| Protocol No: | ECCT/21/06/12 | Date of Protocol: | 18-05-2021 |
| Study Title: |
A parallel-group, Phase III, multi-stage, modified double-blind, multi-armed study to assess the
efficacy, safety, and immunogenicity of two SARS-CoV-2 Adjuvanted Recombinant Protein
Vaccines (monovalent and bivalent) for prevention against COVID-19 in adults 18 years of age
and older
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| A parallel-group, Phase III, multi-stage, modified double-blind, multi-armed study to assess the efficacy, safety, and immunogenicity of two SARS-CoV-2 Adjuvanted Recombinant Protein Vaccines (monovalent and bivalent) for prevention against COVID-19 in adults 18 years of age and older as a primary series and open-label extension to assess immunogenicity, safety, efficacy of a monovalent booster dose of SARS-CoV2 Adjuvanted Recombinant Protein Vaccine | |
| Study Objectives: |
Key Primary objectives
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| Laymans Summary: |
1. Monovalent: SARS-CoV2 prefusion Spike delta TM with AS03 adjuvant, monovalent D614 (CoV2 preS dTMAS03 [D614])
2. Bivalent: SARS-CoV2 prefusion Spike delta TM with AS03 adjuvant, bivalent D614/B.1.351 (CoV2 preS dTM-AS03 [D614 + B.1.351])
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| 1 | The amendments are basically information related to the Crossover and/or Booster parts that are being added to the study and possible risks from the study product. Before anything is done for the new parts of the study, all participants in Stage 1 and Stage 2 will be told whether they got the vaccine or the placebo. This is known as “unblinding”. The participants will also be informed and they will be able to ask questions about early results from Stage 2 of the study. For the Crossover, if the participant was offered placebo in the initial part of the study, they may be offered either the monovalent D614 vaccine that was tested in Stage 1 of the study, or be advised to get an authorized/approved vaccine (outside of the study) if one is available in your area. For the Booster part of the study, participants who are eligible will get a booster dose of a study vaccine after receiving a primary vaccination series to help to “boost” their immune system to create more antibodies to help maintain the protection. The booster vaccine will be a monovalent vaccine similar to the one tested in Stage 1 of the initial part of the study, but it will contain a different variant called B.1.351 (beta variant). This vaccine is called “monovalent beta booster vaccine”. The time lines have changed with the new crossover and booster additions to: 1. If a participant got the bivalent D614+B.1.351 study vaccine tested in Stage 2 in the initial part of the study: their participation will last to about 12 months after they get the monovalent beta booster vaccine (about 18 to 24 months total) 2. If a participant got the placebo in the initial part of the study: their participation will last about 4 months after getting the second dose of the monovalent D614 vaccine in the Crossover, and then for about another 12 months as part of the Booster (about 28 to 34 months total) |
| Abstract of Study: |
Background
SARS-CoV-2 is a novel coronavirus that emerged in the human population and has led to a pandemic of acute respiratory disease named COVID-19. The burden of SARS-CoV-2 morbidity and mortality has been catastrophic with greater than 2.8 million deaths recorded since first emerging in December 2019 among over 131.9 million confirmed cases (as of 06 April 2021) (2). In many locations, the rapid emergence of COVID-19 has overwhelmed the capacity of health systems to provide care for COVID-19-affected patients, let alone unaffected patients. Interventions to reduce transmission through reduction of population contact (also called social distancing) has had profound economic consequences. Safe and effective vaccines with sufficient supply would be vital to address the significant medical and societal burden caused by the pandemic. The CoV2 preS dTM-AS03 vaccines developed by Sanofi Pasteur utilize a recombinant protein approach in combination with an oil-in-water adjuvant, AS03 provided by GlaxoSmithKline (GSK). The CoV2 preS dTM-AS03 vaccines belong to the pharmacotherapeutic group of “covid19 vaccines”. The vaccines contain recombinant S protein, stabilized to maintain native prefusion trimer configuration as present on the viral envelope. The purpose of the study is to assess the efficacy, safety, and immunogenicity of two CoV2 preS dTM-AS03 vaccines (monovalent and bivalent) in adults 18 years of age and older in a multi-stage approach.
