are based on evaluable populations
for immunogenicity (seeSection 4for definition). These estimands estimate vaccine effect
in the hypothetical 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 availabl e.
The estimands to evaluate the efficacyobjectives are based on evaluable populations for
efficacy(seeSection 4for definition). These estimands estimate vaccine effect in the
hypothetical setting where participants follow the study schedules and protocol requirements
as directed. In addition, VE w ill be anal yzed by the all-available efficacy population s.
Missing laboratory results will not be imputed for the primary analysis, but missing data
imputation for the efficacy endpoint may be performed as a sensitivity analysis.
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TMF Doc ID: 98.03Table2.List of Primary andSecondary Objectives, Estimands, and Endpoints for
Phase 1
Objectives Estimands Endpoints
Primary: Primary: Primary:
To describe the safety and tolerability
profiles of prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses.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
Adverse events (AEs) from
Dose1 to 1 month after the last
dose
Serious AEs (SAEs) from Dose 1
to 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 mus cle
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 the protocol,
Section 10.2 .
Secondary: Secondary: Secondary:
To describe the immune responses
elicited by prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses.In participants complying with the key
protocol criteria (evaluable
participants) at the following time
points after receipt of study
intervention :7 and 21days after Dose
1; 7and 14 daysand1, 6, 12,and 24
months 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-foldrise from before
vaccination to each subsequent
time point after vaccinationSARS-CoV-2 neutralizing titers
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-foldrise from before
vaccination to each subsequent
time point after vaccinationS1-binding IgGlevels and RBD -
binding IgGlevels
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TMF Doc ID: 98.03Table2.List of Primary andSecondary Objectives, Estimands, and Endpoints for
Phase 1
Objectives Estimands Endpoints
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 pointSARS-CoV-2 neutralizing titers
S1-binding IgGlevels
RBD-binding IgGlevels
Table3. List of Primary, Secondary, and Tertiary/Exploratory Objectives,
Estimands, and Endpoints for Phase 2/3
ObjectivesaEstimands Endpoints
Primary 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
vaccination .In 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 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 vaccination .In participants complying with the key
protocol criteria (evalu able
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 per 1000 person -
years of follow -up based on central
laboratory or locally confirmed NAAT .
Primary 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 seconddose
SAEs from Dose 1 to 7 days after
the seconddoseLocal reactions (pain at the
injection site, redness, and
swelling).
Systemic eve nts (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 2/3 .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 1 month after
the seconddose
SAEs from Dose 1 to 6 months
after the seconddoseAEs
SAEs
In a subset of at least 6000
participants:
oLocal reactions (pain at the
injection site, redness, and
swelling).
oSystemic events (fever,
fatigue, headache, chills,
vomiting, diarrhea, new or
worsened muscle pain, and
new or worsened joint pain) .
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TMF Doc ID: 98.03Table3. List of Primary, Secondary, and Tertiary/Exploratory Objectives,
Estimands, and Endpoints for Phase 2/3
ObjectivesaEstimands Endpoints
To define the safety profile of
prophylactic BNT162b2 in participants
12 to 15 years of age in Phase 3 .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 1 month after
the seconddose
SAEs from Dose 1 to 6 months
after the seconddoseLocal 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
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
vaccination .In 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
1000person-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 vaccination .In 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
1000person-years of follow -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 vaccination.In participants complying with the key
protocol criteria (evaluable
participants)
at least 7 days
and
at least 14 days
after receipt of the seconddose of study
intervention:
100 × (1 –IRR) [ratio of active vaccine
to placebo]Confirmed 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 eff icacy 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 vaccination.In participants complying with the key
protocol criteri a (evaluable
participants)
at least 7 days
and
at least 14 days
after receipt of the seconddose of study
intervention:
100 × (1 –IRR) [ratio of active vaccine
to placebo]Confirmed severe COVID -19 incidence
per 1000 person -years of follow -up.
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
vaccination .In participants complying with the key
protocol criteria (evaluable
participants)
at least 7 days
and
at least 14 days
after receipt of the seconddose of study
intervention: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 .
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TMF Doc ID: 98.03Table3. List of Primary, Secondary, and Tertiary/Exploratory Objectives,
Estimands, and Endpoints for Phase 2/3
ObjectivesaEstimands Endpoints
100 × (1 –IRR) [ratio of active vaccine
to placebo]
To describe the efficacy o f 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
vaccination .In participants complying with the key
protocol criteria (evaluable
participants)
at least 7 days
and
at least 14 days
after receipt of the seconddose 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 NAA .T
Secondary Immunogenicity
Todemonstrate 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 age .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 month after completion of
vaccination .SARS-CoV-2 neutralizing titers in
participants with no serological or
virological evidence (up to 1 month
after receipt of the seconddose) of past
SARS-CoV-2 infection .
Exploratory
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
vaccination .GMC/GMT, GMFR, and percentage of
participants with titers greater than
defined threshold(s), at baseline and 1,
6, 12, and 24 months after comp letion
of vaccination .S1-binding IgG levels and/or
RBD-binding IgG levels
SARS-CoV-2 neutralizing titers
To evaluate the immune response
(non-S) to SARS -CoV-2 in participants
with and without confirmed COVID -19
during the study .N-binding antibody
To describe the serological responses to
the BNT vaccine candidate in cases of:
Confirmed COVID-19
Confirmed severe COVID -19
SARS-CoV-2 infection without
confirmed COVID -19S1-binding IgG levels and/or
RBD-binding IgG levels
SARS-CoV-2 neutralizing titers
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”bAll safety endpoints described
above
SARS-CoV-2 neutralizing titers
a.HIV-positive participants in Phase 3 will not be included in analyses of the objectives, with the exceptio n
of the specific exploratory objective.
b.See the protocol, Section 6.1.1, for description of the manufacturing process.
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TMF Doc ID: 98.032.2.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 protocol, Section 1.2).
The study will evaluate the safet y, tolerability , and immunogenicit y of 2 different
SARS-CoV-2 R NAvaccinecandidate s against COVID-19and the efficacy of 1 candidate:
As a 2-dose (separated by 21 days) schedule ;
At variousdifferent dose levels in Phase 1;
In 3 age groups ( Phase 1: 18 to 55 y ears of age, 65 to 85 y ears of age ; Phase 2/3: ≥12
years 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 facilitat e rapid review of data in real time, sponsor staff will be unblinded to vaccine
allocation for the participants in Phase 1.
2.2.2.Phase1
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.
For each vaccine candidate/dose level/age group, the following apply:
Additional safetyassessments (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.
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TMF Doc ID: 98.03Thefirst 5 participants must be observed by blinded site staff for at least 4 hours
after vaccination for any acute reactions.
Vaccination of the remaining participants will commence no sooner than 24hours
after the fifthparticipant 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
Germany (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 candidate 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 datafor the RNA
platformhave been deemed acceptable at the same, or a higher, dose level in the 18 -to
55-year age cohort by the IRC.
In this phase, 13groups will be studied, corresponding to a total of 195participants.
The IRC will select 1 vaccine candi date that, in Phase1, has an established dose level per age
group based on induction of a post–Dose 2immune response, including neutralizing
antibodies, whichis expected to be associated with protection against COVID -19, for
progressioninto Phase 2/3.
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 ≥12 years 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 pa rticipants 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 selected for Phase 2/3 evaluation is BNT162b2 at a dose
of 30µg.
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TMF Doc ID: 98.03Phase 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 seconddose of the primary series
of the candidate vaccine will be sufficient to provide 90% power to conclude true VE >30%
with high probability . 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 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 recipients. 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.
The first 360 participants enrolled (180 to active vaccine and 180 to placebo, stratified
equally between 18 to 55years 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 theDMC, 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” portion of the study .
In Phase 3, up to approximately 2000participants, 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 25years of age will be
assessed bas ed on the GM Rof SARS-CoV-2 neutralizing titers using a 1.5 -fold margin. A
sample size of 2 00 evaluable participants (or 250 vaccine recipients) per age group will
provide a power of 90.8 % to declare the noninferiority in terms of GM R(lower limit of 95%
CI forGMR>0.67). A random sample of 250 participant s from each of the 2 age groups
(12to 15 years and 16 to 25 y ears) will be selected as an immunogenicity subsetfor 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 immunogenicit y of prophylactic BNT162b2 in individuals 16 to
55 years of age vaccinated with “Process 1” and each lot of “Process 2” study intervention
will be described. A random sample of 250 participants from those vaccinated with study
intervention produced b y manufac turing “Process 1” will be selected for this descriptive
analysis.
