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EudraCT No: 2020 -001038 -36 Statistical Analysis Plan Version: Final 4.0
BioNTech_BNT162 -01_SAP_final_V4.0 Confidential 1 Title Page
EudraCT Number: 2020 -001038 -36
WHO UTN: U1111 -1249 -4220
Trial Title: A Multi -site, Phase I/II, 2 -Part, Dose -Escalation Trial Investigating the
Safety and Immunogenicity of four Prophylactic SARS -CoV-2 RNA
Vaccines Against COVID -19 Using Different Dosing Regimens in
Healthy and Immunocompromised Adults
Protocol Version : 10.0
Protocol Date : 28OCT 2020
Compound s: BNT162a1, BNT162b1, BNT162b2 and BNT162c2
SAP Version: Final 4.0
SAP Date: 18Nov2020
Sponsor Name: BioNTech RNA Pharmaceuticals GmbH
An der Goldgrube 12
55131 Mainz, Germany
CRO Name: CRS Clinical Research Services Mannheim GmbH
Grenadierstrasse 1
68167 Mannheim, Germany
Author: Susanne Steinhauser
Staburo GmbH
Aschauer Str. 26b
81549 München, Germany
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EudraCT No: 2020 -001038 -36 Statistical Analysis Plan Version: Final 4.0
BioNTech_BNT162 -01_SAP_final_V4.0 Confidential 3 Version History
This Statistical Analysis Plan for study BNT162 -01 is based on the protocol dated
28OCT 2020 .
Table 1 SAP Version History Summary
SAP
Version Approval
Date Change Rationale
1 08JUN2020 Not Applicable Original
version
2 04SEP2020 • BNT162c2 also P/B
• Additional time points to evaluate endpoints
• Older subjects included in the trial Adaptation to
version 8 of
the protocol
• Analyses added for local and systemic reactions
• Analyses added for TEAEs Additional
analyses
required
• IMM set based on data of functional antibody titer
• SD and C is will only be calculated if data of at least
3 subjects is available
• Days since last immunization was harmonized with
the rules for duration
• Functional antibody titers with values below LLOD
or above ULOD will not be imputed, as this is
already implemented in the received SDTM data
• No overall tables will be created, as the tables will
be created per vaccine
• Clarification of definition of concomitant
medication
• Analysis of l ocal and systemic reactions only based
on data assessed in the diary
• Local and systemic reactions: denominator changed
in the table s
• Clarification of definition of TEAEs
• Change in interval of the TEAE analysis
• Denomin ator changed in analysis of seroconversion
• Change in reporting convention for functional
antibody response Clarifications
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BioNTech_BNT162 -01_SAP_final_V4.0 Confidential 4 3 16NOV2020 • Expansion cohorts
• Part B will no longer be conducted
• Changed wording: ‘dose level’ to ‘cohort’
• Specification of analysis of older subjects Adaptation to
version 10 of
the protocol
• Listing for completers sets added
• Analyses added for local and systemic reactions
• New functional antibody res ponses Additional
analyses
required
• Clarification of AE table by worst severity Clarification
4 18NOV2020 • Changed ‘elderly’ to ‘older’
• Clarified definition of concomitant medication Clarification
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EudraCT No: 2020 -001038 -36 Statistical Analysis Plan Version: Final 4.0
BioNTech_BNT162 -01_SAP_final_V4.0 Confidential 5 Table of Contents
Contents
Title Page ................................ ................................ .............................. 1
Signature Page ................................ ................................ ...................... 2
Version History ................................ ................................ .................... 3
Table of Contents ................................ ................................ ................. 5
1. Introduction ................................ ................................ ........... 7
1.1. Objectives and Endpoints ................................ ....................... 7
1.2. Study Design ................................ ................................ ......... 10
1.1. Schedule of Visits and Procedures ................................ ........ 12
2. Statistical Hypotheses ................................ ......................... 13
3. Interim Analyses ................................ ................................ . 14
3.1. Data Monitoring Committee (DMC) ................................ .... 14
4. Sample Size Determination ................................ ................ 15
5. Analysis Sets and Subgroups ................................ ............. 16
5.1. Analysis Sets ................................ ................................ ......... 16
5.2. Protocol Deviations ................................ ............................... 17
5.3. Subgroups ................................ ................................ ............. 17
6. Statistical Analyses ................................ ............................. 18
6.1. General Considerations ................................ ......................... 18
6.1.1. Tables and Listings ................................ ............................... 18
6.1.2. Definitions and Derivations ................................ .................. 19
6.1.3. Missing data ................................ ................................ .......... 20
6.2. Subject Dispositions ................................ ............................. 20
6.3. Baseline Characteristics ................................ ........................ 21
6.3.1. Demographics ................................ ................................ ....... 21
6.3.2. Concomitant Medication ................................ ....................... 21
6.3.3. Medical History ................................ ................................ .... 21
6.4. Prima ry Analyses ................................ ................................ .. 21
6.4.1. Solicited local reactions ................................ ........................ 22
6.4.2. Solicited systemic reactions ................................ .................. 23
6.4.3. Adverse events ................................ ................................ ...... 24
6.5. Secondary Analyses ................................ .............................. 26
6.5.1. Functional antibody response ................................ ............... 26
6.5.2. Functional antibody titers fold increase ................................ 27
6.5.3. Seroconversion ................................ ................................ ...... 27
6.6. Explora tory Analyses ................................ ............................ 27
6.7. Further Safety Analyses ................................ ........................ 27
6.7.1. Compliance ................................ ................................ ........... 28
6.7.2. Laborator y Assessments ................................ ....................... 28
6.7.3. Vital Signs ................................ ................................ ............. 29
6.7.4. ECG ................................ ................................ ....................... 30
6.7.5. Further Safety data ................................ ................................ 30
7. Supporting Documentation ................................ ................ 31
7.1. Appendix 1: Changes to Protocol -Planned Analyses ........... 31
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BioNTech_BNT162 -01_SAP_final_V4.0 Confidential 6 7.2. Appendix 2: List of Abbreviations ................................ ....... 31
7.3. Appendix 3: Reporting Conventions ................................ .... 33
8. References ................................ ................................ ............ 34
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BioNTech_BNT162 -01_SAP_final_V4.0 Confidential 9 Table 3 Primary and secondary endpoints
Objective
Clinical
Category Statistical
Category Variable/
Endpoint SD or
P/B Time point a Analysis Set
Primary Objective: To describe the safety and tolerability profiles of prophylactic BNT162 vaccines in healthy adults after SD or P/B immunization.
