C4591001 — Protocol and Amendments (Pfizer pivotal Phase 1/2/3 — BNT162b2 / Comirnaty in adults 16+, later 12+)

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• Following regulatory feedback:
• Modified exclusion criteria and prohibited inhaled/nebulized corticosteroids for sentinel participants in Stage 1
• Clarified that the rapid test for prior COVID-19 infection for sentinel participants in Stage 1 will be used only for screening purposes
• Removed time frames for stopping rules
• Stated that data supporting the selection of vaccine candidate(s)/dose level(s) and schedule(s) for Stages 2 and 3 will be submitted to the FDA for review
• Following preliminary experience in the BioNTech study conducted in Germany (BNT162-01):
• Decreased the dose levels for BNT162a1 and BNT162c2 Additionally:
• Clarified the roles of BioNTech and Pfizer
• Amended text so that the IRC decision to progress group(s) into Stages 2 and 3 can be based upon safety and immunogenicity data after Dose 1 or 2
• Clarified safety data requirements to permit dose escalation
• Amended text so that the progression to participants 65 to 85 years of age can be based upon data from the same RNA platform
• Incorporated a protocol administrative change to correct the variant designation and the encoded antigen to BNT162c2
• Clarified that the SARS-CoV-2 neutralizing assay does not employ wild-type virus
• Clarified that the SARS-CoV-2 spike protein– binding antibody assay is specific for the S1 subunit
• Clarified that efficacy against COVID-19 is based upon illness (not infection) rate ratio
• Incorporated a protocol administrative change to state that the study placebo may be supplied in a glass or plastic vial
• Corrected a typographical error in Section 6.5.1 regarding the time frame for prior receipt of blood/plasma products or immunoglobulins
• Corrected a typographical error in Table 2 regarding the lower limit of diameter (cm) for mild redness and swelling
• Updated the °C fever scale in Table 4 to ensure that all potential °F values are correctly assigned
• Incorporated a protocol administrative change to clarify that a rapid test for prior COVID-19 infection will be performed for sentinel participants in Stage 1, and a serum sample will be drawn for potential future assessment
• Clarified that, after screening, physical examinations in sentinel participants in Stage 1 will be directed
• Clarified the descriptions of the populations for analysis to align with the statistical analysis plan
• Added a complete safety and immunogenicity analysis approximately 6 months after Dose 2 for all participants in Stage 3
• Amended text so that the stopping rules apply to an RNA platform rather than a specific vaccine candidate

Given the urgent nature of the pandemic situation, the following changes allow determination of the appropriate human dose level for both younger and older adults to move speedily into the next phase of clinical evaluation:

• Added a new vaccine candidate, BNT162b3, modRNA encoding a membrane-anchored RBD
• Added a 50-µg dose level for vaccine candidates based on the modRNA platform (ie, BNT162b1, BNT162b2, and BNT162b3)
• Modified the criteria required for the IRC to determine dose escalation in the 18- to 55-year age cohort and advancement to groups of participants 65 to 85 years of age In addition:
• Removed hemoglobin change-from-baseline abnormalities from the laboratory abnormality grading scale as abnormalities should be graded based upon absolute values

As data have become available from this study and the BNT162-01 study in Germany, the following decisions were made:

• Not to study the BNT162a1 and BNT162c2 vaccine candidates at this time. Therefore, these candidates have been removed from the protocol.
• To study further lower dose levels of the modRNA candidates. Therefore, a 20-µg dose level is formally included for BNT162b1 and BNT162b2.
• To permit individual and group dosing alterations for the second dose of study intervention. Following regulatory feedback, the BNT162b3 vaccine candidate has been removed from the protocol until further nonclinical data are available to support study in humans. Given the rapidly evolving pandemic situation, additional blood draws for exploratory COVID-19 research, intended to establish an immunological surrogate of protection, will be taken from selected participants who consent. In order to increase flexibility enrolling participants, an extended screening window (increased from 14 to 28 days) for sentinel participants in Stage 1 has been added. This is considered acceptable since eligible participants are expected to be either healthy or have stable medical conditions. To increase the number of doses that can be obtained from available vaccine vials, not all dose levels will result in a dosing volume of 0.5 mL. Precise dosing instructions will be provided in the IP manual. To facilitate the reporting of COVID-19 illness diagnoses and potential symptoms to the investigator, participants may utilize a COVID-19 illness e-diary.

