C4591024 — Protocol Amendment Summary of Changes (Pfizer BNT162b2 in immunocompromised participants ≥2 years)

Pfizer/BioNTech’s Phase 2b open-label study of BNT162b2 in immunocompromised participants ≥2 years — covering transplant recipients, certain cancer patients (NSCLC, CLL), patients on hemodialysis, those receiving immunomodulator therapy for autoimmune inflammatory disorders, and other groups whose vaccine response is typically blunted. As of Amendment 5 (13 January 2023), Pfizer stopped recruiting new participants because enrollment in this population proved challenging. C4591024 is not in the PHMPT FOIA release; the source PDF (Pfizer’s Final Protocol Amendment 5) was retrieved from clinicaltrials.gov via the Wayback Machine.

Coverage at a glance

Latest protocol we have: c4591024-amendment-5-2023-01-13.pdf

Category	Count	Amendments
Total documents in the history (Original + Amendments 1–5)	6
Direct PDFs available	1	Protocol amendment 5
Summary-only (date and rationale recorded here, no full PDF available)	5	Protocol amendments 1, 2, 3, 4; Original protocol

Amendment timeline

Document	Date	Available documents	Main rationale for the amendment
Protocol amendment 5	13 January 2023	c4591024-amendment-5-2023-01-13.pdfclinicaltrials.gov (NCT04895982) — via Wayback Machine	Section # and Name Description of Change Brief Rationale Sections 1.1 Overall Design, 1.1 Number of Participants, and 4.1 Overall Design Updated the number of participants in each group based on actual recruitment figures Due to the challenging recruitment of immunocompromised participants in this study, a decision was made to stop recruiting new participants Section 5.4 Screen Failures Included content from the PACL dated 25 October 2022 to clarify the definition of screen failures This is to align with the protocol template wording for screen failure Sections 8.9.8 Visit 8 – Vaccination 4 (91 to 189 Days After Visit 5), 8.9.9 Visit 9 – 1-Month Follow-Up Visit (After Vaccination 4) (28 to 35 Days After Visit 8), 8.9.10 Visit 10 – 6-Month Follow-Up Visit (After Vaccination 4) (175 to 189 Days After Visit 8), Included content from the PACL dated 05 October 2022 to clarify the requirements for study procedures after protocol amendment 4 This is to ensure participants can continue to perform study activities, as appropriate, if they do not consent to a fourth dose PF-07302048 (BNT162b2 RNA-Based COVID-19 Vaccine) Protocol C4591024 Final Protocol Amendment 5, 13 January 2023 PFIZER CONFIDENTIAL Page 3
Protocol amendment 4	21 January 2022	Summary only — no full PDF of this version available	Updating procedures to allow a fourth dose (booster), reducing the window for provision of Dose 3, and allowing vaccination with the age-appropriate dose
Protocol amendment 3	15 September 2021	Summary only — no full PDF of this version available	To remain in alignment with changing regulatory guidance on administering Dose 3
Protocol amendment 2	05 August 2021	Summary only — no full PDF of this version available	As individuals with compromised immune systems are at significant risk of morbidity and mortality due to SARS-CoV-2 infection, it is imperative that the safety, tolerability, and immune response to vaccination among these individuals be investigated. Therefore, the conditions for study participants ≥18 years of age include NSCLC, CLL, hemodialysis treatment secondary to end-stage renal disease, and participants ≥2 to <18 years of age with representative conditions, including those with inflammatory and autoimmune inflammatory disorders receiving immunomodulators, those who have undergone organ transplant and are receiving maintenance antirejection modulators, and those who have undergone bone marrow or stem cell transplant. The changes in this amendment include the removal of the upper age limit for the cohort of participants on active immunomodulator therapy (eg, TNFα inhibitors, tofacitinib, or MTX) for an autoimmune inflammatory disorder (eg, inflammatory arthritis, such as rheumatoid arthritis, psoriatic arthritis, and juvenile idiopathic arthritis, and inflammatory bowel disease, such as ulcerative colitis and Crohn’s disease) and the addition of risks associated with myocarditis and pericarditis as well as their subsequent unplanned visits, as committed to CBER.
Protocol amendment 1	24 June 2021	Summary only — no full PDF of this version available	Addition of dose levels for participants ≥5 to <12 and <5 years of age
Original protocol	16 April 2021	Summary only — no full PDF of this version available	(no main-rationale paragraph in source)