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TMF Doc ID: 98.03Participants are expected to participate for up to a maximum of approximately 26 months.
The duration of stud y follow-up may be shorter among participants enrolled in Phase 1
dosing arms t hatare not evaluated in Phase 2/3.
3.ENDPOINTS AND BASELINE VARIAB LES:DEFINITIONS AND
CONVENTIONS
3.1.Primary Endpoints
3.1.1.Safety Endpoints
For all participants in Phase1, and a subset of at least 6000 participants randomized in
Phase2/3,receiving at least 1 dose of study intervention, 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 /tiredness, 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 .
For all participants randomized in Phase 1 and Phase 2/3, receiving at least 1 dose of study
intervention, below are the primary safety endpoints for AEs and SAEs (the last dose in
Phase 1 is the second dose):
AEs from Dose 1to 1 month after the second dose.
SAEs from Dose 1 to 6 months after the second dose.
In addition, for 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 seconddose.
SAEs from Dose 1 to 7 day safter the seconddose.
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 descr ibes derivations with details for the assessment of local reactions:
presence, severity level, duration, and onset day .
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TMF Doc ID: 98.03Presence or Absence
For the data summary of the presence (y es or no) of a local reaction during the interval from
Day1 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:
Presence (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 ea ch local reaction by maximum se verity on any day (Day 1
through Day 7).
For each local reaction and any local reaction on any day,Table4explains 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 .
Table4. Derived Variables for Presence o f Each and Any Local Reaction Within
7Daysfor Each Dose
VariableaYes (1) No (0) Missing (.)
Presence of each local
reaction.Participant reportsthe
reaction as “yes”onany
day (Day1through
Day7).Participant reports the
reaction as “no” on all
7 days (Day 1 through
Day7) 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 through
Day7).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 through
Day7).
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 Table5. 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 participant as absent, mild, moderate, or severe
according the grading scale in Table5.
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TMF Doc ID: 98.03Table5.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 .
Redness >2.0cm to 5.0 cm
(5 to 10measuring
device units) .>5.0cm 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) .>5.0cm to 10.0 cm
(11 to 20measuring
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 during 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 Table5), the maximum duration (last day of reaction –first day of reaction + 1)
will be derived for each study vaccination. Resolution of the reactionis the last day on
which the reaction is recorded in the e -diary or the date the reactionends if it is unresolved
during the participant e-diaryrecording 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 reactionis ongoing at the 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 severity.
For the onset day of each local reaction, if participant s report change in s everity of the local
reaction, onl y the first day of reporting that specific local reaction will be counted.
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TMF Doc ID: 98.033.1.1.2.Systemic Events ( Systemic Event Symptoms and Fever)
The systemic events assessed and recorded in the e-diary are vomiting, diarrhea, headache,
fatigue/tiredness, chills, new or worsened muscle pain, and new or worsened joint pain from
Day1 through Day 7, where Day 1 is the day of each dose . The derivations for s ystemic
events will be handled in a way similar to the way local reactions are handl ed for presence of
event, severity 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 ( see Section 3.1.1.1). Maximum temperature range over
the period from Day 1 through Day 7 will be mapped into the ranges described in Table7for
summary of maximum temperature.
The symptoms will be assessed by the participant as absent, mild, moderate, or severe
according to the grading scale in Table6.
Table6.Systemic Event Grading Scale
Mild
(Grade 1)Moderate
(Grade 2)Severe
(Grade 3)Potentially Life
Threatening
(Grade 4)
Vomiting 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 24hours.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/tiredness 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.
Oraltemperature will be collected in the evening, daily,for 7 days following each dose
(Days 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. Feveris defined as an oral temperature of ≥38.0°C (100.4 °F). The
highest temperature for each day will be recorded in the e -diary.
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TMF Doc ID: 98.03Temperature will be measured and recorded to 1 decimal place. Temperatures recorded in
degrees Fahrenheit will be programmatically converted to degrees Celsius for reporting.
Temperature s <35.0°C and >42.0°C will be excluded from the anal ysis. Fever will be
grouped into ranges for the anal ysis according to Table7below.
Table7.Scalefor 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 antipyretic 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 same 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 medic ation.
The use of antip yreticmedication will be summarized and included in the sy stemic event
summary tablesbut 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.
The primary endpoint “ AEs from Dose 1 to1 month after the second dose”and other AE
endpoints will be summarized by SOCand PT at the participant level.
This primary endpoint will 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 reporting 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 Phase2/3 only, a3-tier approach will be used to summarize AEs. Underthis approach,
AEs are classified into 1 of 3 tiers. Different analy ses will be performed for different tiers :
Tier1 events: These are prespecified events of clinical importance and are identified
in a list in the product’s Safety Review Plan .
Tier2 events: These are events that are not Tier1 but are considered “relatively
common.”A MedDRA PTis defined as a Ti er2 event if there are at least 1%
participant s with the AE term in at least 1vaccine group.
Tier3 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 seconddose of study intervention (Visit 8 for Phase1
participants and Visit 4 for Phase2/3 participants).
The safetyendpoint “SAEs from Dose 1to 6 months after the second dose”will be
summarized by SOCand PT at the participant level.
3.1.1.6.Hematology and Chemistry Laboratory Param eters(for Phase 1 Only)
For participants in Phase1, below are the additional primary safety endpoints:
Abnormal hematology and chemistry laboratory values1 and 7 day s 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 day s after Dose 2.
The following safet y laboratory tests will be performed at the times defined in the protocol,
Section 1.3 (schedule 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
additional collection of blood. Unscheduled clinical laboratory measurements may be
obtained at an y time during the stud y to assess any perceived safety issues.
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TMF Doc ID: 98.03Hematology Chemistry
Hemoglobin
Hematocrit
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 ( Table8).Additionally , the primary criterion
for abnorma lity will follow the Pfizer safet y rule book.
Table8.Laboratory Abnormality Grading Scale
Hematology Mild
(Grade 1) Moderate
(Grade 2) Severe
(Grade 3) Potentially Life
Threatening
(Grade 4)
Hemoglobin
(Female) -g/dL 11.0 –12.0 9.5 –10.9 8.0 –9.4 <8.0
Hemoglobin
(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
Liver function tests -
ALT, AST
increase by factor 1.1 –2.5 ×ULN 2.6 –5.0 ×ULN 5.1 –10 ×ULN >10 ×ULN
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TMF Doc ID: 98.03Table8.Laboratory Abnormality Grading Scale
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
normal -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 norma l; WBC = white blood cell.
3.1.2. 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 7 days after receipt of the seconddose)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 ).
3.2. 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 secondary immunogenicit y endpoints for Phase1:
SARS-CoV-2 neutralizing titers .
S1-binding IgG levels.
RBD-binding IgG levels .
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TMF Doc ID: 98.03Phase 2/3
In participants with no serological or virological evidence of past SARS -CoV-2 infection,
12 to 15 y ears of age and 16 to 25 y ears of age complying with the key protocol criteria
(evaluable participants) 1 month after Dose 2, b elow isthe secondary immunogenicity
endpoint for Phase 2/3:
SARS-CoV-2 neutralizing titers.
3.2.1.1.Neutralizing Titers
Titers 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,
this calculation may be adjusted based upon additional data from the assay . LLOQ results
will be included in the analy sis specification once they are available.
3.2.1.2.IgG Concentrations
Results will be reported as IgG concentrations. IgG concentrations 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, this calculation may be
adjusted based upon additional data from the assay . LLOQ results will be included in the
analysis specification once they are available.
To support the secondary immunogenicit y endpoints, the GMTs or concentrations at all time
points, GMFR from before vaccination to each subsequent time point after vaccination, and
proportion of participan ts achieving ≥4 -fold rise from before vaccination to each subsequent
time point after vaccination will be calculated and summarized by vaccine group.
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 ( priorto 14 days 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 (priorto 7 days and priorto
14 days 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 ).
Confirmed 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) .