Given the rapidly evolving pandemic situation, and the need to demonstrate VE as soon as possible, the protocol has been amended to be powered to meet new efficacy objectives. These new efficacy objectives and corresponding endpoints have been added to Section 3. Further nonclinical data are available to support the study of the BNT162b3 candidate in humans, and the candidate has been added to the protocol. The 6-month safety follow-up telephone contact has been changed to an in-person visit for Stage 3 participants, to allow collection of an immunogenicity blood sample. The COVID-19 illness visit has now added flexibility to permit a remote or in-person visit. The COVID-19 illness symptoms have been updated to align with the FDA-accepted definitions; this change is also reflected in the criteria for temporary delay of enrollment. AEs that occur between consent and dosing will now be reported on the AE (rather than Medical History) CRF, to align with the latest Pfizer protocol template. Changes have been made to the headings to align with the latest Pfizer protocol template. Clarified that only an unblinded site staff member may obtain the participant’s randomization number and study intervention allocation. Additional interim analyses have been added to evaluate VE and futility during the study. As a result of regulatory feedback, an appendix has been added to outline the stopping and alert rules to monitor for potential enhanced COVID-19.

Following regulatory feedback:

• Renamed Stage 1 to Phase 1, removed Stage 2, and renamed Stage 3 to Phase 2/3.
• Clarified that a single vaccine candidate, administered as 2 doses 21 days apart, will be studied in Phase 2/3.
• Stated that the vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.
• Removed the potential to study BNT162b3.
• Immunogenicity data will be summarized for the first 360 participants through 1 month after Dose 2, rather than through 21 days after Dose 1.
• Provided further details of sponsor staff that will be unblinded in Phase 2/3.
• Clarified which stopping rules apply to which phase of the study. In addition:
• Clarified the AE reporting requirements for potential COVID-19 illnesses.
• Updated that Visit 1 may be conducted across 2 consecutive days in Phase 2/3.
• Moved the immunogenicity objectives in Phase 2/3 to become exploratory.
• Added an additional inclusion criterion to enroll participants who, in the judgment of the investigator, are at risk for acquiring COVID-19.
• Modified exclusion criterion 5, so that participants with a previous clinical or microbiological diagnosis of COVID-19 are excluded from all phases of the study.
• Clarified that there will be 2 all-available efficacy populations.
• Clarified that immunogenicity samples will be drawn for all participants; analyses will be based upon results from subsets of samples, according to the purpose.
• Updated that the 3-tier approach to summarizing AEs will only be performed in Phase 2/3.
• Updated that at each interim analysis for efficacy, only the first primary objective will be evaluated.
• Changed to use the same posterior probability (99.5%) for all interim analyses, resulting in case split changes in Tables 5, 6, and 7.
• Updated the stopping and alert rule parameters for enhanced COVID-19.

• Reordered some procedures in the Phase 2/3 schedule of activities for consistency with the main body of the protocol.
• Corrected the window for the 6-month follow-up visit to be approximately 6 months after Vaccination 2.
• Reduced the volume of blood draws to ~20 mL.
• Removed the need to have safety data reported for participants to be included in the safety objective assessment.
• Added an exploratory objective to describe safety, immunogenicity, and efficacy in participants with stable HIV disease.
• Increased the sample size for Phase 2/3 to ~43,998.
• Clarified that inclusion criterion 4 (ie, participants at higher risk for acquiring COVID-19) is applicable for Phase 2/3 only, and provided some examples.
• Removed exclusion criterion 2 (ie, known infection with HIV, HCV, or HBV) for Phase 3 and added criteria for HIV-positive participants.
• Decreased the lower age limit and removed the upper age limit for inclusion in Phase 2/3 in order to evaluate BNT162b2 30 µg in older adolescents and those over 85 years of age; updated the title and other references to adults to align with this change.
• Renamed the immunological assays to align with other program-level documents.
• Removed reference to the SARS-CoV-2 full- length, P2 mutant, prefusion spike glycoprotein (P2 S) being “heads up.”
• Clarified that a positive SARS-CoV-2 NAAT result without symptoms should not result in discontinuation of study intervention.
• Added clarification that potential COVID-19 illnesses that are consistent with the clinical endpoint definition should not be recorded as AEs.
• Updated the analysis population descriptions to align with the study SAP.

• According to regulatory request, inclusion criterion 1 now specifies that participants less than 18 years of age will not be enrolled in the EU.