Detailed change-tables per amendment

For each amendment that ships a ‘Summary of Major Changes’ table in the source PDF, the full Section / Description / Rationale rows are reproduced below. The Original protocol typically has no change-table (nothing to compare against).

Protocol amendment 5 — 13 January 2023 (9 change rows)

Section # and Name	Description of Change	Brief Rationale
Sections 1.1 Overall Design, 1.1 Number of Participants, and 4.1 Overall Design	Updated the number of participants in each group based on actual recruitment figures	Due to the challenging recruitment of immunocompromised participants in this study, a decision was made to stop recruiting new participants
Section 5.4 Screen Failures	Included content from the PACL dated 25 October 2022 to clarify the definition of screen failures	This is to align with the protocol template wording for screen failure
Sections 8.9.8 Visit 8 – Vaccination 4 (91 to 189 Days After Visit 5), 8.9.9 Visit 9 – 1-Month Follow-Up Visit (After Vaccination 4) (28 to 35 Days After Visit 8), 8.9.10 Visit 10 – 6-Month Follow-Up Visit (After Vaccination 4) (175 to 189 Days After Visit 8),	Included content from the PACL dated 05 October 2022 to clarify the requirements for study procedures after protocol amendment 4	This is to ensure participants can continue to perform study activities, as appropriate, if they do not consent to a fourth dose
1.3 Schedule of Activities, and 7.1 Discontinuation of Study Intervention
Sections 8 Study Assessments and Procedures, 9.3.4 Exploratory Endpoint(s)/Estimand(s) Analysis, and 1.3 Schedule of Activities	Removed further blood draws for participants who have consented to PBMC sampling	Only 1 participant to date has been enrolled in the PBMC subset due to the challenges with study enrollment overall; with too few participants to make a meaningful analysis, further collection of blood for PBMC assessment is not required
Section 8.9.8 Visit 8 – Vaccination 4 (91 to 189 Days After Visit 5)	Included content from the PACL dated 19 May 2022 to correct a typographical error	This is to reflect the accurate study procedures listed in Section 1.3 Schedule of Activities
Section 8.11.1 Potential COVID-19/MIS-C Illness Visit (Optimally Within 3 Days After Potential COVID-19 Illness Onset)	Included content from the PACL dated 09 March 2022 to clarify nasal swab collection for participants in study sites in Mexico	This is to clarify that participants will not self-collect nasal swabs in Mexico
Section 9.3.1 General Considerations	Added the following wording: Analyses for certain cohorts may be combined if the number of participants is small	This is in case of low recruitment
Section 9.4.1 Analysis Timing	Streamlined the text in this section	This is to clarify the language

Protocol amendment 4 — 21 January 2022 (7 change rows)