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TMF Doc ID: 98.03According to the CDC -defined symptoms, 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 ( priorto 7 days and priorto
14 days after receipt of the seconddose) 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 symptoms, COVID -19 incidence per 1000
person-years of follow -up based on central laboratory or locally confirmed NAAT
(counting cases from 7 day s and 14 day s after the second dose) .
3.3.Exploratory Endpoints
3.3.1.Immunogenicity En dpoints(for Phase 2/3 Only)
In participants compl ying with the key protocol criteria (evaluable participants) at the
following time points after receipt of stud y intervention:
Baselineand1, 6, 12, and 24 months after completion of vaccination.
Below are the exploratory immunogenicit y endpoints for P hase2/3:
SARS-CoV-2 neutralizing titers .
S1-binding IgGlevelsand/or RBD-binding IgG levels .
N-binding antibody .
SARS-CoV-2 detection by NAAT .
3.3.2.Additional Endpoints (for Phase 2/3 Only)
All safety, immunogenicity ,and efficacy endpoints described above will be
summarized separately forparticipants with confirmed stable HIV .
All safety endpoints described above , 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 “P rocess 1” and each lot of “Process 2 .”All
participants who received “Process 2” vaccine and a random 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 su mmary of “Process 1” and
each lot of “Process 2.”
3.4.Baseline and Other Variables
Measurements or samples collected prior to Dose 1are considered the baseline data for the
assessments.
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TMF Doc ID: 98.033.4.1.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
includedin the demographic variables .
Age at the time of vaccinati on (in years) will be derived based on the participant ’s birthday .
For example, if the vaccination day is 1 day before the participant ’s 19thbirthday, 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 categor ized according to MedDRA. Comorbidities that increasethe
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 significant 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, and a subset of at least 6000 in Phase 2/3, an e- diary will be
considered transmitted if any data for the local reactions, sy stemic events, or use of
antipyretic 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.
An e-diary willbe considered completed if all expected data for all 7 days are available
(ie,not missing). Otherwise, the e -diary will be considered incomplete. For any 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 day s 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).
Prohibited medications listed in the protocol , Section 6.5.1 , will be recorded, to include
start and stop dates, name of the medication, dose, unit, route, and frequency .
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TMF Doc ID: 98.03In addition, for participan ts 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
safety 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 databaseand
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 system.
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 determinate immunogenicity result from
theblood collection within an appropriate window after Dose 1
(same as visit w indow, ie,within 19-23 days after Dose 1) , and
have no other important protocol deviations as determined by the
clinician.
Dose 2 evaluable
immunogenicit 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 days after
Dose 1), have at least 1 valid and determinate immunogenicit y
result after Dose 2from the blood collection within an
appropriate window after Dose 2( within 6-8 days after Dose 2
for Phase 1 and within 28- 42 days after Dose 2 for P hase 2/3),
and have no other important protocol deviations as determined b y
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 valid 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 after Dose 2.
Evaluable efficacy
(7 days)All eligible randomized participants who receive all
vaccination(s) as randomized , with Dose 2 received within the
predefined wind ow(within 19 -42 days after Dose 1) and have no
other important protocol deviations as determined by the clinician
on or before 7 day s after Dose 2 .
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TMF Doc ID: 98.03Population Description
Evaluable efficacy
(14 days)All eligible randomized participants who receive all
vaccination(s) as randomized, with Dose 2 received within the
predefined window (within 19 -42 days after Dose 1) and have no
other important protocol deviations as determined by the clinician
on or befor e 14days after Dose 2.
All-available efficacy Dose 1 all -available efficacy : All randomized participants who
receive at least 1 vaccination.
Dose 2 all -available efficacy : All randomized participants who
complete 2 vaccination doses.
Safety All random ized participants who receive at least 1 dose of the
study 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 Phase2/3 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 assays 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 Hypothesis
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 p lacebo group
(see Appendix 3fordetails on the calculation of IRR and VE) . The assessment of VE will be
based on posterior probabilities of VE1>30% and VE2>30%using beta-binomial models.
VE1represents 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 particip ants after vaccination.
For participants with multiple confirmed cases, only the first case will contribute to the VE
calculation for each h ypothesis.VE1and VE 2 will be evaluated sequentially to control the
overall ty pe I error to the desired level of 2 .5%. VEis demonstrated if there is sufficient
evidence ( high posterior probability ) that either VE1>30% or both VE 1and VE 2are >30%.
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TMF Doc ID: 98.03The assessment for the primary analysis will be based on posterior probability using a
beta-binomial model(see Appendix 2for details) .
5.1.2.Immunogenicity Hypothesis
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 immunogenicity population will be used for the following hy pothesis
testing:
H0: ln(µ2) –ln(µ1) ≤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 t he 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 16-25
years of age) is >0.67, the noninferiorit y objective is met.
5.1.3.Sample Size
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.
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 ca ses 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 t he 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
underlying VE, and a potential earl y stop for efficacy or futility .
In Phase 3, approximately 2000 participants are anticipated to be 12 to 15 years of age. A
random sample of 250participant 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, asample size of 200 evaluable participants (or 250 vaccine recipients) per age group
will provide a power of 90.8% 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 Table9).
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TMF Doc ID: 98.03For safety outcomes, Table10shows 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 v accine group, there is 72% probability of observing at least
1AE.
Table9.Power Analysis for Noninferiority Assessment
Criteria Standard Deviation
(Log Value)aAssumed Observed
GMT Difference
(Log Scale)Number of
Evaluable
Participants per
Age GroupPowerb
Lower limit of 95%
CI for GMR
(12-15/16-25) >0.670.623 -0.2 200 90.8%
Abbreviation: GMR = geometric mean ratio.
a. Reference: 1 monthafterDose 2, BNT162b2 (30µg), 18-to 55-year age group (C4591001 Phase 1 ,
N=12). Calculation may be updated if additional information becomes available to better estimate the
standard deviation.
b.At 0.05 alpha level (2 -sided).
Table10.Probability of Observing at Least 1 AE by Assumed True Event Rates
With Different Sample Sizes
Assumed True
Event Rate of
an AEN=12 N=45 N=180 N=3000 N=6000 N=9000 N=15000
0.01% 0.00 0.00 0.02 0.26 0.45 0.59 0.78
0.02% 0.00 0.01 0.04 0.45 0.70 0.83 0.95
0.04% 0.00 0.02 0.07 0.70 0.91 0.97 >0.99
0.06% 0.01 0.03 0.10 0.83 0.97 0.99 >0.99
0.08% 0.01 0.04 0.13 0.91 0.99 0.99 >0.99
0.10% 0.01 0.04 0.16 0.95 0.99 0.99 >0.99
0.15% 0.02 0.07 0.24 0.99 0.99 >0.99 >0.99
0.20% 0.02 0.09 0.30 >0.99 >0.99 >0.99 >0.99
0.25% 0.03 0.11 0.36 >0.99 >0.99 >0.99 >0.99
0.30% 0.04 0.13 0.42 >0.99 >0.99 >0.99 >0.99
0.35% 0.04 0.15 0.47 >0.99 >0.99 >0.99 >0.99
0.50% 0.06 0.20 0.59 >0.99 >0.99 >0.99 >0.99
1.00% 0.11 0.36 0.84 >0.99 >0.99 >0.99 >0.99
2.00% 0.22 0.60 0.97 >0.99 >0.99 >0.99 >0.99
3.00% 0.31 0.75 >0.99 >0.99 >0.99 >0.99 >0.99
5.00% 0.46 0.90 >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
10.00% 0.72 0.99 >0.99 >0.99 >0.99 >0.99 >0.99
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TMF Doc ID: 98.035.1.4.Multiplicity Considerations
For Phase1, there is no hy pothesis testing. For Phase2/3, a Bayesian approach will be
applied for the firstprimary efficacy endpoint at the interim and final analyses. The
boundaries for declaring efficacy at interim analyses and success criteria for the final analy sis
are adjusted appropriately to control the t ype I errorat 0.025 ( Table13).
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 presen ted 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, a nd 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 Phase2/3 only, the 3-tier approach will be used to summarize AEs. For both Tier 1
(ifany are identified during the stud y) and Tier2 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 asymptotic p-values will also be presented for the
difference in proportions, based on the same test statistic a nd under the assumption that the
test statistic is asy mptotically normally distributed. For Tier3 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 Continuous Data
Unless otherwise stated, descriptive statistics for continuous variables are n, mean, median,
standard deviation, minimum, and maximum.
