Document text
PF-07302048 (BNT162 b2 RNA- Based COVID -19 Vaccine)
Protocol C4591007
Final Protocol Amendment 21, 05 March 06Aug 2021
PFIZER CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 1A PHASE 1 ,OPEN-LABEL DOSE -FINDING STUDY TO EVALUATE S AFETY,
TOLERABILITY , AND IMMUNOGENICITY AND PHASE 2/3
PLACEBO -CONTROLLED, OBSERVER- BLINDED SAFETY, TOLERABILIT Y,
AND IMMUNOGENICITY STUDY OF A SARS -COV -2 RNA VACCI NE
CANDIDATE AGAINST CO VID-19 IN HEALTHY CHILDREN
<12YEARS OF AGE AND YOUNG ADULTS
Study Sponsor BioNTech
Study Conducted By Pfizer
Study Intervention Number : PF-07302048
Study Intervention Name: RNA -Based COVID -19 Vaccine
USIND Number: 19736
EudraCT Number: 2020- 005442- 42
Protocol Number: C4591007
Phase: 1/2/3
Short Title :A Phase 1 /2/3Study to Evaluate the Safety ,Tolerabilit y, and Immunogenicit y
of an RNA Vaccine Candidate Against COVID -19 in Healthy Children andYoung Adults
<12 Years of Ag e
This document and accompanying materials contain confidential information belonging to Pfizer. Except as
otherwise agreed to in writing, by accepting or reviewing these document s, you agree to hold this information
in confidence and not copy or disclose it to others (except where required by app licable law) or use it for
unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer must be
promptly notified.
090177e197c0b08c\Approved\Approved On: 06-Aug-2021 19:39 (GMT)
FDA-CBER-2021-5683-1077063
PF-07302048 (BNT162 b2 RNA- Based COVID -19 Vaccine)
Protocol C4591007
Final Protocol Amendment 21, 05 March 06Aug 2021
PFIZER CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 2Protocol Amendment Summary of Changes Table
Document History
Document Version Date Summary and Rationale for Changes
Amendment 2 06Aug 2021 Made the following updates in response to
commitments made to CBER concerning myocarditis
and pericarditis :
Insertion of a dditional row in risk assessment
table in risk assessment section
Addition of myocarditis and pericarditis in
Adverse Events of Special Interest section
Addition of a procedure to any visit that occurs
sooner than 1 month after any vaccination
Addition of an unplanned visit to capture data
pertaining to myocarditis and pe ricarditis
Revised protocol title to reflect the changes in age
and dose evaluation.
Updated to allow anadditional 2250 Phase 2/3
selected -dose participants to enlarge the size of the
pediatric safety database.
Added Phase 1/2/3 evaluation of low er dose levels
for children and young adults with corresponding
objectives .
Revised the order of Visit 1 activities to clarify when
procedures should be conducted in relation to study
intervention administration when the visit occurs
over 2 consecutive days .
Added updates and reformatt edactivities in the S oA
Removed the requirement to conduct a potential
COVID -19 convalescent visit following each
potential COVID -19 illness visit . The collection of
the blood sample w as to support an exploratory
endpoint ,which will be addressed with external data
and thereby reduce burden to participants and
caregivers .
Added a country -specific appendix that allow s
flexibility to conduct scheduled visits in the
participant’s home ,ie, site -arranged home health
visits, as perm itted per local guidelines (applicable to
Poland only ).
Amendment 1 05Mar 2021 Added 2age groups to the study: participants ≥2 to
<5 years and ≥6 months to <2 years of age ,to also
study safety and immunogenicity in these age groups .
Updated e fficacy objectives to apply across ag es
in which immunobridging has been successful, if
22 cases are accrued.
Made u pdates to match Pfizer’s response to
04February 2021 CBER comments regarding this
study, ie :
090177e197c0b08c\Approved\Approved On: 06-Aug-2021 19:39 (GMT)
FDA-CBER-2021-5683-1077064
PF-07302048 (BNT162 b2 RNA- Based COVID -19 Vaccine)
Protocol C4591007
Final Protocol Amendment 21, 05 March 06Aug 2021
PFIZER CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 3Document History
Document Version Date Summary and Rationale for Changes
Exclusion criteri on3 applied to all study
participants rather than just to Phase 1
participants.
References to “noninferiority ”updated to
“immunobridging. ”
Made a ddition sto the exclusion criteria for previous
or current diagnosis of MIS -C.
Addedto the exclusion criteria receipt of any passive
antibody therapy specific to COVID -19 within
90days prior to enrol lment.
Specified that placebo recipients who decline
BNT162b2 will be follow ed for 24 months ( Visits X
and Y) .
Temporary delay of study intervention criteria
regarding nonstudy vaccination updated to be most
permissive, ie, to allow easier scheduling around
childhood routine vaccinations.
Added the following symptoms as prompts to
complete the COVID -19/MIS -C illness e- diary:
Inability to eat/poor feeding in participants
<5years of age;
Abdominal pain;
Hospitalization due to confirmed COVID -19
infection.
Follow ing updates made to the first confirmed
COVID -19 case definition to accommodate inclusion
of participants <5 years of age:
Definition of diarrhea added.
Inability to e at/poor feeding in participants
<5years of age added as an additional symptom.
Definition of SARS -CoV -2–related hospitalization
added.
RR and HR required to meet the SARS -CoV -2–
related severe case definition specified by participant
age. Table 4 inserted.
Added that c ell-mediated immune responses will be
described follow ing isolation of PBMCs in a subset of
Phase 2/3 participants ≥10years of age.
Corresponding visit (Visit 3) added approximately 7
days after Dose 2.
Original p rotocol 05Feb2021 N/A
This amendment incorporates all revisions to date, including amendments made at the
request of country health authorities and IRBs/ECs.
090177e197c0b08c\Approved\Approved On: 06-Aug-2021 19:39 (GMT)
FDA-CBER-2021-5683-1077065
PF-07302048 (BNT162 b2 RNA- Based COVID -19 Vaccine)
Protocol C4591007
Final Protocol Amendment 21, 05 March 06Aug 2021
PFIZER CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 4TABLE OF CONTENTS
LIST OF TABLES ................................ ................................ ................................ ................... 11
1. PROTOCOL SUMMARY ................................ ................................ ................................ ...12
1.1. Sy nopsis ................................ ................................ ................................ .................. 12
1.2. Schema ................................ ................................ ................................ .................... 31
1.3. Schedule of Activ ities ................................ ................................ ............................. 34
1.3.1. Phase 1 Dose Finding ................................ ................................ ................. 34
1.3.2. Phase 1 Evaluation of L ower Dose Levels ................................ ................. 38
1.3.3. Phase 2/3 Selected Dose ................................ ................................ ............. 40
1.3.3.1. Phase 2/3 Selected Dose: Participants Who Originall y
Received BNT162b2 or Placebo Recipients Who Decline
BNT162b2 ................................ ................................ ......................... 44
1.3.3.2. Phase 2/3 Selected Dose: Participants Who Originall y
Received Placebo ................................ ................................ ............... 45
1.3.4. Phase 2/3 Evaluation of L ower Dose Levels ................................ .............. 48
2. INTRODUCTION ................................ ................................ ................................ ............... 51
2.1. Study Rationale ................................ ................................ ................................ .......51
2.2. Background ................................ ................................ ................................ ............. 51
2.2.1. Clinical Overview ................................ ................................ ....................... 53
2.3. Benefit/Risk Assessment................................ ................................ ......................... 54
2.3.1. Risk Assessment ................................ ................................ ......................... 56
2.3.2. Ben efit Assessment ................................ ................................ ..................... 59
2.3.3. Overall Benefit/Risk Conclusion ................................ ................................ 59
3. OBJECTI VES, ESTIMANDS, AND ENDPOINTS ...........................................................59
3.1. Phase 1 ................................ ................................ ................................ ..................... 59
3.2. Phase 2/3 ................................ ................................ ................................ ................. 61
4. STUDY DESIGN ................................ ................................ ................................ ................. 68
4.1. Overall Design ................................ ................................ ................................ ......... 68
4.1.1. Phase 1 ................................ ................................ ................................ ........ 69
4.1.2. Phase 2/3................................ ................................ ................................ .....70
4.1.3. Number of Participants................................ ................................ ............... 70
4.1.3.1. Phase 2/3: Safety, Tolerability , Immunogenicity , and
Efficacy ................................ ................................ .............................. 71
090177e197c0b08c\Approved\Approved On: 06-Aug-2021 19:39 (GMT)
FDA-CBER-2021-5683-1077066
PF-07302048 (BNT162 b2 RNA- Based COVID -19 Vaccine)
Protocol C4591007
Final Protocol Amendment 21, 05 March 06Aug 2021
PFIZER CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 54.1.4. I ntervention Groups and Duration ................................ .............................. 73
4.2. Scientific Rationale for Study Design ................................ ................................ .....74
4.3. Justification for Dose ................................ ................................ .............................. 75
4.4. End of Study Definition ................................ ................................ .......................... 75
5. STUDY POPUL ATION ................................ ................................ ................................ ......75
5.1. I nclusion Criteria................................ ................................ ................................ .....75
5.2. Exclusion Criteria ................................ ................................ ................................ ....77
5.3. L ifesty le Considerations ................................ ................................ .......................... 78
5.3.1. Contraception ................................ ................................ .............................. 78
5.4. Screen Failures ................................ ................................ ................................ ........ 79
5.5. Criteria for Temporarily Delay ing Enrollment/Randomization/Study
Intervention Administration ................................ ................................ ...................... 79
6. STUDY INTERVENTIO N................................ ................................ ................................ ..80
6.1. Study Intervention(s) Administered ................................ ................................ ........ 80
6.1.1. Administration ................................ ................................ ............................ 81
6.2. Preparation/Handling/Storage/Accountability ................................ ........................ 81
6.2.1. Preparation and Dispensing ................................ ................................ ........ 82
6.3. Measures to Minimize Bias: Randomization and Blinding ................................ .....83
6.3.1. Allocation to Study Intervention ................................ ................................ 83
6.3.2. Blinding of Site Personnel (Phase 2/3 Selected Dose Onl y)...................... 83
6.3.3. Blinding of the Sponsor................................ ................................ .............. 83
6.3.4. Breaking the Blind ................................ ................................ ...................... 84
6.4. Stu dy Intervention Compliance ................................ ................................ ............... 85
6.5. Concomitant Therapy ................................ ................................ .............................. 85
6.5.1. Prohibited During the Study ................................ ................................ .......85
6.5.2. Permitted During the Study ................................ ................................ ........ 87
6.5.3. Recording Nonstudy Vaccination and Concomitant Medications..............87
6.6. Dose Modification ................................ ................................ ................................ ...87
6.7. I ntervention After the End of the Study ................................ ................................ ..88
7. DI SCONTINUATION O F STUDY INTERVENTION AND PARTI CIPANT
DISCONTINUATION/WI THDRAWAL ................................ ................................ ........... 88
7.1. Discontinuation of Study Intervention ................................ ................................ ....88
090177e197c0b08c\Approved\Approved On: 06-Aug-2021 19:39 (GMT)
FDA-CBER-2021-5683-1077067
PF-07302048 (BNT162 b2 RNA- Based COVID -19 Vaccine)
Protocol C4591007
Final Protocol Amendment 21, 05 March 06Aug 2021
PFIZER CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 67.2. Participant Discontinuation/Withdrawal From the Study ................................ .......89
7.2.1. Withdrawal of Consent ................................ ................................ ............... 90
7.3. L ost to Follow -up ................................ ................................ ................................ ....90
8. STUDY ASSESSMENTS AND PROCEDURES ................................ ............................... 92
8.1. Efficacy and/or Immunogenicity Assessments ................................ ....................... 93
8.1.1. I mmunogenicity................................ ................................ .......................... 97
8.1.2. Biological Samples ................................ ................................ ..................... 98
8.2. Saf ety Assessments ................................ ................................ ................................ .98
8.2.1. Phy sical Examinations ................................ ................................ ................ 99
8.2.2. Vital Signs ................................ ................................ ................................ ..99
8.2.3. Clinical Safety Laboratory Assessments ................................ .................... 99
8.2.4. Electronic Diary ................................ ................................ .......................... 99
8.2.4.1. Grading Scales ................................ ................................ ......... 100
8.2.4.2. L ocal Reactions ................................ ................................ .......100
8.2.4.3. Sy stemic Events ................................ ................................ ......102
8.2.4.4. Fever ................................ ................................ ........................ 104
8.2.4.5. Antipy retic Medication ................................ ........................... 104
8.2.5. Phase 1 Stopping Rules ................................ ................................ ............ 105
8.2.6. Randomization and Vaccination After a Stopping Rule Is Met in
Phase 1 ................................ ................................ ................................ ........... 106
8.2.7. Pregnancy Testing ................................ ................................ .................... 106
8.3. Adverse Events and Serious Adverse Events........................................................106
8.3.1. Time Period and Frequency for Collecting AE and SAE Information .....107
8.3.1.1. Reporting SAEs to Pfizer Safety ................................ ............. 108
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF................. 108
8.3.2. Method of Detecting AEs and SAEs ................................ ........................ 108
8.3.3. Follow -up of AEs and SAEs ................................ ................................ .....109
8.3.4. Regulatory Reporting Requirements for SAEs ................................ ......... 109
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational
Exposure ................................ ................................ ................................ ........ 109
8.3.5.1. Exposure Duri ng Pregnancy ................................ .................... 109
8.3.5.2. Exposure During Breastfeeding ................................ .............. 111
090177e197c0b08c\Approved\Approved On: 06-Aug-2021 19:39 (GMT)
FDA-CBER-2021-5683-1077068
PF-07302048 (BNT162 b2 RNA- Based COVID -19 Vaccine)
Protocol C4591007
Final Protocol Amendment 21, 05 March 06Aug 2021
PFIZER CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 78.3.5.3. Occupational Exposure ................................ ........................... 112
8.3.6. Cardiovascular and Death Events ................................ ............................. 112
8.3.7. Disease -Related Events and/or Disease -Related Outcomes Not
Qualify ing as AEs or SAEs For Dose Finding/Selected Dose
partici pants ................................ ................................ ................................ .....112
8.3.8. Adverse Events of Special Interest................................ ........................... 113
8.3.8.1. Lack of Efficacy ................................ ................................ ......113
8.3.9. Medical Device Deficiencies ................................ ................................ ....113
8.3.10. Medication Errors ................................ ................................ ................... 113
8.4. Treatment of Overdose................................ ................................ .......................... 114
8.5. P harmacokinetics ................................ ................................ ................................ ..114
8.6.Pharmacod ynamics ................................ ................................ ................................ 114
8.7. Genetics ................................ ................................ ................................ ................. 115
8.8. Biomarkers ................................ ................................ ................................ ............ 115
8.9. I mmunogenicit y Assessments ................................ ................................ ............... 115
8.10. Health Economics ................................ ................................ ............................... 115
8.11. Study Procedures ................................ ................................ ................................ .115
8.11.1. Phase 1 Dose Finding ................................ ................................ ............. 115
8.11.1.1. Visit 1 – Dose 1 (Day 1)................................ ........................ 115
8.11.1.2. Visit 2 – Dose 2 (19 to 23 Day s After Visit 1) ...................... 118
8.11.1.3. Visit 3 – 7- Day Follow -up Visit (1 Week After Dose 2, 6
to 8 Day s After Visit 2) ................................ ................................ ...121
8.11.1.4. Visit 4 – 1- Month Follow -up Visit (28 to 35 Day s After
Visit 2) ................................ ................................ ............................. 122
8.11.1.5. Visit 5 – 6- Month Follow -up Visit (175 to 189 Days
After Visit 2) ................................ ................................ .................... 122
8.11.1.6. Visit 6 – 12- Month Follow -up Visit (350 to 378 Day s
After Visit 2) ................................ ................................ .................... 123
8.11.1.7 . Visit 7 – 24- Month Follow -up Visit (714 to 742 Day s
After Visit 2) ................................ ................................ .................... 123
8.11.2. Phase 1 Evaluation of L ower Dose Levels ................................ ............. 124
8.11.2.1. Visit 101 – Dose 1 (Day 1)................................ .................... 124
8.11.2.2. Visit 102 – Dose 2 (19 to 23 Day s After Visit 101) .............. 126
090177e197c0b08c\Approved\Approved On: 06-Aug-2021 19:39 (GMT)
FDA-CBER-2021-5683-1077069
PF-07302048 (BNT162 b2 RNA- Based COVID -19 Vaccine)
Protocol C4591007
Final Protocol Amendment 21, 05 March 06Aug 2021
PFIZER CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 88.11.2.3. Visit 103 – 7- Day Follow-up Visit (1 Week After Dose
2, 6 to 8 Day s After Visit 102) ................................ ........................ 129
8.11.2.4. Visit 104 – 1- Month Follow -up Visit (28 to 35 Day s
After Visit 102) ................................ ................................ ................ 129
8.11.2.5. Visit 105 – 6- Month Follow -up Visit (175 to 189 Day s
After Visit 102) ................................ ................................ ................ 130
8.11.3. Phase 2/3 Selected Dose ................................ ................................ ......... 131
8.11.3.1. Visit 1 – Dose 1 (Day 1)................................ ........................ 131
8.11.3.2. Visit 2 – Dose 2 (19 to 23 Day s After Visit 1) ...................... 134
8.11.3.3. Visit 3 – 1- Week Follow -up Visit (After Visit 2) (6 to 8
Days After Visit 2): Only for Those Participants Having Blood
Drawn for PBMC Isolation ................................ ............................. 136
8.11.3.4. Visit 4 – 1- Month Follow -up Visit (After Visit 2) (28 to
35 Day s After Visit 2) ................................ ................................ .....137
8.11.3.5. Visit 5 – 6- Month Follow -up Visit (175 to 189 Days
After Visit 2) ................................ ................................ .................... 138
8.11.4. Phase 2/3 Selected Dose: Participants Who Originall y Received
BNT162b2 or Placebo Recipients Who Decline BNT162b2 ........................ 139
8.11.4.1. Visit X – 12- Month Follow -up Visit (350 to 378 Day s
After Visit 2) ................................ ................................ .................... 139
8.11.4.2. Visit Y – 24- Month Follow -up Visit (714 to 742 Day s
After Visit 2) ................................ ................................ .................... 140
8.11.5. Phase 2/3 Selected Dose: Participants Who Originall y Received
Placebo ................................ ................................ ................................ ........... 141
8.11.5.1. Visit A – Dose 3 (175 to 189 Day s After Dose 2 and
Same Date as Visit 5) ................................ ................................ ......141
8.11.5.2. Visit B – Dose 4 (19 to 23 Days After Visit A) .................... 143
8.11.5.3. Visit C – 1- Month Follow -up Telephone Contact (After
Dose 4) (28 to 35 Day s After Visit B) ................................ ............. 145
8.11.5.4. Visit D – 6- Month Follow -up Telephone Contact (After
Dose 4) (175 to 189 Days After Visit B) ................................ ......... 146
8.11.5.5. Visit E – 12-Month Follow -up Telephone Contact (After
Dose 4) (350 to 378 Days After Visit B) ................................ ......... 146
8.11.5.6. Visit F – 18 -Month Follow -up Telephone Contact (After
Dose 4) (532 to 560 Days After Visit B) ................................ ......... 147
8.11.6. Phase 2/3 Evaluation of L ower Dose Levels ................................ .......... 147
090177e197c0b08c\Approved\Approved On: 06-Aug-2021 19:39 (GMT)
FDA-CBER-2021-5683-1077070
PF-07302048 (BNT162 b2 RNA- Based COVID -19 Vaccine)
Protocol C4591007
Final Protocol Amendment 21, 05 March 06Aug 2021
PFIZER CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 98.11.6.1. Visit 201 – Dose 1 (Day 1)................................ .................... 147
8.11.6.2. Visit 202 – Dose 2 (19 to 23 Day s After Visit 201) .............. 150
8.11.6.3. Visit 203 – 1- Month Follow -up Visit (After Visit 2) (28
to 35 Day s After Visit 202) ................................ ............................. 152
8.11.6.4. Visit 204 – 6- Month Follow -up Visit (175 to 189 Day s
After Visit 202) ................................ ................................ ................ 153
8.12. Unscheduled Visit for Fever or a Grade 3 or Suspected Grade 4 Reaction ........ 154
8.13. COVID -19 and M IS-C Surveillance (Dose Finding/Selected Dose
Participants) ................................ ................................ ................................ ............. 155
8.13.1. Potential COVI D-19/MI S-C Illness Visit (Optimally Within 3 Day s
After Potential COVID -19 Illness Onset) ................................ ...................... 156
8.13.2. Potential COVI D-19/MI S-C Convalescent Visit (28 to 35 Day s
After Potential COVID -19 Illness Visit) ................................ ....................... 158
8.14. Communication and Use of Technology ................................ ............................. 159
8.15. SARS -CoV -2 NAAT Nasal (Anterior Nares) Swab Result s .............................. 160
9. STATI STICAL CONSI DERATIONS ................................ ................................ .............. 160
9.1. Estimands and Statistical Hy potheses ................................ ................................ ...161
9.1.1. Estimands ................................ ................................ ................................ ..161
9.1.2. Statistic al Hy pothesis ................................ ................................ ................ 161
9.1.2.1. Statistical Hy pothesis Evaluation for Immunogenicity ........... 161
9.1.2.2. Statistical Hy pothesis Evaluation for Efficacy ........................ 162
9.1.3. Multiplicity Considerations ................................ ................................ ......163
9.2. Sample Size Determination ................................ ................................ ................... 163
9.3. Analy sis Sets ................................ ................................ ................................ ......... 167
9.4. Statistical Analy ses................................ ................................ ............................... 168
9.4.1. General Considerations ................................ ................................ ............. 168
9.4.1.1. Analy ses for Binary Data ................................ ........................ 169
9.4.1.2. Analy ses for Continuous Data ................................ ................. 169
9.4.2. Primary Endpoint(s) ................................ ................................ .................. 170
9.4.3. Secondary Endpoint(s) ................................ ................................ .............. 172
9.4.4. Exploratory Endpoint(s) ................................ ................................ ........... 175
9.5. Interim Anal yses................................ ................................ ................................ ...176
9.5.1. Analy sis Timing ................................ ................................ ........................ 176