Section # and Name	Description of Change	Brief Rationale
Section 1.1 – Synopsis, Section 1.3 – Schedule of Activities, Section 4.1 – Overall Design, Section 4.3 – Justification for Dose, and Section 6: Study Intervention(s) and Concomitant Therapy Section 8.9 – Study Procedures	Added a fourth dose (booster), and 1 and 6 months post-Dose 3 visits, with associated objectives Reduced the Visit 5 window for provision of Dose 3 Clarified that if Visit 4 and Visit 5 occur on the same day, duplicate procedures need not be conducted Updated procedures to allow vaccination with the age-appropriate dose	In line with regulatory recommendations for providing third/fourth doses of BNT162b2 to immunocompromised individuals
Section 1.3 – Schedule of Activities	Removed immunogenicity blood collection at Visit 5 and Visit 6 Removed PBMC collection at Visit 5 and Visit 7 Updated Visit 6 to allow conducting via telephone for participants not in the PBMC subset	To streamline the schedule of visits and blood draws, taking into account the fixed timing of Dose 3 and the addition of a fourth dose (booster)
Section 9.2 – Analysis Sets Section 9.3 – Statistical Analyses	Clarified the definition of Dose 3 and Dose 4 evaluable immunogenicity analysis sets	In line with regulatory recommendations for providing third/fourth doses of BNT162b2 to
Section 9.4 – Interim Analyses	Updated wording to align with the modified objectives and endpoints Removed the analysis timing at 1 month after Dose 2 and added the 1 month after Dose 4 analysis	immunocompromised individuals
Section 10.2.4 – Reporting of SAEs	Added a mechanism for reporting SAEs electronically	To allow multiple routes to report SAEs
Section 1.1 – Synopsis, Section 1.3 – Schedule of Activities, Section 4.1 – Overall Design, Section 4.3 – Justification for Dose, and Section 8.9 – Study Procedures	Updated the Visit 5 window to allow its occurrence as early as 28 days after Visit 2 Clarified that if Visit 4 and Visit 5 occur on the same day, duplicate procedures need not be conducted; Visit 5 immunogenicity blood draws are not required in this circumstance	In line with regulatory recommendations for providing a third dose of BNT162b2 to immunocompromised individuals
Section 9.3.4 – Exploratory Endpoint(s)/Estimand(s) Analysis	Updated wording to allow subgroup analysis of immunogenicity endpoints based on various time points for Dose 3 administration	This analysis may be performed in line with regulatory recommendations for providing a third dose of BNT162b2 to immunocompromised individuals, as the vaccination window may vary

Protocol amendment 3 — 15 September 2021 (6 change rows)

Section # and Name	Description of Change	Brief Rationale
Section 9.4 – Interim Analyses	Updated wording to align with the modified objectives and endpoints Removed the analysis timing at 1 month after Dose 2 and added the 1 month after Dose 4 analysis	immunocompromised individuals
Section 10.2.4 – Reporting of SAEs	Added a mechanism for reporting SAEs electronically	To allow multiple routes to report SAEs
Section 1.1 – Synopsis, Section 1.3 – Schedule of Activities, Section 4.1 – Overall Design, Section 4.3 – Justification for Dose, and Section 8.9 – Study Procedures	Updated the Visit 5 window to allow its occurrence as early as 28 days after Visit 2 Clarified that if Visit 4 and Visit 5 occur on the same day, duplicate procedures need not be conducted; Visit 5 immunogenicity blood draws are not required in this circumstance	In line with regulatory recommendations for providing a third dose of BNT162b2 to immunocompromised individuals
Section 9.3.4 – Exploratory Endpoint(s)/Estimand(s) Analysis	Updated wording to allow subgroup analysis of immunogenicity endpoints based on various time points for Dose 3 administration	This analysis may be performed in line with regulatory recommendations for providing a third dose of BNT162b2 to immunocompromised individuals, as the vaccination window may vary
Section 2.3.1 – Risk Assessment	Updated the risk assessment for participants in this study	Risk assessment has been further informed, including the very rare cases of myocarditis, pericarditis, and anaphylaxis reported after authorization in recipients of BNT162b2
Section 3 – Objectives, Endpoints, and Estimands	Added primary and exploratory safety, tolerability, and immune response objectives for the expanded cohort of participants on active immunomodulator therapy	This update has been implemented to allow the expanded cohort to follow the same primary and exploratory objectives as the other cohorts in the study

Protocol amendment 2 — 05 August 2021 (19 change rows)