5.2.2.1. Geometric Means
For immunogenicity results of SARS -CoV-2 neutralizing titers, the GMTs will be computed
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 exponen tiating the confidence limits . Similarly, GMCs and 95% CI swill be calculated
for S1-binding IgGlevelsand RBD-binding IgG levels .
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TMF Doc ID: 98.035.2.2.2. 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 logarithmicall y transformed
neutralization titers or antibody levels (later result minus earlier result ) andexponentiating
the mean. The associated 2- sided 95% CIs are obtained by constructing CIs using Student’s
t-distribution for the mean difference on the natural log scaleand exponentiating the
confidence limits.
5.2.2.3. Geometric Mean Ratios
For SARS -CoV-2 neutralizing titers and S1-binding IgGlevelsand 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
IgGlevels/RBD-binding IgG level sat 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 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 logarithmically transformed assay resultsand exponentiating the
confidence limits.
For SARS-CoV-2 neutralizing titers in participants 12 to 15 years 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.
5.2.2.4. 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 IgGlevelat 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 vaccination to the
corresponding antibody level at the time point before vaccination .
5.2.2.5.Reverse Cumulative Distribution Curves
Empirical RCDCswill 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.
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TMF Doc ID: 98.035.3. Methods to Manage Missing Data
For endpoints, the m issing data handling rules are described in the corresponding endpoint
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 Phase2/3 for computing VEwill be imputed in the
sensitivity analysis.Details are included in Section 6.1.2.1.2.
6.ANALYSES AND SUMMARIES
6.1.Primary Endpoint (s)
6.1.1.Safety Endpoints
The safety analyses are based on the safet y population. Participants will be summarized by
vaccine group according to the studyinterventions they actually received. Missing e -diary
data will not be imputed; missing AE dates will be handled according to the Pfizer safet y
rules.
6.1.1.1.Local Reactions
6.1.1.1.1. MainAnalysis
Estimand: The percentage of participants reporting local reactions (redness, swelling ,and
pain at the injection site) within7 days after each dose(Section 2.1).
Analysis set:Safety population (Section 4).
Analysis time point: Within 7 day s after each dose .
Analysis methodology : Descriptive statistics (Section 5.2.1).
Intercurrent events and missing data: The participants without any e-diary data
throughout the 7 day s aftervaccination 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 each dose in
each vaccine group will be presented b y maximum severity across severity 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 associated 2-sided Clopper-Pearson 95% CI s.
6.1.1.1.2. 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 analysis time point andanalysis
population , analysis methodology ,and appropriate reporting results. Confirmed e -diary
errors will be excluded from these anal yses.
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TMF Doc ID: 98.03Duration (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 days 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.
6.1.1.2.Systemic Events
6.1.1.2.1. MainAnalysis
Estimand: The percentage of participants reporting s ystemic events (fever,
fatigue/tiredness, headache, chills, vomiting, diarrhea, new or worsened muscle pain, and
new or worsened joint pain) within 7 day s after each dose (Section 2.1).
Analysis set: Safety population (Section 4).
Analysis time point: Within 7 day s after each dose .
Analysis methodology : Descriptive statistics (Section 5.2.1).
Intercurrent events and missing data: The participants without any e-diary data
throughout the 7 day s aftervaccination 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 across severity levels. Descriptive
summary statistics will include counts an d 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 group.
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TMF Doc ID: 98.03The use of antip yretic medication (see Section 3.1.1.3) will be summarized similarly to
systemic events, except that there is no severity 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
severity categories to highlight the proportions of participant s by severity.
6.1.1.3.Adverse Events
6.1.1.3.1. MainAnalysis
Estimand: The percentage of participants reporting AEs from Dose 1 to 1 month after the
second dosefor all phases, and from Dose 1 to 7 day s after the seconddose for the first
360 participants randomized in Phase 2 (Section 2.1).
Analysis set: Safety population (Section 4).
Analysis time point: Dose 1 to 1 month after thesecond dosefor all phases, Dose 1 to 7
days after the second dose for the first 360 participants randomized in Phase 2.
Analysis methodology : Descriptive statistics ( Section 5.2.1) for all phases and additional
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% CIs for the difference between the active vaccine and placebo groups in the
percentage of participants reporting the events based on the Mietti nen and Nurminen2
methodwill be provided. In addition, for Tier 1 events, the as ymptotic p-values will also
be presented for the difference between groups in the percentage of participants reporting
the events, based on the same test statistic and under the assumption that the test statistic
is asymptoticall 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 af ter 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 months after
the second dosefor all phases, and from Dose 1 to 7 day s after the seconddose for the
first 360 participants randomized in Phase 2 (Section 2.1).
Analysis set: Safety population (Section 4).
Analysis time point: Dose 1 to 6 month safter the second dosefor all phases, Dose 1 to 7
days after the second dose for the first 360 participants randomized in Phase 2 .
Analysis 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 from Dose 1 to
6months/7 day safter the second dose will be provided for each vaccine group.
6.1.1.5.Hematology and Chemistry Parameters (for Phase 1Only)
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
Dose2 and 7 day s after Dose 2 ( Section 2.1).
Analysis set: Safety population ( Section 4).
Analysis time point: 1 and 7 day s after Dose 1; and 7 day s after Dose 2.
Analysis methodology : Descriptive statistics including counts and percentage
(Section 5.2.1 ).
Intercurrent events and missing data: Missing values will not be imputed.
Reporting 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.
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TMF Doc ID: 98.036.1.2. Vaccine Efficacy Endpoints (for Phase 2/3 Only)
6.1.2.1.COVID-19 Incidence per 1000 Person -Years of Follow -up
6.1.2.1.1. 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 infection
(prior to 7 day s after receipt of the second dose) for the active vaccine group to the
placebogroup (Section 2.1)].
100 × (1 – IRR) [ratio of confirmed COVID -19 illness from 7 days 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)].
Analysis set: Evaluable efficacy (7 days) and all-available efficacy populations
(Section 4).
Analysis time point: At interim anal yses and final analysis when the surveillance period
ends.
Analysis 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 correspondi ng
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%|da ta]) at 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 (symptomis present without
laboratory testing data) will not be imputed in the main anal yses.
Reporting results: The point estim ate of VE, 95% credible intervals using the 2.5th
percentile and the 97.5thpercentile, and Bay esian posterior probability of VE greater than
30% will be provided (details can be found in Appendix 2).
6.1.2.1.2. 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 meth od.3 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 withoutthe MAR assumption may be explored, eg , atipping point
analysis.
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TMF Doc ID: 98.03All COVI D-19 cases after Dose 1 may be analyzed using the Dose 1 all- available efficacy
population. COVI D-19 disease -related information may be summarized or listed.
Efficacy could also be assessed over a longer time period using time -to-event data anal ysis
methods (eg, Cox model) 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 -19cases over 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, arank-preserving structural failure time
model 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.SecondaryEndpoints
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 anal ysis based on the evaluable
immunogenicit y populations. An additional analysis will be performed based on the
all-available populations if there is a largeenough 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 no t be imputed.
Phase 2/3
Thestatistical analysis 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 Dose 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.
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TMF Doc ID: 98.036.2.1.1.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 vacci nation (Section 2.1 ).
Analysis set: Dose 1 and Dose 2 evaluable and all-available immunogenicity population s
(Section 4).
Analysis time point s: 7 and 21 day s after Dose 1; 7 and 14 days and 1, 6, 12 and
24months after Dose 2 .
Analysis methodology : GMs and the associated 2 -sided CIs 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 5.2.2.1).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 – earlier time point) and exponentiated to transform results
back to the original scale. Two- sided CIs will be obtained by calculating CIs using
Student’s t -distribution for the mean difference of the logarithmically transformed assay
results and exponentiating the confidence limits (Section 5.2.2.2).Percentages of
participants 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 to0.5 × 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 , GMFRsfrom before vaccination to each
subsequent time point a fter vaccination , and the percent ages of partic ipants achieving
≥4-fold riseand the associated 2-sided 95% CIs from before vaccination toeach time
pointafter vaccination .