090177e197c0b08c\Approved\Approved On: 06-Aug-2021 19:39 (GMT)
FDA-CBER-2021-5683-1077071
PF-07302048 (BNT162 b2 RNA- Based COVID -19 Vaccine)
Protocol C4591007
Final Protocol Amendment 21, 05 March 06Aug 2021
PFIZER CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 109.6. Data Monitoring Committee or Other Independent Oversight Committee ........... 177
10. SUPPORTING DOCUMENTATION AND O PERATI ONAL
CONSI DERATIONS ................................ ................................ ................................ ........ 179
10.1. Appendix 1: Regulatory , Ethical, and Study Oversight Considerations ............. 179
10.1.1. Regulatory and Ethical Considerations ................................ .................. 179
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the
Protocol or I CH GCP ................................ ................................ .......179
10.1.2. Financial Disclosure ................................ ................................ ............... 180
10.1.3. Informed Consent Process ................................ ................................ ......180
10.1.4. Data Protection ................................ ................................ ....................... 181
10.1.5. Dissemination of Clinical Study Data ................................ .................... 182
10.1.6. Data Qualit y Assurance ................................ ................................ .......... 183
10.1.7. Source Documents ................................ ................................ .................. 184
10.1.8. Study and Site Start and Closure ................................ ............................ 184
10.1.9. Publication Policy................................ ................................ ................... 185
10.1.10. Sponsor’s Qualified Medical Personnel ................................ ............... 186
10.2. Appendix 2: Clinical Laboratory Tests ................................ ............................... 186
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recor ding,
Evaluating, Follow -up, and Reporting ................................ ................................ ....187
10.3.1. Definition of AE ................................ ................................ ..................... 187
10.3.2. Definition of SAE................................ ................................ ................... 188
10.3.3 . Recording/Reporting and Follow- up of AEs and/or SAEs ..................... 190
10.3.4. Reporting of SAEs................................ ................................ .................. 193
10.4. Appendix 4: Contraceptive Guidance ................................ ................................ .194
10.4.1. Male Participant Reproductive Inclusion Criteria ................................ ..194
10.4.2. Female Participant Reproductive Inclusion Criteria ............................... 194
10.4.3. Woman of Childbearing Potential ................................ .......................... 195
10.4.4. Contraception Methods ................................ ................................ ........... 196
10.5. Appendix 5: Li ver Safety : Suggested Actions and Follow -up Assessments ......197
10.6. Appendix 6: Abbreviations ................................ ................................ ................. 199
10.7. Appendix 7: Criteria for Allowing Inclusion of Participants With Chronic
Stable HIV, HCV, or HBV Infection ................................ ................................ ......203
11. REFERENCES ................................ ................................ ................................ ................ 205
090177e197c0b08c\Approved\Approved On: 06-Aug-2021 19:39 (GMT)
FDA-CBER-2021-5683-1077072
PF-07302048 (BNT162 b2 RNA- Based COVID -19 Vaccine)
Protocol C4591007
Final Protocol Amendment 21, 05 March 06Aug 2021
PFIZER CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 11LIST OF TABLES
Table 1. Dose Levels for Each Age Group in the Phase 1 and 2/3 Dose
Finding/Selected Dose and Evaluation of Lower Dose ............................ 33
Table 2. Phase 1 Dose Finding Participants ................................ ........................... 71
Table 3. Phase 1 L ower Dose Evaluation Participants ................................ ........... 71
Table 4. Phase 2/3 Sel ected Dose Participants –Blood Draws for
Immunogenicit y/Efficacy Assessments ................................ .................... 72
Table 5. Phase 2/3 Selected Dose Participants –Safet y and
Tolerability /Efficacy Assessments ................................ ........................... 72
Table 6. Phase 2/3 L ower Dose Evaluation Participants – Blood Draws for
Immunogenici ty/Efficacy Assessments ................................ .................... 73
Table 7. Phase 2/3 L ower Dose Evaluation Participants – Safety and
Tolerability /Efficacy Assessments ................................ ........................... 73
Table 8. RR and HR, by Age, Indicative of Severe S ystemic I llness ..................... 95
Table 9. Local Reaction Grading Scale ................................ ................................ 101
Table 10. Systemic Event Grading Scale for Participants ≥2 Years of Age .......... 102
Table 11. Systemic Event Grading Scale for Participants <2 Years of Age ..........103
Table 12. Scale for Fever ................................ ................................ ........................ 104
Table 13. Power Anal ysis for Immunobridging Assessment ................................ .164
Table 14. Precision of SARS- CoV -2 Neutralizing Titer GMT .............................. 165
Table 15. Power for Vaccine Efficacy Assessment ................................ ................ 165
Table 16. Probability of Observing at Least 1 AE by Assumed True Event
Rates With Different Sample Sizes ................................ ........................ 166
090177e197c0b08c\Approved\Approved On: 06-Aug-2021 19:39 (GMT)
FDA-CBER-2021-5683-1077073
PF-07302048 (BNT162 b2 RNA- Based COVID -19 Vaccine)
Protocol C4591007
Final Protocol Amendment 21, 05 March 06Aug 2021
PFIZER CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 121.PROTOCOL SUMMARY
1.1.Synopsis
Short Title: A Phase 1/2/3 Study to Evaluate the Safety ,Tolerabilit y, and Immunogenicit y
of an RNA Vaccine Candidate Against COVID -19 in Healthy Children < 12Years of Age and
Young Adults.
Rationale
A pneumonia of unknown cause detected in Wuhan, China, was first reported in
December 2019. InJanuary 2020, the pathogen causing this outbreak was identified as a
novel coronavirus 2019. On11 March 2020 , the WHO upgraded the status of the COVID -19
outbreak from epidemic to pandemic , which is now rapidly spreading worldwide. Children
have been affected b y both the primary COVID -19 disease and the less common secondary
inflammatory complications, including MIS-C.
There are currently no licensed vaccines to prevent infection with SARS -CoV -2or
COVID -19. Given the rapid transmission of COVID -19 and incidence of disease in the
United States and elsewhere, the rapid development of an effective vaccine is of utmost
importance .
A Phase 1/2/3 study (C4591001 )is currentl y being conducted in healthy individual s 12years
of age and older to investigate the safety , tolerability , immunogenicity ,and efficacy of the
prophy lactic BNT162 vaccine candidates against COVID -19. The vaccine candidate
selected for evaluation in the C4591001 P hase 2/3 study is BNT162b2 at a 30 -µg dose level .
The v accine is administered as 2 doses approximately 21 day s apart. On 18 November 2020,
the primary efficacy analy sis results were announced, which demonstrate dBNT162b2 to be
95% effective against COVID -19 beginning 28 day s after the first dose; 170 confirmed cases
of COVID -19 were evaluated, with 162 observed in the placebo group versus 8 in the
vaccine group .Safet y data from approximately 38,000 participants randomized 1:1 with a
median of 2 months of follow -up after the second dose of vaccine showed a favorable safety
profile at a dose of 30 μg in participants 16 y ears of age and older. On 11 December 2020,
the US FDA issued an EUA for use in individuals 16 years of age and older. Other countries
have also granted EUA (eg, Canada, Mexico, Bahrain), and Pfizer and BioNTech are
anticipating further regulatory decisions in other countries. On 10 May 2021, the US FDA
issued an EUA for use in individual s12 to 15 years of age. Other countries have also granted
EUA or other authorization/approval for this age group (eg, EMA, UK, Switzerland, and t he
Philippines).
This Phase 1/2/3 study (C4591007) willinitially evaluate up to 3dose levels of BNT162b2 in
up to 3 age groups (participants ≥5 to <12 y ears, ≥2 to <5 y ears, and ≥ 6months to <2 years
of age) for safet y, tolerability , immunogenicit y, and efficacy (depending on successful
immunobridging and accrual of asufficient number of cases). Phase 1 include sthe dose -
finding portion. I nitiation of dose finding in participants ≥5 to <12 y ears of age is based on
acceptable blinded safet y data demonstrated in 2260 59 12 -through 15-year-oldsat the 30-µ g
dose level in the C4591001 study .ThePhase 2/3 BNT162b 2dose level to be used in each
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Page 13age group in this study will be selected based on the Phase 1 safety , tolerability ,and
immunogenicit y data from the same age group. Phase 2/3 (referred to as the selected -dose
portion of the study )includes animmunobridging analysisof immune responses in
participants within each age group (participants ≥5 to <12 years, ≥2 to <5 y ears, and ≥ 6
months to <2 years of age) to those in participants 16 to 25years of age inthe Phase 3
C4591001 efficacy study .Safety , tolerability ,and e fficacy (depending on successful
immunobridging and accrual of a sufficient number of cases) will also be evaluated in Phase
2/3 of this study .
Theauthorized dose of BNT162b 2in adolescents and y oung adults 12 years of age and older
is 30µg,whereas the following doses were selected in the ongoing C4591007 Phase 2/3
portion: 10 µgin participants 5 to <12 years of age and 3 µg in participants 6 months to < 5
yearsof age . With the robust immune responses elicited in adolescents to minimize
reactogenicity and risk of other AEs and to potentially unify the dose levels across children
and y oung adults, additional lower dose levels of BNT162b2 (3 µg, 10 µg)will be evaluated
to determine whether similar immune responses are elicited .For this lower -dose evaluation
portion, a new cohort of Phase 1 participants will be enrolled in3age groups: >5 to <12, 12
to <16, and 16 to <30years of age to assess safety, tolerability , and immunogenicity . The
Phase 2/3 BNT162b2 dose level will be selected based on the Phase 1 assessments with an
immunobridging analysis of immune responses in participants within each age group to
participants in the 30-µgPhase 3 C4591001 efficacy study .
Objectives , Estiman ds,and Endpoints
The age groups referred to in the objectives and estimands below are participants ≥5to
<12years, ≥2to <5 y ears, and ≥6 months to <2 y ears of age .
Phase 1
Objectives Estimands Endpoints
Primary: Primary: Primary:
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Page 14Phase 1
Objectives Estimands Endpoints
To describe the safety and tolerability
profiles of prophylactic BNT162 b2at
each dose level in each age groupIn participants receiving at least 1 dose
of study intervention, the percentage of
participants in each age group
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 Dose 2
SAEs from Dose 1 to 6
months after Dose 2Participants 16 to , 12 to <16, ≥5 to <12
years and ≥ 2 to <5 years of age:
Local reactions (pain at the
injection site, redness, and swelling)
Systemic events (fever,
fatigue, headache, chills, vomiting,
diarrhea, new or worsened muscle pain,
and new or worsened joint pain)
AEs
SAEs
Participants ≥6 months to <2 age:
Local reactions (tenderness at
the injection site, redness, and
swelling)
Systemic events (fever,
decreased appetite, drowsiness, and
irritability)
AEs
SAEs
Secondary: Secondary: Secondary:
To describe the immune responses
elicited by prophylactic BNT162 b2at
each dose level in each age groupIn participants complying with the key
protocol criteria (evaluable
participants) in each age group :
At baseline , before Dose 2 ,and7 days
after Dose 2 ,
GMTs at each time point 7
days after Dose 2
GMFR from before Dose 1
(baseline) to each subsequent time
point after vaccination SARS CoV 2 neutralizing
titers
Exploratory : Exploratory : Exploratory :
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Page 15Phase 1
Objectives Estimands Endpoints
To describe COVID 19and severe
COVID -19 cases with and without
serological or virological evidence of
past SARS CoV 2 infection Confirmed COVID 19cases
Confirmed severe COVID 19
cases
To describe MIS C cases with and
without evidence of past SARS CoV 2
infection Confirmed cases as per CDC
criteria
Phase 2/3
Objectives Estimands Endpoints
Primary Safety : Primary Safety : Primary Safety :
To define the safety profile of
prophylactic BNT162b2 at the selected
dose level inthe participants included
in the Phase 2/3 immunobridging
analysis in each age groupIn participants receiving at least 1 dose
of study intervention, from each
vaccine group, the percentage of
participants in each age group
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 Dose 2
SAEs from Dose 1 to 1
month after Dose 2Participants ≥5 to <12 years and ≥2 to
<5 years of age:
Local reactions (pain at the
injection site, redness, and swelling)
Systemic events (fever,
fatigue, headache, chills, vomiting,
diarrhea, new or worsened muscle pain,
and new or wo rsened joint pain)
AEs
SAEs
Participants ≥6 months to <2 years of
age:
Local reactions ( tenderness at
the injection site, redness, and
swelling)
Systemic events (fever,
decreased appetite, drowsiness, and
irritability )
AEs
SAEs
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Page 16Phase 2/3
Objectives Estimands Endpoints
To define the safety profile of
prophylactic BNT162b2 atthe selected
dose level in all participants
randomized in Phase 2/3 in each age
groupIn participants receiving at least 1 dose
of study intervention from each vaccine
group , the percentage of participants in
each age group 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 Dose 2
SAEs from Dose 1 to 6
months after Dose 2Participants 16 to , 12 to <16, ≥5to <12
years and ≥ 2 to <5 years of age:
Local reactions (pain at the
injection site, redness, and swelling)
Systemic events (fever,
fatigue, headache, chills, vomiting,
diarrhea, new or worsened muscle pain,
and new or worsened joint pain)
AEs
SAEs
Participants ≥6 months to <2 years of
age:
Local reactions ( tenderness at
the injection site, redness, and
swelling)
Systemic events (fever,
decreased appetite, drowsiness, and
irritability )
AEs
SAEs
Primary Immunogenicity : Primary Immunogenicity : Primary Immunogenicity :
To demonstrate immunobridging of the
immune response elicited by
prophylactic BNT162b2 at the dose
level selected in each per age group
inPhase 2/3 participants without
serological or virological evidence (up
to 1month after receipt of Dose 2) of
past SARS -CoV -2 infection:In participants complying with the key
protocol criteria (evaluable
participants) and no serological or
virological evidence (up to 1 month
after receipt of Dose 2) of past
SARS CoV 2 infection : SARS CoV 2 neutralizing
titers
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Page 17Phase 2/3
Objectives Estimands Endpoints
In participants ≥5 to <12
years of age compared to participants
16 to 25years of age from Phase 2/3 of
theC4591001 studyGMR, estimated by the ratio of the
geometric mean of SARS -CoV -2
neutralizing titers in participants ≥5 to
<12years of age to those in participants
16to 25years of age 1 month after
Dose 2
The difference in percentages
of participants with seroresponseain
participants ≥5 to <12 years of age and
16 to 25 years of age from Phase 2/3 of
the C4591001 study
In participants ≥2 to <5 years
of age compared to participants 16 to
25years of age from Phase 2/3 of
theC4591001 studyGMR, estimated by the ratio of the
geometric mean of SARS -CoV -2
neutralizing titers in participants ≥2 to
<5 years of age to those in participants
16to 25years of age 1 month after
Dose 2
The difference in percentages
of participants with seroresponse in
participants ≥2 to <5 years of age and
16 to years of age from Phase 2/3 of the
C4591001 study
In participants ≥6 months to
<2years of age compared to
participants 16 to 25years of age from
Phase 2/3 of the C4591001 studyGMR, estimated by the ratio of the
geometric mean of SARS -CoV -2
neutralizing titers in participants ≥6
months to <2 years of age to those in
participants 16 to 25years of age 1
month after Dose 2
The difference in percentages
of participants with seroresponse in
participants ≥6 months to <2 years of
ageand 16 to 25 years of age from
Phase 2/3 of the C4591001 study
Secondary Immunogenicity Lower : Secondary Immunogenicity: Secondary Immunogenicity :
In participants complying with key
protocol criteria (evaluable
participants) and no serological or
virological evidence (up to 1 month
after receipt of Dose 2) of past
SARS CoV 2 infection:SARS CoV 2 neutralizing titers
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Page 18Phase 2/3
Objectives Estimands Endpoints
In participants ≥5 to <12 years of age
compared to participants 16 to 25years
of age from Phase 2/3 of
theC4591001 studyGMR, estimated by the ratio of the
geometric mean of SARS -CoV -2
neutralizing titers in participants ≥5 to
<12years of age to those in participants
16to 25years of age 1 month after
Dose 2
The difference in percentages of
participants with seroresponse in
participants ≥5 to <12 years of age and
16 to 25 years of age from Phase 2/3 of
the C4591001 study
In participants 12to 1years of age
compared to participants 16 to 25years
of age from Phase 2/3 of
theC4591001 studyGMR, estimated by the ratio of the
geometric mean of SARS CoV 2
neutralizing titers in participants 12 to
years of age to those in participants 16
to 25 y ears of age 1 month after Dose 2
The difference in percentages of
participants with seroresponse in
participants 12 toyears of age and 16 to
25 years of age from Phase 2/3 of the
C4591001 study
In participants 16 to years of age
compared to participants 16 to 55years
of age from Phase 2/3 of
theC4591001 studyGMR, estimated by the ratio of the
geometric mean of SARS CoV 2
neutralizing titers in participants 16
toyears of age to those in participants
16to 55 years of age 1 month after
Dose 2
The difference in percentages of
participants with seroresponse in
participants 16 to years of age and 16
to 55 years of age from Phase 2/3 of the
C4591001 study
Secondary Immunogenicity /Efficacy : Secondary Immunogenicity /Efficacy :Secondary Immunogenicity/Efficacy :
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Page 19Phase 2/3
Objectives Estimands Endpoints
To describe the immune responses
elicited by prophylactic BNT162b2 at
the dose level selected in each per age
group and persistence of immune
response in Phase 2/3 participants
without serological or virologic al
evidence of pastSARS CoV 2
infectionIn evaluable participants with no
serological or virological evidence of
past SARS CoV 2 infection from each
vaccine and age group:
At baseline (before Dose 1) and 1, 6, 12
(for the original BNT162b2 group
only), and 24 (for the original
BNT162b2 group on ly) months after
Dose 2,
GMTs at each time point
GMFRs from before Dose 1
to each subsequent time point after
Dose 2 SARS CoV 2 neutralizing
titers
In ≥5 to <12 years of age group all age
groups in the part of the study ,ifwhere
immunobridging is successful and, if at
least 22 cases are accrued across those
age groups :
To evaluate the efficacy of prophylactic
BNT162b2 against confirmed
COVID 19 occurring from 7 days after
Dose 2 during blinded follow up period
in participants in the selected dose part
of the study without evidence of past
SARS CoV 2 infection In participants complying with the key
protocol criteria (evaluable
participants) and with no serological or
virological evidence (prior to 7 days
after receipt of Dose 2 ) of past
SARS CoV 2 infection:
100 × (1 IRR) [ratio of active vaccine
to placebo] Confirmed COVID 19
incidence from 7 days after Dose 2 per
1000 person -years of blinded follow -up
In ≥5 to <12 years of age group in the
selected dose part of the study, if
immunobridging is successful and if at
least 22 cases are accrued100 × (1 IRR) [ratio of active vaccine
to placebo]
In ≥6 months to <2 years and ≥2 to
<5years age groups in the sele cted
dose part of the study where
immunobridging is successful, if at
least 22 cases are accrued across those
age groups100 × (1 IRR) [ratio of active vaccine
to placebo]
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Page 20Phase 2/3
Objectives Estimands Endpoints
In all age groups in the selected dose
part of the study where
immunobridging is successful, if at
least 22 cases are accrued across those
age groups and if the above two
individual age groups (≥5 to <12 years
of age, ≥6 months to <2 years and ≥2 to
<5years age combined) did not accrue
22 cases 100 × (1 IRR) [ratio of active vaccine
to placebo]
In ≥6 months to < 2years and ≥2 to
<5years age group s in the selected
dose part of the study where if, ifand
To evaluate the efficacy of prophylactic
BNT162b2 against confirmed
COVID 19 occurring from 7 days after
Dose 2 in participants without evidence
of past SARS -CoV -2 infection In participants complying with the key
protocol criteria (evaluable
participants) and with no serological or
virological evidence (prior to 7 days
after receipt of Dose 2) of past
SARS -CoV -2 infection:
100 × (1 IRR) [ratio of active vaccine
to placebo]Confirmed COVID 19 incidence from
7 days after Dose 2 per 1000 person
years of follow -up
In ≥5 to <12 years of age group all age
groups in the part of the study where
immunobridging is successful, i f at
least 22 cases are accrued across those
age groups :
To evaluate the efficacy of prophylactic
BNT162b2 against confirmed
COVID 19 occurring from 7 days after
Dose 2 during the blinded follow -up
period in participants in the selected
dose part of the study with or without
evidence of past SARS -CoV -2
infection In participants complying with the key
protocol criteria (evaluable
participants) and with o r without
serological or virological evidence
(prior to 7 days after receipt of Dose 2)
of past SARS CoV 2 infection:
100 × (1 IRR) [ratio of active vaccine
to placebo] Confirmed COVID 19
incidence from 7 days after Dose 2 per
1000 person years of blinded follow up
In ≥5 to <12 years of age group in the
selected dose part of the study, if
immunobridging is successful and if at
least 22 cases are accrued100 × (1 IRR) [ratio of active vaccine
to placebo]
In ≥6 months to <2 years and ≥2 to
<5years age groups in the selected
dose part of the study where
immunobridging is successful, if at
least 22 cases are accrued across those
age groups100 × (1 IRR) [ratio of active vaccine
to placebo]
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Page 21Phase 2/3
Objectives Estimands Endpoints
In all age groups in the selected dose
part of the study where
immunobridging is successful, if at
least 22 cases are accrued across those
age groups and if the above two
individual age groups (≥5 to <12 years
of age, ≥6 months to <2 years and ≥2 to
<5years age combined) did not accrue
22 cases 100 × (1 IRR) [ratio of active vaccine
to placebo]
≥6 months to < 2years and ≥2 to
<5yearsallwhere if, ifandthe two those
To evaluate the efficacy of prophylactic
BNT162b2 against confirmed
COVID -19 occurring from 7 days after
Dose 2 in participants with or without
evidence of past SARS CoV 2
infection In participants complying with the key
protocol criteria (evaluable
participants) and with o r without
serological or virological evidence
(prior to 7 days after receipt of Dose 2)
of past SARS -CoV -2 infection:
100 × (1 IRR) [ratio of active vaccine
to placebo]Confirmed COVID 19 incidence from
7 days after Dose 2 per 1000 person
years of follow -up
To describe the efficacy of prophylactic
BNT162b2 against asymptomatic
infection in participants in the selected
dose part of the study without evidence
of past SARS CoV 2 infectionIn evaluable participants without
serological or virological evidence of
past SARS CoV 2 infection from each
vaccine group:
100 × (1 IRR) [ratio of active vaccine
to placebo] Incidence of asymptomatic
infection of SARS -CoV -2 based on N -
binding antibody seroconversion
Exploratory: Exploratory: Exploratory:
To describe the efficacy of prophylactic
BNT162b2 against confirmed COVID
19 occurring from 7 days after Dose 2
through the blinded follow up period in
participants in the selected dose part of
the study without, and with and
without ,evidence of past SARS CoV 2
infection in each age group and in all
age groups combinedIn participants complying with the key
protocol criteria (evaluable
participants) 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 blinded
follow up based on central
laboratory or locally
confirmed NAAT
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Page 22Phase 2/3
Objectives Estimands Endpoints
To evaluate the immune response over
time to prophylactic BNT162b2 at the
dose level selected in each per age
group and persistence of immune
response in Phase 2/3 participants with
and without serological or virological
evidence of past SARS CoV 2
infectionIn evaluable participants with or
without serological or virological
evidence of past SARS CoV 2
infection from each vaccine gro up:
At baseline and at 1, 6, 12 (for the
original BNT162b2 group only), and 24
(for the original BNT162b2 group
only) months after Dose 2,
GMTs at each time point
GMFRs from before Dose 1
to each subsequent time point after
Dose 2 SARS CoV 2 neutralizing
titers
To evaluate the immune response
(non-S) to SARS -CoV -2 in Phase 2/3
participants with and without
confirmed COVID 19 during the study Nbinding antibody
To describe COVID 19 and severe
COVID -19 cases in all participants in
the selected dose level part of the study
with and without serological or
virological evidence of past
SARS CoV 2 infection Confirmed COVID 19 cases
Confirmed COVID 19 cases
resulting in hospitalization
Confirmed severe COVID 19
cases
To describe MIS C cases with and
without evidence of past SARS-CoV -2
infection in participants in the sel ected
dose level part of the study Confirmed cases as per CDC
criteria
To describe the serological responses in
Phase 2/3 participants in the selected
dose level part of the study to
BNT162b 2atthedose level selected in
eachper age group in cases of:
Confirmed COVID-19
Confirmed severe COVID -19
SARS -CoV -2 infection
without confirmed COVID 19 SARS CoV 2 neutralizing
titers
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Page 23Phase 2/3
Objectives Estimands Endpoints
To describe the safety and
immunogenicity of prophylactic
BNT162b2 at the dose level selected in
eachper age group in children with
stable HIV disease All safety and
immunogenicity endpoints described
above will be analyzed descriptively
To describe the cell-mediated immune
response, and additional humoral
immune response parameters, to the
reference strain in a subset of
participants:
At baseline and at 7 days and
1 and 6 months after Dose 2
a.Seroresponse is defined as achieving ≥4 fold rise from baseline (before Dose 1). If the baseline measurement is below
LLOQ, the postvaccination measure of ≥4 ×LLOQ is considered seroresponse .