• Reduced the lower age range to include adolescents 12 to 15 years of age and added corresponding objectives.
• Removed reference to COVID-19 antibody testing in Section 2.3.2.
• Clarified with efficacy estimands and endpoints that last dose refers to second dose.
• Added an additional exploratory objective to describe safety and immunogenicity in participants 16 to 55 years of age vaccinated with study intervention produced by manufacturing “Process 1” or “Process 2.”
• Clarified exclusion criterion 5.
• Added Section 6.1.1 to describe manufacturing “Process 1” and “Process 2.”
• Clarified the degree of unblinding on the unblinded submissions team in Section 6.3.3.
• Made provision for a second dose of BNT162b2 in participants who were affected by a medication error at Visit 2 in Section 6.6.
• Provided further clarification regarding discontinuation of study intervention in Section 7.1.
• Modified the circumstances in which a local NAAT result may be used in the COVID-19 case definition.
• Added that 2 periods of potential COVID-19 symptoms within 4 days will be considered as a single illness.
• Provided guidance in Section 8.13 regarding circumstances in which a SARS-CoV-2 test might be required even if symptoms within 7 days following each vaccination are considered more likely due to vaccine reactogenicity.
• Made allowance in Section 8.13 for a second SARS-CoV-2 test to be performed within the same potential COVID-19 illness if it is in accordance with routine practice.
• Added Section 8.15 to describe the reporting of SARS-CoV-2 test results and their implications for participants receiving a second vaccine dose.
• Added statistical hypothesis and power analysis for evaluation of noninferiority of the immune response to BNT162b2 in participants 12 to 15 years of age to the response in participants 16 to 25 years of age.
• Amended scope of analyses of safety data in Section 9.5.1.
• Made various editorial changes.

• Removed “N-binding antibody” and “SARS-CoV- 2 detection by NAAT” as endpoints from the third exploratory objective, as these results are used for the determination of the population, and are not endpoints.
• Clarified that the “Process 1” participants included in the descriptive analysis of “Process 1”- and “Process 2”-manufactured study interventions will be selected randomly.
• Clarified that surveillance of potential COVID-19 symptoms should continue even if a participant has a positive SARS-CoV-2 test earlier in the study.
• Further modified the circumstances in which a local NAAT result may be used in the COVID-19 case definition.
• Clarified that for participants who are not in the reactogenicity subset, local reactions and systemic events following vaccination should be detected and reported as AEs.
• Clarified that premenarchal females are not WOCBP.
• Made various editorial changes.

• To better align with the natural history of SARS-CoV-2 infection, added Phase 2/3 secondary efficacy objectives, estimands, and endpoints to include COVID-19 cases that occur from 14 days after the second dose; also modified the existing secondary efficacy objectives, estimands, and endpoints to include COVID-19 cases that occur from 14 days, as well as 7 days, after the second dose;
• Made corresponding changes to the study design, study assessments and procedures, and statistical analysis sections.
• For operational reasons, removed the interim analysis planned after accrual of 32 cases.
• Clarified that interim analyses will be conducted after accrual of at least 62, 92, and 120 cases.
• Included any participants 16 through 17 years of age enrolled under this amendment in the reactogenicity subset.
• Added an unblinded clinical scientist to support DMC activities.
• Clarified that serology data after a postbaseline positive SARS-CoV-2 test result will not be included in the analysis based on the evaluable immunogenicity populations.

• Added the possibility of administering BNT162b2 to participants who originally received placebo, following any local or national recommendations.
• Added the possibility of administering BNT162b2 to participants who originally received placebo, following completion of the active safety surveillance period.
• Added corresponding exploratory objectives and statistical analysis details.
• Removed immunogenicity analyses of titers greater than defined threshold(s).
• Removed the need for blinded COVID-19 case review after the final efficacy analysis.
• Included the possibility, due to local circumstances related to the COVID-19 pandemic, that study procedures that do not require in-person participant contact may be performed by telehealth.
• In light of additional information to better estimate the standard deviation of SARS-CoV-2 neutralizing titers, increased the sample size for the noninferiority immunogenicity analysis in adolescents 12 to 15 years of age.

• Added approaches to evaluate efficacy against asymptomatic SARS-CoV-2 infection:
• Added objectives, estimands, and endpoints, and statistical methods, for assessment via N-binding antibody seroconversion;
• Added a potential intensive surveillance period for nasal swabbing, for assessment via NAAT:
• Corresponding objectives, estimands, and endpoints added
• Corresponding SoA and procedures added
• Details added in the statistical methods sections.
• Added the possibility of assessing full-length S-binding, instead of S1-binding, IgG levels in Phase 2/3.
• Clarified in Section 4.1.1 that any Phase 1 placebo recipient who has not already been offered the opportunity to receive BNT162b2 will be given this opportunity at the approximate time participants in Phase 2/3 reach Visit 4, for consistency with other sections.
• Added a sentence to reflect that assent is obtained from participants <18 years of age.