Figures:
Empirical RCDCs will be provided for SARS-CoV-2 neutralizing titers after Dose 1 and
after Dose 2 (Section 5.2.2.5).
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TMF Doc ID: 98.036.2.1.2.S1-Binding IgG Levelsand 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 risefrom before vaccination to each
subsequent time point after vaccination ( Section 2.1).
Analysis set: Dose 1 and Dose 2 evaluable and all-available immunogenicity population s
(Section 4).
Analysis time point s: 7 and 21 day s after Dose 1; 7 and 14 days and 1, 6, 12, and
24months after Dose 2 .
Analysis methodology : GMs and the associated 2 -sided CIs 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 5.2.2.1). GMFRs will be limited to participants
with nonmissing values prior to the first dose and at the postvaccination time point. The
GMFR will be cal culated by exponentiating the mean of the difference of logarithmically
transformed assay results (later time point – earlier time point). Two -sided CIs 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 5.2.2.2). Percentages 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 percentages of partic ipants with ≥4-fold rise
and the associated 2 -sided 95% CI s will be provided for each study intervention
(active/placebo) within each group before vaccination and at each time point.
Figures:
Empirical RCDCs will be provided for S1-binding IgGlevelsand RBD-binding IgG levels
after Dose 1 and after Dose 2 (Section 5.2.2.5).
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TMF Doc ID: 98.036.2.1.3.GMR of SARS -CoV-2 Neutralizing T iter to SARS-CoV-2S1-Binding IgG
Levelsand RBD-Binding IgG Levels(Phase 1)
6.2.1.3.1. Main Analyses
Estimand s:
GMRof SARS-CoV-2 neutralizing titersto S1-binding IgGlevels(Section 2.1).
GMR of SARS -CoV-2 neutralizing titer sto RBD-binding IgG levels (Section 2.1).
Analysis set: Dose 1 and Dose 2 evaluable and all-available immunogenicity population s
(Section 4).
Analysis time point s: 7 and 21 day s after Dose 1; 7 and 14 days and 1, 6, 12, and
24months after Dose 2 .
Analysis methodology : GMRs will be limited to participants with nonmissing values fo r
both SARS -CoV-2 neutralizing titers and S1-binding IgGlevelor RBD-binding IgG
levelat 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 IgGlevelsfor each participant) and exponentiat ing the mean
(Section 5.2.2.3).Two-sided CIs will be obtained by calculating CIs using Student’s
t-distribution for the mean difference of the logarithmically transformed assay resultsand
exponentiating the confidence limits(Section 5.2.2.3).
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 GMRsand 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.GMR of SARS -CoV-2 Neutralizing Titer sin Participants 12 to 15 Years of Age
to 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 meanof SARS -CoV-2
neutralizing titers in the 2 age groups (12 -15 years of age to 16- 25 years of age) 1 month
after comp letion of vaccination ( Section 2.1).
Analysis set: Dose 2 evaluable and all -available immunogenicit y populations ( Section 4).
Analysis time points: 1 month after Dose 2 .
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TMF Doc ID: 98.03Analysis 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 5.2.2.3).
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.
6.2.2.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 from14 days 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
placebogroup (Section 2.1)].
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 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)].
Analysis set: Evaluable efficacy (14 days) and all-available efficacy populations
(Section 4).
Analysis time point: End of the surveillance period or at IAs if requested.
Analysis methodology : the same method used for primary VE endpoints will be applied
(Section 6.1.2.1.1).
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 6.1.2.1.1).
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TMF Doc ID: 98.036.2.2.2.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 days after the second dose per 1000 person -years of follow -up in participants
without evidence of infection (prior to 7 day s and14 days after receipt of the second
dose) for the active vaccine group to the placebo group (Section 2.1)].
100 × (1 – IRR) [ratio of confirmed severe COVID -19 illness from 7 day s andfrom
14 days 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)].
Analysis set: Evaluable efficacy and all-available efficacy populations ( Section 4).
Analysis time point: End of the surveillance period or at IAs if requested .
Analysis methodology : the same method used for primary VE endpoints will be applied
(Section 6.1.2.1.1).
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 6.1.2.1.1).
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 e vidence of infection (prior to 7 days
and 14 day s after receipt of the second dose) for the active vaccine group to the
placebogroup (Section 2.1)].
Analysis set: Evaluable efficacy and all-available efficacy populations ( Section 4).
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TMF Doc ID: 98.03Analysis time point: End of the surveillance period.
Analysis methodology : Assessment of VE will be performed for centrally confirmed
COVID-19 according to the CDC -defined symptoms from 7 day s and from 14 day s after
the receipt of the seconddose 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 symptoms per 1000 person -years of follow -up in the active vaccine
group to the corresp onding illness rate in the placebo group after the seconddose.
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 will be provided.
6.3.Exploratory Endpoints
6.3.1.Immunogenicity Endpoints (for Phase 2/3 Only)
6.3.1.1.SARS-CoV-2 Neutralizing Titers, and S1-Binding IgGLevelsand RBD-Binding
IgG Levels
6.3.1.1.1. Main Analyses
Estimands:
GMTs/GMCs(Section 2.1).
GMFR from before vaccination to each subsequent time point after vaccination
(Section 2.1 ).
Percentage of participants with antibody levels ≥ predefined threshold(s) for
SARS-CoV-2 serological parameters .
Analysis set: Dose 1 and Dose 2 evaluable and all -available immunogenicity populations
(Section 4).
Analysis time points: 1, 6, 12, and 24 months after completion of vaccination in
participants with and without serological or virological evidence of SARS -CoV-2
infection before vaccination .
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TMF Doc ID: 98.03Analysis methodology : GMs and the associated 2 -sided CIs 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 5.2.2.1). 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 CIs 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 5.2.2.2). Percentages of participants with antibody levels ≥ predefined
threshold(s) for SARS -CoV-2 serological parameters will be calculated with the
associated 2- sided 95% CI s (Clopper -Pearson method).
Intercurrent events and missing data: Serology data deemed unevaluable because of
noncomplian ce with the key protocol criteria will be excluded. Titers /concentrations
below the LLOQ or denoted as BLQ will be set to 0.5 × LLOQ for anal ysis. However,
this calculation may be adjusted based upon additional data from the assay . Missing data
will notbe imputed.
Reporting results: the GMTs/GMCs at each time point, GMFRs from before vaccination
to each subsequent time point after vaccination, and the percentages of participants with
antibody levels ≥ predefined threshold(s) for baseline SARS- CoV-2 serological
parameters and the associated 2 -sided 95% CIs from before vaccination to each time
point after vaccination will be provided.
6.3.1.1.2. Additional Exploratory Analyses
The aboveanalyses will be performed by baseline SARS -CoV-2status(positive or negative) .
6.3.1.2. N-B inding Antibody
Estimands:
Percentage of participants with seroconversionby N-binding antibody .
Analysis set: Dose 1 and Dose 2 evaluable and all -available immunogenicity
populations ( Section 4).
Analysis time points: 1, 6, 12, and 24 months after completion of vaccination in
participants with and without serological or virological evidence of SARS -CoV-2
infection before vaccination .
Analysis methodology :Descriptive statistics (Section 5.2.1).
Intercurrent events and missing data: Miss ing data will not be imputed.
Reporting results: Percentages of participants with seroconversion by N-binding antibody
will be calculated with the associated 2 -sided 95% CI s (Clopper -Pearson method) at
baseline and each time point after vaccination .
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TMF Doc ID: 98.036.3.1.3.Serological Responses in Participants With Confirmed COVID- 19, Confirmed
Severe COVID -19, and SARS -CoV-2Infection Without Confirmed COVID -19
The analyses described above for exploratory immunogenicit y endpoints may be applied to
the participants with confirmed COVID -19, confirmed severe COVID -19, and SARS -CoV-2
infection without confirmed COVID -19.
6.3.2.Additional Analysis
The ratios of (GMFR A to GMFR B) and (GMFR A to GMFR C) may be explored, where
GMFR A is the geometric mean of the ratio of the SARS- CoV-2 neutralizing titer at the
postvaccination time point to the corresponding titer at the pre vaccination timepoint, GMFR
B is the geometric mean of the ratio of the S1-binding IgGlevelat the post vaccination time
point to the corresponding antibod y levelat the prevaccination timepoint, and GMFR C is
the geometric mean of the ratio of the RBD-binding IgG level at the post vaccination time
point to the corresponding antibod y level at the pre vaccination timepoint(Section 5.2.2.4).