Methods
This study is designed to maximize representation of the broader population by minimizing exclusionary eligibility criteria and allowing the participation of individuals with a broad range of medical conditions, including controlled HIV infection, Hepatitis B and Hepatitis C, and conditions associated with an increased risk of severe COVID-19. It is also designed to be inclusive of other subpopulations affected by COVID-19, including older adults as well as ethnic and racial minorities. Participants will be screened for eligibility criteria at the time of inclusion and then randomized to either the investigational vaccine or placebo in a 1:1 ratio in each stage. • Stage 1: eligible participants will be randomized to receive either 2 injections of CoV2 preS dTM-AS03 (D614) vaccine or Placebo 1 (participants who receive the placebo as part of Stage 1) administered 21 days apart • Stage 2: eligible participants will be randomized to receive 2 injections of either CoV2 preS dTM-AS03 (D614 + B.1.351) vaccine or Placebo 2 (participants who receive placebo as part of Stage 2) administered 21 days apart. Randomization will be stratified by age groups (18-59 years of age and 60 years of age and older), baseline SARS-CoV-2 rapid serodiagnostic test positivity, and site. In the event that the enrollment in Stage 1 overlaps with enrollment of Stage 2, participants will continue to be randomly allocated to one of the investigational vaccine groups and their matched placebo group in a 1:1 ratio.
Approximately 37 430 participants are planned to be enrolled (8000 per study intervention group in Stage 1 and 10 715 per study intervention group in Stage 2)The duration of the study for each participant will be 365 days post-last injection (ie, approximately 386 days total). The study includes 8 visits at D01, D22, D43, D78, D134, D202, D292, and D387. Participants will be contacted once a week over the entire duration of the study to inquire about the development of symptoms of COVID-19-like-illness and to remind participants to contact study staff if they experience symptoms of COVID-19-like illness. Additional visits and procedures are included for participants with verified COVID-19-like illness
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| 1 | Title Page
Summary of Changes
Date and version changed to Version 8.0 dated 08 September 2022
Rationale for Change
Protocol updated from Version 5.0 to Version 8.0
Document History and Overall Rationale for the Protocol Update; Appendix 10.10
Summary of Changes
Revised document history - Added rationale for major changes from version 5.0 to version 8.0 - Moved changes from previous versions to Appendix 10.10
Rationale for Change
Updates due to change in version, per Common Protocol Template instructions
Throughout the protocol
Summary of Changes
From version 5.0 to version 6.0:
Added Unblinded Crossover / Booster study design, objectives/endpoints, justification, new booster vaccine study intervention.
“Stage 1 participants will be invited upon consent to continue participation as part of an unblinded crossover / booster study design. The participant unblinding and consent will trigger the endof the initial double-blind primary series design and the start of the Crossover / Booster design, which includes a primary series vaccination for initial placebo recipients (ie, crossover vaccination) and a booster for both initial placebo and vaccine recipients (ie, booster vaccination). Initial Stage 1 and Stage 2 design is now referred to as “initial, double-blind, primary series study design” Based on an interim/final efficacy analysis and the recommendation of the Study OG, primary series followed by a booster dose will be offered to initial placebo recipients and a booster will be offered to initial vaccine recipients to participants in Stage 2. The investigational product to be in used in the Stage 2 unblinded crossover vaccinations will be determined based on available efficacy data.”
Rationale for Change
From version 5.0 to version 6.0: Crossover/Booster design added for Stage 1 based on decisions of the Study Oversight Group (OG). After unblinding, participants who were initially in the placebo group will be offered vaccination. In addition, a booster vaccination will be available participants in both placebo and vaccine groups to provide additional protection. Similar procedures are proposed for participants in Stage 2 based on OG recommendations when results from Stage 2 are available.