Overall Design
This is a Phase 1/2/3 study inhealthy children and y oung adults <12years of age .
Dependent upon safet y and/or immunogenicit y data generated during the course of this
study , and the resulting assessment of benefit -risk, the safet y, tolerability , and
immunogenicit y of BNT162b2 in participants <6 months of age may subsequently be
evaluate d.Participants will range from ≥6 months to <30 y ears of age ,with different dose
levels assessed in each group .
Dose Levels for Each Age Group in the Phase 1 and Phase 2/3 Dose- Finding/Selected -Dose and Lower -
Dose Evaluation s
Phase 1 Open -Label Dose -Finding Evaluation
≥6 Months
to <2 Years≥2 to <5
Years≥5 to <12
Years12 to <16
Years16 to <30
YearsTotal
Dose level 3µg 3/10 µg 10/20/30 µg
Participant s 16a16/32a16/16/16b112
Phase 2/3 Observer- Blinded, Placebo -Controlled Selected -Dose Evaluation
Dose level 3 µg 3 µg 10µg
Participant s 1125
(active 750;
placebo 375)1125
(active 750;
placebo 375)4500
(active 3000;
placebo
1500)6750
Phase 1 Open -Label Lower- Dose Evaluation
Planned
dose level (s) 3 µg 3/10 µgc3/10 µgc
Participant s 32 32/32 32/32 160
Phase 2/3 Open -Label Lower- Dose Evaluation
Planned
dose level TBD TBD TBD
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Page 24Participant s 300 300 300 900
a.Actual number of participants recruited inthe≥6 months to <2 y ears and ≥2 to <5 yearsage groups .
b.Actual number of participants recruited in the ≥5 to <12 years age group . Dose 1: 16 out of 16 received
30-µgdose level ; Dose 2: 4out of 16 received 30 -µgdose level and 12 of 16 received 10-µgdose level .
c.Both dose levels will start concurrently .
Phase 1
Dose -finding: Is the open -label dose -finding portion of the study that will evaluate safet y,
tolerability, and immunogenicity of BNT162b2 administered on a 2 -dose (separated b y
approximately 21 day s) schedule in up to 3 age groups (participants ≥5 to <12 y ears, ≥2 to <5
years, and ≥6 months to <2 y ears of age).
Dose finding is being initiated in this study in participants ≥5 to <12 y ears of age based on
the acceptable blinded safety assessment of the 30- µg dose in 12 -to 15 -year-olds in the
C4591001 study .
The purpose of P hase 1 is to identify preferred dose level(s) of BNT162b2 from up to
3different dose levels in each age group.
Dependent upon safet y and/or immunogenicit y data generated during the course of this
study , it is possible that dose levels may not be started, may be terminated early, and/or may
be added with dose levels below the lowest stated dose.
Participants will have blood drawn prior to both Dose 1and Dose 2and 7 day s after Dose 2
to assess immunogenicity to determine the selected BNT162b 2dose level for Phase 2/3.
Lower -dose evaluation :Is the open- label lower -dose evaluation portion of the study that
willevaluate safet y, tolerability , and immunogenicity of BNT162b2 on a 2-dose (separated
by approximately 21 days) schedule in up to 3 age groups ( participants ≥5 to <12 y ears, 12 to
<16years, and 16to <30years of age) .
The purpose of the Phase 1 lower -dose evaluation is to evaluate safety and immunogenicit y
of BNT162b2 from up to 2different dose levels in each age group.
Participants will have blood drawn prior to both Dose 1 and Dose 2 and 7 day s after Dose 2
to assess immunogenicity to determine the selected BNT162b2 dose level for the Phase 2/3
lower -dose evaluation portion of the study .
Phase 2 /3
Selected -dose:Is the portion of the study that will evaluate the safet y, tolerability , and
immunogenicit yin each age group at theselected dose level from the Phase 1 dose-finding
portion of the study . Efficacy will be evaluated within or acros sage groups across all a ge
groups in which immunobridging is successful, depending on accrual of a sufficient number
of cases across in those age groups .
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CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 25All p Participants will have blood drawn at baseline prior to Dose 1 and 6 months after Dose
2. Immunobridging to participants 16 to 25 y ears of age in the C4591001 study will be based
on immunogenicit y data collected at baseline and 1 month after Dose 2. The persistence of
the immune response will be based on immunogenicity data collected in participants at
baseline and at 1, 6, 12 ( original BNT162b2 group only ),and24months after Dose 2
(original BNT162b2 group only ).In addition, efficacy against confirmed COVID -19 and
against as ymptomatic infection will also be assessed.
At designated US sites, an addi tional optional whole blood sample of approximately 10mL
will be obtained prior to Dose 1and at 7 day s and 6 months after Dose 2 from up to
approximately 60 participants ≥10yearsof age. Thesesample swill be used on an
exploratory basis to investigate the postvaccination cell -mediated immune response at these
time points.
At the 6- month follow -up visit ,all participants will be unblinded. P articipants who originall y
received placebo will be offered the opportunit y to receive BNT162b2 as part of the st udy.
Participants ≥12 years of age who originall y received placebo and become eligible for receipt
of BNT162b2 according to recommendations (detailed separatel y and available in the
electronic stud y reference portal) will have the opportunity to receive BN T162b2.
Lower -doseevaluation : Is the portion of the study that will evaluate the safety , tolerability ,
and immunogenicit yin each age group at the selected dose level from the Phase 1 lower -dose
evaluation .
In this open -label stud y, all participants will have blood drawn at baseline prior to Dose 1
andat 1 and 6 months after Dose 2. Immunobridging to comparator participants inthe
C4591001 study will be based on immunogenicity data collected at baseline and 1 month
after Dose 2. The persistence of the immune response will be based on immunogenicit y data
collected in participants at baseline and1and 6 months after Dose 2.
Number of Participants
Phase 1: Open -Label Dose -Finding and Lower -Dose Evaluation
Phase 1 isanopen -label study thatwill consist of up to 3 different dose levels in each age
group ,with a minimum of 16 participants per dose level (total of 144 participants) forthe
dose-finding evaluation and a minimum of 32 participants per dose level (total of 160
participants) for the lower -dose evaluation .
Phase 1 Dose -Finding Participants
Age Group Total Up to 3 Dose Levels of BNT162b2aActive Placebo
≥5 to <12 Years 48 16/16/16 16 N/A
≥2 to <5Years 48 16/16/16 16 N/A
≥6Months to <2years 48 16/16/16 16 N/A
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PFIZER CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 26a.A dose level may be expanded to enroll more than 16 subjects per dose level.
Phase 1 Lower -Dose Evaluation Participants
Age Group Total Up to 2Dose Levels of BNT162b 2aActive Placebo
≥5 to <12 Years 32 32 32 N/A
12 to <16 Years 64 32/32 32 N/A
16 to <30Years 64 32/32 32 N/A
a.A dose level may be expanded to enroll more than 32subjects per dose level.
Phase 2 /3: Safety, Tolerability, Immunogenicity, and Efficacy
Selected -dose: Is the portion of the study that will evaluate thesafet y, tolerability ,and
immunogenicit yof the selected dose level in each age group from the Phase 1 dose-finding
portion of the study ,with a total of approximately 4500 6750 participants as an additional
2250 participants will be included to enlarge the size of the pediatric safet y database .
Participants will be randomized in a 2:1ratio to receive active vaccine or placebo .
Approximately 450 participants (300 intheactive vaccine group and 150 in the placebo
group ) randomized in each age group in this phase will contribute to the immunobridging
analysis at 1month after Dose 2 and will contribute to the overall anal ysis of the persistence
of immune response at 6 months after Dose 2. These participants will be enrolled from both
US and EU sites to ensure this subset is representative of the whole stud y.
For the persistence time points of 12 and 24 months after Dose 2 ,approximately
70participants from each age group in the original BNT162b 2vaccine group will have an
immunogenicit yblood draw in order to contribute to the anal ysis.All approximately 4500
6750 participants will contribute to the VE analysis for conditional VEand asymptomatic
infection . Efficacy will be evaluated across all within or across age groups in which
immunobridging is successful, depending on accrual of a sufficient number of cases across in
those age groups.
Phase 2/3 Selected -Dose Participants –Blood Draws for Immunogenicity/Efficacy Assessments
All Age Groups ≥5 to <12 Years of Age ≥2 to <5 Years and ≥6
Months to <2 Years of Agea
Total Active Placebo Total Active Placebo Total Active Placebo
Baseline blood draw 6750
4500450030
003000150
04500
2250300015
0015007501125 750 375
1 Month after Dose 2 1350 900 450 450 300 150 450 300 150
6 Months after Dose 2 4500 3000 1500 2250 1500 750 1125 750 375
12 Months after Dose 2 210 210 N/A 70 70 N/A 70 70 N/A
24 Months after Dose 2 210 210 N/A 70 70 N/A 70 70 N/A
a.Number of participants shown is for each of these 2younger age groups .
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CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 27Allparticipants will contribute to the safet y,tolerability , and efficacy assessments.
Phase 2/3 Selected -Dose Participants –Safety and Tolerability /Efficacy Assessment s
Age Total Active Placebo
≥5 to <12 Years 4500 3000 1500
≥2 to <5 Years 1125 750 375
≥6 Months to <2 Years 1125 750 375
Allage groups 6750 4500 2250
Lower -dose evaluation : Is the open -label portion of the study that will evaluate the safet y,
tolerability ,and immunogenicity of the selected dose level in each age group from the Phase
1lower -dose evaluation, with a total of approximately 900active participants.
Approximately 300active participants in each age group in this phase will contribute to the
immunobridging anal ysis at 1 month after Dose 2 and the overall anal ysis of the persistence
of immune response at 6 months after Dose 2. These participants will be enrolled from both
US and EU sites to ensure this subset is representative of the whole stud y.
Phase 2/3 Lower -Dose Evaluation Participants –Blood Draws for Immunogenicity /Efficacy
Assessments
All Age Groups ≥5 to <12 , 12 to 16 Years , and 16 to
<30Years of Agea
Total Active Active Placebo
Baseline blood draw 900 900 300 N/A
1 Month after Dose 2 900 900 300 N/A
6 Months after Dose 2 900 900 300 N/A
a. Number of participants shown is for each of these 2 older age groups.
All participants will contribute to the safet y,tolerability , and efficacy assessments.
Phase 2/3 Lower -Dose Evaluation Participants –Safety and Tolerability /Efficacy Assessments
Total Active Placebo
900 900 N/A
Intervention Groups and Duration
Phase 1
Dose -finding : Dosing will begin at the low-dose level in participants ≥5 to <12 y ears of age .
Controlled enrollment will be required for the first dose level studied in each age group.
Only a limited number of participants (~4) are dosed before allowing dosing in the remaining
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CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 28participants (~12) i n the same age and dose -level group. The IRC will review safety data (e -
diary and AE) acquired up to 7 day s after Dose 1 for the low -dose level group ; upon
confirmation of an acceptable safet y assessment by the IRC:
Dosing may commence at the mid -dose level in the same age group, and
Dosing may commence at the low -dose level in participants ≥2 to <5 y ears of age.
The same process will be followed when moving updose level s in each age group, and when
progressing between age groups at the low- dose level as shown in Section 1.2. Dosing may
commence at the low -dose level in participants ≥ 6 months to <2 y ears of age after IRC
review of safet y data (e -diary and AE) acquired up to 7 day s after Dose 1 at the low -dose
level from participants ≥2 to <5 y ears of age.
In each age group, i f the low -dose level is considered notacceptable based on safet y
assessment after Dose 1 , the mid-dose level or high -dose level will not commence . In this
case, an optional lower dose level may commence. Dependent on the results obtained, dose
level (s)may be omitted. In each age group, i fthe mid -dose level is considered not
acceptable based on saf ety assessment after Dose 1, the high-dose level will not commence.
Based on safet y assessments, t he second dose may be given at a lower dose level .
Duration of the dose-f inding portion of the study: Participants are expected to participate
for up to a maximum of approximately 26months.
Lower -dose e valuation :As higher doses have been assessed in each age group, all age/dose
levels will proceed concurrentl y.
Duration ofthe lower -doseevaluation portion of the study :Participants are expected to
participate for up to a maximum of approximately 6months.
Phase 2/3
Selected -dose: Progression of each age group into Phase 2/3 will occur independentl y; it is
therefore possible that each age group may not start Phase 2/3 concurrentl y and the dose
level selected for Phase 2/3 may differ b y age group. For each age group t o proceed to
Phase 2/3, safet y, tolerability ,and immunogenicity data from 7 day s after Dose2 for the
selected vaccine dose level in that age group from Phase 1 will be confirmed to be
acceptable .
Duration of the selected -doseportion of the study :PParticipants are expected to
participate for up to a maximum of approximately 26months.
Lower -dose e valuation : Progression of each age group into Phase 2/3 will occur
independentl y; it is therefore possible that each age group may not start Phase 2/3
concurrently ,and the dose level selected for Phase 2/3 may differ b y age group. For each
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PFIZER CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 29age group t o proceed to Phase 2/3, safet y, tolerability , and immunogenicity data from 7 day s
after Dose 2 for the selected vaccine dose level in that age group from Phase 1 will be
confirmed to be acceptable .
Duration of the lower -dose evaluation portion of the study : Participants are expected to
participate for up to a maximum of approximately 6months.
Data Monitoring Committee or Other Independent Oversight Committee
The study will utilize an IRC, an internal Pfizer committee that will review data to allow
dose finding in Phase 1.
An external DMC will review cumulative unblinded data and monitor vaccine safet y
throughout the stud y.
Statistical Methods
Immunobridging of the immune response to prophy lactic BNT162b2 in participants within
each age group totherespo nse in participants 16to 25 y ears of age in the comparator group
from Phase 2/3 of the C4591001 study will be assessed separatel y for each age group and
based on the GMR of SARS -CoV -2 neutralizing titers using a 1.5 -fold margin and the
difference in percentages of participants with seroresponse using a 10% margin.
Within each age group , immunobridging based on GMR and seroresponse difference will be
assessed sequentially in the order specified .Immunobridging success based on GMR will be
declared if the lower limit of the 95% CI for the GMR (each age group to the 16to 25
yearcomparator age group from the C4591001 study )is >0.67 and the point estimate of the
GMR is ≥0.8. Immunobridging success based on the seroresponse difference will be
declare d if the lower limit of the 95% CI for the difference in percentages of participants with
seroresponse is > -10%. Since seroresponse is not directly linked to an antibody level
associated with protection against COVID -19, if the seroresponse endpoint nearl y misses the
noninferiority criteria, the totality of evidence willbe evaluated, including RCDCs and the
proporti on of participants with neutralizing titers ≥ LLOQ .
A sample size of 225evaluable participants in each age group evaluated in this study and the
corresponding comparator group from the C4591001 study will provide a power of 90. 4%
and 92.6% to declare immunobridging success based on GMR and seroresponse difference,
respectivel y. The immunogenicity data from the 300 active vaccine recipients in
approximately 450participant s randomized in each age group in the Phase 2 /3selected- dose
portion of the study , and approximately 300 participants enrolled in each age group in the
Phase 2/3 lower -dose evaluation portion of the study , will be used for the immunobridging
assessment.