The safety data and immunogenicity results for individuals with confirmed stable HIV
disease will be summarized descriptivel y. Furthermore, VE may be asses sed if there is a
sufficient number of COVID -19 cases in this group of participants.
The safety and immunogenicity results for individuals 16 to 55 y ears of age vaccinated with
study intervention produced b y manufacturing “Process 1” and each lot of “Process 2” will
be summarized descriptively .
All severe COVID -19 cases occurr ingafter Dose 1 will be summarized descriptively .
6.4.Subgroup Analysis
Subgroup anal yses based on age, race, ethnicity , sex, country, and baseline SARS-CoV-2
statuswill be performed o n all primary safetyand efficacy endpoints (as supplemental
analyses)for Phase 2/3.
6.5.Baseline and OtherSummaries and Analyses
6.5.1.Baseline Summaries
6.5.1.1.Demographic Characteristics
Demographic characteristics ,including age group, sex, race, ethnicit y,and classification of
BMIwill be summarized for the safet y population for each vaccine group and overall.
6.5.1.2.Medical History
Each reported medical history term will be mapped to a SOCand PTaccording to MedDRA.
The number and percentage of vaccinated participants having at least 1 diagnosis, overall and
at each SOCand PTlevel, will be summarized by vaccine group for the overall safety
population .
The number and proportion of participants with comorbidities that increase the risk for
severe COVID -19 illness will be summarized by each vaccine group.
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TMF Doc ID: 98.036.5.2.Study Conduct and Participant Disposition
6.5.2.1. Participant Disposition
The number and percentage of randomized participants will be included in the participant
disposition summary . In addition, the number sand percent agesof participants who received
vaccinations (Dose s 1and 2), who completed the follow- up visits (1 month after the second
dose), and who withdrew before each follow -up visit along with the reasons for withdrawal
will be tabulated b y vaccine group (accor ding to randomized group assignment). The
reasons for withdrawal will be those as specified in the database.
Participant s excluded from each anal ysis population will also be summarized separatel y
along with the reasons for exclusion ,by vaccine group .
Participants f ollow-up time after completion of vaccinations will be summarized by vaccine
group.
6.5.2.2.Blood Samples for Assay
The number and percentage of randomized participants providing blood samples within and
outside of protocol -specified time frames will be tabulated separatel y foreach time point .
6.5.2.3. E-D iaries
The participants who were vaccinated and completed e-diaries aftereach dose will be
summarized according to the vaccine actuall y received. Besides the anal ysis described in
Section 6.1.1.1andSection 6.1.1.2, the summary will also include the number sand
percentage sof vaccinated participants not transmitting the e -diary,andtransmitting the
e-diaryfor any day in the required reporting period ,by as-received vaccine group for each
dose.
The safety population will be used.
6.5.3.Study Vaccination Exposure
6.5.3.1.Vaccination Timing and Administration
For each dose, t he number and percentage of participants randomized and receiving each
study intervention within the protocol -specified time frame, as well as before and after t he
specified time frame, will be tabulated for each vaccine group and overall for all randomized
participants. The denominator for the percentages is the total number of randomized
participants in the given vaccine group or overall.
In addition, the relat ion of randomized vaccine to actual vaccine received will be presented
as a cross tabulation of the actual vaccine received versus the randomized vaccine.
A listing of participants showing the randomized vaccine and the vaccine actually received at
each dose will be presented.
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TMF Doc ID: 98.036.5.4. Prior/Concomitant Vaccination and Concomitant Medications
Each prior/concomitant vaccine will be summarized according to the ATC 4 th-level
classification. Allvaccinesreceived within 28 days before Dose 1 will be listed. The
number and percentage of participants receiving each concomitant vaccine afterDose 1 will
be tabulated by vaccine group . Asummarywill be provided forthe interval between Dose 1
and 1 month after the second dose.The safety population will be used. Concomitant
medications will be summarized in a similar way as concomitant vaccine s.
6.6. Safety Summaries and Analyses
Local reaction, s ystemic event, AE,andSAE summaries and anal yses are described under
Primary Endpoint (s)(Section 6.1).
7.ANALYSES TIMING
7.1. Introduction of Interim Analysis
As this is a sponsor open- label study during Phase 1,the sponsor may conduct unblinded
reviews of the data during the course of the study for the purpose of safet y assessment,
facilitating dose escalation decisions, and/or supporting clinical development.
During Phase 2/3, 4 IAs were planned tobe performed by an unblinded statistical team after
accrual of at least 32, 62, 92, and 120 cases. However, for operational reasons, the first
planned IA was not performed. Consequently , 3 IAs are now planned to be performed after
accrual of at least 62, 92, and 1 20 cases. At theseIAs, futility and VE with respect to the
first primary endpoint will be assessed as follows:
VE for the first primary objective will be evaluated. Overwhelming efficacy will be
declared if the first primary study objective is met. Thecriteria for success at an interim
analysis are based on the posterior probability (ie, P[VE >30% |data]) at the current
number of cases. Overwhelming efficacy will be declared if the posterior probability is
higher than the success threshold. The succes s threshold for each interim anal ysis will be
calibrated to protect overall ty pe I error at 2.5%. Additional details about the success
threshold or boundary calculation at each interim anal ysis can be found in Appendix 2.
The study will stop for lack of benefit (futility) if the predicted probability of success at
the final anal ysis or study success is <5%. The posterior predictive POS will be
calculated using a beta -binomial model. The futility assessment will be performed for the
first primary endpoint,and the futility boundary may be subject to change to reflect
subsequent program -related decisions b y the sponsor.
Efficacy and futility boundaries will be applied in a nonbinding way .
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TMF Doc ID: 98.03Bayesian approaches require specification of a prior distribution for the possible values of the
unknown vaccine effect, thereb y accounting for uncertaint y in its value. A minimally
informative beta prior, beta (0.700102, 1), is proposed for θ = (1 -VE)/(2-VE). The prior is
centered at θ = 0.4118 (VE=30%) ,which can be considered pessimistic. The prior allows
considerable uncertainty ; the 95% interval for θ is (0.005, 0.964) and the corresponding 95%
interval for VE is ( -26.2, 0.995).
Table11illustrates the boundary for efficacy and futility if, for example, IAs are performed
after accrua l of 32, 62, 92, and 120 cases in participants without evidence of infection before
vaccination. Note that although the first IA was not performed, the statistical criterion for
demonstrating success (posterior probability threshold) at the interim (>0.99 5) and final
(>0.986) anal yses remains unchanged. Similarly, the futility boundaries are not changed.
Table11.Interim Analysis Plan and Boundaries for Efficacy and Futility
Analysis Number of
CasesSuccess CriteriaaFutility Boundary
VE Point Estim ate
(Case Split)VE Point Estim ate
(Case Split)
IA1 32 76.9% (6:26) 11.8% (15:17)
IA2 62 68.1% (15:47) 27.8% (26:36)
IA3 92 62.7%(25:67) 38.6% (35:57)
IA4 120 58.8% (35:85) N/A
Final 164 52.3%(53:111)
Abbreviations: IA = interim analysis; N/A = not applicable; VE = vaccine efficacy.
Note: Case split = vaccine : placebo.
a.Interim efficacy claim: P(VE >30%|data) > 0.995; success at the final analysis: P(VE >30%|data) > 0.986.
Additional design operating characteristics (the boundary based on the number of case s
observed in the vaccine group; the probabilities for efficacy and futility given assumed
various VEs with a 1:1 randomization ratio) are listed in Table12and Table13for IAs
conducted at 32, 62, 92, and 120 cases and the final anal ysis at 164 cases. Although the IA at
32 cases was not performed, the overall Ty pe I error (overall probability of success when true
VE=30%) will still be strictly controlled at 0.025 with the originall y proposed success/futility
boundaries.