Safety Primary Solicited local reactions at the
injection site SD and
P/B recorded up to 7 d after each immunization SAF/ completers
sets
Primary Solicited systemic reactions SD and
P/B recorded up to 7 d after each immunization. SAF/ completers
sets
Primary The proportion of subjects with at least
1 unsolicited TEAE P/B occurring up to 21 d after the prime immunization
and 28 d after the boost immunization. SAF/SAFB /
completers sets
SD occurring up to 28 d after the immunization. SAF/SAFB /
completers sets
Secondary Objective : To describe the immune response in healthy adults after SD or P/B immunization measured by a functional antibody titer, e.g.,
virus neutralization assay or an equivalent assay available by the time of trial conduct.
Immuno -
genicity Secondary Functional antibody responses P/B:
at 7 and 21 d after primary immunization and at 7, 14b, 21, 28 ,
63, and 162 d after the boost immunization.
SD:
at 7, 21, 28, 42, 84, and 183 d after the primary immunization. IMM/
IMMPP
Secondary Fold increase in functional antibody
titers IMM/
IMMPP
Secondary Seroconversion IMM/
IMMPP
SAF = Safety Set , SAFB = Safety boost set, IMM = Immunogenicity set, IMMPP = Immunogenicity per -protocol set , TEAE = Treatment Emergent Adverse Event
a) The given days are approximate; the respective schedule of activities defines assessment windows.
b) Only cohorts starting prime dosing after approval of amendment 09.
The completers sets comprise Prime + 7 Days Completer Set, Prime to Boost or Prime + 28 Days Completer Set, Boost + 7 Days Co mpleter Se t, Boost + 28 Days Completer Set and
Prime or Boost + 28 Days Completer Set.
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BioNTech_BNT162 -01_SAP_final_V4.0 Confidential 10 1.2. Study Design
Study Design The present study is a multi -site, phase I/II, dose -
escalation trial investigating the safety and
immunogenicity of four prophylactic SARS -CoV -2 RNA
vaccines against COVID -19 using different dosing
regimens in healthy and immunocompromised adults .
The dose-finding part (Part A) includes several dose
cohorts (treatment groups) for each vaccine .
Study Population Part A: Healthy and immunocompromised adults aged 18
to 85 years.
A detailed description of the inclusion and exclusion
criteria can be found in section 5.1 and 5.2 of the protocol.
Geographic Regions Part A: Multiple s ites in Germany
Investigational Medical
Products Name :
BNT162 vaccines - Anti-viral RNA vaccines for active
immunization against COVID -19
Part A:
Type :
RNA -LNP vaccines utilizing different BioNTech RNA
formats, i.e., uRNA (product code BNT162a1), modRNA
(two variants, product codes BNT162b1 and BNT162b2)
and saRNA (product code BNT162c2) .
The vaccines BNT162a1, BNT162b1, BNT162b2 and
BNT162c2 will be administered using a P/B regimen. The
vaccine BNT162c2 will additionally be administered using
an SD regimen.
Dose :
The doses are detailed in the protocol Table 1 , 2 and 3 .
Dose frequency :
One injection or two injections 21 d ays apart. Injection
volumes will be up to 1.5 mL.
Administration route: Intramuscular
Trial subjects with the first -in-human immunization will
be immunized using a sentinel dosing/subject staggering .
Treatment and Study Duration In total, the planned trial duration for subjects is expected
to be approximately 214 d for Cohorts 1 to 10 and 760 d
for Cohorts 11 to 13.
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BioNTech_BNT162 -01_SAP_final_V4.0 Confidential 11 Planned Number of Subject s For each vaccine, 12 subjects for each cohort are required
in Part A for non – expansion cohorts . For the expansion
cohorts , 30 subjects will be included in cohort 11, 90
subjects in cohort 12 and 30 subjects in cohort 13.
Randomization and Blinding No randomization , open-label
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BioNTech_BNT162 -01_SAP_final_V4.0 Confidential 12 1.1. Schedule of Visits and Procedures
The schedule of visits and procedures can be found in the protocol in Table 5, 6 and 7.
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BioNTech_BNT162 -01_SAP_final_V4.0 Confidential 13 2. Statistical Hypotheses
In Part A, t here is no formal statistical hypothesis under test.
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BioNTech_BNT162 -01_SAP_final_V4.0 Confidential 14 3. Interim Analyses
In Part A, n o formal interim statistical analysis will be performed. However, preliminary
analyses based on all data collected until a pre -defined data cut -off date (snapshot analyses) may
be performed for each cohort once subjects within a cohort will have been follo wed up for at
least 7 d ays following the dose.
Furthermore, a n analysis update will be performed once all subjects will have completed Visit
10.