The other immunogenicity objectives will be evaluated descripti vely by GMT, GMFR ,and
the associated 95% CIs for SARS -CoV -2 neutralizing titers at the various time points.
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CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 30The secondary efficacy objectives are to evaluate VE, defined as 100 ×(1–IRR),against the
confirmed COVID -19 illness , in each of the 2 age groups ( ≥5 to <12 years ,≥6 months to
<2yearsand ≥2to <5yearscombined )oracross allage group swhere immunobridging
success is declared in the Phase 2/3 selected- dose portion of the study (if the required number
ofcases are not accrued in either ofthe 2 individual age groups) . IRR is calculated as the
ratio of the first confirmed COVID -19 illness rate in the vaccine group to the corresponding
illness rate in the placebo group. With the assumption of a true VE of 75%, 22 cases will
provide 70% power to conclude true VE >20%. Hypothesis testing for the specific age
group s (≥5 to <12 years, ≥6 months to <2 years and ≥2 to <5 years combined ) will be
conducted onl y ifat least 22 cases are accrued in those age group s. With the assumption of a
true VE of 75%, 22 cases will provide 70% power to conclude true VE >20%. Howev er, if
22 cases are not accrued in either of the 2 age groups (≥5 to <12 y ears, ≥6 months to <2 years
and ≥2 to <5 years combined) where immunobridging success is declared, but 22 cases are
accrued across all the age groups where immunobridging success is dec lared, then hypothesis
testing will be conducted across the age group swith imm unobridging s uccess.
VEagainst as ymptomatic infection will be evaluated descriptively. VE estimate and 2 -sided
95% CI for VE will be provided using the Clopper -Pearson method.
The primary safet y objective will be evaluated b y descriptive summary statistics for local
reactions, s ystemic events ,andAEs/SAEs for each vaccine and age group. A 3- tier approach
will be used to summarize AEs in the Phase 2/3 selected- dose portion of the study .
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CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 311.2.Schema
≥5 to <12 Years ≥2 to <5 Years ≥6 Months to <2 Years
Phase 1
All participants receive BNT162b2Phase 1
Allparticipants receive BNT162b2Phase 1
All participants receive BNT162b2
Low -dose level (n=16)aLow -doselevel (n=16)aLow -doselevel (n=16)a
IRC IRCbIRC IRCbIRC
Mid-dose level (n=16) Mid-doselevel (n=16) Mid-doselevel (n=16)
IRC IRC IRC
High -dose level (n=16) High -doselevel (n=16) High -doselevel (n=16)
IRC cIRC cIRC c
Phase 2/3
Participants randomized to receive 2:1
BNT162b2 : placeboPhase 2/3
Participants randomized to receive
2:1 BNT162b2 : placeboPhase 2/3
Participants randomized to receive 2:1
BNT162b2 : placebo
a.In each age group, if the low -dose level is considered not acceptable based on safety assessment after Dose 1, the mid -dose lev el or high-dose level will not commence. In
this case, an optional lower dose level may commence.
b. The IRC will review safety data (e -diary and AE) acquired up to 7 days after Dose 1 in the low -dose -level group, and d osing may commence at the low -dose level in the
next age group based upon confirmation of an acceptable safety assessment at this review.
c. IRC choice of dose level for each age group. Dependent on safety, tolerability, and immunogenicity data from 7 days after Dose 2 in each age gr oup.
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CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 32Phase 1/2/3 Lower -Dose Evaluation
≥5 to <12 Years 12 to <16 Years 16 to <30Years
Phase 1
All participants receive BNT162b2
Low -dose level (n=32)Phase 1
All participants receive BNT162b2
Low -doselevel (n= 32)and
Mid-doselevel (n= 32)aPhase 1
All participants receive BNT162b2
Low -doselevel (n= 32)and
Mid-doselevel (n= 32)a
IRCbIRCbIRCb
Phase 2/3
All participants to receive BNT162b2Phase 2/3
All participants to receive BNT162b2Phase 2/3
All participants to receive BNT162b2
a. Low -and mid -dose levels will start concurrently.
b. IRC choice of dose level for each age group. Dependent on safety, tolerability, and immunogenicity data from 7 days after Dose 2 in each age group.
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PFIZER CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 33Dose Levels for Each Age Group in the Phase 1 andPhase 2/3Dose -Finding/Selected -Dose and Lower -Dose Evaluations
Phase 1 Open -Label Dose -Finding Evalu ation
≥6 Months to
<2Years≥2 to <5 Years ≥5 to <12 Years 12 to <16 Years 16 to <30 Years Total
Dose level 3µg 3/10µg 10/20/30 µg
Participant 16a16/32a16/16/16b112
Phase 2/3 Observer- Blinded, Placebo -Controlled Selected -Dose Evaluation
Dose level 3 µg 3µg 10µg
Participant 1125
(active 750; placebo
375)1125
(active 750; placebo
375)4500
(active 3000 ;
placebo 1500 )6750
Phase 1 Open -Label Lower -Dose Evaluation
Planned dose
level (s)3 µg 3/10 µgc3/10 µgc
Participant 32 32/32 32/32 160
Phase 2/3 Open -Label Lower -Dose Evaluation
Planned dose level TBD TBD TBD
Participant 300 300 300 900
a.Actual number of participants r ecruited inthe ≥6 months to <2 y ears and ≥2 to <5 yearsage groups .
b.Actual number of participants recruited in the ≥5 to <12 years age group . Dose 1 :16out of 16 received 30-µgdose level ; Dose 2: 4out of 1 6 received
30-µgdose level and 12 of 16 received 10-µgdose level .
c.Both dose levels will start concurrently .
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CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 341.3. S chedule of Activ ities
The SoA table provides an overview of the protocol visits and procedures. Refer to the Study Assessments a nd Procedures section of
the protocol for detailed information on each procedure and assessment required for compliance with the protocol.
The investigator may sche dule visits (unplanned visits) in additio n to those listed in the SoA table , in order to conduct evaluations or
assessments required to protect the well -being of the participant .
1.3.1. Phase 1 Dose -Finding Portion
An unplanned potential COVID-19 /MIS-Cillness visit and unplanned potential COVID 19/MIS C convalescent visit are isrequired at
any time for the duration of the study that COVID -19/MIS-Csymptoms are reported . During the 7 day s following each dose,
potential COVID -19/MIS -Csymptoms that overlap with specific s ystemic events (ie, fever, c hills, new or increased muscle pain,
diarrhea, vomiting) should not trigger a potential COVID-19 /MIS-C illness visit unless, in the investigator’s opinion ,the clinical
picture is more indicative of a possible COVID -19/MIS-C illness rather than vaccine rea ctogenicit y.For details, see Section
1.1.Section 8.13 .
Visit Number 1 2 3 4 5 6 7 Unplanned Unplanned
Visit Description Dose
1aDose 2 7 Day
Follow -up
Visit
(1 W eek
After
Dose 2)1-Month
Follow -up
Visit6-Month
Follow -up
Visit12-Month
Follow -up
Visit24-Month
Follow -up
VisitPotential COVID -19/ MIS -
C Illness
VisitbPotential COVID
19/
MIS -C
Convalescent
Visit
Visit Window (Days) Day 1 19 to 23
Days
After
Visit 16 to 8
Days
After
Visit 228 to 35 Days
After Visit 2175 to 189
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2Optimally Within 3 Days
After Potential
COVID -19/MIS -CIllness
Onset28 to 35 Days After
Potential COVID
19/MISC
Illness Visit
Type of Visit Clinic Clinic Clinic Clinic or
TelephonecfTelephone Telephone Clinic or
TelephoneClinic or
Telehea lthClinic
Obtain informed consent and assent (if
appropriate)X
Assign participant number X
Obtain demography and significant medical
history dataX
Confirm use of contraceptives
(ifappropriate)X X X X
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Page 35Visit Number 1 2 3 4 5 6 7 Unplanned Unplanned
Visit Description Dose
1aDose 2 7 Day
Follow -up
Visit
(1 W eek
After
Dose 2)1-Month
Follow -up
Visit6-Month
Follow -up
Visit12-Month
Follow -up
Visit24-Month
Follow -up
VisitPotential COVID -19/ MIS -
C Illness
VisitbPotential COVID
19/
MIS C
Convalescent
Visit
Visit Window (Days) Day 1 19 to 23
Days
After
Visit 16 to 8
Days
After
Visit 228 to 35 Days
After Visit 2175 to 189
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2Optimally Within 3 Days
After Potential
COVID -19/MIS -CIllness
Onset28 to 35 Days After
Potential COVID -
19/MISC
Illness Visit
Type of Visit Clinic Clinic Clinic Clinic or
TelephonecfTelephone Telephone Clinic or
TelephoneClinic or
Telehea lthClinic
Collect nonstudy vaccine information X X X X X
Collect prohibited medication use X X X X X X X
Confirm eligibility X X
Review temporary delay criteria X X
Measure vital signs (including body
temperature )X X
Measure vital signs (including body
temperature)X X
Perform targeted physical examination
(including height and weig ht)dX X
Perform u rine p regnancy test (only for
female participants biologically capable of
having children)X X
Obtain randomization number and study
intervention allocationX
Obtain anterior nasal swab X X X
Collect blood sample for immunogenicity ~5 mL ~5mL ~5 mL ~5 mL
Administer study intervention X X
Assess acute reactions for at least 30
minutes after study intervention
administrationX X
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Page 36Visit Number 1 2 3 4 5 6 7 Unplanned Unplanned
Visit Description Dose
1aDose 2 7 Day
Follow -up
Visit
(1 W eek
After
Dose 2)1-Month
Follow -up
Visit6-Month
Follow -up
Visit12-Month
Follow -up
Visit24-Month
Follow -up
VisitPotential COVID -19/ MIS -
C Illness
VisitbPotential COVID
19/
MIS C
Convalescent
Visit
Visit Window (Days) Day 1 19 to 23
Days
After
Visit 16 to 8
Days
After
Visit 228 to 35 Days
After Visit 2175 to 189
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2Optimally Within 3 Days
After Potential
COVID -19/MIS -CIllness
Onset28 to 35 Days After
Potential COVID -
19/MISC
Illness Visit
Type of Visit Clinic Clinic Clinic Clinic or
TelephonecfTelephone Telephone Clinic or
TelephoneClinic or
Telehea lthClinic
Explain communication methods (including
for e-diary completion), assist with
downloading the app, or issue provisioned
device, if requiredX
Provide a thermometer and caliper
(measuring) deviceX
Reactivate reactogenicity e -diary X
Ensure the participant ’sparent(s)/legal
guardian /has a caliper device and
thermometerX
Ask the participant ’sparent (s)/legal
guardian to complete e-d iary and ensure the
participant’s parent(s)/legal guardian
remains comfortable with chosen e -diary
platformX X
Review reactogenicity e-diary data (daily
review is optimal during the active diary
period)
Review ongoing reactogenicity e-diary
symptoms and obtain stop dates X X
Collect AEse X X X X X X
Collect SAEsfe X X X X X X X
090177e197c0b08c\Approved\Approved On: 06-Aug-2021 19:39 (GMT)
FDA-CBER-2021-5683-1077098
PF-07302048 (BNT162 b2 RNA- Based COVID -19 Vaccine)
Protocol C4591007
Final Protocol Amendment 21, 05 March 06Aug 2021
PFIZER CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 37Visit Number 1 2 3 4 5 6 7 Unplanned Unplanned
Visit Description Dose
1aDose 2 7 Day
Follow -up
Visit
(1 W eek
After
Dose 2)1-Month
Follow -up
Visit6-Month
Follow -up
Visit12-Month
Follow -up
Visit24-Month
Follow -up
VisitPotential COVID -19/ MIS -
C Illness
VisitbPotential COVID
19/
MIS C
Convalescent
Visit
Visit Window (Days) Day 1 19 to 23
Days
After
Visit 16 to 8
Days
After
Visit 228 to 35 Days
After Visit 2175 to 189
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2Optimally Within 3 Days
After Potential
COVID -19/MIS -CIllness
Onset28 to 35 Days After
Potential COVID -
19/MISC
Illness Visit
Type of Visit Clinic Clinic Clinic Clinic or
TelephonecfTelephone Telephone Clinic or
TelephoneClinic or
Telehea lthClinic
Collect e -diary or assist the participant’s
parent(s)/legal guardian to delete applicationX
Collection of COVID -19/MIS -C–related
clinical and laboratory information
(including local diagnosis)X X
Abbreviations: CRF = case report form; MIS-C = multisystem inflammatory syndrome in children; SMS = short message service .
a. The visit may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and exclusion criteria onwards must be conducted on the day of
vaccination please refer to Section 8.11.1.1 .
b. Potential MIS -C visit: Hospitalization for a severe illness with no other alternative etiology.
c. Contact can be made via email or SMS. If no response is obtained or responses do not satisfy visit requirements, a telephone call should be made.
d. A ph ysical examination will include, at a minimum, assessments of general appearance, lungs, cardiovascular system, and lymph nod esurvey . Height and weight will be
collected only at Visit 1.
e. Any AEs occurring up to 48 hours after blood draw and anterior nasal swab collection must be recorded (see Section 8.3.1 ).Note: Potential COVID- 19/MIS -C illnesses and
their sequelae that are consistent with the clinical endpoint definition ( Section 8.1) should not be recorded as AEs. These data will be captured to describe disease endpoints for
lack-of-efficacy assessment data only on the relevant pages of the CRF, as these are expected e ndpoints.
f. Refer to Section 8.3.1 for the time period for collecting SAEs.
090177e197c0b08c\Approved\Approved On: 06-Aug-2021 19:39 (GMT)
FDA-CBER-2021-5683-1077099
PF-07302048 (BNT162 b2 RNA- Based COVID -19 Vaccine)
Protocol C4591007
Final Protocol Amendment 21, 05 March 06Aug 2021
PFIZER CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 381.3.2. Phase 1 Lower -Dose Evaluation
Visit Number 101 102 103 104 105
Visit Description Dose 1aDose 2 7-Day Follow -up Visit
(1 Week After Dose 2)1-Month
Follow -up Visit6-Month
Follow -up Visit
Visit Window (Days) Day 1 19 to 23 Days
After Visit 16 to 8 Days
After Visit 228 to 35 Days
After Visit 2175 to 189 Days
After Visit 2
Type of Visit Clinic Clinic Clinic Clinic or TelephonebTelephone
Obtain informed consent and assent (if appropriate) X
Assign participant number X
Obtain demography and significant medical history data X
Confirm use of contraceptives (if appropriate) X X X X
Collect nonstudy vaccine information X X X X X
Collect prohibited medication use X X X X
Confirm eligibility X X
Review temporary delay criteria X X
Measure vital signs (including body temperature) X X
Perform clinical assessmen tc X X
Perform u rine p regnancy test (only for female participants
biologically capable of having children)X X
Obtain randomization number and study intervention
allocationX
Obtain anterior nasal swab X X
Collect blood sample for immunogenicityd~20 mL/~10 mL/
~5mL~20 mL/~10 mL/
~5mL~20 mL/~10 mL/
~5mL
Administer study intervention X X
Assess acute reactions for at least 30 minutes after study
intervention administrationX X
Explain communication methods (including for e -diary
completion), assist with downloading the app, or issue
provisioned device, if requiredX
Provide a thermometer and caliper (measuring) device X
090177e197c0b08c\Approved\Approved On: 06-Aug-2021 19:39 (GMT)
FDA-CBER-2021-5683-1077100
PF-07302048 (BNT162 b2 RNA- Based COVID -19 Vaccine)
Protocol C4591007
Final Protocol Amendment 21, 05 March 06Aug 2021
PFIZER CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 39Visit Number 101 102 103 104 105
Visit Description Dose 1aDose 2 7-Day Follow -up Visit
(1 Week After Dose 2)1-Month
Follow -up Visit6-Month
Follow -up Visit
Visit Window (Days) Day 1 19 to 23 Days
After Visit 16 to 8 Days
After Visit 228 to 35 Days
After Visit 2175 to 189 Days
After Visit 2
Type of Visit Clinic Clinic Clinic Clinic or TelephonebTelephone
Reactivate reactogenicity e -diary X
Ensure the participant or participant’s parent(s)/legal
guardian has a caliper device and thermometerX
Ask the participant or participant’s parent(s)/legal
guardian to complete e-diary and ensure the participant’s
parent(s)/legal guardian remains comfortable with chosen
e-diary platformX X
Review reactogenicity e-diary data (daily review is
optimal during the active diary period)
Review ongoing reactogenicity e-diary symptoms and
obtain stop dates X X
Collect AEse X X X X X
Collect SAEsf X X X X X
Collect e -diary or assist the participant or participant’s
parent(s)/legal guardian to delete application
Abbreviations: CRF = case report form; SMS = short message service .
a. The visit may be conducted across 2 consecutive days; if so, please refer to Section 8.11.2.1 .
b. Contact can be made via email or SMS. If no response is obtained or responses do not satisfy visit requirements, a telephone call should be made.
c. Including, if indicated, a physical examination.
d. 20 mL is to be collected from participants ≥16 years of age; 10 mL is to be collected from participants 12 to <16years of age ;5 mL is to be collected from participants 5to
<12years of age.
e. Any AEs occurring up to 48 hours after blood draw and anterior nasal swab collection must be recorded (see Section 8.3.1 ).
f. Refer to Section 8.3.1 for the time period for collecting SAEs.
090177e197c0b08c\Approved\Approved On: 06-Aug-2021 19:39 (GMT)
FDA-CBER-2021-5683-1077101
PF-07302048 (BNT162 b2 RNA- Based COVID -19 Vaccine)
Protocol C4591007
Final Protocol Amendment 21, 05 March 06Aug 2021
PFIZER CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 401.3.2. 1.3.3. Phase 2/3 Selected -Dose Portion
An unplanned potential COVID-19 /MIS- C illness visit and unplanned potential COVID 19/MIS C convalescent visit are isrequired at
any time for the duration of the study that potential COVID -19/MIS-C symptoms are reported .During the 7 day s following each
dose, potential COVID -19/MIS-Csymptoms that overlap with specific s ystemic events (ie, fever, chills, new or increased muscle
pain, diarrhea, vomiting) should not trigger a potential COVI D-19 /MIS-Cillness visit unless, in the investigator’s opinion ,the clinical
picture is more indicative of a possible COVID -19/MIS-C illness rather than vaccine reactogenicit y.For details, see Section
8.13Sectio n 1.1.
At the 6- month ( Visit 5 ) follow -up visit , all participants will be unblinded. Participants who originally received placebo will be
offered the opportunit y to receive BNT162b2 as part of t he stud y.Parti cipants who become eligible for receipt of BNT162b2 or
another COVID -19 vaccine according to local or national recommendations prior to Visit 5 (detailed separately , and available in the
electronic stud y reference portal )willhave the opportunity to receive the EUA -approved dose level of BNT162b2.