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TMF Doc ID: 98.03Table12. Statistical Design Operating Characteristics: Probability of Success or
Failure for Interim Analyses
Vaccine
Efficacy
(%)Interim Analysis 1
(Total Cases = 32)Interim Analysis 2
(Total Cases = 62)Interim Analysis 3
(Total Cases = 92)Interim
Analysis 4
(Total Cases =
120)
Probability
of Success
(Cases in
Vaccine
Group ≤6)Probability
of Failure
(Cases in
Vaccine
Group ≥15)Probability
of Success
(Cases in
Vaccine
Group ≤15)Probability
of Failure
(Cases in
Vaccine
Group ≥26)Probability
of Success
(Cases in
Vaccine
Group ≤25)Probability
of Failure
(Cases in
Vaccine
Group ≥35)Probability of
Success (Cases
Vaccine Group
≤35)
30 0.006 0.315 0.003 0.231 0.002 0.239 0.002
50 0.054 0.078 0.051 0.056 0.063 0.103 0.075
60 0.150 0.021 0.160 0.010 0.175 0.019 0.160
70 0.368 0.003 0.310 <0.001 0.195 0.001 0.085
80 0.722 <0.001 0.238 <0.001 0.037 <0.001 0.003
Table13.Statistical Design Operating Characteristics: Probability of Success for
Final Analysis and Overall
Vaccine Efficacy (%) Final Analysis
(Total Cases = 164)Overall Probability of Success
Probability of Success (Cases in Vaccine
Group ≤53)
30 0.007 0.021
50 0.196 0.439
60 0.220 0.866
70 0.036 >0.999
80 <0.001 >0.999
If neither success nor futility has been declared after all IAs, the final anal ysis will be
performed and the first primary objective will have been met if there are 53 or fewer cases
observed in the vaccine group out of a total of 164 first confirmed cases from 7days after
receipt of the seconddose ofstudy intervention onwards.
Only the first primary endpoint will be analy zed at an IA.If the first primary objective is
met, the second primary objective will be evaluated at the final anal ysis. After the primary
objectives are met, the first 6 seconda ry VE endpoints will be evaluated sequentially in the
following orderby the same method used for the evaluation of primary VE endpoints: (1)
confirmed COVID -19 occurring from 14 day s after the second dose in participants without
evidence of infection and (2) in all participants ;(3)confirmed severe COVID -19 occurring
from 7 day s after the second dose in participants without evidence of infection and (4) in all
participants; (5) confirmed severe COVID -19 occurring from 14days after the second dose
in participants without evidence of infection and ( 6) in all participants .
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TMF Doc ID: 98.03Success thresholds for secondary VE endpoints will be appropriatel y chosen to control
overall type I error at 2.5%. The remaining secondary VE endpoints will be evaluated
descriptivel y to calculate the observed VE with 95% CI s.
7.2.Interim Analyses and Summaries
Statistical analy ses will be carried outwhen the following data are available:
Complete safet y and immunogenicit y analysis approximately 1 month after Dose 2
for Phase 1.
Safety data through 7 day s after Dose 2 and immunogenicity data through 1 month
after Dose 2 from the first 360 participants enrolled (180 to active vaccine and 180 to
placebo, stratified equally between 18 to 55 years and >55 to 85 years) in Phase 2/3.
Safety datathrough 1 month after Dose 2 from at least 6000 participants enrolled
(3000 to active vaccine and 3000 to placebo) in Phase 2/3. Additional analy ses of
safety data (with longer follow -up and/or additional participants ) may be conducted if
required for re gulatory purposes.
IAs for efficacy after accrual of at least 62, 92, and 120 cases and futility after accrual
of at least 62 and 92 cases.
Safety data through 1 month after Dose 2 and noninferiorit y comparison of
SARS-CoV-2 neutralizing titers in participants 12 to 15 years of age compared to
those in participants 16 to 25 years of age ,1 month after Dose 2.
Descriptive anal ysis of immunogenicit y and safety of “Process 1” and “Process 2”
material, 1 month after Dose 2.
Complete safet y and immunogen icity analysis approximately 6 months after Dose 2
for all participants in Phase 2/3.
Complete efficacy and persistence -of-immunogenicity analysis after complete data
are available or at the end of the study .
All analyses conducted on Phase 2/3 data while the study is ongoing will be performed by an
unblinded statistical team.
7.2.1.Data Monitoring Committee
This study will use an IRC, a DMC, and a group of internal case reviewers. The I RC is
independent of the stud y team and includes onl y internal members. The DMC is independent
of the study team and includes only external members. The IRC and DMC charters describe
the role of the IRC and DMC in more detail.
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TMF Doc ID: 98.038.REFERENCES
1. Agresti A. Introduction: distributions and inference for categorical data. In: Agresti A, ed.
Categorical data anal ysis. 2nd ed. Hoboken, NJ: John Wiley & Sons; 2002:1-35.
2.Miettinen O, Nurminen M. Comparative anal ysis of two rates. Stat Med
1985;4(2):213 -26.
3.van Buuren S. Multiple imputation of discrete and continuous data by fully conditional
specification. Stat Methods Med Res 2007;16(3):219-42.
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TMF Doc ID: 98.039.APPENDICES
Appendix 1.List of Abbreviations
Abbreviation Term
Abs absolute
AE adverse event
ALT alanine aminotransferase
AST aspartate aminotransferase
ATC Anatomic Therapeutic Chemical
BLQ below the level of quantitation
BMI body mass index
BUN blood urea nitrogen
CDC Centers for Disease Control and Prevention
CI confidence interval
COVID-19 coronavirus disease 2019
CRF case report form
DBP diastolic blood pressure
DMC data monitoring committee
ECMO extracorporeal membrane oxygenation
e-diary electronic diary
FiO2 fraction of inspired oxygen
GM geometric mean
GMC geometric mean concentration
GMFR geometric mean fold rise
GMR geometric mean ratio
GMT geometric mean titer
HIV human immunodeficiency virus
HR heart rate
IA interim analysis
ICD informed consent document
ICU intensive care unit
IgG immunoglobulin G
IND indeterminate
IRC internal review committee
IRR illness rate ratio
IWR interactive Web -based response
LLOQ lower limit of quantitation
MAR missing at random
MCH mean corpuscular hemoglobin
MCHC mean corpuscular hemoglobin concentration
MCV mean corpuscular volume
MedDRA Medical Dictionary for Regulatory Activities
N/A not applicable
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TMF Doc ID: 98.03Abbreviation Term
NAAT nucleic acid amplification test
PaO2 partial pressure of oxygen, arterial
POS probability of success
PT preferred term
RBC red blood cell
RBD receptor-binding domain
RCDC reverse cumulative distribution curve
RNA ribonucleic acid
RR respiratory rate
RT-PCR reverse transcription –polymerase chain reaction
S1 spike protein S1 subunit
SAE serious adverse event
SAP statistical analysis plan
SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
SBP systolic blood pressure
SOC system organ class
SOP standard operating procedure
SpO2 oxygen saturation as measured by pulse oximetry
VE vaccine efficacy
WBC white blood cell
WHO World Health Organization
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TMF Doc ID: 98.03Appendix 2. Details for Bayesian Design
Bayesian group sequential design will be implemented in the Phase3 for this study .
Notation
(1) Let VE be vaccine efficacy , θ be the case rate (number of cases in the active vaccine group
divided by the total number of cases) , T1bethe total person -time in the active vaccine group,
T0be the total person -time in the placebogroup, and r be the ratio of T1and T0, ie,r = T1/T0.
Notethat. = ( )
( ) and =1−
( ).
(2) Let pbe the posterior probability of VE greater than or equal to 30% given the observed
data on subset of enrolled participants, ie :
p=Pr(VE >30% | observed data fromsubset of enrolled participants)
= Pr (θ < ( %)
( %) | observed data fromsubset of enrolled participants )
Under the assumption that the numbers of cases in both vaccine groups, s 1and s0for cases in
the active vaccine group andcases in the placebo group , respectively , follow a Poisson
distribution with parameter λ1(incidence rate) for the active vaccine group and λ 0for the
placebo group, we can assume that s 1is binomially distributed with Binomial (s, θ) ,
conditional on s, the total number of cases, and with θ = T1λ1/ (T1λ1+ T0λ0).