3.1. Data Monitoring Committee (DMC)
In Part A, no DMC is planned.
There will be a Safety Review Committee (SRC). For details see protocol section 10.1.5.
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BioNTech_BNT162 -01_SAP_final_V4.0 Confidential 15 4. Sample Size Determination
No formal sample size calculations have been performed.
For further details regarding the sample size calculations see protocol section 9.2.
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BioNTech_BNT162 -01_SAP_final_V4.0 Confidential 16 5. Analysis Sets and Subgroups
5.1. Analysis Sets
Screened Set (SCR)
The screened set is defined as all subjects who signed informed consent .
Safety Set (SAF)
The safety set is defined as all subjects who received at least one dose of Investigational
Medicinal Product (IMP).
Prime + 7 Days Completer Set
All subjects who are included in the SAF and received the prime immunization and who were in
the trial at least up to day 7 (inclusive) after prime immunization .
Prime to Boost or Prime + 28 Days Completer Set
All subjects who are included in the SAF and r eceived the prime immunization and who either
received also the boost immunization or who were in the trial at least up to day 28 (inclusive)
after prime immunization.
Boost + 7 Days Completer Set
All subjects who are included in the SAF and received the b oost immunization and who were in
the trial at least up to day 7 (inclusive) after boost immunization.
Boost + 28 Days Completer Set
All subjects who are included in the SAF and received the boost immunization and who were in
the trial at least up to day 2 8 (inclusive) after boost immunization.
Prime or Boost + 28 Days Completer Set
All subjects who are included in the SAF and received the prime immunization and
• who either received also the boost immunization and were in the trial at least up to day 28
(inclusive) after boost immunization
or
• who didn’t receive the boost immunization and were in the trial at least up to day 28
(inclusive) after prime immunization.
Note to completer s sets:
Subjects were not in the trial up to a certain day if, for example, they drop ped out before or
didn’t complete the time interval due to the cut -off of a snapshot analysis.
Safety Boost Set (SAFB)
The safety boost set is defined as all subjects who received two doses of IMP (prime and boost
immunization).
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BioNTech_BNT162 -01_SAP_final_V4.0 Confidential 17 Note: Subjects receiving BNT162c2 as SD will be excluded from the SAFB as they receive only
a prime immunization according to protocol.
Immunogenicity set (IMM)
The immunogenicity set is defined as all subjects who received at least one dos e of IMP and
have at least one post -baseline functional antibody titer immunogenicity assessment.
Immunogenicity per -protocol set (IMMPP)
The immunogenicity per -protocol set is defined as all subjects included in the immunogenicity
set that have no major protocol deviations as determined by the clinician.
Note: In all analysis sets, subjects will be assigned to the groups (i.e. vaccine type and cohort )
according to the actual treatment they received (“as treated”).
5.2. Protocol Deviations
Protocol deviations are failures to adhere to the inclusion/exclusion criteria and protocol
requirements and will be classified into major protocol deviations and minor protocol deviations .
Major protocol deviations are those that are considered to have a significant effect on the
treatment efficacy .
Major protocol deviations will be identified by medical review prior to database snapshot for
main analysis .
The following criteria might be considered as major protocol deviations :
(1) Violation of major inclusion or exclusion criteria
(2) Assignment to incorrect vaccine /dose (i.e. actual vaccine /dose taken differs from the
scheduled)
(3) Non -Compliance ( only one vaccine was administered of P/B vaccines o r no vaccine was
administered)
(4) Intake of prohibited concomitant medication
Protocol deviations will be reported as related to COVID -19 or not.
Major protocol deviations will be presented in a listing. [Mock Listing 16.2. 1-2.X] For each
vaccine, t he number and percentage of subject s with major protocol deviations will be
summari zed in total and by protocol deviation type and by cohort and cohort -total.
5.3. Subgroups
In Part A, n o subgroup analysis is planned. But u nless otherwise specified, additional totals for
younger (18 to 55 years) and older (56 to 85 years) subjects will be given .
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BioNTech_BNT162 -01_SAP_final_V4.0 Confidential 18 6. Statistical Analyses
6.1. General Considerations
The following described statistical analys es only refer to Part A of the study.
No formal statistical testing will be done.
Unless otherwise specified, analyses will be based on data pooled across all study sites.
6.1.1. Tables and Listings
Tables
In general, data will be summarized by groups (i.e., by vaccine type [BNT162a1, BNT162b1,
BNT162b2, BNT162c2 SD and BNT162c2 P/B] and cohort ) and all cohort s combined for each
type ( cohort -total). Furthermore, selected cohort s may be combined . The cohort s and cohort -total
will be presented in columns and the different vaccine types in different tables.
There will be additional total columns for younger (18 to 55 years) and older (56 to 85 years)
subject s.
Continuous variables will be summarized by group using the following descriptive statistics:
number of subject s with non -missing data (n), mean, standard deviation (SD), median, minimum
(min) and maximum (max).
Descriptive statistics of titer and fold increase of titer will additionally include geometric mean
and its two-sided 95% confidence interval (CI) . The geometric mean titer (GMT) is calculated as
the mean of the logarithm of the functional antibody titers , back -transformed into the original
scale. Two-sided CIs will be obtained by calculating CIs using t-distribution for the mean of the
logarithmically transformed assay results and transforming the limits back to the original scale.
Geometric mean fold rise (GMFR) is calculated as the mean of the difference of logarithmically
transformed assay results (p ost vaccination time point – pre vaccination time point) and back -
transformed into 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 result s
and transforming the limits back to the original scale.
Categorical variables will be summarized by group presenting absolute and relative frequencies
(n and %) of subject s in each category (including the category ‘missing’ if applicable).