Visit Number 1 2 3 4 5 Unplanned Unplanned
Visit Description Dose 1aDose 2 1-Week
Follow -up
Visitb1-Month
Follow -up
Visit6-Month
Follow -up
VisitcPotential COVID -19
Illness/MIS-C VisitdPotential COVID 19/
MIS C Convalescent
Visit
Visit Window (Days) Day 1 19 to 23
Days After
Visit 16 to 8 Days
After Visit
228 to 35 Days
After Visit 2175 to 189
Days After
Visit 2Optimally Within 3 Days
After Potential
COVID -19/MIS -C Illness
Onset28 to 35 Days After
Potential COVID
19/MIS C Illness Visit
Type of Visit Clinic Clinic Clinic Clinic or
Telephonee iClinic Clinic or
TelehealthClinic
Obtain informed consent and assent (if appropriate) X
Assign participant number X
Obtain demography and significant medical history
dataX
Measure vital signs (including body temperature) X X
Perform targeted physical examination including
height and weighte X X
For participants who are HIV positive, record latest
CD4 count and HIV viral loadX X X
Perform urine pregnancy test (only for female
participants biologically capable of having children)X X
090177e197c0b08c\Approved\Approved On: 06-Aug-2021 19:39 (GMT)
FDA-CBER-2021-5683-1077102
PF-07302048 (BNT162 b2 RNA- Based COVID -19 Vaccine)
Protocol C4591007
Final Protocol Amendment 21, 05 March 06Aug 2021
PFIZER CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 41Visit Number 1 2 3 4 5 Unplanned Unplanned
Visit Description Dose 1aDose 2 1-Week
Follow -up
Visitb1-Month
Follow -up
Visit6-Month
Follow -up
VisitcPotential COVID -19
Illness/MIS-C VisitdPotential COVID 19/
MIS -C Convalescent
Visit
Visit Window (Days) Day 1 19 to 23
Days After
Visit 16 to 8 Days
After Visit
228 to 35 Days
After Visit 2175 to 189
Days After
Visit 2Optimally Within 3 Days
After Potential
COVID -19/MIS -C Illness
Onset28 to 35 Days After
Potential COVID
19/MIS C Illness Visit
Type of Visit Clinic Clinic Clinic Clinic or
Telephonee iClinic Clinic or
TelehealthClinic
Confirm use of contraceptives (if appropriate) X X X X
Collect nonstudy vaccine information X X X X X
Collect prohibited medication use X X X X X X
Review temporary delay criteria X X
Confirm eligibility X X
Review temporary delay criteria X X
Measure vital signs (including body temperature) X X
Perform physical examination (including height and
weight )f X X
Perform urine pregnancy test (only for female
participants biologically capable of having children)X X
()fObtain randomization number and study
intervention allocationX
Obtain anterior nasal swab X X X
Collect blood sample for immunogenicity ~5mL ~5mLfmLg~5mLhj5mL
Collect blood sample for PBMC isolationb~10mL ~10mL ~10mL
Administer study intervention X X
Assess acute reactions for at least 30 minutes after
study intervention administrationX X
Explain communication methods (including for e -
diary completion), assist with downloading the app,
or issue provisioned device, if requiredX
Provide thermometer and c aliper (measuring) device X
Reactivate reactogenicity e -diary X
090177e197c0b08c\Approved\Approved On: 06-Aug-2021 19:39 (GMT)
FDA-CBER-2021-5683-1077103
PF-07302048 (BNT162 b2 RNA- Based COVID -19 Vaccine)
Protocol C4591007
Final Protocol Amendment 21, 05 March 06Aug 2021
PFIZER CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 42Visit Number 1 2 3 4 5 Unplanned Unplanned
Visit Description Dose 1aDose 2 1-Week
Follow -up
Visitb1-Month
Follow -up
Visit6-Month
Follow -up
VisitcPotential COVID -19
Illness/MIS-C VisitdPotential COVID 19/
MIS -C Convalescent
Visit
Visit Window (Days) Day 1 19 to 23
Days After
Visit 16 to 8 Days
After Visit
228 to 35 Days
After Visit 2175 to 189
Days After
Visit 2Optimally Within 3 Days
After Potential
COVID -19/MIS -C Illness
Onset28 to 35 Days After
Potential COVID
19/MIS C Illness Visit
Type of Visit Clinic Clinic Clinic Clinic or
Telephonee iClinic Clinic or
TelehealthClinic
Reactivate reactogenicity e diary X
Ensure the participant’s parent(s)/legal guardian has
a caliper device and thermometerX
Ask the participant’s parent(s)/legal guardian to
complete e -diary and ensure the participant’s
parent(s)/legal guardian remains comfortable with
chosen e -diary platform X X
Review reactogenicity e -diary data (daily review is
optimal during the acti ve diary period)
Review ongoing reactogenicity e -diary symptoms
and obtain stop datesX X
Collect AEs as appropriateigX X X X X X X
Collect SAEs as appropriatejhX X X X X X X
Unblind the participant and move to either
Section 1.3.3.1 or Section 1.3.3.2X
Collection of COVID -19/MIS -C–related clinical and
laboratory information (including local diagnosis)X X
Abbreviation s: CRF = case report form; HIV = human immunodeficiency virus ; MIS -C = multisystem inflammatory syndrome in children; PBMC = peripheral blood
mononuclear cell ; SMS = shor t message service .
a. This visit may be conducted across 2 consecutive dates; if so, all steps from assessing the inclusion and exclusion criteria onwards must be conducted on the day of
vaccination please refer to S ection 8.11.3.1 .
b. Applicable at designated sites only for participants ≥10years of age who separent(s)/legal guardian have given consent for this additional blood draw.
c. For Phase 2/3 participants who originally received placebo, it is prefera ble that Visit 5and Visit A (Section 1.3.3.2 ) occur on the same day.
d. Potential MIS -C visit: Hospitalization for a severe illness with no other alternative etiology.
e. Contact can be made via email or SMS. If no response is obtained or responses do not satisfy visit requirements, a telephone call should be made.
f. A physical examination will include, at a minimum, assessments of general appearance, lungs, cardiovascular system, and lymph node survey. Height and weight will be
collected only at Visit 1.
090177e197c0b08c\Approved\Approved On: 06-Aug-2021 19:39 (GMT)
FDA-CBER-2021-5683-1077104
PF-07302048 (BNT162 b2 RNA- Based COVID -19 Vaccine)
Protocol C4591007
Final Protocol Amendment 21, 05 March 06Aug 2021
PFIZER CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 43Visit Number 1 2 3 4 5 Unplanned Unplanned
Visit Description Dose 1aDose 2 1-Week
Follow -up
Visitb1-Month
Follow -up
Visit6-Month
Follow -up
VisitcPotential COVID -19
Illness/MIS-C VisitdPotential COVID 19/
MIS -C Convalescent
Visit
Visit Window (Days) Day 1 19 to 23
Days After
Visit 16 to 8 Days
After Visit
228 to 35 Days
After Visit 2175 to 189
Days After
Visit 2Optimally Within 3 Days
After Potential
COVID -19/MIS -C Illness
Onset28 to 35 Days After
Potential COVID
19/MIS C Illness Visit
Type of Visit Clinic Clinic Clinic Clinic or
Telephonee iClinic Clinic or
TelehealthClinic
g. Approximately 450 randomized participants i n each age group will have blood drawn at 1 month after Dose 2.
h. Not required for the additional 2250 participants included to enlarge the size of the pediatric safety database.
i. Any AEs occurring up to 48 hours after blood draw and anterior nasal swab collection must be recorded (see Section 8.3.1 ). Note: Potential COVID -19/MIS -C illnesses and
their sequelae that are consistent with the clinical endpoint definition ( Section 8.1) should not be recorded as AEs. These data will be captured to describe disease endpoints for
lack-of-efficacy assessment data only on the relevant pages of the CRF, as these are expected e ndpoints.
j. Refer to Section 8.3.1 for the time period for collecting SAEs.
090177e197c0b08c\Approved\Approved On: 06-Aug-2021 19:39 (GMT)
FDA-CBER-2021-5683-1077105
PF-07302048 (BNT162 b2 RNA- Based COVID -19 Vaccine)
Protocol C4591007
Final Protocol Amendment 21, 05 March 06Aug 2021
PFIZER CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 441.3.2.1. 1.3.3.1. Phase 2/3 Selected -Dose Portion : Participants Who Originally Received BNT162b2 or Placebo Recipients Who
Decline BNT162b2
After unblinding at Visit 5 , participants who originally received BNT162b2 or placebo recipients who decline BNT162b2 will follow
this SoA for their remaining visits.
An unplanned potential COVID-19 /MIS- C illness visit and unplanned potential COVID 19/MIS C convalescent visit isarerequired at
any time for the duration of the study that potential COVID -19/MIS-C symptoms are reported.
Visit Number Visit X Visit Y Unplanned Unplanned
Visit Description 12-Month Follow -up
Visit24-Month Follow -up
VisitPotential COVID -19
Illness/MIS-C VisitaPotential COVID
19/MIS C Convalescent
Visit
Visit Window (Days) 350 to 378 Days After
Visit 2714 to 742 Days After
Visit 2Optimally Within 3
Days After Potential
COVID -19/MIS -C
Illness Onset28 to 35 Days After
Potential COVID -
19/MISCIllness Visit
Type of Visit Clinic or TelephonebdClinic or Telephone Clinic or Telehealth Clinic
For participants who are HIV positive, record latest CD4 count and
HIV viral loadX X
Collect prohibited medication use X X X X
Obtain anterior nasal swab X
Collect blood sample for immunogenicitycb~5mLc~5mLc ~5mL
Collect A Es as appropriatedc X X X X
Collect e -diary or assist the participant’s parent(s)/legal guardian to
delete applicationX
Collection of COVID -19/MIS -C–related clinical and laboratory
information (including local diagnosis)X X
Abbreviation s: CRF = case report form; HIV = human immunodeficiency virus ; MIS -C = multisystem inflammatory syndrome in children ; SMS = short message service .
a. Potential MIS -C visit: Hospitalization for a severe illness with no other alternative etiology .
b. Contact can be made via email or SMS. If no response is obtained or responses do not satisfy visit requirements, a telephone call should be made.
c. If the participants had an unplanned potential COVID 19/MIS C convalescent visit within ≤ 42days before the scheduled visit ( Visit X or Visit Y ) and if a blood sample was
collected as part of the convalescent visit, or if the participant originally received placebo and declines the offer of BNT162b2, blood sample collection at the scheduled visit
isnot required.
c.The participants who are part of the evaluation of persistence of immune response will have blood drawn either at Visit X or Visit Y.
090177e197c0b08c\Approved\Approved On: 06-Aug-2021 19:39 (GMT)
FDA-CBER-2021-5683-1077106
PF-07302048 (BNT162 b2 RNA- Based COVID -19 Vaccine)
Protocol C4591007
Final Protocol Amendment 21, 05 March 06Aug 2021
PFIZER CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 45Visit Number Visit X Visit Y Unplanned Unplanned
Visit Description 12-Month Follow -up
Visit24-Month Follow -up
VisitPotential COVID -19
Illness/MIS- C VisitaPotential COVID
19/MIS -C Convalescent
Visit
Visit Window (Days) 350 to 378 Days After
Visit 2714 to 742 Days After
Visit 2Optimally Within 3
Days After Potential
COVID -19/MIS -C
Illness Onset28 to 35 Days After
Potential COVID
19/MISCIllness Visit
Type of Visit Clinic or TelephonebdClinic or Telephone Clinic or Telehealth Clinic
d. Any AEs occurring up to 48 hours after blood draw and anterior nasal swab collection must be recorded (see Section 8.3.1 ). Note: Potential COVID -19/MIS -C illnesses and
their sequelae that are consistent with the clinical en dpoint definition ( Section 8.1) should not be recorded as AEs. These data will be captured to describe disease endpoints
for lack -of-efficacy assessment data only on the relevant pages of the CRF, as these are expected endpoints.
1.3.2.2. 1.3.3.2. Phase 2/3 Selected -Dose Portion : Participants Who Ori ginally Received Placebo
At the 6- month (Visit 5) follow -up visit, all participants will be unblinded. Participants who originally received placebo will be
offered the opportunit y to receive BNT162b2 as part of the stud y. Participants who become eligibl e for receipt of BNT162b2 or
another COVID -19 vaccine according to local or national recommendations prior to Visit 5 (detailed separately , and available in the
electronic stud y reference portal) will have the opportunity to receive the EUA- approved dose l evel of BNT162b2.
An unplanned potential COVID-19/MIS- C illness visit and unplanned potential COVID 19/MIS C convalescent visit are isrequired at
any time for the duration of the study that potential COVID -19/MIS-C symptoms are reported. During the 7 day s following each
dose, potential COVID -19/MIS-Csymptoms that overlap with specific s ystemic events (ie, fever, chills, new or increased muscle
pain, diarrhea, vomiting) should not trigger a potential COVI D-19 /MIS-Cillness visit unless, in the investigator’s opinion, the clinical
picture is more indicative of a possible COVID -19 illness rather than vaccine reactogenicit y.For details, see Section 8.13Section 1.1.
090177e197c0b08c\Approved\Approved On: 06-Aug-2021 19:39 (GMT)
FDA-CBER-2021-5683-1077107
PF-07302048 (BNT162 b2 RNA- Based COVID -19 Vaccine)
Protocol C4591007
Final Protocol Amendment 21, 05 March 06Aug 2021
PFIZER CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 46Visit Number A B C D E F Unplanned Unplanned
Visit Description Dose 3 Dose 4 1-Month
Follow -up
Visit6-Month
Follow -up
Visit12-Month
Follow -up
Visit18-Month
Follow -up
VisitPotential COVID -19
Illness/MIS-C VisitaPotential
COVID -19/MIS -C
Convalescent Visit
Visit Window (Days) 175 to 189
Days After
Dose 219 to 23
Days
After Visit
A28 to 35 Days
After Visit B175 to 189
Days After
Visit B350 to 378
Days After
Visit B532to 560
Days After
Visit BOptimally Within 3
Days After Potential
COVID -19 Illness
Onset28 to 35 Days After
Potential COVID 19
Illness Visit
Type of Visit Clinic Clinic TelephonebTelephone Telephone Clinic or
TelephoneClinic or Telehealth Clinic
Confirm participant originally
received placeboX
For participants who are HIV-
positive, record latest CD4 count
and HIV viral loadX X X X X
Confirm use of contraceptives
(ifappropriate)X X X
Collect prohibited medication use X X X X X X X
Review and consider eligibility X X
Review temporary delay criteria X X
Measure vital signs (including
body temperature)X X
Perform targeted physical
examinationcX X
For participants who are HIV
positive, record latest CD4 count
and HIV viral loadX X X X X
Perform urine pregnancy test (only
for female participants biologically
capable of having children)X X
Confirm use of contraceptives
(ifappropriate)X X X
Collect prohibited medication use X X X X X X X X
Obtain anterior nasal swab X X X
090177e197c0b08c\Approved\Approved On: 06-Aug-2021 19:39 (GMT)
FDA-CBER-2021-5683-1077108
PF-07302048 (BNT162 b2 RNA- Based COVID -19 Vaccine)
Protocol C4591007
Final Protocol Amendment 21, 05 March 06Aug 2021
PFIZER CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 47Visit Number A B C D E F Unplanned Unplanned
Visit Description Dose 3 Dose 4 1-Month
Follow -up
Visit6-Month
Follow -up
Visit12-Month
Follow -up
Visit18-Month
Follow -up
VisitPotential COVID -19
Illness/MIS-C VisitaPotential
COVID -19/MIS -C
Convalescent Visit
Visit Window (Days) 175 to 189
Days After
Dose 219 to 23
Days
After Visit
A28 to 35 Days
After Visit B175 to 189
Days After
Visit B350 to 378
Days After
Visit B532to 560
Days After
Visit BOptimally Within 3
Days After Potential
COVID -19 Illness
Onset28 to 35 Days After
Potential COVID 19
Illness Visit
Type of Visit Clinic Clinic TelephonebTelephone Telephone Clinic or
TelephoneClinic or Telehealth Clinic
Collect blood sample for
immunogenicityXd~5 mL
Review temporary delay criteria X X
Review and consider eligibility X X
Obtain vaccine vial allocation via
IRTX
Administer BNT162b2 X X
Assess acute reactions for at least
30 minutes after study intervention
administrationX X
Collect A Es as appropriatebe X X X X X
Collect SAEs as appropriatecfX X X X X X
Collect e -diary or assist the
participant’s parent(s)/legal
guardian to delete applicationX
090177e197c0b08c\Approved\Approved On: 06-Aug-2021 19:39 (GMT)
FDA-CBER-2021-5683-1077109
PF-07302048 (BNT162 b2 RNA- Based COVID -19 Vaccine)
Protocol C4591007
Final Protocol Amendment 21, 05 March 06Aug 2021
PFIZER CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (15 May 2020)
Page 48Visit Number A B C D E F Unplanned Unplanned
Visit Description Dose 3 Dose 4 1-Month
Follow -up
Visit6-Month
Follow -up
Visit12-Month
Follow -up
Visit18-Month
Follow -up
VisitPotential COVID -19
Illness/MIS-C VisitaPotential
COVID -19/MIS -C
Convalescent Visit
Visit Window (Days) 175 to 189
Days After
Dose 219 to 23
Days
After Visit
A28 to 35 Days
After Visit B175 to 189
Days After
Visit B350 to 378
Days After
Visit B532to 560
Days After
Visit BOptimally Within 3
Days After Potential
COVID -19 Illness
Onset28 to 35 Days After
Potential COVID 19
Illness Visit
Type of Visit Clinic Clinic TelephonebTelephone Telephone Clinic or
TelephoneClinic or Telehealth Clinic
Collection of COVID -19/MIS -C–
related clinical and laboratory
information (including local
diagnosis)X X
Abbreviation s: CRF = case report form; HIV = human immunodeficiency virus; IRT = interactive response technology; MIS-C = multisystem inflammatory syndrome in children ;
SMS = short message service .
a. Potential MIS -C visit: Hospitalization for a severe illness with no other alternative etiology .
b. Contact can be made via email or SMS. If no response is obtained or responses do not satisfy visit requirements, a telephone call should be made.
c. A physical examination will include, at a minimum, assessments of general appearance, lungs, cardiovascular system, and lymph node survey.
d. Blood draw is only for participants who become eligible for receipt of BNT162b2 or another COVID -19 vaccine according to local or national recommendations prior to
Visit 5.
e. Any A Es occurring up to 48 hours after blood draw and anterior nasal swab collection must be recorded (see Section 8.3.1 ). Note: Potential COVID- 19/MIS -C illnesses and
their sequ elae that are consistent with the clinical endpoint definition (Section 8.1) should not be recorded as AE s. These data will be captured to describe disease endpoints for
lack-of-efficacy assessment data only on the relevant pages of the CRF, as these are expected endpoints.
f. Refer to Section 8.3.1 forthetime period for collecting SAEs .
1.3.4. Phase 2/3 Lower -Dose Evaluation
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Page 49Visit Number 201 202 203 204
Visit Description Dose 1aDose 2 1-Month
Follow -up Visit6-Month
Follow -up Visit
Visit Window (Days) Day 1 19 to 23 Days After Visit 1 28 to 35 Days After Visit 2 175 to 189 Days After Visit
2
Type of Visit Clinic Clinic Clinic Clinic
Obtain informed consent and assent (if appropriate) X
Assign participant number X
Obtain demography and significant medical history data X
For participants who are HIV-positive, record latest CD4
count and HIV viral loadX X X
Confirm use of contraceptives (if appropriate) X X X
Collect nonstudy vaccine information X X X X
Collect prohibited medication use X X X
Confirm eligibility X X
Review temporary delay criteria X X
Measure vital signs (including body temperature) X X
Perform clinical assessmentbX X
Perform urine pregnancy test (only for female participants
biologically capable of having children)X X
Obtain randomization number and study intervention
allocationX
Obtain anterior nasal swab X X
Collect blood sample for immunogenicityc~20 mL/~10 mL /~5mL ~20 mL/~10 mL/~5 mL ~20 mL/~10 mL/~5 mL
Administer study intervention X X
Assess acute reactions for at least 30 minutes after study
intervention administrationX X
Explain communication methods (including for e -diary
completion), assist with downloading the app, or issue
provisioned device, if requiredX
Provide thermometer and c aliper (measuring) device X
Reactivate reactogenicity e-diary X
Ensure the participant or participant’s parent(s)/legal
guardian has a caliper device and thermometerX
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Page 50Visit Number 201 202 203 204
Visit Description Dose 1aDose 2 1-Month
Follow -up Visit6-Month
Follow -up Visit
Visit Window (Days) Day 1 19 to 23 Days After Visit 1 28 to 35 Days After Visit 2 175 to 189 Days After Visit
2
Type of Visit Clinic Clinic Clinic Clinic
Ask the participant or participant’s parent(s)/legal guardian
to complete e -diary and ensure the participant or
participant’s parent(s)/legal guardian remains comfortable
with chosen e -diary platform X X
Review reactogenicity e -diary data (daily review is optimal
during the active diary period)
Review ongoing reactogenicity e -diary symptoms and
obtain stop datesX X
Collect AEs as appropriatedX X X X
Collect SAEs as appropriateeX X X X
Collection of COVID -19/MIS -C–related clinical and
laboratory information (including local diagnosis)
Abbreviation s: CRF = case report form; HIV = human immunodeficiency virus .
a. This visit may be conducted across 2 consecutive dates; if so, please refer to Section 8.11.6.1 .
b. Including, if indicated, a physical examination.
c. 20 mL is to be collected from participants ≥16 years of age; 10 mL is to be collected from participants 12 to <16 years of age; 5 mL is to be collected from participants 5 to
<12 years of age .
d. Any AEs occurring up to 48 hours after blood draw and anterior nasal swab collection must be recorded (see Section 8.3.1 ).
e. Refer to Section 8.3.1 for the time period for c ollecting SAEs.
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Page 512.INTRODUCTION
The BNT162b2 RNA -based COVID -19 vaccine is being investigated for prevention of
COVID -19 in healthy children.
2.1.Study Rationale
The purpose of the dose-finding/selected -dose study is to rapidly describe the safet y,
tolerability ,immunogenicity , and efficacy (depending on accrual of sufficient cases) of the
BNT162b2 RNA -based COVID -19 vaccine candidate against COVID- 19 in healthy children.
There are currently no licensed vaccines to prevent infection with SARS -CoV -2or
development of COVID -19. Given the global crisis of COVID -19 and fast expansion of the
disease in the United States and elsewhere, the rapid development of an effe ctive vaccine is
of utmost importance.