A minimally informative beta prior, Beta(0.700102, 1) is selected as the prior distribution of
θ. The prior distribution is chosen such that the mean is equal to 0.4118 corresponding to VE
= 30% which can be considered pessimistic. Meanwhile, the prior a llows for considerable
uncertaint y, ie,95% credible interval for θ is (0.005, 0.964) corresponding to 95% credible
interval, ( -26.2, 0.995), for VE.
Decision Algorithm for Efficacy
At certaininterim analy sis and final anal ysis, let nbe the total number of observed cases and
nvbe the number of observed cases from the vaccine group. For beta-binomial model , the
posterior distribution of θ will be derived as Beta( α’=0.700102 + n v, β’=1 + n-nv). At each
interim and final anal ysis pwill be used for efficacy decision making in the following way :
(a) At interim analy ses, efficacy is declared if p> 99.50%.
(b) At final analy sis, efficacy is declared if p > 98.60%.
In participants without evidence of infection prior to 7 days after the second dose ,IAs will be
performed after accrual of at least 62, 92,and 120 cases, and final anal ysis will beperformed
after accrual of at least164 cases.
Based on the criterion (b), at final anal ysis, efficacy willbe declared if there are less than or
equal to 53 cases observed in the vaccine group among the total number of 164 cases.
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TMF Doc ID: 98.03Bayesian 95% credible interval for θ can be calculated using the 2.5thpercentile and the
97.5thpercentile of posterior distribution , ie,Beta(α’=0.700102 + n v, β’=1 + n-nv).Thus,
the 95% credible interval for VE can be obtained correspondingl y due tothe relationship
between VE and θ, where =1−
( ).
Decision Algorithm for Futility
Let Y be the random variable for the number of cases in the vaccin e groupat the final
analysis. At certaininterim analy sis given the total number of observed cases n and the
number of observed cases from the vaccine group nv,the posterior probability of success
qcan be expressed as:
q= Pr (Y ≤ 53 | observed data , ie,nand nv, from subset of enrolled participants)
qcan be calculated anal ytically using posterior predictive distribution of Y,
ie,Beta-Binomial distribution with parameter s ( ’,α’,β’). The probability mass function of
the posterior predictive distribution is:
Pr( = | ’,α’,β’)= ’
( +α’, ’− +β’)
(α’,β’)
Thusthe posterior probability of success at the interim anal ysis can be calculated as:
q= Pr (Y ≤ 53 –nv|n’= 164 –n, α’=0.700102 + nv, β’=1 + n-nv)
At interim analy ses, futility is declared if q< 5.0%.
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TMF Doc ID: 98.03Appendix 3.IRRand VE Derivation
COVID-19 Case Definition
Twodefinitions of SARS -CoV-2–related cases, and SARS-CoV-2–related severe cases,will
be considered (for both, the onset date of the case will be the date that s ymptoms were first
experienced b y the participant; if new sy mptoms are reported within 4 day s after resolution
of all previous s ymptoms, they will be considered as part of a single illness):
Confirmed COVID -19: presence of at least 1 of the following s ymptoms and SARS -CoV-2
NAAT positive during, or within 4 day s before or after, the s ymptomatic period, either at the
central laboratory or at a local testing facility (using an acceptable test):
Fever;
New or increased cough;
New or increased shortness of breath;
Chills;
New or increased muscle pain;
New loss of taste or smell;
Sore throat;
Diarrhea;
Vomiting.
The second definition, which may be updated as more is learned about COVID -19, will
include the following additional sy mptoms defined by the CDC (listed at
https://www.cdc.gov/coronavirus/2019 -ncov/symptoms-testing/sy mptoms.html):
Fatigue;
Headache;
Nasal congestion or runny nose;
Nausea.
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TMF Doc ID: 98.03Confirmed severe COVID- 19: confirmed COVID -19 and presence of at least 1 of the
following:
Clinical signs at rest indicative of severe s ystemic illness (RR ≥30 breaths per minute,
HR ≥125 beats per minute, SpO 2≤93% on room air at sea level, or PaO 2/FiO2
<300mm Hg);
Respiratory failure (defined as needing high -flow oxygen, noninvasive ventilation,
mechanical ventilation, or ECMO);
Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiring vasopressors);
Significant acute renal, hepatic, or neurologic d ysfunction*;
Admission to an I CU;
Death.
The DMC may recommend modification of the definition of severe disease according to
emerging information.
* Three blinded case reviewers ( medically qualified Pfizer staff members )will review all
potential COVID -19 illness events. If a NAAT -confirmed case in Phase 2/3 may be
considered severe, or not, solely on the basis of this criterion, the blinded data will be
reviewed b y the case reviewers to assess whether the criterion is met; the majority opinion
will prevail.
In addition, a serological definition will be used for parti cipants without clinical presentation
of COVID -19:
Confirmed seroconversion to SARS -CoV-2 without confirmed COVID -19: positive
N-binding antibody result in a participant with a prior negative N- binding antibody result
Surveillance Times
Fundamental to this VE trial is the surveillance for cases satisfy ing various endpoints within
each participant that may occur during the trial. Endpoint and participant combinations
where surveillance is applicable require identification of the start and the end of the
surveillance period in order to determine the participant -level endpoint surveillance time.
For all VE -related endpoints in this study , the start-of-surveillance times are summarized as
follows:
Endpoint's Associated Participant -Level Popu lation Start-of-Surveillance Time
Evaluable efficacy(7 days) Dose 2+7days
Dose 2 all-available efficacy Dose 2 + 7 days
Evaluable efficacy (14 days) Dose 2 + 14 days
Dose 2 all-available efficacy Dose 2 + 14 days
Dose 1 all-available efficacy Dose 1
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TMF Doc ID: 98.03For all VE -related endpoints in this study , the end of a surveillance period for each
participant is the earliest of the following events:
When the first COVID-19 case occurs.
When the participant ’s end of the study occursdue to, eg withdrawal or death or trial
completion and etc .
When the participant has first important protocol violation .
Specific information regarding VE -related endpoint surveillance start and end times by
endpoint will be provided in Analy sis and Reporting Plan specification documents.
Once the COVID -19 cases and surveillance period have been identified, VE can be
calculated as 100 × (1 –IRR), where IRR is the ratio of confirmed COVID- 19 illness per
1000 person- years of follow -up for the active va ccine group to the placebo group .
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TMF Doc ID: 98.03Flowchart
1.The flowchart for deriving t he COVID -19 cases included below f or the first primary
endpoints in evaluable efficacy participants with no serological or virological evidence of
past SARS -CoV-2 infection:
The central laboratory NAAT result will be used for the case definition, unless no result is
available from the central laboratory , in which case a local NAAT result may be used if it
was obtained using 1 of the following assay s:
a.Cepheid Xpert Xpress SARS -CoV-2
b.Roche cobas SARS -CoV-2 real-time RT-PCR test (EUA200009/A001)
c.Abbott Molecular/RealTime SARS-CoV-2 assay (EUA200023/A001)
Evaluable efficacy population (7 days)
No virological evidence by NAAT prior to 7
days after receipt of the second dose
NAAT positive for COVID -19 at central laboratory or acceptable
local test within the date window that sy mptoms were present
Presence of at least 1 of the following symptoms: fever, new or increased
cough, new or increased shortness of breath, chills, new or increased
muscle pain, new loss of taste or smell, sore throat, diarrhea, or vomiting.
Onset date, ie, the date that first sy mptom
occurs, is at least 7 day s after receipt of the
N-binding antibody negative at
COVID-19 cases for first primary VE objective
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TMF Doc ID: 98.032.The flowchart for deriving the COVID -19 cases included below for the second primary
endpoints in evaluable efficacy participants :
The flowchart sfor the first 2 secondary vaccine efficacy endpoint sare similar to the primary
endpoints except that the case co unting starts from 14 day s after receipt of the second dose.
Evaluable efficacy population (7 day s)
NAAT positive for COVID -19 at central laborat ory or acceptable
local test within the date window that sy mptoms were present
Presence of at least 1 of the following s ymptoms: fever, new or increased
cough, new or increased shortness of breath, chills, new or increased muscle
pain, new loss of taste or smell, sore throat, diarrhea, or vomiting.
Onset date, ie, the date that fir st symptom occurs,
is at least 7 day s after receipt of the second dose
COVID-19 cases for second primary VE objective
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