Percentages wi ll be calculated based on the number of subject s in the respective analysis set (N)
as denominator if not stated differently . Percentages may be presented with exact 95% Clopper -
Pearson CIs .
SDs as well as C Is will only be calculated if values of at least 3 subjects are available.
Listings
Important Case Report Form (CRF) data as well as all relevant generated and transformed
variables together with the original data items will be listed. Separate listings will be provided
for each vaccine type. Unless otherwise specified, cohort will always be included in listings, and
listings will be sorted first by cohort , then by subject number and finally, if applicable, by visit
number and/or a relevant date (e.g. date of onset of AE).
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BioNTech_BNT162 -01_SAP_final_V4.0 Confidential 19 Mock tables, figures and listings
The referenced mock tables, figures and listings are given in the following documents:
• BNT162 -01_TFLshells_14.1_Disposition_and_Baseline Characteristics_ final_v1.0
• BNT162 -01_TFLshells_14.2_Primary_Endpoints_(Safety)_ final_v1.0
• BNT162 -01_TFLshells_14.3_Secondary_Endpoints_(Immunogenicity)_ final_v1.0
• BNT162 -01_TFLshells_14.4_Further_Safety_Endpoints_ final_v1.0
Programming
SAS® (version 9.4 or higher) programming will be performed according to Staburo GmbH
standards as defined in SOP001_PROGRAMMING [1] and related work instructions. Special
attention will be paid to planning and performance of quality control measures as documen ted in
the quality control plan for the analysis of this study (see also SOP002_PROGRAM_QC [2]).
Analysis Sets
The SCR will be used for disposition. The SAF will be used for analysis of safety and adverse
events data. Some analyses of the adverse events will be repeated using the SAFB if the SAF and
the SAFB sets differ regarding subjects with a planned boost immunization (for example due to a
snapshot analysis during study conduct or drop-outs). The completers sets will be used for
analysis of local and systemic reactions as well as adverse events. The IMM will be used for the
analysis of immunogenicity data. The analys es of all vaccines will be repeated using the IMMPP
if the two analysis sets di ffer significantly (≥ 10% difference in subjects belonging to the sets).
If subjects by accident receive two different doses or vaccines, they will switch the group and
will be displayed for each immunization with the corresponding group. For combined ana lyses,
subjects who received two different doses will be assigned to the lower dose.
Data of subjects who failed to complete all visits of the study (dropout or withdrawal) will be
reported as far as their data is available.
6.1.2. Definitions and Derivations
Unscheduled visits
Unscheduled visits will not be included in the summary tables but will be included in the listings.
Variables
Baseline is defined as last value prior to first dose of IMP .
Change from baseline will be calculated as follows:
• Change from baseline = post -baseline assessment value – baseline assessment value.
Duration [days] will be calculated as follows:
• Duration [days] = last observation date – first observation date + 1
•
Time from first immunization to first reaction will be calculated as follows:
Time from first immunization to first reaction [days] = first reaction date – prime immunization date + 1
Time from first reaction to last reaction will be calculated as follows:
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Days since last immunization will be calculated as follows:
Days since last immunization = onset date of AE – date of last immunization +1
For conversion of days to months or years the following rules will be applied:
• 1 month = 30.25 days
• 1 year = 365.25 days
Study Day and Treatment Day are defined as follows:
• Study da y:
o If study date < date of first dosing , then study day = study date – date of first dosing
o If study date >= date of first dosing, then study day = study date – date of first dosing + 1
Fold increase will be calculated as follows:
• Fold increase = post -dose value / baseline value
6.1.3. Missing data
As a general rule, missing data will not be substituted (i.e., missing data will not be replaced but
will be handled as “missing” in the statistical evaluation), with the following exception for
summary analyses:
Clinical laboratory variables below the lower limit of quantification (LLOQ) will be ev aluated as
0.5 * LLOQ in the summary tables . In the listings they will be displayed as “<LLOQ” or similar.
6.2. Subject Dispositions
For the SCR , the number and percentage of subjects having failed screening will be presented
along with a summary of the primary reason for screening failure. [Mock Table 14 .1-1]
Subject disposition will be listed with date of informed consent, date of screening, date of
immunization and date of study completion/discontinuation. [Mock Listing 16.2. 1-1.X]
The number and perce ntage of subject s in the analysis sets will be summarized by group (i.e. by
vaccine type and cohort ) and cohort -total for the subject s in the SAF. [Mock Table 14. 1-2.X]
For the SAF, number and percentage of subject s having prematurely discontinued the study with
a summary of the primary reason (e.g., adverse events, death, withdrawal by subject, lost to
follow -up) will be presented by group (i.e. by vaccine type and cohort ) and cohort -total. [Mock
Table 14. 1-3.1 and 3.2.X ]
Subjects having prematurely discontinued will be listed with date and reason for premature
discontinuation. [Mock Listing 16.2. 1-3.X]
Subjects in the SCR but excluded from SAF, subjects in SAF but excluded from SAFB/ IMM /
IMMPP will be listed with reason for exclusion. [Mock Listing 16.2. 1-4.1.X] Subjects inclusion
in the completers sets will be listed.
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BioNTech_BNT162 -01_SAP_final_V4.0 Confidential 21 6.3. Baseline Characteristics
6.3.1. Demographics
Demographic and baseline variables will be summarized for subject s in the SAF analysis set.