Section # and Name	Description of Change	Brief Rationale
Section 2.3.1 – Risk Assessment	Updated the risk assessment for participants in this study	Risk assessment has been further informed, including the very rare cases of myocarditis, pericarditis, and anaphylaxis reported after authorization in recipients of BNT162b2
Section 3 – Objectives, Endpoints, and Estimands	Added primary and exploratory safety, tolerability, and immune response objectives for the expanded cohort of participants on active immunomodulator therapy	This update has been implemented to allow the expanded cohort to follow the same primary and exploratory objectives as the other cohorts in the study
Section 4.1 – Overall Design	Clarified wording on participants in the cohort who are taking active immunomodulator therapy	This update clearly documents the intended therapies for participants who are part of this cohort
Section 5 – Study Population	Clarified wording on diversity of recruitment	This addition will enable collection of race and ethnicity data in prescreeners
Section 5.1 – Inclusion Criteria	Clarified wording on inclusion criterion 4 to specify that the participant or participant’s parent(s)/legal guardians, as age appropriate, need to be able to be contacted by telephone throughout the study	This update clearly documents the intended criterion for participants to meet in order to be enrolled into this study
Section 6.8.1 – Prohibited During the Study	Included explanatory text on the removal of prohibition on concomitant vaccinations within 28 days before and after vaccination with BNT162b2	This update has been implemented in line with CDC guidelines as of June 2021
Section 6.8.2 – Permitted During the Study	Inserted text to allow flexibility of immunomodulator administration before and after vaccination with BNT162b2	This update has been implemented to clarify that the alteration of immunomodulator administration is permitted according to local guidelines
Section 8 – Study Assessments and Procedures	Expanded the subset of participants participating in PBMC collection	This update has been implemented to allow the expanded cohort to follow similar procedures to other participants who have consented to PBMC collection
Section 8.3.8 – Adverse Events of Special Interest	Added myocarditis and pericarditis	This update has been implemented in response to commitments made to CBER
Section 8.9 – Study Procedures	Added a visit procedure to any visit that occurs sooner than 1 month after any vaccination requesting that participants or participant’s parent(s)/legal guardian to contact site staff or the investigator if the participant experiences acute chest pain, shortness of breath, or palpitations	This update has been implemented in response to commitments made to CBER
Section 8.12 – Additional Procedures for Monitoring of Potential Myocarditis or Pericarditis	Added an unplanned visit to capture data pertaining to myocarditis and pericarditis	This visit has been implemented in response to commitments made to CBER
Section 9.4.1 – Analysis Timing	Updated wording to reflect the addition of the new cohort of participants ≥18 years of age receiving treatment for an autoimmune inflammatory disorder	This update clearly reflects the new number of cohorts in the study
Section 10.7 – Appendix 7: Protocol Amendment History	Added Appendix 7 to include the protocol amendment history and moved the Protocol Amendment Summary of Changes Table for Protocol Amendment 1 from the beginning of the document to this new section	This update ensures only the latest Protocol Amendment Summary of Changes Table for the current amendment is located directly before the table of contents
Section 2.3 – Benefit/Risk Assessment	Added safety text indicating that no specific safety concerns were identified by subgroup analysis by age, race, ethnicity, medical comorbidities, or prior SARS-CoV-2 infection	Benefit/risk assessment has been further informed by the C4591001 study data
Section 3 – Objectives, Endpoints, and Estimands	Removed the exploratory objective to describe viral shedding in line with the removal of the convalescent visit	As the convalescent visit will no longer be conducted, the swabs intended for this exploratory analysis will no longer be collected
Section 5.2 – Exclusion Criteria	Added the exclusion criterion for participants with insufficient deltoid muscle mass	This exclusion criterion was added to ensure participant safety, so that those with insufficient muscle mass are not vaccinated
Section 5.5 – Criteria for Temporarily Delaying Enrollment/Randomization/ Administration of Study Intervention	Clarified that symptoms indicative of COVID-19 illness, in the opinion of the investigator, meet the criteria for temporarily delaying vaccine administration	This clarification was added in line with other C459 program studies
Section 6 – Study Intervention(s) and Concomitant Therapy	Clarified that study age groups are assigned by age at Visit 1; participants will receive the same dose level at all 3 vaccination visits	This clarification was added in response to Investigator questions
Section 6.1 – Study Intervention(s) Administered	Added the 10-µg dose level for participants ≥5 to <12 years of age	This dose level was determined by data from the C4591007 study