Throughout the protocol
Summary of Changes
From version 6.0 to version 7.0: Updated Unblinded Crossover / Booster study design for Stage 1 and added same design for Stage 2. “All participants in Stage 1 and Stage 2 will be unblinded and informed of the results of the study. Study Investigators will discuss the possibility of receiving the (authorized/approved) vaccines available to them outside of the study. Based on decisions of the Study Oversight Group (OG), participants will be invited upon consent to continue participation as part of an unblinded crossover / booster study design. The participant unblinding and consent will trigger the end of the initial doubleblind primary series design and the start of the Crossover / Booster design, which includes a primary series vaccination for initial placebo recipients (ie, crossover vaccination) and a booster for both initial placebo and vaccine recipients (ie, booster vaccination). Non-naïve participants who initially received placebo and are 18-59 years of age will be offered the opportunity to receive the investigational CoV2 preS dTM-AS03 monovalent (D614) vaccine if authorized/approved vaccines are not available or if they choose not to receive an authorized/approved vaccine series. Naïve participants 18-59 years of age and all participants ≥ 60 years of age who initially received placebo will be recommended to receive an authorized/approved vaccination series. If initial placebo recipients of any age received the complete primary series of an authorized/approved vaccine outside of the study or the investigational study vaccine as a primary series, they will also be offered the opportunity to receive Sanofi Pasteur’s investigational Cov2 preS dTM-AS03 monovalent (B.1.351) booster vaccine ≥ 4 months post-last dose of the primary series or encouraged to receive an authorized/approved vaccine according to local guidance. Participants who initially received the complete primary series of the CoV2 preS dTM-AS03 monovalent (D614) vaccine (Stage 1) or CoV2 preS dTM-AS03 bivalent (D614+B.1.351) vaccine (Stage 2) will be offered the opportunity to receive Sanofi Pasteur’s investigational CoV2 preS dTM-AS03 monovalent (B.1.351) booster vaccine ≥ 4 months post-last dose of the primary series or encouraged to receive an authorized/approved vaccine according to local guidance. If participants do not consent to continue with the unblinded Crossover / Booster, all study procedures will be stopped, and participants will be discontinued from the study and recommended to receive the authorized/approved vaccination series per local guidance investigational CoV2 preS dTM-AS03 monovalent (B.1.351) booster vaccine ≥ 4 months post-last dose of the primary series or encouraged to receive an authorized/approved vaccine according to local guidance. If participants do not consent to continue with the unblinded Crossover / Booster, all study procedures will be stopped, and participants will be discontinued from the study and recommended to receive the authorized/approved vaccination series per local guidance.”
Rationale for Change
From version 6.0 to version 7.0: Crossover/Booster design revised for Stage 1 and same procedures added for Stage 2 based on available data and decisions of the Study Oversight Group (OG). Recommendations from the OG were based on the latest available results, where efficacy was demonstrated in non-naïve participants 18-59 years of age. Data were limited in other populations which precluded any valid conclusion and subsequent recommendation. Text changed: - From:“…at least 1 dose of primary series…” - To: “…the complete primary series…” Reason: To ensure the booster dose is administered to participants who have completed their primary series vaccination schedule to ensure best protection.
Document History and Overall Rationale for the Protocol Update
Summary of Changes
From Protocol version 5.0 to protocol version 6.0: Added text as shown below: “This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European Union.”
Rationale for Change
From Protocol version 5.0 to protocol version 6.0: This change was considered as a substantial amendment from v5.0 to v6.0 (protocol v6.0 categorized as substantial) because the primary objective of the study was changed for Stage 2 and the design of the crossover/booster part of the study was incorporated into the protocol. Text added to follow Common Protocol Template requirements.
Document History and Overall Rationale for the Protocol Update
Summary of Changes
From Protocol version 6.0 to protocol version 7.0: Added text as shown below: “This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European Union because it neither significantly impacts the safety or physical/mental integrity of participants nor the scientific value of the study.
Rationale for Change
From Protocol version 6.0 to protocol version 7.0 Changes from v6.0 to v7.0 considered as non-substantial as only additional details were added. Stage 2 was already present in previous version without details. Text revised to be non-substantial to follow Common Protocol Template requirements
Throughout the protocol
Changes
Replaced “Sanofi Pasteur” with “Sanofi”
Rationale for Change
Company name updated to reflect change made within the organization.
Synopsis: Rationale
Changes
Updated variants of concern text.