Age [years ], weight [kg], height [cm], and body mass index (BMI) (kg/m2) will be summarized
as continuous data by group and cohort -total. [Mock Table 14.1 -4.1.X]
Sex (male vs female) , ethnicity ( Hispanic or Latino, Not Hispanic or Latino, Not reported,
Unknown ) and race ( White, B lack or African American, Asian, American Indian or Alaska
Native, Native Hawaiian or Other Pacific Islander, Not reported, Unknown, Other ) will be
summarized as categorical data by group and cohort -total. [Mock Table 14.1 -4.2.X]
A listing of demography will be provided. [Mock Listing 16.2. 1-5.X]
6.3.2. Concomitant Medication
Prior and concomitant medications will be defined using start and stop dates recorded, relative to
the first and last dose of study medication. Any medication taken before 28 days prior to the start
date of IMP will not be classified as prior or concomitan t medication. A prior medication will be
defined as any therapy taken 28 days prior up to (but not including) the start date of IMP. A
concomitant medication will be defined as any medication either
• taken prior to (but not including) the start date of IMP and
o ongoing at the first vaccination
o or with a missing end date ,
• or with a start date on or after the date of the first vaccination up to 28 days after the
second vaccination .
If a medication cannot be clearly assigned to prior medication due to missing dates, it will be
evaluated as concomitant medication.
Medications will be code d using the WHO Global (Drug Insight) March 2020 B3 standard drug
codes resulting in Anatomical -Therapeutic -Chemical (ATC) code s indicating therapeutic
classification.
Listing s of prior and concomitant medications will be provided. [Mock Listing 16.2.1 -6.1.X and
6.2.X]
6.3.3. Medical History
Medical history data will be coded using the Updated Version Medical Dictionary for Regulatory
Activities (MedDRA®) coding system 23.0 including specific terms for COVID -19.
A listing of medical history data will be provided. [Mock Listing 16.2.1 -7.X]
6.4. Primary Analyses
Hereinafter , the primary analyses for Part A are describe d.
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BioNTech_BNT162 -01_SAP_final_V4.0 Confidential 22 The primary endpoints are s olicited local reactions at the in jection site , solicited systemic
reactions and t he proportion of subjects with at least 1 unsolicited treatment emergent adverse
event (TEAE) . All primary analyses will be performed using the SAF and analyses of adverse
events will possibly be repeated using the SAFB .
All primary analysis endpoints will be summarized by group (i.e. by vaccine type and cohort )
and all cohort s combined for each type ( cohort -total).
6.4.1. Solicited local reactions
Definition
Solicited l ocal reactions at the injection site are assessed and reported by the study subject in a
diary and consist of pain, tenderness, erythema/redness or induration/swelling . The local
reactions assessed by the investigator will not be anal yzed.
Local reactions will be graded based on the criteria given in US Food and Drug Administration
(FDA ) Guidance for Industry ‘ Toxicity Grading Scale for Healthy Adult and Adolescent
Volunteers Enrolled in Preventive Vaccine Clinical Trials ’ for ‘Local Reaction to Injectable
Products ’. The grading of local reactions to injectable product is detailed in section 8.2.9 of the
protocol. The gra des are Grade 0 (Absent ), Grade 1 (Mild), Grade 2 (Moderate), Grad e 3
(Severe) and Grade 4 (Potentially life threatening).
The solicited local reactions will be evaluated for the following time intervals:
• Prime immunization up to day 7 (inclusive) after initial immunization
• Boost immunization up to day 7 (inclusive) aft er boost immunization
• Both intervals combined
The intervals will start with the date and time of the immunization.
Clarification: The interval ‘prime immunization up to day 7 after initial immunization ’ includes
study day 1 to study day 8. This applies to the other intervals accordingly .
All local reactions qualifying as AE will additionally be included in the adverse events tables.
Analysis
Local reactions with missing time and occurring on the day of prime immunization will be
assigned to all intervals starting with the prime immunization. Local reactions with missing time
and occurring on the day of the boost immunization will be assigned to all intervals including the
boost immunization . Local reactions with missing date will be assigned to each of the respective
interval s if it cannot be ruled out, that it belongs to the time interval.
The number and percentage of subjects reporting at least one local reaction in each time interval
will be summarized for each of the following types:
• Any local reactions
• Grade ≥3 local reactions . [Mock Table 14. 2.1-1.X]
The denominator of the percentages will be the number of subjects with any information on local
reactions in the diary available in the respective time interval.
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BioNTech_BNT162 -01_SAP_final_V4.0 Confidential 23 Furthermore, this table will be repeated showing only completers: the denominator of the
percentages will be the number of subjects with any information on local reactions in the diary
available in the respective time int erval and which are included in the respective completer s set.
The number and percentage of subjects reporting at least one local reaction will be summarized
by local reaction type ( pain, tenderness, erythema/redness and induration/swelling ) and by worst
grade for each time interval . [Mock Table 14 .2.1-2.X] The denominator of the percentages will
be the number of subjects with any information on local reactions in the diary available in the
respective time interval.
Furth ermore, this table will also be repeated showing only completers as described above .
Time after prime and after boost from
• first dose to first local reaction,
• first dose to first local reaction with grade >=3,
• first local reaction to last local reaction and
• first local reaction with grade >=3 to last local reaction with grade >= 3
will be summarized descriptively overall and by local reaction term .
The same variables will be described for any reaction (local or systemic) .
The compliance with the diary from each immunization up to 7 days after each immunization
will be presented. Therefore, a table giving the number and percentage of subjects with any
informat ion on local reactions in the diary (overall and by local reaction term) available per day
will be given. The compliance with the diary based on any information on any reaction (local or
systemic) will also be given.
All local reactions from the study will be listed. [Mock Table 16.2.2 -1.X] Additionally, all days
with information on local reactions in the diary will be listed.
For each vaccine type , local reactions will be presented graphically using a bar plot [Mock
Figure 14.2.1 -3.X].