With the robust immune responses elicited in adolescents with BNT162b2, t he purpose of the
lower -dose evaluation is to determine whether additional lower dose levels of BNT162b2
(3µg, 10 µg) will not only [to minimize reactogenicity and risk of other AEs but as well to
potentially unify the dose levels across children and y oung adults.
2.2.Background
In December 2019, a pneumonia outbreak of unknown cause occurred in Wuhan, China.
InJanuary 2020, it became clear that a novel coronavirus (2019- nCoV) was the underl ying
cause. Later in January , the genetic sequence of the 2019 -nCoV became available to the
WHO and public (MN908947.3), and the virus was categorized in the Betacoronavirus
subfamily . By sequence analysis, the phy logenetic tree revealed a closer relationship to
SARS virus isolates than to another coronavirus infecting humans, the MERS virus.1,2
SARS -CoV -2 infections and the resulting disease, COVID -19, have spread globall y,
affecting a growing numb er of infections in countries worldwide . Children have been
affected b y both the primary COVID -19 disease and the less common secondary
inflammatory complications, including MIS-C.3,4
On 11 March 2020, the WHO characterized the COVID -19 outbreak as a pandemic.5
TheWHO Weekly Epidemiology Update Report dated 27September 2020 noted more than
32.7 million COVID -19 cases and 991, 000 deaths globall y, including 16,233,110 confirmed
cases with 546,864 deaths in the Americas.6 COVID -19 is generally milder in children than
adults, possibly because common risk factors for severe COVID -19 in adults are generall y
less prevalent in pediatric age groups. Children present with fever and dry cough over half
the time and symptoms can include GIsymptoms, including diarrhea and vomiting, and in
some cases canbe the only presenting features. Pulmonary involvement in sy mptomatic
children is generally mild.7,8,9Nevertheless, severe cases, including those requiring intensive
care support, have bee n reported.3Of US children diagnosed with COVID -19,5.7% to 20%
were hospitalized , including 0.58% to 2.0% admitted to an I CU.10
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Page 52MIS-C, an emerging condition that appears to be temporally related to recent exposure to
SARS -CoV -2, has been described and frequentl y requires ICU admission, and may have a
fatal outcome.4,11MIS-C is a febrile hy perinflammatory condition with frequent evidence of
cardiac damage and dermatologic, mucocutaneous, and GI features .11The sy ndrome appears
to have some overlap with Kawasaki disease shock sy ndrome.12,13Compared with Kawasaki
disease, patients with MIS- C are older, have more cardiac injury , and are more likely to be
black, Hispanic, or of South Asian descent.14As of 29June 2020, approximately 1000 cases
have been reported.14As of 29 July 2020, a total of 570 cases were reported in the US to the
CDC. Of these, 86.0% involved 4or more organ sy stems, 63.9% of patients required ICU
admission, and severe complications included cardiac d ysfunction (40.6%), shock (35.4%),
myocarditis (22.8%), coronary artery dilation or aneury sm (18.6%), and acute kidney injury
(18.4%) .15Death rates of 2% to 4% have been reported.14MIS-C has been reported in many
countries throughout North America, Europe, Asia, and Latin America ,16including the
US,4,11Italy,17and France.18The United States currently has the most reported cases
globally,with the number of confirmed cases continu ingto rise globall y. There are currently
no licensed vaccines or effective antiviral drugs to prevent SARS -CoV -2 infections or the
disease it causes, COVID -19.19
A proph ylactic, RNA -based SARS -CoV -2 vaccine provides one of the most flexible and
fastest approaches available to immunize against the emerging virus.20,21
The development of an RNA -based vaccine encoding a viral antigen, which is then expressed
by the vaccine recipient as a protein capable of eliciting protective immune responses,
provides significant advantages over more traditional vaccine approaches. Unlike live
attenuated vaccines, RNA vaccines do not carry the risks associated with infection and may
be given to people who cannot be administered live virus (eg, pregnant women and
immunocompromised persons). RNA -based vaccines are manufactured via a cell- free in
vitro transcription process, which allows an eas y and rapid production and the prospect of
producing high numbers of vaccination doses within a shorter time period than achieved with
traditional vaccine approaches. This capability is pivotal to enable the most effective
response in outbreak scenarios.20,21
A Phase 1/2/3 study (C4591001 )is being conducted in healthy individuals 1 2years of age
and older to investigat e the safet y, tolerability , immunogenicit y,and efficacy of the
prophy lactic BNT162 vaccine candidates against COVID -19. The vaccine candidate
selected for evaluation in the C4591001 Phase 2/3 study is BNT162b2 at a dose level of
30µg and as 2 doses given approximately 21 days apart. On 18 November 2020, the primary
efficacy anal ysis results were announced, which demonstrate dBNT162b2 to be 95%
effective against COVID -19 beginning 28 7 day s after the first second dose; 170 confirmed
cases of CO VID-19 were evaluated, with 162 observed in the placebo group versus 8 in the
vaccine group .Safet y data from approximately 38,000 participants randomized 1:1 with a
median of 2 months of follow -up after the second dose of vaccine showed a favorable safety
profile at a dose of 30 μg in participants 16 y ears of age and older .22On 11 December 2020,
the US FDA issued an EUA for use in individuals 16 y ears of age and older. Other countries
have also granted EUA (eg, Canada, Mexico, Bahrain), and Pfizer and Bio NTech are
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Page 53anticipating further regulatory decisions in other countries .23On 10 May 2021, the US FDA
issued an EUA for use in individuals 12 to 15 y ears of age. Other countries have also granted
EUA or other authorization/approval for this age group (eg, EMA, UK, Switzerland, andthe
Philippines).
This Phase 1/2/3 study (C4591007) will initially evaluate up to 3 different dose levels of
BNT162b2 in children in up to 3 age groups ( participants ≥5 to <12 y ears, ≥2 to <5 y ears,
and ≥6months to <2 years of age). S afety, tolerability , immunogenicit y,and efficacy
(depending on successful immunobridging and accrual of a sufficient number of cases ) will
be evaluated .Phase 1 includes the dose -finding portion . Initiation of dose finding in
participants ≥5 to < 12years of age will be based on the acceptable blinded safet y data
demonstrated in 226059 12 -through 15-year-oldsat the 30-µ g dose level in the C4591001
study .24The Phase 2/3 BNT162b2 dose level to be used in each age group in this study will
be selected based on the Phase 1 safet y, tolerability, and immunogenicit y data from the same
age group . Phase 2/3 (referred to as the selected- dose portion of the study )includes an
immunobridging anal ysisofimmune responses in participants ≥6 month sto <12 years of age
to those in participants 16to 25 y ears of age in the Phase 3 C45 91001 efficacy study . Safety ,
tolerability ,and efficacy (depending on successful immunobridging and accrual of a
sufficient number of cases) will also be evaluated in Phase 2/3 of this study .
The authorized dose of BNT162b2 in adolescents and y oung adults 12 y ears and older is
30µg,whereas in the Phase 2/3 portion of the ongoing C4591007 study the following doses
were selected: 10 µgin participants 5 to <12 years of ageand 3 µg in participants 6 months
to <5 y earsof age . With the robust immune responses elicited in adolescents to minimize
reactogenicity and the risk of other AEs and to potentially unify the dose levels across
children and young adults, additional lower dose levels of BNT162b2 (3 µg, 10 µg) will be
evaluated to determine whether similar immune responses are elicited. For this lower -dose
evaluation portion, a new co hort of Phase 1 participants will be enrolled in 3 age groups: >5
to <12, 12 to <16, 16 to <30 years of age to assess safet y, tolerabilit y, and immunogenicit y.
The Phase 2/3 BNT162b2 dose level will be selected based on the Phase 1 assessments with
an immu nobridging analysis of immune responses in participants within each age group to
participants in the 30 -µgPhase 3 C4591001 efficacy study .
2.2.1. Clinical Overview
The BNT162 vaccine candidates use an RNA to deliver genetic information to cells, where it
is use d to express proteins for the therapeutic effect. This vaccine is for the prevention of
COVID -19. Prior to this study , clinical data from the BNT162b2 vaccine established a
favorable safety profile ,with mild, localized, and transient effects. The C4591001 study25is
currentl y in Phase 3, which includes >40,000 individuals in the US and other countries ,of
whom >21,000 participants have now been administered BNT162b2 at the 30 -µg dose level
ona 2-dose schedule .26Vaccine -related enhanced disease for vaccines against related
coronaviruses (SARS -CoV -1 and MERS) has been reported onl y in animal models.27,28To
date, no enhanced disease has been observed in SARS -CoV -2 animal models with any
SARS -CoV -2 vaccine platform, including RNA -based vaccines. Such effects have not been
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Page 54documented so far for SARS -CoV -2.The currently available safet y and immunogenicit y
data are presented in the BNT162 IB.
2.3.Benefit/Risk Assessment
There is an ongoing global pandemic of COVID -19 with no approved or licensed preventive
options available. However, based on the data available from the C4591001 study , multiple
temporary or emer gency use authorizations have been granted. The available safet y and
immunogenicit y data from the ongoing Pfizer/BioNTech clinical trial combined with
available nonclinical data with BNT162 vaccines, and data from nonclinical studies and
clinical trials w ith the same or related RNA components, or antigens, support a favorable
benefit/risk profile and support continued clinical development of BNT162b2.
In the C4591001 stud y, BNT162b2 has been shown to elicit increased local and systemic
adverse reactions a s compared to those in the placebo arm, usuall y lasting a few days. The
most common solicited adverse reactions were injection site reactions (84.1%), fatigue
(62.9%), headache (55.1%), muscle pain (38.3%), chills (31.9%), joint pain (23.6%), and
fever (14.2%). Adverse reactions characterized as reactogenicity were generally mild to
moderate. The number of participants reporting hy persensitivity -related AE s was
numericall y higher in the active vaccine group compared with the placebo group
(137 [0.63%] vs 111 [0.51%]). Severe adverse reactions occurred in 0.0% to 4.6% of
participants, were more frequent after Dose 2 than after Dose 1, and were generall y less
frequent in older adults (>55 years of age) (<2.8%) as compared to y ounger participants
(≤4.6%). Among reported unsolicited A Es, lymphadenopathy occurred much more
frequentl y in the active vaccine group than the placebo group and is plausibly related to
vaccination. SAEs, while uncommon (<1.0%), represented medical events that occur in the
general population at similar frequency as observed in the study .22
No specific safet y concerns were identified in subgroup anal yses by age, race, ethnicit y,
medical comorbidities, or prior SARS CoV 2 infection. Although participants 16 through
17years of ag e were enrolled in the Phase 3 trial, safet y data for this age group are limited.
However, available data are consistent with the safety profile in the adult population, and it is
biologicall y reasonable to extrapolate the greater safet y experience in adu lts, in particular
younger adults, to the oldest pediatric age group of 16 through 17 years. The potential risks
are based on the observed safet y profile to date, which shows mostly mild reactogenicity , low
incidence of severe or serious events, and no cl inically concerning safet y observations. The
preponderance of severe cases of COVID 19 in the placebo group relative to the BNT162b2
group (9 of 10) suggests no evidence of VAED.22
In order for the stud y population to be as representative and diverse as possible, the inclusion
of participants with known chronic stable HIV, HCV, or HBV is permitted in Phase 2/3.
Individuals with chronic viral diseases are at increased risk for COVID 19 complications and
severe disease. In addition, with the currently available therapies for their treatment, man y
individuals with chronic stable HIV, HCV, orHBV infections are less likely to be at
increased safety risk as a participant in this vaccine study than individuals with other chronic
stable medical conditions.
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Page 55More detailed information about the known and expected benefits and risks and reasonabl y
expected AEs of BNT162 b2RNA based COVID 19 vaccine may be found in the IB, which
is the SRSD for this study.
No specific safet y concerns were identified in subgroup anal yses by age, race, ethnicit y,
medical comorbidities, or prior SARS -CoV -2 infection. The risks are based on the observed
safet y profile to date, which shows mostly mild reactogenicit y, low incidence of severe or
serious events, and no clinically concerning safet y observations. The preponderance of
severe cases of COVID -19 in the placebo group relative to the BNT162 b2 group (9 of 10)
suggests no evidence of VAED. Continued clinical investigation is justified given the:
Urgent need for the development of a more stable prophy lactic vaccine for COVID -19;
Threat posed b y the increasing number of globally distributed outbreaks of SARS -CoV -2
infection ;
Potential of the BioNTech platform of RNA -based vaccines to rapidly deliver high
numbers of vaccine doses in a single production campaign.
More detailed information about the known and expected benefits and risks and reasonabl y
expected AEs of BNT162b2 may be found in the IB, which is the SRSD for this study .
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Page 562.3.1. Risk Assessment
Potential Risk of Clinical Significance Summary of Dat a/Rationale for Risk Mitigation Strategy
Study Intervention(s) [ BNT162b2 RNA- Based COVID-19 Vaccine]
Potential for greater local reactions (injection site
redness, injection site swelling, and injection site
pain) and systemic events (fever, fatigue, headache,
chills, vomiting, diarrhea, muscle pain, and joint
pain) following vaccination as compared to
adults /adolescents in the C4591001 study .
Local and systemic reactions to the vaccine may
occur (injection site redness, injection site swelling,
and injection site pain, fever, fatigue, headache,
chills, muscle pain, and joint pain) following
vaccination.These are common adver se reactions seen with
other vaccines, as noted in the FDA CBER
guidelines on toxicity grading scales for healthy
adult and adolescent volunteers in preventive
vaccine clinical trials .29The most common events
reported in C4591001 w ere mild to moderate pain
at the injection site, fatigue, and headache.22
These are common adverse reactions seen with
other vaccines as well as the COVID -19 vaccine.
The most comm on events reported in the
C4591001 study were mild to moderate pain at the
injection site, fatigue ,and headache.To address reactogenicity concerns, dose finding
has been included as outlined. In addition, the study
employs the use of a reactogenicity e diary to
monitor local reactions and systemic events in real
time. All study participants will be observed for at
least 30 minutes after vaccination.
The study employs the use of a reactogenicit y
e-diary to monitor local reactions and systemic
events in real time.
All study participants will be observed for at
least 30 minutes after vaccination.
The s afety profile of a novel vaccine is not yet fully
characterized.
Adverse reactions (risks) identified from the
postauthorization safety data include: Anaphylaxis,
other hypersensitivity reactions (eg ,rash, pruritus,
urticaria, angioedema), and pain in extremity
(injected arm) .Data available from the C4591001 study showed
low incidence of severe or serious events, and no
clinically concerning safety observations across
the safety population and within demographic
subgroups based on age, sex, race/ethnicity,
country, and baseline SARS -CoV -2 status.
Postauthorization safety data surveillance has
confirmed the safety profile observed in the
C4591001 study and has resulted in identification
of some additional adverse reactions (risks) as
noted in this table.AE and SAE reports will be collected from the
signing of the ICD to 1 month after the second
dose of vaccine.
DMC willreview all safety data throughout the
study .
All participants will be observed for at least 30
minutes after vaccination.
Unknown A Es with a novel vaccine in children
≥6months to<12years of age .Data available from the C4591001 study showed
low incidence of severe or serious events, and no
clinically concerning safety observations. The
vaccine appears to be safe and w ell-tolerated
across the safety population and within The current Phase 3 C4591001 study include s
participants 12years of age and older .
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Page 57Potential Risk of Clinical Significance Summary of Dat a/Rationale for Risk Mitigation Strategy
demographic subgroups based on age, sex,
race/ethnicity, country, and baseline SARS -CoV -2
status.
Potential for COVID -19 enhancement. Disease enhancement has been seen following
vaccination with RSV, feline coronavirus, and
Dengue virus vaccines.
Disease enhancement has been seen following
RSV, feline coronavirus, and dengue virus
vaccin ations . No evidence of disease enhancement
has been seen in a large -scale clinical study of
BNT162b2 in humans or in postauthorization
surveillance.No evidence of disease enhancement has been
reported in the C4591001 study to date.26
Temporary delay criter ia defer vaccination of
participants with symptoms of potential
COVID -19. All participants , with the exception
of Phase 2/3 lower-dose evaluation
participants, are followed for any potential
COVID -19 illness, including markers of
severity , and have blood samples taken for
potential measurement of SARS -CoV -2
neutralizing titers.
For Phase 1/2/3 low er-dose evaluation
participants ,cases of COVID -19 developing
during the study are m onitored and will be
reported as AESIs.
MIS-C. Febrile hyperinflammatory condition with
multisystem (≥2)organ involvement as defined in
Section 8.1.MIS-C will be prospectively collected as a potential
for COVID -19/MIS -Cillness visit sfor the duration
of study participation.
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Study Procedures
Participants will be required to attend healthcare
facilities during the global SARS -CoV -2 pandemic.Without appropriate social distancing and PPE,
there is a potential for increased exposure to
SARS -CoV- 2.Pfizer w ill work with sites to ensure an appropriate
COVID -19 prevention strategy. Poten tial
COVID -19/MIS -Cillness visits can be conducted
via telehealth, without the need for an in -person
visit, if required, with the participant ’s
parent(s)/legal guardian performing a n anterior
nasal swab for the participant .
Venipuncture will be performed during the study. There is the risk of bleeding, bruising, hematoma
formation, and infection at the venipuncture site.Only appropriately qualified personnel w illobtain
the blood draw .To m inimize the total amount of
blood drawn, all participants in Phase 1 and
participants contributing to the immunogenicity
analysis in Phase 2/3 will have at most 3 planned
blood draws ,with all remaining participants having
2planned blood draw s.
Very rare cases of anaphylaxis, myocarditis ,and
pericarditis have been reported after authorization in
recipients of BNT162b2 .Anaphylaxis: The estimated rate is 5.0 per million
doses administered .
Myocarditis and pericarditis: Very rare cases of
myocarditis and pericarditis have been reported
following vaccination with mRNA COVID -19
vaccines. Typically, the cases have occurred more
often in younger men and after the second dose of
the vaccine and w ithin 14 days after vaccination.
These are generally mild cases and individuals tend
to recover wi thin a short time following standard
treatment and rest. Healthcare professionals should
be alert to the signs and symptoms of myocarditis
and pericarditis in vaccine recipients.Specific reference to these risks ismade within the
ICD, with instruction to contact a healthcare
professional if a case issuspected .
For anaphylaxis, there is an on-sitefor a 30-minute
observation period after vaccination .
Instruction s forhandling suspected cases of
myocarditis and pericarditis are found in Section
8.14.
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Page 592.3.2. Benefit Assessment
Benefits to individual participants may include:
Receipt of a n efficacious COVID-19 vaccine during a global pandemic
Access to COVID -19 diagnostic testing
Contributing to research to help others in a time of global pandemic
2.3.3. Overall Benefit /Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in this
study , the potential risks identified in association with BNT162b2 RNA -based COVID -19
vaccine are justified b y the anticipated benefits that may be afforded to healthy participants.
3.OBJECTIVES, ESTIMAND S, AND ENDPOINTS
The age groups referred to in the objectives and estimands below are participants ≥5 to
<12years, ≥2 to <5 y ears, and ≥ 6months to <2 years of age .The dose-finding/selected -dose
age groups referred to in the objectives and estimands below are participants ≥5 to <12 years,
≥2 to <5 y ears, and ≥ 6months to <2 years of age .
The lower -dose age groups referred to in the objectives and estimands below are a separate
cohort of participants ≥5to <12 years, 12 to <16 years, and 16 to < 30 years of age.