Rationale for Change
Update according to most recent epidemiology and variants of concern circulation
Synopsis: Procedures
Changes
Follow-up of participants who report symptoms of myocarditis and/or pericarditis within 6 weeks of vaccination is now described.
Rationale for Change
Text added to address how risk of myocarditis and/or pericarditis will be mitigated by the Sponsor with regards to signal detection, case evaluation and management, and discontinuation from further vaccination.
Synopsis: Data Monitoring/Other Committee
Changes
Statement added: “In the event that a participant develops symptoms that are suspected to be caused by myocarditis and/or pericarditis, the case will be referred to an external cardiac adjudication committee for assessment and confirmation.”
Rationale for change
External cardiac adjudication committee will be utilized for facilitate signal management of suspected cases of myocarditis and/or pericarditis.
Efficacy Objectives/Endpoints:
Changes
From version 5.0 to version 6.0: Primary Efficacy: Original primary efficacy objective now specified as Stage 1 only, and a new primary efficacy added specific to Stage 2 as below:“To assess, in all participants regardless of prior SARS-CoV-2 infection, the clinical efficacy of the CoV2 preS dTM-AS03 vaccines for prevention of symptomatic COVID-19 ≥ 14 days after the second injection.”
Key Secondary and Other Secondary Efficacy Objectives (tables and body text): Clarified as to which stage they applied, where necessary Added objective #12 as shown below (note that this was further revised in changes from version 6.0 to version 7.0, see row below): “Stage 2 only: To assess, in participants who are SARS-CoV-2 naïve, the clinical efficacy of the CoV2 preS dTM-AS03 vaccines for the prevention of symptomatic COVID-19 occurring ≥ 14 days after the second injection.”
Rationale for Change
From Protocol version 5.0 to protocol version 6.0: Given the current global epidemiological situation where most of the population has already been infected, the primary population for the assessment of vaccine efficacy in Stage 2 was changed from naïve participants to all participants who meet per-protocol defined criteria. Therefore, an additional secondary objective for the assessment of vaccine efficacy in the naïve population in Stage 2 was incorporated.
Objectives for each of the stages were specified for clarity
Other Secondary Efficacy Objectives/Endpoints (Synopsis and Table 3.2):
Changes
From Protocol version 6.0 to protocol version 7.0 Revised Objectives #4 and #12 as shown below: Objective #4: Stage 1 only: To assess, in all participants regardless of prior SARSCoV-2 infection, the clinical efficacy of the CoV2 preS dTM-AS03 vaccines for: • Prevention of symptomatic COVID-19 • Prevention of severe COVID-19 Endpoints for #4
Specified as Stage 1 only. Objective/endpoints #12: Added severe COVID-19 Stage 2 only: To assess, in participants who are SARS-CoV-2 naïve, the clinical efficacy of the CoV2 preS dTM-AS03 vaccines for: • Prevention of symptomatic COVID-19 • Prevention of severe COVID-19
Rationale for Change
From Protocol version 6.0 to protocol version 7.0 Assessment of efficacy against symptomatic COVID-19 in all participants regardless of baseline status is now the primary endpoint for Stage 2 and assessment of efficacy against severe cases in all participants regardless of baseline status is now a key secondary endpoint for Stage 2; therefore, they were removed from Objective 4. Efficacy against severe cases was added in objective/endpoint to cover this endpoint for Stage 2.
Exploratory Efficacy Objectives/Endpoints
Changes
Added exploratory efficacy objective #15: To describe the relative efficacy against symptomatic COVID-19 by variants between the monovalent and bivalent vaccines.
Rationale for Change
Additional analyses planned to be able to
compare the two vaccines within the same
study.
Synopsis and Table 4.1: Countries
Changes
- Stage 1: removed Uganda and Sri Lanka - Stage 2: removed Sri Lanka and Nigeria; and added Ukraine and Mexico
Rationale for Change
Updated list since previous protocol version
Tables 1.1 and 1.2 and Tables 4.1 and 4.2
Changes
Revised sample size for Random Immunogenicity Subset.