6.4.2. Solicited syst emic reactions
Definition
Solicited systemic reactions are assessed and reported by the study subject in a diary and consist
of nausea, vomiting, diarrhea, headache, fatigue, myalgia, arthralgia, chills, loss of appetite,
malaise, or fever. The systemic reactions assessed by the investigator will not be analyzed.
Solicited systemic reactions will be graded based on the criteria given in US Food and Drug
Administration (FDA) Guidance for Industry ‘Toxicity Grading Scale for Healthy Adult and
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials’. The grades are Grade 0
(Absent), Grade 1 (Mild), Grade 2 (Moderate), Grade 3 (Severe) and Grade 4 (Potentially life
threatening). Fever is graded as Mild (38.0 -38.4°C), Moderate (38.5 -38.9°C), Severe (39.0 -
40.0°C and Potentially life threatening (>40.0°C).
The solicited systemic reactions will be evaluated for the following time intervals:
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BioNTech_BNT162 -01_SAP_final_V4.0 Confidential 24 • Prime immunization up to day 7 (inclusive) after initial immunization
• Boost immunization up to day 7 (inclusive) after boost immunization
• Both intervals combined
The interval s will start with the date and time of the immunization.
Clarification: The interval ‘prime immunization up to day 7 after initial immunization’ includes
study day 1 to study day 8. This applies to the other intervals accordingly.
All systemic reactions qualifying as AE will additionally be included in the adverse events
tables.
Analysis
Solicited systemic reactions will be analyzed in the same way as solicited local reactions (see
Section 6.4.1 of the SAP).
6.4.3. Adverse events
Definition
For detailed information on adverse events see section 10.3 of the protocol.
Adverse events (A Es) will be coded using the Updated Version MedDRA® 23.0 including
specific terms for COVID -19 to get a system organ class (SOC) and preferred term (PT) for each
AE.
A treatment emergent adverse event (TEAE) is defined as any AE with an onset after the first
immunization (if the AE was absent before the f irst immunization ) or worsened after the first
immunization (if the AE was present before the first immunization ). AEs with an onset date
more than 28 days after the last immunization will be considered as treatment emergent only if
assessed as related to IMP by the investigator. AEs that cannot be determined to not be treatment
emergent due to missing date or time will be defined as TEAE.
Clarification: AEs with an onset date at the date of the first immunization will only be considered
as treatment emerg ent, if the AE occurred after the first immunization.
The TEAEs will be evaluated for the following time intervals , clarifying and harmonizing the
intervals defined in the protocol :
• Prime immunization up to day 7 (inclusive) after initial immunization
• Prime immunization up to boost immunization or day 28 (inclusive) after initial
immunization (whatever comes first)
• Boost immunization up to day 7 (inclusive) after boost immunization
• Boost immunization up to day 28 (inclusive) after boost immunization
• Prime immunization up to day 28 (inclusive) after boost immunization or after prime
immunization (if no boost was given)
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BioNTech_BNT162 -01_SAP_final_V4.0 Confidential 25 The intervals starting or ending with an immunization, will start or end with the date and time of
the immunization. TEAEs are assigned to the time intervals according to their start date and
time.
Adverse events of special interest (AESI)
Enhanced respiratory disease or flu -like symptomatology not resolved after 7 days or with
symptom kinetics that are inconsistent wi th a relationship to RNA immunization will considered
AESI s. AESIs are marked in the CRF.
Analysis
TEAEs with missing time and occurring on the day of prime immunization will be assigned to all
interval s starting with the prime immunization . TEAEs with missing time and occurring on the
day of the boost immunization will be assigned to all intervals including the boost immunization .
TEAEs with missing date will be assigned to all the respective interval s if it cannot be ruled out,
that it bel ongs to a time interval.
The following TEAE types will be analyzed:
• Any TEAE
• Related TEAE
• Grade >=3 TEAE
• Related grade >=3 TEAE
• Any treatment emergent serious adverse event (TESAE)
• Related TESAE
Overall summary of TEAEs
The number and percentage of subje cts reporting at least one TEAE and the number of TEAEs
will be summarized for all TEAE types defined above for each defined time interval [Mock
Table 14.2.3 -1.1.X]
The same analysis will be repeated using the respective completers set for each time interval.
The same analysis will be done excluding TEAEs which were based on solicited reporting via
subjects diaries and had a duration of <= 7 days (end date – start date + 1). Subjects with missing
start or end date will be included.
The same analys is will be done for treatment emergent AESIs (TEAESIs ) by time intervals .
[Mock Table 14.2.3 -1.2.X]
For each defined time interval , the number and percentage of subjects reporting at least one
TEAE will be summarized by PT nested within SOC for ea ch of the defined AE types . [Mock
Tables 14.2.3 -2.1.X to 2.6.X]
The same analysis will be repeated using the respective completers set for each time interval.
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BioNTech_BNT162 -01_SAP_final_V4.0 Confidential 26 The same analysis will be done excluding TEAEs which were based on solicited reporting via
subjects diaries and had a duration of <= 7 days (end date – start date + 1). Subjects with missing
start or end date will be included.
If a S OC / PT is reported more than once for a subject, the subject will only be counted once for
this SOC / PT. All TEAE summary tables will be sorted alphabetically by SOC and PT within
SOC.
TEAE by grade
The number and percentage of subjects with TEAEs will be summarized by worst grade by PT
nested within SOC by time interval. [Mock Table 14. 2.3-3.X] The w orst grade will be counted if
a TEAE is reported more than once by the same subject for this SOC / PT in one time interval .