3.1.Phase 1
Phase 1
Objectives Estimands Endpoints
Primary: Primary: Primary:
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Page 60Phase 1
Objectives Estimands Endpoints
To describe the safety and tolerability
profiles of prophylactic BNT162b2 at
each dose level in each age group.In participants receiving at least 1 dose
of study intervention, the percentage of
participants in each age group
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
Dose 2
SAEs from Dose 1 to 6 months
after Dose 2Participants 16 to <30, 12 to <16, ≥5 to
<12years ,and ≥ 2 to <5 years of age:
Local reactions (pain at the
injection site, redness, and
swelling)
Systemic events (fever, fatigue,
headache, chills, vomiting,
diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)
AEs
SAEs
Participants ≥6months to <2 years of
age:
Local reactions ( tenderness at the
injection site, redness, and
swelling)
Systemic events (fever, decreased
appet ite, drowsiness, and
irritability )
AEs
SAEs
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Page 61Phase 1
Objectives Estimands Endpoints
Secondary: Secondary: Secondary:
To describe the immune responses
elicited by prophylactic BNT162b2 at
each dose level in each age groupIn participants complying with the key
protocol criteria (evaluable
participants) in each age group :
At baseline , before Dose 2, and 7 days
after Dose 2,
GMTs at each time point 7 days
after Dose 2
GMFR from before Dose 1
(baseline) to each subsequent time
point after vaccination SARS -CoV -2 neutralizing titers
Exploratory: Exploratory: Exploratory:
To describe COVID -19 and severe
COVID -19 cases with and without
serological or virological evidence of
past SARS -CoV -2 infection Confirmed COVID-19 cases
Confirmed severe COVID -19
cases
To describe MIS -C cases with and
without evidence of past SARS-CoV -2
infection Confirmed cases as per CDC
criteria
3.2.Phase 2/3
Phase 2/3
Objectives Estimands Endpoints
Primary Safety: Primary Safety: Primary Safety:
To define the safety profile of
prophylactic BNT162b2 at the selected
dose level in participants included in
the Phase 2/3 immunobridging analysis
in each age groupIn participants receiving at least 1 dose
of study intervention ,from each
vaccine group, the percentage of
participants in each age group
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
Dose 2
SAEs from Dose 1 to 1 month
after Dose 2Participants ≥5 to <12 years and ≥2 to
<5 years of age:
Local reactions (pain at the
injection site, redness, and
swelling)
Systemic events (fever, fatigue,
headache, chills, vomiting,
diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)
AEs
SAEs
Participants ≥6 months to <2 years of
age:
Local reactions ( tenderness at the
injection site, redness, and
swelling)
Systemic events (fever, decreased
appetite, drowsiness, and
irritability )
AEs
SAEs
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Page 62Phase 2/3
Objectives Estimands Endpoints
To define the safety profile of
prophylactic BNT162b2 at the selected
dose level in all participants
randomized in Phase 2/3 in each age
groupIn participants receiving at least 1 dose
of study intervention from each vaccine
group, the percentage of partic ipants in
each age group 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
Dose 2
SAEs from Dose 1 to 6 months
after Dose 2Participants 16 to <30, 12 to <16, ≥5 to
<12,years and ≥ 2 to <5 years of age:
Local reactions (pain at the
injection site, redness, and
swelling)
Systemic events (fever, fatigue,
headache, chills, vomiting,
diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)
AEs
SAEs
Participants ≥6 months to <2 years of
age:
Local reactions ( tenderness at the
injection site, redness, and
swelling)
Systemic events (fever, decreased
appetite, drowsiness, and
irritability )
AEs
SAEs
Primary Immunogenicity (Selected -
Dose) : Primary Immunogenicity (Selected -
Dose) :Primary Immunogenicity (Selected -
Dose) :
To immunobridge the immune
response elicited by prophylactic
BNT162b2 between Phase 2/3
participants at the dose selected in each
age group and participants 16 to 25
years of age from the C4591001 study
without serological or virological
evidence (up to 1 month after receipt of
Dose 2) of past SARS -CoV -2
infection To demonstrate
immunobridging of the immune
response elicited by
prophylactic BNT162b2 at the dose
level selected in eachper age group
inPhase 2/3 participants without
serological or virological evidence (up
to 1 month after receipt of Dose 2) of
past SARS -CoV -2 infection :In participants complying with the key
protocol criteria (evaluable
participants) and no serological or
virological evidence (up to 1 month
after receipt of Dose 2) of past
SARS -CoV -2 infection: SARS -CoV -2 neutralizing titers
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Objectives Estimands Endpoints
In participants ≥5 to <12 years of
age compared to participants 1 6to
25years of age from Phase 2/3 of
theC4591001 study GMR, estimated by the ratio of the
geometric mean of SARS -CoV -2
neutralizing titers in participants
≥5 to <12 years of age to those in
participants 16-25 years of age 1
month after Dose 2 from Phase 2/3
of the C4591001 study
The difference in percentages of
participants with seroresponseain
participants ≥5 to <12 years of age
and participants 16 to 25 years of
age from Phase 2/3 of the
C4591001 study
In participants ≥2 to <5 years of
age compared to participants 16 to
25years of age from Phase 2/3 of
theC4591001 study GMR, estimated by the ratio of the
geometric mean of SARS -CoV -2
neutralizing titers in participants
≥2 to <5 years of age to those in
participants 16 to 25 years of age 1
month after Dose 2 from Phase 2/3
of the C4591001 study
The difference in percentages of
participants with seroresponse in
participants ≥2 to <5 years of age
and participants 16 to 25years of
age from Phase 2/3 of the
C4591001 study
In participants ≥6 months to
<2years of age compared to
participants 16 to 25 years of
agefrom Phase 2/3 of
theC4591001 study GMR, estimated by the ratio of the
geometric mean of SARS -CoV -2
neutralizing titers in participants
≥6 months to <2 years of age to
those in participants 16 to 25 years
of age 1 month after Dose 2 from
Phase 2/3 of the C4591001 study
The difference in percentages of
participants with seroresponse in
participants ≥6 months to <2 years
of age and participants 16 to 25
years of age from Phase 2/3 of the
C4591001
Secondary Immunogenicity (Lower -
Dose Evaluation):Secondary Immunogenicity (Lower -
Dose Evaluation):Secondary Immunogenicity (Lower -
Dose Evaluation):
To immunobridge the immune
response elicited by prophylactic
BNT162b2 between Phase 2/3
participants at the lower dose level
selected in each age group and
participants 16 to 25 years of age from
the C4591001 study without
serological or virological evidence (up
to 1 month after receipt of Dose 2) of
past SARS -CoV -2 infecti on:In participants complying with the key
protocol criteria (evaluable
participants) and no serological or
virological evidence (up to 1 month
after receipt of Dose 2) of past
SARS -CoV -2 infection: SARS -CoV -2 neutralizing titers
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Objectives Estimands Endpoints
In participants ≥5 to <12 year s of
age compared to participants 16 to
25years of age from Phase 2/3 of
theC4591001 study GMR, estimated by the ratio of the
geometric mean of SARS -CoV -2
neutralizing titers in participants
≥5 to <12 years of age to those in
participants 16 to 25years of age 1
month after Dose 2 from Phase 2/3
of the C4591001 study
The difference in percentages of
participants with seroresponse in
participants ≥5 to <12 years of age
and participants 16 to 25 years of
age from Phase 2/3 of the
C4591001 study
In participants 12to <16 years of
age compared to participants 16 to
25years of age from Phase 2/3 of
theC4591001 study GMR, estimated by the ratio of the
geometric mean of SARS -CoV -2
neutralizing titers in participants
12 to <16 years of age to those i n
participants 16 to 25 y ears of age 1
month after Dose 2 from Phase 2/3
of the C4591001 study
The difference in percentages of
participants with seroresponse in
participants 12 to <16years of age
and participants 16 to 25 years of
age from Phase 2/3 of the
C4591001 study
In participants 16 to <30 years of
age compared to participants 16 to
55years of age from Phase 2/3 of
theC4591001 study GMR, estimated by the ratio of the
geometric mean of SARS -CoV -2
neutralizing titers in participants
16 to <30 years of age to those in
participants 16 to 55 years of age 1
month after Dose 2 from Phase 2/3
of the C4591001 study
The difference in percentages of
participants with seroresponse in
participants 16 to < 30years of age
and 16 to 55 years of age from
Phas e 2/3 of the C4591001 study
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Objectives Estimands Endpoints
Secondary Immunogenicity/Efficacy: Secondary Immunogenicity/Efficacy: Secondary Immunogenicity/Efficacy:
To describe the immune responses
elicited by prophylactic BNT162b2 at
the dose level selected in each perage
group and persistence of immune
response in Phase 2/3 participants
without serological or virological
evidence of past SARS -CoV -2
infectionIn evaluable participants with no
serological or virological evidence of
past SARS -CoV -2 infection from each
vaccine and age group:
At baseline (before Dose 1) and 1, 6, 12
(for the original BNT162b2 group
only), and 24 (for the original
BNT162b2 group only) months after
Dose 2,
GMTs at each time point
GMFRs from before Dose 1 to
each subsequent time point after
Dose 2 SAR S-CoV -2 neutralizing titers
In all age groups where
immunobridging is successful, if at
least 22 cases are accrued across those
age groups:
To evaluate the efficacy of prophylactic
BNT162b2 against confirmed
COVID -19 occurring from 7 days after
Dose 2 during the blinded follow -up
period in participants in the selected -
dose portion of the study without
evidence of past SARS -CoV -2
infection In participants complying with the key
protocol criteria (evaluable
participants) and with no serological or
virological evidence (prior to 7 days
after receipt of Dose 2) of past
SARS -CoV -2 infection:
100 × (1 IRR) [ratio of active vaccine
to placebo] Confirmed COVID-19 incidence
from 7 days after Dose 2 per 1000
person -years of blinded follow -up
Confirmed COVID 19 incidence
from 7 days after Dose 2 per 1000
person years of follow up
Incidence of asymptomatic
infection of SARS CoV 2 based
on N binding antibody
seroconversion
In the ≥5 to <12 years age group
in the selected -dose portion of the
study, if immunobridging is
successful and if at least 22 cases
are accrued In all age groups
where immunobridging is
successful, if at least 22 cases
are accrued across those age
groups:
To evaluate the efficacy of
prophylactic BNT162b2
against co nfirmed COVID 19
occurring from 7 days after
Dose 2 in participants with or
without evidence of past
SARS CoV 2 infection In participants complying with
the key protocol criteria
(evaluable participants) and
with or without serological or
virological evid ence (prior to 7
days after receipt of Dose 2) of
past SARS CoV 2 infection:
100 × (1 –IRR) [ratio of active
vaccine to placebo]
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Page 66Phase 2/3
Objectives Estimands Endpoints
In the ≥6 months to <2 years and
≥2 to <5 years age groups in the
selected -dose portion of the study
where immunobridging is
successful, if at least 22 cases are
accrued across those age groups
To describe the efficacy of
prophylactic BNT162b2
against asymptomatic infection
in participants without
evidence of past SARS CoV 2
infection
In ev aluable participants
without serological or
virological evidence of past
SARS CoV 2 infection from
each vaccine group:
100 × (1 –IRR) [ratio of active
vaccine to placebo]
In all age groups in the selected-
dose portion of the study where
immunobridging is successful, if
at least 22 cases are accrued across
those age groups and if the above
2individual age groups ( ≥5 to <12
years, ≥6 months to <2 years and
≥2 to <5 years combined) did not
accrue 22 cases100 × (1 –IRR) [ra tio of active
vaccine to placebo]
To evaluate the efficacy of prophylactic
BNT162b2 against confirmed
COVID -19 occurring from 7 days after
Dose 2 during the blinded follow -up
period in participants in the selected -
dose portion of the study with or
withou t evidence of past SARS -CoV -2
infection In participants complying with the key
protocol criteria (evaluable
participants) and with o r without
serological or virological evidence
(prior to 7 days after receipt of Dose 2)
of past SARS -CoV -2 infection: Confirmed COVID-19 incidence
from 7 days after Dose 2 per 1000
person -years of blinded follow -up
In ≥5 to <12 years age group in
the selected -dose portion of the
study, if immunobridging is
successful and if at least 22 cases
are accrued 100 × (1 – IRR) [ratio of active
vaccine to placebo]
In ≥6 months to <2 years and ≥2
to <5 years age groups in the
selected -dose portion of the study
where immunobridging is
successful, if at least 22 cases are
accrued across those age groups 100 × (1 –IRR) [ratio of active
vaccine to placebo]
In all age groups in the selected-
dose portion of the study where
immunobridging is successful, if
at least 22 cases are accrued across
those age groups and if the above
two individual age groups ( ≥5 to
<12 years of age, ≥6 mon ths to
<2years and ≥2 to <5 years
combined) did not accrue 22 cases 100 × (1 –IRR) [ratio of active
vaccine to placebo]
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Page 67Phase 2/3
Objectives Estimands Endpoints
To describe the efficacy of prophylactic
BNT162b2 against asymptomatic
infection in participants in the selected -
dose portion of the study without
evidence of past SARS -CoV -2
infectionIn evaluable participants without
serological or virological evidence of
past SARS -CoV -2 infection from each
vaccine group:
100 × (1 –IRR) [ratio of active vaccine
to placebo]Incidence of asymptomatic infection of
SARS -CoV -2 based on N -binding
antibody seroconversion
Exploratory: Exploratory: Exploratory:
To describe the efficacy of prophylactic
BNT162b2 against confirmed
COVID -19 occurring from 7 days after
Dose 2 through the blinded follow-up
period in participants in the selected -
dose portion of the study without, and
with and without, evidence of past
SARS CoV -2 infection in each age
group and in all age groups combinedIn pa rticipants complying with the key
protocol criteria (evaluable
participants) 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 blinded
follow -up based o n central
laboratory or locally confirmed
NAAT
To evaluate the immune response over
time to prophylactic BNT162b2 at the
dose level selected in each perage
group and persistence of immune
response in Phase 2/3 participants with
and without serological or virological
evidence of past SARS -CoV -2
infectionIn evaluable participants with or
without serological or virological
evidence of past SARS -CoV -2
infection from each vaccine group:
At baseline and at 1, 6, 12 (for the
original BNT162b2 group only), and 2 4
(for the original BNT162b2 group
only) months after Dose 2,
GMCs and/or GMTs at each time
point
GMFRs from before Dose 1 to
each subsequent time point after
Dose 2 Full-length S -binding IgG levels
and/or SARS -CoV -2 neutralizing
titers
To evaluate the immune response
(non S) to SARS CoV 2 in Phase 2/3
participants with and without
confirmed COVID 19 during the study N-binding antibody
To describe COVID -19 and severe
COVID -19 cases in participants in the
selected -dose portion of the study with
and without serological or virological
evidence of past SARS -CoV -2
infection Confirmed COVID-19 cases
Confirmed COVID-19 cases
resulting in hospitalization
Confirmed severe COVID -19
cases
To describe MIS -C cases with and
without evidence of past SARS-CoV -2
infection in participants in the selected -
dose portion of the study Confirmed cases as per CDC
criteria
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Page 68Phase 2/3
Objectives Estimands Endpoints
To describe the serological responses in
Phase 2/3 participants in participants in
the selected -dose portion of the study
to BNT162b2 at the dose level selected
in each perage group in cases of:
Confirmed COVID-19
Confirmed severe COVID -19
SARS -CoV -2 infection without
confirmed COVID -19 SARS -CoV -2 neutralizing titers
To describe the safety and
immunogenicity of prophylactic
BNT162b2 at the dose level selected in
eachperage group in children with
stable HIV disease All safety and immunogenicity
endpoints described above will be
analyzed descriptively
To describe the cell-mediated immune
response, and additional humoral
immune response parameters, to the
reference strain in a subset of
participants:
At baseline and at 7 days and 1
and 6 months after Dose 2
a. Seroresponse is defined as achieving a ≥4 -fold rise from baseline (before Dose 1). If the baseline measurement is below
the LLOQ, the postvaccination measure of ≥ 4 ×LLOQ is considered seroresponse.
4.STUDY DESIGN
4.1.Overall Design
This is a Phase 1/2/3 study in healthy children and y oung adults.
Dependent upon safet y and/or immunogenicit y data generated during the course of this
study , and the resulting assessment of benefit -risk, the safet y, tolerability , and
immunogenicit y of BNT162b2 in participants <6 months of age may subsequently be
evaluated. Participants will r ange from ≥6 months to <30 y ears of a gewith different dose
levels assessed in each group .
Table 1.Dose Levels for Each Age Group in the Phase 1 and Phase 2/3 Dose -
Finding/Selected -Dose and Lower -Dose Evaluations
Phase 1 Open -Label Dose -Finding Evaluation
≥6 Months
to <2 Years≥2 to <5
Years≥5 to <12
Years12 to <16
Years16 to <30
YearsTotal
Dose level 3µg 3/10 µg 10/20/30 µg
Participant s 16a16/32a16/16/16b112
Phase 2/3 Observer- Blinded, Placebo -Controlled Selected -Dose Evaluation
Dose level 3 µg 3 µg 10µg
Participant s 1125
(active 750;
placebo 375)1125
(active 750;
placebo 375)4500
(active 3000;
placebo
1500)6750
Phase 1 Open -Label Lower -Dose Evaluation
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Page 69Planned
dose level (s) 3 µg 3/10 µgc3/10 µgc
Participant s 32 32/32 32/32 160
Phase 2/3 Open -Label Lower -Dose Evaluation
Planned
dose level TBD TBD TBD
Participant s 300 300 300 900
a.Actual number of participants recruited in the ≥6 months to <2 y ears and ≥2 to <5 yearsage groups .
b.Actual number of participants recruited inthe≥5 to <12 years age group . Dose 1: 16 out of 16 received
30-µgdose level ; Dose 2: 4out of 16 received 30 -µgdose level and 12 of 16 received 10-µgdose level .
c.Both dose levels will start concurrently .
4.1.1. Phase 1
Dose -finding: Phase 1 Iis the open- label dose -finding portion of the study to that will
evaluate safet y, tolerability , and immunogenicit y of BNT162b2 administered on a 2-dose
(separated b y approximately 21 days) schedule in up to 3 age groups ( participants ≥5 to <12
years, ≥2 to <5 years, and ≥6 months to <2 years of age).
Dosefinding is being initiated in this study in particip ants ≥5 to <12 y ears of age based on
the acceptable blinded safety assessment of the 30-µ g dose in 12 -to 15-year-olds in the
C4591001 study .
The purpose of P hase 1 is to identify preferred dose level(s) of BNT162b2 from up to 3
different dose levels in each age group.
Dependent upon safet y and/or immunogenicit y data generated during the course of this
study , it is possible that dose levels may not be started, may be terminated early , and/or may
beadded with dose levels below the lowest stated dose.
Participants will have blood drawn prior to both Dose 1 and Dose 2 and 7 day s after Dose 2
to assess for immunogenicity to determine the final BNT162b2 dose level for the Phase 2/3.
Lower -doseevaluation :Is the open- label lower -dose evaluation portion of the study that
willevaluate safet y, tolera bility , and immunogenicity of BNT162b2 on a 2-dose (separated
by approximately 21 days) schedule in up to 3 age groups ( participants ≥5 to <12 y ears, 12 to
<16 y ears, and 16 to <30years of age) .
The purpose of the Phase 1 lower -dose evaluation is to evaluate safety and immunogenicit y
of BNT162b2 from up to 2different dose levels in each age group.
Participants will have blood drawn prior to both Dose 1 and Dose 2 and 7 day s after Dose 2
to assess immunogenicity to determine the selected BNT162b2 dose level for the Phase 2/3
lower -dose evaluation portion of the study .
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Page 704.1.2. Phase 2/3
Selected -dose: Phase 2/3 Is the portion of the study that will evaluate safety , tolerability , and
immunogenicit y in each age group at the selected dose level from the Phase 1 dose-finding
portion of the study . Efficacy will be evaluated across all within or across age groups in
which immunobridging is successful, depending on accrual of a sufficient number of cases
across in those age groups.
All pParticipants will have blood drawn at baseline prior to Dose 1 and 6 months after Dose
2. Immunobridging to participants 1 6to 25 years of age in the C4591001 study will be based
on immunogenicit y data collected at baseline and 1 month after Dose 2. The p ersistence of
the immune response will be based on immunogenicity data collected in participants at
baseline and at 1, 6, 12 (original BNT162b2 group only ),and24 month safter Dose 2
(original BNT162b2 group only ). In addition, efficacy against confirmed COVID -19 and
against as ymptomatic infection will also be assessed.
At designated US sites, an additional optional whole blood sample of approximately 10 mL
will be obtained prior to Dose 1 and at 7 day s and 6 months after Dose 2 from up to
approximately 60 participants ≥10 years of age. These samples will be used on an
exploratory basis to investigate the postvaccination cell -mediated immune response at these
time points.
At a 6-month follow -up visit, all participants will be unblinded. Participants who originall y
received placebo will be offered the opportunit y to receive BNT162b2 as part of the stud y.
Participants ≥12years of age who originall y received placebo and become eligible for receipt
of BNT162b2 according to recommendations (detailed separatel y, and available in the
electronic stud y reference portal )will have the opportunity to receive BNT162b2.
Lower -dose evaluation :Is the portion of the study that will evaluate the safety , tolerability ,
and immunogenicit y in each age group at the selected dose level from the Phase 1 lower -dose
evaluation .
In this open -label stud y, all participants will have blood drawn at baseline prior to Dose 1
and at 1 and 6 months after Dose 2. Immunobridging to comparator participants in the
C4591001 study will be based on immunogenicity data collected at baseline and 1 month
after Dose 2. The persistence of the immune response will be based on immunogenicit y data
collected in participants at baseline and1 and 6 months after Dose 2.
4.1.3. Number of Part icipants
4.1.3.1. Phase 1 : Open-L abel Dose-Finding and Lower -Dose Evaluation
Phase 1 is an open- label study that will consist of up to 3 different dose levels in each age
group, with a minimum of 16 participants per dose level (total of 144participants) for the
dose-finding evaluation and a minimum of 32 participants per dose leve l (total of 160
participants) for the lower -dose evaluation ; This open label dose finding phase will consist
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Page 71of up to different dose levels in each age group ,with 16participants per dose level ,and a
total of 144 participants; seeTable 2and Table 3.