Rationale for change
Corrected error to align with Table 10.6
Table 1.5 and Table 1.6
Changes
Table note added to “Safety follow-up (MAAEs, SAEs, and AESIs)” row: AESIs (serious and non-serious) will be collected throughout the study and will be communicated to the Sponsor in an expedited manner similar to the reporting of SAEs and followed-up until the end of the follow-up period or resolution, as per the assigned causality. These include: Anaphylactic reactions, Generalized convulsion, Thrombocytopenia, Thrombosis withThrombocytopenia Syndrome, Myocarditis, Pericarditis, and potential immune-mediated diseases (pIMDs). Thrombocytopenia Syndrome, Myocarditis, Pericarditis, and potential immune-mediated diseases (pIMDs).
Rationale for Changes
Added for clarity and consistency with Table 1.3.
Throughout the Protocol
Efficacy/Safety follow-up for those who initially received placebo added and changed from 6 months post-booster to 12 months postbooster. Therefore, 12-month post-booster phone call added. With new study duration as specified below: “For participants who initially received placebo: ≥ 4 months postlast dose of the primary series + 6 12 months post-booster (ie, approximately 28 to 34 months”
Rationale for Change
No changes in safety assessment made for the study initial schedule. Additional detail is provided to describe safety follow up for unblinded crossover and booster vaccinations and to ensure the 12-month safety follow-up period after booster for both initial vaccine and placebo recipients, per CBERs request.
Synopsis and Section 9.3: Modified Full Analysis Set post-dose 2 (mFAS-PD2) row
Changes
Text added as shown below for bullet #2: “Participants with onset of symptomatic COVID-19 episode between the date of the first injection and before 14 days after the second injection.”
Rationale for changes
Text revised to add clarity and to be consistent with the primary objective.
Synopsis and Section 9.4.2.2: Primary Safety Endpoints
Changes
Method revised as shown below: “The corresponding 95% CIs for incidence rates will be calculated based on the Poisson method, and 95% CI for percentages or proportions will be calculated based on Person-Clopper method”
Rationale for Changes
Poisson method is more accurate due to shortened follow-up time.
Sample size determination
Changes
Added text as shown below: “Because Omicron is the prevalent variant during case accrual for Stage 2 and the expected vaccine efficacy against Omicron is expected to be lower than the original assumption of 70%, the expected true VE for symptomatic COVID-19 for Stage 2 was estimated at 60%. Therefore, a total of approximately 125 symptomatic COVID-19 events will be required to achieve 80% power with 1-side type I error rate of 0.025.”
Rationale for Change
Changes made to adjust for the most prevalent circulation of the Omicron variant during Stage 2 study conduct and the expected lower vaccine efficacy against this strain.
Synopsis and Section 4.1
Changes
Added text as below: “If the participant is unblinded or receives the authorized/approved vaccine, this information would be collected. These study participants will be allowed to continue study participation if they choose to do so but will not be allowed to crossover; while continuation in the study will include all study procedures including safety follow-up, they will be censored from that point onward for efficacy and immunogenicity analysis for the primary vaccination series.”
Rationale for change
Text added to be clear that these unblinded participants will not be part of crossover.
Synopsis and Section 9.4.2.1: Primary efficacy endpoint
changes
“Stage 1”, “Stage 2”, or “each stage” specified as appropriate.
Rationale for changes
Text revised to align with efficacy objectives changes noted above
Throughout the Protocol
changes
AESIs: include myocarditis and pericarditis
Rationale for change
Myocarditis and pericarditis have been detected as safety signals for other COVID-19 vaccine platforms. They have been added as AESIs to the VAT00002 study protocol. To keep the list of AESIs aligned across the different clinical studies in the project these adverse events are added to the list of AESIs for VAT00008 as well.
Section 2
Changes
Introduced an investigator sponsored study, VAT00013 - COVIBOOST
Rationale for Change
Introduced in Section 2 before presenting data in Section 2.3.2 to support benefit of the study vaccine, particularly against the omicron variant.
Section 2.2
changes
1. Updated previous experience in humans for the monovalent D614 vaccine and nonclinical studies with the bivalent D614+B.1.351 vaccines and the monovalent D614 and monovalent B.1.351 vaccines.