• Because of a formatting error in protocol amendment 11, exclusion criterion 4 was inadvertently added to exclusion criterion 3 and the subsequent criteria renumbered. This amendment corrects that error.
• Because of a change in the pace with which participants ≥16 years of age who originally received placebo will become eligible for receipt of BNT162b2, text was updated throughout the protocol to reflect that this will happen in a phased manner, with recommendations detailed separately and available in the electronic study reference portal.
• Clarified that participants who are unblinded because they become potentially eligible for receipt of BNT162b2 will not participate in surveillance for asymptomatic SARS CoV-2 infection.
• Corrected the exploratory objective to describe non-S seroconversion to SARS-CoV-2 to clarify that this will only include participants who received BNT162b2 at initial randomization (since those who received it subsequently do not have blood drawn).
• In line with current recommendations, removed the requirement to discontinue study intervention because of a diagnosis of COVID-19 during the study.

• In order to describe the boostability of BNT162, an additional dose of BNT162b2 at 30 µg will be given to Phase 1 participants approximately 6 to 12 months after their second dose of BNT162b1 or BNT162b2:
• Added corresponding objectives, estimands, and endpoints
• Added corresponding SoA and procedures
• Added details in the statistical methods sections.
• Clarified the population used for analysis of reactogenicity endpoints.
• To align with current recommendations, investigators may exercise judgment on review of inclusion and exclusion criteria ahead of vaccination with BNT162b2 for participants who originally received placebo.
• Clarified that if a participant has previously withdrawn consent and wishes to receive a COVID-19 vaccine outside the study, they may request to know which study intervention they received for Vaccination(s) 1/2 without needing to reconsent.
• Participants who provide biweekly swabs for surveillance of asymptomatic infection should now continue to swab even after unblinding if they originally received BNT162b2, to maximize the numbers of swabs to be collected.
• Clarified the procedures for unscheduled visits to administer a second dose in the event a participant received only 1 dose of BNT162b2.

• In order to further describe duration of protection, and heterologous/homologous protection against the emerging VOCs, an additional dose of BNT162b2 or BNT162b2SA will be given to approximately 600 Phase 3 participants approximately 5 to 7 months after their second dose of BNT162b2; a further dose of BNT162b2SA will be given to approximately 30 of those participants who receive BNT162b2SA:
• Added corresponding objectives, estimands, and endpoints
• Added corresponding SoA and procedures
• Added details in the statistical methods sections.
• Approximately 300 BNT162b2-naïve participants will be enrolled and receive 2 doses of BNT162b2SA to describe heterologous/homologous protection against the emerging VOCs and reference strains:
• Added corresponding objectives, estimands, and endpoints
• Added corresponding SoA and procedures
• Added details in the statistical methods sections.
• Cell-mediated immune responses will also be described following isolations of PBMCs in a subset of both the Phase 3 participants who receive a single booster vaccination and the BNT162b2-naïve group who receive BNT162b2SA
• Added the asymptomatic case definitions in Section 8.1 and further clarified the secondary definition for asymptomatic case based on seroconversion of N- binding antibody.
• Defined the analysis populations used for evaluation of asymptomatic infection based on seroconversion of N-binding antibody and based on NAAT from participants who consent to active surveillance.
• Clarified that unblinding for a nonemergency reason should be conducted outside of the IRT system.
• Clarified that if multiple visits occur on the same day, all procedures for all visits must be conducted (including collection of all blood samples).
• Clarified the plan for stepwise unblinding of the sponsor in the study.

• In order to further characterize booster responses induced by BNT162b2, 2 additional lower-dose booster groups have been added to the subset for evaluation of boostability and protection against emerging VOCs. An additional 5-µg or 10-µg dose of BNT162b2 will be given to approximately 144 Phase 3 participants approximately 5 to 7 months after their second dose of BNT162b2.
• To further describe cell-mediated immune responses following isolations of PBMCs in a subset of both the Phase 3 participants who receive a single booster vaccination and the BNT162b2-naïve group who receive BNT162b2SA, additional genetic testing may also be performed; corresponding details and an appendix have been added.
• An exploratory objective was added for Phase 3 participants to describe the immune response to a third dose of BNT162b2 or a third or fourth dose of BNT162b2SA at later time points to align with analyses and corresponding changes detailed in the statistical section.
• Removed the lower age limit for eligibility for administration of BNT162b2 to those originally assigned to placebo: this will now be covered in the recommendations detailed separately, and available in the electronic study reference portal.
• Allowed administration of BNT162b2 at Visits 101 and 102 to pregnant participants in certain circumstances.
• To align with contraception requirements, reduced the EDP reporting period to 28 days after the last dose of study intervention.