As described in section 10. 3.1.7 of the protocol version 8, the grading changed during the study
from a 3 -point scale to a 4 -point scale. The assessment of AE and/or SAE intensity should be done
consistently for all subjects treated w ith the same treatment and dose.
AE listings
All AEs and SAEs will be listed. [Mock Listing 14.2.3 -4.X and 16.2.2-3.X]
TEAE figures
For each vaccine type , the most frequent TEAEs (preferred term ≥ 5% in the vaccine ) will be
presented graphically using a bar plot. [Mock Figure 14.2.3-4.X]
6.5. Secondary Analyses
Hereinafter, the secondary analyses for Part A are described.
Secondary endpoints are functional antibody response s, fold increase in functional antibody titers
and the number of subjects with seroconversion. All secondary analyses will be performed using
the IMM and possibly additionally the IMM PP population, see section 5.1.
All secondary analysis endpoints will be summarized by group (i.e. by vaccine type and cohort )
and all cohort s combined for each type ( cohort -total).
The functional antibody response will be assessed at the time points indicated in the tables 5, 6
and 7 of the protocol.
6.5.1. Functional antibody response
Definition
For data from VisMederi Srl, t he functional antibody response is based on the virus
neutralization test (VNT). For each subject and each time point two functional antibody titers
will be determined, as each sample will be measured in replicate . The f unctional antibody
response per subject and timepoint is defined as the geometric mean of the two f unctional
antibody titers .
Other data on functional antibody response will be presented as included in the SDTM data .
Analysis
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BioNTech_BNT162 -01_SAP_final_V4.0 Confidential 27 Functional antibody titers will be summarized using descriptive statistics for all time points.
Additionally, GMT with 95% CI will be presented. [Mock Table 14.3.1 -1.X]
The functional antibody response will be listed.
Figure: For each vaccine type, functional antibody titers will be presented graphically displaying
GMT with 95% CI at all time points.
6.5.2. Functional antibody titers fold increase
Definition
The fold increase of the functional antibody response will be calculated for all post-baseline time
points as post-dose value / baseline value .
Analysis
The fold increase in functional antibody titers will be summarized using descriptive statistics for
all post-baseline time points . Additionally, GMT with 95% CI will be presented. [Mock Table
14.3.2 -1.X]
Functional antibody titers fold increase will be listed.
6.5.3. Seroconversion
Definition
Seroconversion is defined as a minimum of 4 -fold increase of functional antibody reponse as
compared to baseline.
Analysis
The n umber of subjects with seroconversion will be summarized by number and percentage with
95% confidence interval for all post-baseline time points . The denominator of the percentages
will be the number of subjects with data available at the respective visit. [Mock Table 14.3.3 -
1.X]
Seroconversion data of the functional antibody titer will be listed.
6.6. Exploratory Analyses
Exploratory analyses will be described in a separate biomarker SAP provided by BioNTech.
6.7. Further Safety Analyses
Hereinafter, the further safety analyses for Part A are described. All analyses will be performed
in the SAF.
Safety data that will be summari zed includes IMP compliance , clinical laboratory assessments,
vital signs , and Electrocardiograms ( ECGs ).
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IMP compliance will be summarized by group (i.e. by vaccine type and cohort ) and cohort -total.
[Table 14. 4.1-1.X]
Drug exposure will be listed. [Mock Listing 16.2. 4-1.X]
6.7.2. Laboratory Assessments
Definition
Clinical laboratory data to be summari zed includes hematology, clinical chemistry, and
urinalysis and will be assessed at the time -points indicated in Table 5, 6 and 7 of the protocol .
The following clinical laboratory variables will be assessed:
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count and differential
(neutrophils, lymphocytes, monocytes, eosinophils, basophils), platelet count.
Clinical chemistry
Alkaline phosphatase, creatinine, ferritin, C -reactive protein, albumin, alanine aminotransferase,
amylase, aspartate aminotransferase, gamma glutamyl transpeptidase, total bilirubin, blood urea
nitrogen, glucose, lipase, sodium, potass ium, calcium.
Follicle -stimulating hormone: In women only.
Urinalysis
Dipstick: glucose, bilirubin, ketone, specific gravity (1 mL ≙ 1 g), blood, pH, protein,
urobilinogen, nitrite, and leukocytes.
Microscopic urinalysis: If warranted by dipstick results, urine sediment will be microscopically
examined for presence of red blood cells, white blood cells, casts, crystals, epithelial cells, and
bacteria.
All laboratory tests are classified as normal or lower or higher than reference range (abnormal).
All abnormal laboratory tests will be classified by the investigator as clinically significant (CS)
or not (NCS) .
Abnormal clinical laboratory data will be gr aded. The abnormal clinical laboratory data is
categorized in grad e 1 (mild), grade 2 (moderate), grad e 3 (severe) and grade 4 (potentially life
threatening).
Analysis
Clinical laboratory variables at each time -point and its change from baseline to each post -
baseline time -point (for continuous variables) will be summarized using descriptive summary
statist ics for each parameter by group and cohort -total. [Mock Table 14.4.2 -1.1.X.X and
1.2.X.X ]
Number and percentage of subjects with low, normal and high clinical laboratory values at each
time-point will be summarized for each parameter by group and cohort -total. [Mock Table
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BioNTech_BNT162 -01_SAP_final_V4.0 Confidential 29 14.4.2 -2.1.X.X] The same table will be provided for the grading scheme (g rades mild, moderate,
severe and life threatening). [Mock Table 14.4.2 -3.X.X]
The number and percentage of subjects with CS abnormal, abnormal (not CS), normal and
missing values will be summarized for each parameter by group and cohort -total. [Mock Table
14.3.4 -2.2.X.X]
Clinical laboratory values for each parameter will be summari zed using shift tables from baseline
to worst post -baseline value with respect to reference range values (low, normal, high) by group .