Table 2.Phase 1 Dose -Finding Participants
Age Group Total Up to 3 D ose Levelsof BNT162b2aActive Placebo
≥5 to <12 Years 48 16/16/16 16 N/A
≥2 to <5Years 48 16/16/ 16 16 N/A
≥6 M onths to <2 years 48 16/16/16 16 N/A
a. A dose level may be expanded to enroll more than 16 subjects per dose level.
Table 3.Phase 1 Lower -Dose Evaluation Participants
Age Group Total Up to 2Dose Levels of BNT162b 2aActive Placebo
≥5 to <12 Years 32 32 32 N/A
12 to <16 Years 64 32/32 32 N/A
16 to <30Years 64 32/32 32 N/A
a. A dose level may be expanded to enroll more than 32 subjects per dose level.
4.1.3.2. Phase 2 /3: Safety, Tolerability ,Immunogenicity, and Efficacy
Selected -dose:Is the portion of the study that willevaluate the safet y, tolerability ,and
immunogenicit yof the selected dose level in each age group at the selected dose level from
Phase 1 dose finding ,with a total of approximately 6750 4500 participants as an additional
2250 participants will be included to enlarge the size of the pediatric safet y database .
Participants will be randomized in a 2:1ratio to receive active vaccine or placebo (Table 4).
Approximately 450 participants (300 in the active vaccine group and 150 i n the placebo
group ) randomized in each age group in this phase will contribute to the immunobridging
analysisat 1month after Dose 2and will contribute to the overall anal ysis of the persistence
of immune response at 6 months after Dose 2. These participants will be enrolled from both
US and EU sites to ensure this subset is representative of the whole study .
For the persistence time points of 12 and 24 months after Dose 2, a pproximately 70
participants from each age group in the original BNT162b2 group will have an
immunogenicit y blood draw in order to contribute to the anal ysis. All approximately 4500
6750 participants will contribute to the VE analysis for conditional VEand asy mptomatic
infection . Efficacy will be evaluated across all within or across age groups in which
immunobridging is successful, depending on accrual of a sufficient number of cases across in
those age groups.
At designated US sites, an additional optional whole blood sample of approximately 10mL
will be obtained prior to Dose 1and at 7 day s and 6 months after Dose 2 from up to
approximately 60 participants ≥10years of age . Thesesample swill be used on an
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Page 72exploratory basis to investigate the postvaccination cell -mediated immune response at these
time points.
Table 4.Phase 2/3 Selected -Dose Participants –Blood Draws for
Immunogenicity/Efficacy A ssessments
All Age Groups ≥5 to <12 Years of Age ≥2 to <5 Years and
≥6Months to <2 Years
of Agea
Total Active Placebo Total Active Placebo Total Active Placebo
Baseline blood
draw6750 4500 4500 3000 3000 1500 4500 2250 3000 1500 1500750 1125 750 375
1 Month after
Dose 21350 900 450 450 300 150 450 300 150
6 Months after
Dose 24500 3000 1500 2250 1500 750 1125 750 375
12 Months
after Dose 2 210 210 N/A 70 70 N/A 70 70 N/A
24 Months
after Dose 2210 210 N/A 70 70 N/A 70 70 N/A
a.Number of participants shown is for each of these 2younger age groups .
All participants will contribute to the safet y,tolerability , and efficacy assessments ( Table 5).
Table 5.Phase 2/3 Selected -Dose Participants –Safety and Tolerability/Efficacy
Assessments
Age Total Active Placebo
≥5 to <12 Years 4500 3000 1500
≥2 to <5 Years 1125 750 375
≥6 Months to <2 Years 1125 750 375
All age groups 6750 4500 2250
Lower -dose evaluation :Is the open -label portion of the study that will evaluate the safety ,
tolerability ,and immunogenicity of the selected dose level in each age group from the
Phase 1lower -dose evaluation ,with a total of approximately 900active participants (Table
6).
Approximately 300active participants in each age group in this phase will contribute to the
immunobridging anal ysis at 1 month after Dose 2 and the overall anal ysis of the persistence
of immune response at 6 months after Dose 2. These participants will be enrolled from both
US and EU sites t o ensure this subset is representative of the whole stud y.
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Page 73Table 6.Phase 2/3 Lower -Dose Evaluation Participants – Blood Draws for
Immunogenicity/Efficacy Assessments
All Age Groups ≥5 to <12, 12 to <16 Years, and 16 to
<30Years of Ag ea
Total Active Active Placebo
Baseline blood draw 900 900 300 N/A
1 Month after Dose 2 900 900 300 N/A
6 Months after Dose 2 900 900 300 N/A
a. Number of participants shown is for each of these 2 older age groups.
All participants will contribute to the safet y,tolerability , and efficacy assessments (Table 7 ).
Table 7.Phase 2/3 Lower -Dose Eval uation Participants – Safety and
Tolerability/Efficacy Assessments
Total Active Placebo
900 900 N/A
4.1.4. Intervention Groups and Duration
Phase 1 open-l abel dose-finding : Dosing will begin at the low -dose level in participants ≥5
to <12 y ears of age .Controlled enrollment will be required for the first dose level studied in
each age group. Only a limited number of participants (~4) are dosed before allowing dosing
in the remaining participants (~12) in the same age and dose- level group. The I RC will
review safet y data (e -diary and AE) acquired up to 7 day s after Dose 1 for the low- dose level
group ; upon confirmation of an acceptable safety assessment by the IRC:
Dosing may commence at the mid -dose level in the same age group, and
Dosing may commence at the low -dose level in participants ≥2 to <5 y ears of age.
The same process will be followed when moving up dose level s in each age group, and when
progressing between age groups at the low -dose level as shown in Section 1.2. Dosing may
commence at the low -dose level in participants ≥ 6 months to <2 y ears of age after IRC
review of safet y data (e -diary and AE) acquired up to 7 day s after Dose 1 at the low -dose
level from participants ≥2 to <5 y ears of age.
In each age group, i f the low -dose level is considered notacceptable based on safet y
assessment after Dose 1, themid-dose level or high- dose level will not commence . In this
case, an optional lower dose level may commence. Dependent on the results obtained, dose
level (s)may be omitted. In each age group, i f the mid -dose level is considered not acceptable
based on safet y assessment after Dose 1, the high -dose level will not commence.
Based on safet y assessment, the second dose may be given at a lower dose level.
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Page 74Phase 2/3 selected -dose: Pprogression of each age group into Phase 2/3 will occur
independentl y; it is therefore possible that each age group may not start Phase 2/3
concurrently and the dose level selected for Phase 2/3 may differ in each age group. For each
age group t o proceed to Phase 2/3, safet y, tolerability , and immunogenicity data from 7 day s
after Dose 2 for the selected vaccine dose level in the age group from Phase 1 will be
confirmed to be acceptable .
Duration: Participants are expected to participate for up to a maximum of approximately
26months.
Phase 1 lower -dose evaluation : As safet y has been assessed at higher dose levels in all 3
age groups , each dose and age level will occur concurrentl y:
≥5 to <12 Years : 3µg
12 to <16 Years, 16 to <30 Years: 3µgand 10µg
The I RC will review safety data (e -diary and AE s) acquired up to 7 day s after Dose 2.
Phase 2/3 l ower -dose evaluation: Progression of each age group into Phase 2/3 will occur
independentl y; it is therefore possible that each age group may not start Phase 2/3
concurrently ,and the dose level selected for Phase 2/3 may differ in each age group. For
each age group t o proceed to Phase 2/3, safet y, tolerability, and immunogenicity data from 7
days after Dose 2 for the selected vaccine dose level in the age group from Phase 1 will be
confirmed to be acceptable.
Duration: Participants are expected to participate for up to a maxi mum of approximately
6months.
4.2.Scientific Rationale for Study Design
Additional surveillance for COVID -19/MIS-C in Phase 1 dose -finding and Phase 2/3
selected- dose participants will be conducted as part of the study , given the potential risk of
disease enhancement . If a participant experiences sy mptoms, as detailed in Section
8.13Section 1.1, a COVID -19/MIS-Cillness visit and subsequent convalescent visit will
occur and an . As part of these visits, samples ( anterior nasal swab and blood [convalescent
visit] ) will be taken for antigen and antibody assessment as well as recording of COVID-
19/MIS-C– related clinical and labor atory information (including local diagnosis). For
participants in the lower -dose evaluation, COVID -19/MI S-C will be reported as AESIs.
Human reproductive safety data are not available for BNT162b2 RNA -based COVID -19
vaccine, but there is no suspicion of human teratogenicity based on the intended mechanism
of action of the compound. Therefore, the use of a highl y effective method of contr aception
is required (see Appendix 4 ) for WOCBP.
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Page 754.3.Justification for Dose
Dose -finding andselected -doseevaluation :Based on acceptable blinded safet y data in
226059 12 -through 1 5-year-olds at the 30- µg dose level in the C4591001 study , dose-
finding is considered in this study using the same vaccine candidate .24 Therefore, this study
will start with a 10-µgdose level for Phase 1 participants ≥5 to <12 y ears of age , which was
well tolerated in adults 18 to 55years of age in C4591001, before moving to another dose
level in this age group or initiating the younger age groups (20 µg, 30 µgwith an option of 3
µg).
Lower -dose e valuation (partici pants 5 to <12, 12 to <16, 16 to <30 years of age ):The
authorized dose of BNT162b2 in adolescents and y oung adults 12 y earsof age and older is
30µg,whereas in the ongoing C4591007 Phase 2/3 portion of the study the following doses
were selected: 10 µgin participants 5 to <12 years of age and 3 µg in participants 6 months
to <5 y earsof age . With the robust immune responses elicited in adolescents to minimize
reactogenicity and risk of other AEs and to potentially unify the dose levels across children
and y oung adults, additional lower dose levels of BNT162b2 (3 µg, 10 µg) will be evaluated
to determine whether similar immune responses are elicited. For this lower -dose evaluation
portion, a new cohort of Phase 1 participants will be enrolled in 3age groups: >5 to <12, 12
to <16, 16 to <30 years of age to assess safet y, tolerability , and immunogenicity . The
Phase 2/3 BNT162b2 dose level will be selected based on the Phase 1 assessments with an
immunobridging anal ysis of immune responses in participants within each age group to
participants in the 30 -µgPhase 3 C4591001 efficacy study .
4.4.End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of
the study ,including the last visit.
The end of the study is defined as the date of the last visit of the last participant in the study .
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participant s are enrolled , including
participants across diverse and representative racial and ethnic backgrounds. Use of a
prescreener for stud y recruitment purposes will include collection of info rmation, that
reflects the enrollment of a diverse participant population including, where permitted under
local regulations, age, sex, and race, and ethnicity. The following eligibility criteria are
designed to select participant s for whom participation in the study is considered appropriate.
All relevant medical and nonmedical conditions should be taken into consideration when
deciding whether a particular participant is suitable for this protocol.
Prospective approval of protocol deviations to recruitm ent and enrollment criteria ,also
known as protocol waivers or exemptions, is not permitted .
5.1. Inclusion Criteria
Participants are eligible to be included in the study onl y if all of the following criteria appl y:
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Page 76Age and Sex :
1.Male or female participants ≥6 months to <12years of age ,at the time of randomization ,
at Visit 1forthedose-finding /selected- dose evaluation and for participants ≥5 to <30
yearsof age , at the time of randomization, at Visit 1 for the lower -dose evaluation .
Refer to Appendix 4 for reproductive criteria for male ( Section 10.4.1 ) and female
(Section 10.4.2 ) participants.
Type of Participant and Disease Characteristics:
2.Participants’ parent (s)/legal guardian(s ) and participants, as age appropriate, who are
willing and able to comply with all scheduled visits, treatment plan, laboratory tests,
lifesty le considerations, and other study procedures.
3.Health y participants who are determined b y medical hist ory, phy sical examination ,and
clinical judgment of the investigator to be eligible for inclusion in the study.
Note: Healthy participants with preexisting stable disease, defined as disease not
requiring significant change in the therap y or hospitalization for worsening disease during
the 6 weeks before enrollment , can be included .
Phase 2/3: Specific criteria for such p articipants with known stable infecti on with HIV,
HCV, or HBV can be found in Section 10.7.
4.Participants are ex pected to be available for the duration of the study and wh ose
parent(s)/legal guardian can be contacted b y telephone during study participation.
5. Negative urine pregnancy test for female participants who are biologically capable of
having children.
6.Female participant of childbearing potential or male participant able to father children
who is willing to use a highl y effective method of c ontraception as outlined in this
protocol for at least 28 days after the last dose of study intervention if at risk of
pregnancy with her/his partner ; or female participant not of childbearing potential or male
participant not able to father children.
Informed Consent:
7.The participant or participant’s parent(s)/legal guardian is c apable of giving signed
informed consent as described in Appendix 1 ,which includes compliance with the
requirements and restrictions listed in the I CDand in this protocol. Depending on the age
of the participant and according to local requirements, participants will also be asked to
provide assent as appropriate (verbal or written).
The investigator, or a person designated b y the investigator, will obtain written or
electronically signed informed consent ( and assent )from each stud yparticipant or
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Page 77participant’s legal guardian (as defined in Appendix 1 )and the participant’s assent, when
applicable, before any study -specific activity is performed . All legal guardians should be
fully informed, and participants should be informed to the fullest extent possible, about the
study in language and terms they are able to understand. The investigator will retain the
original cop y of each participant's signed consent /assent document.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply :
Medical Conditions:
1.Phase 1 only: Past clinical (based on COVID -19 sy mptoms/signs alone, if a
SARS -CoV -2 NAAT result was notavailable) or microbiological (based on COVID -19
symptoms/signs and a positive SARS -CoV -2 NAAT result) diagnosis of COVID -19.
2.Phase 1 only: Known infection with HIV, HCV, or HBV.
3.Receipt of medications intended to prevent COVID -19.
4. P revious or current diagnosis of MIS-C.
5.Other medical or psy chiatric condition including recent (within the past year) or active
suicidal ideation /behavior or labo ratory abnormality that may increase the risk of study
participation or , in the investig ator’s judgment, make the participant inappropriate for the
study .Note: T his incl udes both conditions that may increase the risk associated with
study intervention administration or a condition that may interfere with the interpretation
of study results
6.History of severe adverse reaction associated with a vaccine and/or severe allergic
reaction (eg, anaph ylaxis) to any component of the study intervention(s).
7.Immunoc ompromised individuals with known or suspected immunodeficiency , as
determined b y history and/or laboratory /physical examination.
8.Individuals with a history of autoimmune disease or an active autoimmune disease
requiring therapeutic intervention, including but not limited to sy stemic lupus
erythematosus. Note: S table type 1 diabetes and hy pothy roidism are permitted .
9. Bleeding diathesis or condition associated with prolonged bleeding that would, in the
opinion of the investigator, contraindicate intramuscular injection.
10.Female who ispregnant or breastfeeding.
Prior/Concomitant Therapy:
11.Previous vaccination with any coronavirus vaccine.
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Page 7812.Individuals who receive treatment with immunosuppressive therapy , including cy totoxic
agents or s ystemic corticosteroids, eg, for cancer or an autoimmune disease, or planned
receipt throughout the study . If s ystemic corticosteroids have been administered short
term (<14 day s) for treatment of an acute illness, participants should not be enrolled into
the study until corticoster oid therap y has been discontinued for at least 28 days before
study intervention administration. Inhaled/ nebulized, intra -articular, intrabursal, or
topical (skin or ey es) corticosteroids are permitted.
13. Receipt of blood/plasma products, immunoglobulin, or monoclonal antibodies, from 60
days before study intervention administration , or receipt of an y passive antibody therapy
specific to COVID -19 from 90 day s before study intervention administration, or planned
receipt throughout the study .
Prior/Concurrent Clinical Study Experience:
14.Participation in other studies involving study intervention within 28 day s prior to study
entry and/or during study participation.
15.Previous participation in other studies involving study intervention containing LNPs .
Diagnostic Assessments:
Not applicable .
Other Exclusions:
16. Participants who are direct descendants (child or grandchild) of investigational site staff
members or Pfizer/Bio NTech emplo yees directl y involved in the conduct of the study ,
site staff otherwise supervised b y the investigator, and their respective family members.
5.3.Lifestyle Considerations
5.3.1. Contraception
All male and female participants who, in the opinion of the investigator, are biologically
capable of having children must agree to use a highly effective metho d of contraception
consistently and correctly for at least 28 day s after the last study vaccination.
The investigator or his or her designee, in consultation with the participant , will confirm that
the participant has selected an appropriate method of cont raception for the individual
participant and his or her partner(s) from the permitted list of contraception methods
(seeAppendix 4 ,Section 10.4.4 )and will confirm that the participant has been instructed in
its consistent and correct use. At time points indicated in the SoA , the investigator or
designee will inform the participant of the need to use highl y effective contraception
consistently and correctly and document the conversation and the participant’s affirmation in
the participant ’s chart ( participant s need to affirm their consistent and correct use of at least 1
of the selected methods of contraception). In addition, the investigator or designee will
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Page 79instruct the participant or participant ’s parent(s)/legal guardi anas applicable to call
immediately if the selected contraception method is discontinued or if pregnancy is known or
suspected in the participant or partner.
5.4.Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but
are not subsequently randomly assigned to study intervention /enrolled in the study . A
minimal set of screen failure information is required to ensure transparent reporting of screen
failure participants to meet the CONSORT publishing requirements and to respond to queries
from regulatory authorities. Minimal information i ncludes demograph y, screen failure
details, eligibility criteria, and any SAE s.
Individuals who do not meet the criteria for participation in this study (screen failure) may be
rescreened under a different participant number.
5.5.Criteria for Temporarily Delay ing Enrollment/Randomization/Study Intervention
Administration
The following conditions are temporary or self -limiting and a participant may be vaccinated
once the condition(s) has/have resolved and no other exclusion criteria are met.
1.Current febrile illn ess (body temperature ≥100.4°F [ ≥38°C]) or other acute illness within
48 hours before study intervention administration. This includes current s ymptoms that
could represent a potential COVID -19 illness (forPhase 1 ,confirmed COVID -19
infection diagnosis is an exclusion criterion):
New or increased cough;
New or increased shortness of breath;
Diarrhea;
Vomiting ;
Chills;
New or increased muscle pain;
New l oss of taste/smell;
Sore throat;
Nausea ;
Abdominal pain ;
Inability to eat/poor feeding in participants <5 y ears of age .
2.Receipt of a ny nonlive vaccine, any seasonal or pandemic influenza vaccine, or any
rotavirus vaccine within 14 day s before study intervention administration, or any other
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Page 80live vaccine (ie ,excluding live influenza and rotavirus vaccines) within 28 day s before
study intervention administration.
2.Receipt of an y nonlive vaccine within 14 day s, or any livevaccine within 28 days,
before stud y intervention administration , including routine child hood immunizations.
3.Anticipated receipt of any vaccine between Dose s 1 and 2, or between Doses 3 and 4, of
study intervention, or within 7 day s after Dose 2 or 4.
4.Receipt of short -term (<14 day s) systemic corticosteroids. Study intervention
administration should be delay ed until sy stemic corticosteroid use has been discontinued
for at least 28 days. Inhaled/nebulized, intra -articular, intrabursal, or topical (skin or
eyes) corticosteroids are permitted.
6.STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s),
placebo, medical device(s) , or study procedure(s) intended to be administered to a study
participant according to the study protocol. In Phase 2/3, the selected -dose portion is
placebo- controlled and the lower -dose evaluation portion is open- label .
Phase 1 will evaluate a 2 -dose (separated b yapproximately 21 day s) schedule of up to
3different dose levels of RNA vaccine candidate BNT162b2 for active immunization against
COVID -19,to determine the fi nal dose level of BNT162b2 in Phase 2/3 for each age group ..
The investigation alRNA vaccine candidate andsaline placebo ,in Phase 2/3 of the selected-
dose portion, are the 2 potential study interventions that may be administered to a study
participant:
BNT162b2 (BNT162 RNA -LNP vaccine utilizing modRNA and encoding the
P2 S): 10µg, 20 µg, and 30µg,with an option for 3 µg, 1 ug or or another
intermediate dose leve l.
Normal saline (0.9% sodium chloride solution for injection).
6.1. Study Intervention(s) Administered
Intervention Name BNT162b2
(BNT162 RNA -LNP V accine Utilizing
modRNA)Saline Placebo (Selected -Dose )
Type Vaccine Placebo
Dose Form ulation modRNA Normal saline (0.9% sodium chloride
solution for injection)
Unit Dose
Strength(s)250 µg/0.5 mL N/A
Dosage Level(s)a10µg, 20µg,or30µg,with an option for
3 µgand 1 µgN/A
Route of
AdministrationIntramuscular injection Intramuscular i
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