Protocol amendment 1 — 24 June 2021 (15 change rows)

Section # and Name	Description of Change	Brief Rationale
Section 2.3 – Benefit/Risk Assessment	Added safety text indicating that no specific safety concerns were identified by subgroup analysis by age, race, ethnicity, medical comorbidities, or prior SARS-CoV-2 infection	Benefit/risk assessment has been further informed by the C4591001 study data
Section 3 – Objectives, Endpoints, and Estimands	Removed the exploratory objective to describe viral shedding in line with the removal of the convalescent visit	As the convalescent visit will no longer be conducted, the swabs intended for this exploratory analysis will no longer be collected
Section 5.2 – Exclusion Criteria	Added the exclusion criterion for participants with insufficient deltoid muscle mass	This exclusion criterion was added to ensure participant safety, so that those with insufficient muscle mass are not vaccinated
Section 5.5 – Criteria for Temporarily Delaying Enrollment/Randomization/ Administration of Study Intervention	Clarified that symptoms indicative of COVID-19 illness, in the opinion of the investigator, meet the criteria for temporarily delaying vaccine administration	This clarification was added in line with other C459 program studies
Section 6 – Study Intervention(s) and Concomitant Therapy	Clarified that study age groups are assigned by age at Visit 1; participants will receive the same dose level at all 3 vaccination visits	This clarification was added in response to Investigator questions
Section 6.1 – Study Intervention(s) Administered	Added the 10-µg dose level for participants ≥5 to <12 years of age	This dose level was determined by data from the C4591007 study
Section 6.1 – Study Intervention(s) Administered	Added the 3-µg dose level for participants <5 years of age	This dose level was determined by data from the C4591007 study
Section 8.9 – Study Procedures	Clarified visit procedures for participants in the PBMC subset	Clarification was added that the PBMC blood draw (and inclusion in the PBMC subset) is only for those participants who are eligible and have consented to this procedure
Section 8.9.3 – Visit 3 – 1-Week Follow-up Visit (After Vaccination 2) (6 to 8 Days After Visit 2)	Added wording to allow Visit 3 to be conducted via telehealth for participants not in the PBMC subset	As in-person procedures are not required for these participants at Visit 3, this visit may be conducted via telehealth
Section 8.11.1 – Potential COVID-19/MIS-C Convalescent Visit (28 to 35 Days After Potential COVID-19 Illness Visit)	Removed the requirement to conduct a potential COVID-19/MIS-C convalescent visit following each COVID-19/MIS-C illness visit	Sufficient data were collected in Study C4591001
Section 9.2 – Analysis Sets	Clarified that participants are not randomized	As this is an open-label study and study intervention will be assigned to participants, no randomization will occur
Section 9.4 – Interim Analyses	Clarified that, as this is an open-label study, the sponsor may conduct reviews of all available safety and immunogenicity data during the course of the study	This update clearly documents the intended data reviews during the study
Section 9.4 – Interim Analyses	Clarified that no formal interim analysis will be conducted for this study, but analyses may be	This update clearly documents the intended
	carried out when the final data for specified objectives for a particular cohort (out of the 6 cohorts; participants ≥18 years of age receiving treatment for CLL, NSCLC, and end-stage renal disease; participants ≥2 to <5, ≥5 to <12, and ≥12 to <18 years of age) are available	data analyses during the study
Section 9.4.1 – Analysis Timing	Removed the analysis at 7 days after Dose 3	Analysis is being conducted 1 month after Dose 3, which is a more appropriate timepoint to look at responses following vaccination in an immunosuppressed population

Original protocol — 16 April 2021 (0 change rows)

(no detailed Section / Description / Rationale table for this amendment in the source PDF)