• Removed the requirement to conduct a potential COVID-19 convalescent visit following each potential COVID-19 illness visit.
• Clarified that only non-Pfizer interventional studies for prevention of COVID-19 are prohibited throughout study participation.
• Clarified that during the 7 days following each vaccination (either as part of this study, co-enrolled C459 studies, or the B7471026 [20vPnC] study), potential COVID-19 symptoms that overlap with specific systemic events (ie, fever, chills, new or increased muscle pain, diarrhea, vomiting) should not trigger a potential COVID-19 illness visit unless, in the investigator’s opinion, the clinical picture is more indicative of a possible COVID-19 illness than vaccine reactogenicity.
• Revised the noninferiority margin from 2-fold to 1.5-fold and added a minimum GMR point estimate of ≥0.8 as another success criterion for Phase 3 booster and VOC immunogenicity assessment. Noninferiority is met if the lower limit of the alpha- adjusted CI for the GMR is >0.67 and the point estimate of the GMR is ≥0.8.
• Added Phase 1 booster participants to the Dose 3 booster immunogenicity population definitions.
• Included a booster safety population definition.
• Clarified that the interim analyses for booster immunogenicity will be conducted when serology data for the reference strain or for the SA strain are available.

• Changed the analysis method for the within-group comparison of seroresponse rates for Phase 3 booster and VOC immunogenicity assessment from the Miettinen and Nurminen method to the adjusted Wald interval to provide tighter CI and higher power for NI in most cases.
• Clarified that any nonstudy coronavirus vaccines are to be recorded at any time they are given during study participation.
• Clarified that participants who are randomized in the C4591031 study should be withdrawn from this study.

• Addition of procedures for monitoring potential myocarditis or pericarditis.
• Addition of a third dose of BNT162b2 for participants who meet specified recommendations and have not yet received a third dose.
• Added corresponding objectives, estimands, and endpoints.
• Added corresponding SoA and procedures.
• Added details in the statistical methods sections.
• Added the instruction that participants who receive COVID-19 vaccines outside of the study from protocol amendment 18 onwards should be withdrawn.

• Inclusion of an additional 30-µg dose of BNT162b2 for eligible participants from protocol amendments 13-15 who received at least 3 doses of BNT162 in the study.
• Added corresponding objectives, estimands, and endpoints.
• Added corresponding SoA and procedures.
• Added details in the statistical methods sections.
• Added language to permit early discontinuation of participants for reasons including but not limited to the increased access and availability of BNT162b2 in the real world, reducing the value of participant involvement and observation in this clinical trial.
• Updated the eligibility window for participants to receive the third (booster) dose under protocol amendment 18 from at least 6 months after Dose 2 to at least 3 months after Dose 2 to provide maximum opportunity to all participants to receive the third dose.
• Updated the existing objectives, estimands, and endpoints in line with the revised schedule and study duration, and where applicable, removed what is no longer relevant.
• Clarified AE/SAE collection requirements for participants enrolled under protocol amendments 18 and 19.
• Updated risk assessment as BNT162b2 is no longer a novel vaccine and there are extensive data available from both clinical trial and real-world settings.

• Added language pertaining to early completion of this clinical trial as agreed with FDA and EMA.
• Updated schedules of assessments and protocol text to identify study visits that no longer need to be completed.
• Updated Study Procedures to describe site actions following approval of protocol amendment 20.
• Removed the objective to describe the safety and immunogenicity of prophylactic BNT162b2 in individuals 16 to 55 years of age vaccinated with study intervention produced by manufacturing “Process 1” or “Process 2” because of the volume of BNT162b2 now distributed and administered globally using manufacturing “Process 2,” making this comparison unwarranted.
• Removed corresponding endpoints.
• Removed corresponding wording throughout the protocol text.
• Added rationale for removal of this objective.
• Added wording regarding return of e-diary devices or removal of application from participants’ personal devices at the end of the study.