Worst post -baseline might be in both directions. Each subject may be counted in the parameter
high and in the parameter lo w category. A subject will only be counted in the normal category if
all post -baseline values are normal. If several post -baseline values are considered as worst post -
baseline value, the first one is taken. [Mock Table 14.2.4 -2.3.X.X]
All clinical laboratory data will be presented in the data listings along with normal ranges [Mock
Listing 16.2. 4-2.X.X]. Abnormal clinical laboratory values will be flagged in the listing.
6.7.3. Vital Signs
Definition
Vital sign parameters to be summari zed include body tem perature [°C], pulse rate [bpm],
respiratory rate [breaths per minute], and systolic and diastolic blood pressure [mmHg] and will
be assessed at the time -points indicated in Table 5, 6 and 7 of the protocol . Only body
temperature assessed at the vital signs assessments will be shown (no body temperature assessed
in the diary). Normal ranges of the vital sign parameters are given in Table 4. If a value is out of
range, it is categorized as CS or not clinically significant (NCS) in the CRF .
Table 4 Normal Ranges for Vital Signs
Parameter Range
Systolic blood pressure 90-140 mmHg
Diastolic blood pressure <= 90 mmHg
Pulse rate 50-100 bpm
Respiration rate 8-20 breaths per minute
Temperature (where applicable) 35.5-37.5 °C
Analysis
Vital sign variables at each time -point, and its change from baseline to each post -baseline time -
point will be summari zed using descriptive summary statistics for each parameter by group and
cohort -total. [Mock Table 14.4.3 -1.X and 2 .X]
Vital sign values for each parameter will be assigned an normal/abnormal classification
according to whether the value is within or outside of the reference range for that parameter (see
Table 4). The number and percentage of subjects with CS abnormal, abnormal (not CS), norma l
and missing values will be summarized for each parameter by group and cohort -total. [Mock
Table 14.4.3 -3.X]
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BioNTech_BNT162 -01_SAP_final_V4.0 Confidential 30 All vital sign data will be presented in the data listings. Abnormal vital signs values and
clinically significant vital sign abnormalities will be flagged in the listing.
6.7.4. ECG
Definition
Standard 12 -lead ECGs will be recorded at the times given in Table 5, 6 and 7 of the protocol
using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT,
and corrected QT intervals. ECGs will be judged by the investigator as CS/NCS ; only the
investigator assessment and heart rate will be rec orded in the CRF.
Analysis
ECG investigator assessment s as well as heart rate will be listed.
6.7.5. Further Safety data
Physical examination, drugs of abuse, alcohol use, viral screening and the SARS -CoV -2 test ing
will be listed.
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7.1. Appendix 1: Changes to Protocol -Planned Analyses
No changes from the protocol.
7.2. Appendix 2: List of A bbreviations
AE Adverse Event
AESI Adverse Event of Special Interest
ATC Anatomical -Therapeutic -Chemical
BMI Body Mass Index
bpm beats per minute
C Celsius
CI Confidence Interval
cm centimeter
CMI Cell-mediated immune testing
CRF Case Report Form
COVID -19 Corona Virus Disease 2019
CS Clinically Significant
D day
d day
DMC Data Monitoring Committee
ECG Electrocardiogram
ELISA Enzyme -Linked Immunosorbent Assay
ELISpot Enzyme -Linked Immuno -Spot
EoT End-of-trial (visit);
FDA Food and Drug Administration
FU Follow -up (visit)
geoMean Geometric Mean
GMFR Geometric Mean Fold Rise
GMT Geometric Mean Titer
h hour
ICH International Conference on Harmonization
IMP Investigational Medicinal Product
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LLN Lower Limit of Normal
LLOD Lower Limit of Detection
m meter
max maximum
MedDRA™ Medical Dictionary for Regulatory Activities
min minimum
min minute
mL millilitre
mmHg millimeter of mercury
N Number of Subject s
n Number of Observations
NCS Not clinically significant
P/B Prime/boost
PT Preferred Term
SAF Safety Set
SAP Statistical Analysis Plan
SARS -CoV -2 The virus leading to COVID -19
SAS Statistical Analysis Software
SCR Screened Set
SD Standard Deviation
SD Single Dose
SOC System Organ Class
SOP Standard Operating Procedures
SRC Safety Review Committee
TEAE Treatment Emergent Adverse Event
TESAE Treatment Emergent Serious Adverse Event
TLF Tables, Listings, and Figures
ULN Upper Limit of Normal
ULOD Upper Limit of Detection
VNT Virus Neutralization Test
WHO DD World Health Organisation Drug Dictionary
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7.3. Appendix 3: Reporting Conventions
SAS version 9. 4, or higher, will be used to produce all tables, listings, and figures.
For summary statistics, the mean , median and SD will be displayed to one decimal place greater
than the original value. Minimum and maximum will be reported to the same decimal places as
the original value. Percentages will be presented with no decimal places.
The functional antibody response is define d as the geometric mean of the functional antibody
titer replicates. Therefore, summary statistics as well as minimum and maximum are displayed
with the same number of decimals for functional antibody response and its fold increase.
WOCBP Women of Childbearing Potential
μg Microgram
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BioNTech_BNT162 -01_SAP_final_V4.0 Confidential 34 8. References
[1] Staburo GmbH, STABURO/SOP001 , “Standard Operating Procedure for Statistical
Programming”, Version 05
[2] Staburo GmbH, STABURO/SOP002, “Standard Operating Procedure for Quality Control of
Programs”, Version 05
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