C4591015 — Protocol Amendment Summary of Changes (Pfizer pregnant-women trial / maternal immunization)

Pfizer/BioNTech’s maternal-immunization study of BNT162b2 in pregnant participants, evaluating two 30 µg doses given during the third trimester (24–34 weeks gestation in the original design). Co-primary endpoints covered safety and immunogenicity in both the mother and the infant, with follow-up through the infant’s first six months. The trial followed the CT02-GSOP Maternal Immunization Protocol Template (a Pfizer pregnancy-specific variant), not the standard clinical-protocol template used by the rest of the C4591xxx series. Enrollment was terminated on 25 October 2021 with approximately 349 of the planned 4,000 maternal participants enrolled. Once COVID-19 vaccines were universally recommended for pregnant individuals and broadly available, Pfizer concluded the placebo-controlled design could no longer be ethically continued and the remaining sample size was insufficient to meet the primary immunogenicity endpoint.

Coverage at a glance

Latest protocol we have: 125742_S2_M5_5351_c4591015-protocol-amend2.pdf

Category	Count	Amendments
Total documents in the history (Original + Amendments 1–2)	3
Direct PDFs available	1	Protocol amendment 2
Summary-only (date and rationale recorded here, no full PDF available)	2	Protocol amendment 1; Original protocol

Amendment-by-amendment table

Show the ‘Summary and Rationale for Changes’ column

Document	Version Date	Available documents	Summary and Rationale for Changes
Original protocol	21 December 2020	Summary only — no full PDF of this version available	N/A
Protocol amendment 1	28 January 2021	Summary only — no full PDF of this version available	Based on availability of BNT162b2 in high-risk pregnant women and evidence of safety in the real-world setting, the sentinel cohort of N=50 in Phase 2 was removed. Based on feedback from an external advisory board, inclusion criterion 10 was updated to allow enrollment of participants with a prepregnancy BMI of ≤40 kg/m2. Protocol Amendment 2, 02 March 2021 TMF Doc ID: 164.01 Clarified language in inclusion criterion 1 that GA dating for maternal participants who underwent assisted reproduction technology can be referenced in the SRM. Corrected the list of prohibited medications under Section 6.5.1. Clarified language in the Objectives, Estimands, and Endpoints table for consistency. Added exploratory objectives to evaluate incidence rates of COVID-19 and asymptomatic SARS-CoV-2 infection through the entire follow-up among the maternal participants receiving BNT162b2. Updated the VE assessment to reflect the reduced accrual of time following the unblinding of participants at 1 month after delivery. Clarified the unblinding at 1 month after delivery for participants originally randomized to placebo who go on to receive BNT162b2. Updated Section 2.3, Benefit-Risk Assessment, to include data from the DART studies. In line with current recommendations, removed the requirement to discontinue study intervention because of a diagnosis of COVID-19 during the study. Added the requirement to record antipyretic medication in the e-diary during the 7-day vaccination period, as this was omitted in error. Protocol Amendment 2, 02 March 2021 TMF Doc ID: 164.01 Added editorial changes in the document to clarify where field workers/site staff may be required to call/visit maternal participants at home (applicable to regions where illiterate participants may be enrolled). Clarified that participants originally randomized to placebo who go on to receive BNT162b2 at 1 month after delivery will not participate in surveillance for asymptomatic SARS-CoV-2 infection. Clarified that AEs will be collected from the signing of the ICD to 1 month after Vaccination 4 (Visit 103) for those maternal participants who originally received placebo and who go on to receive BNT162b2 at 1 month after delivery.
Protocol amendment 2	02 March 2021	125742_S2_M5_5351_c4591015-protocol-amend2.pdfPHMPT individual	Section 1.3.1 and Section 1.3.2: expanded the 1-month postdelivery visit window by 1 week to allow for potential earlier vaccination of BNT162b2 to participants originally randomized to receive placebo. Section 1.3.3: removed “equivalent visit number for maternal participants” from the Infant SoA since this will differ for maternal participants originally randomized to placebo who will go on to receive BNT162b2 at 1 month after delivery and follow a different SoA. Section 2.3: added a sentence to clarify that the protocol is a PASS. Section 5.1.1: corrected the calculation of GA in the third trimester, replacing “second trimester” with “third trimester,” and updated the discrepancy of days between the LMP-determined GA from >10 to >21 days. Removed references to thumbprinting the ICD, since illiterate participants will not be enrolled from certain regions. Clarified in Section 8.2.2 that field workers would be used in the case of poor network connection for e-diary completion. Section 5.1.1, Section 8.16.3, and Section 10.4: added criteria for inclusion of maternal participants with stable HIV, hepatitis B, or hepatitis C in Phase 3. Protocol Amendment 2, 02 March 2021 TMF Doc ID: 164.01 Updated the Objectives, Estimands, and Endpoints to add a safety objective for the first 600 randomized maternal participants to support interim analysis/submission report. Per CBER feedback, updated the term “NI” to “immunobridging” to describe the immunogenicity comparison between nonrandomized populations in the protocol. Added a footnote to clarify that HIV-infected participants will not be included in analyses of the objectives. Analyses among HIV-infected women and their infants will be summarized separately. Section 8.1.1 and Section 8.13.1: added a second definition of symptoms of severe COVID-19 disease per the CDC definition. Section 8.2.3: clarified that stopping rules are in place during Phase 2 only, with no overlap into Phase 3. Clarified that a study pause may not prevent administration of Dose 2 for enrolled participants. Modified stopping rule 7 to include a trigger of preterm premature rupture of membranes. Stopping rule 4: removed assessment of laboratory abnormalities, as these data are not collected in this study. Protocol Amendment 2, 02 March 2021 TMF Doc ID: 164.01 Section 8.11.1, Visit 1: removed the requirement of a repeat fetal scan to clarify that an earlier scan done at ≥18 weeks’ GA can be used to confirm singleton pregnancy and rule out fetal anomalies. Section 8.15: clarified that exclusion criterion 2 is not met if the participant meets the criteria for confirmed COVID-19 with or without symptoms and can receive Vaccination 2. Section 8.16: 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. Section 8.3.1 and Section 8.3.7: inserted language to clarify that potential COVID-19/MIS-C illnesses and their sequelae that are consistent with the clinical endpoint definition should not be recorded as AEs. Appendix 3: removed an erroneous partially completed sentence from the second paragraph.