2. Background updated with new sub-section for Clinical data for the CoV2 preS dTM-AS03 bivalent (D614+B.1.351) vaccine
Rationale for Change
1. Updates made with data available at the time of this amendment to support Crossover / Booster study design and use of Beta Booster
2. New efficacy and safety data for VAT00008 Stage 2 available at the time of this amendment to support crossover.
Section 2.3
Changes
- Updated Benefit risk with new data from VAT00008 and VAT00002 - Updated VAED text - Updated narcolepsy text.
Rationale for Changes
Updates made with data available at the time of this amendment in line with updates also to the CoV2 preS dTM-AS03 IB as well as GSK’s most recent AS03 adjuvant IB.
Table 2.2
Changes
- Updated Risk Table with new disclaimer note in the “Enhanced COVID-19/VAED” row as shown below:
"Risk not applicable for the booster vaccination: Vaccine Associated Enhanced Disease (VAED) including Vaccine Associated Enhanced Respiratory Disease (VAERD) is a risk in the naïve population as per Brighton Collaboration case definition. Since the booster dose is administered in already vaccinated individuals, this potential risk is not considered for the booster vaccination.”
- Text added to clarify that, although no safety concern has been identified for the CoV2 preS dTM vaccine to date, myocarditis and pericarditis have been reported following vaccination with other COVID-19 vaccines manufactured using both the mRNA and protein/adjuvant platforms. Available data on the epidemiology and clinical course of myocarditis and pericarditis were included.
Rationale for Change
Updates made with data available at the time of this amendment in line with updates also to the CoV2 preS dTM-AS03 IB as well as GSK’s most recent AS03 adjuvant IB.
- Added clarity of known risks based on data from Stage 1 and Stage 2.
- Text added to communicate risk of myocarditis and/or pericarditis due to vaccination with a COVID-19 vaccine.
Section 2.3
Change
Added text as shown below: “Other potential risks, which apply to COVID-19 vaccines using other platforms than the study vaccines, are blood clotting, myocarditis, and pericarditis. Thrombosis with thrombocytopenia syndrome, myocarditis, and pericarditis represent AESIs in the study accordingly. However, these events were not included into the Risk Management Plan (RMP) as potential risks of the study vaccinesbecause, based on currently available evidence, no safety concern was identified for the CoV2 preS dTM vaccine. Myocarditis and pericarditis have been reported following vaccination with mRNA COVID-19 vaccines, mainly in males under the age of 40 years within 14 days after a second dose. However, cases have also been reported in older males, in females, and following other doses. The observed risk is highest in males 12 to 17 years of age. While some cases required intensive care support, available data from short-term follow-up suggest that symptoms resolve in most individuals with conservative management. Information is not yet available about potential longterm sequelae (64). Myocarditis and pericarditis events have also been detected in clinical studies and post-authorization surveillance of the Novavax COVID 19 vaccine, which is manufactured using a protein/adjuvant platform and a different adjuvant system than the CoV2 preS dTM vaccine (65). Based on this potential risk, participants will be advised to seek immediate medical attention and notify study site staff if symptoms compatible with myocarditis or pericarditis occur following vaccination. Participants with events of myocarditis and/or pericarditis will be discontinued from further vaccination and followed for subsequent visits as per the protocol for safety, immunogenicity, and efficacy endpoints.”
Rationale for the change
Added wording into this section mentioning blood clotting, myocarditis and pericarditis in order to communicate the risk associated with COVID-19 vaccines. Indicated these events were not included into RMP since no safety concern has been identified for the study vaccine.
Section 2.3.2 and 2.3.3
Change
Added benefits of Beta booster vaccination, specifically for omicron variant.
Rationale for the Change
Summary added to support benefits of Beta Booster to be used for the Booster vaccination in the study.
Section 4.1 Overall Design: Procedures
Changes
Follow-up of participants who report symptoms of myocarditis and/or pericarditis within 6 weeks of vaccination is now described
Rationale for Change
Text added to address how risk of myocarditis and/or pericarditis will be mitigated by the Sponsor with regards to signal detection, case evaluation and management, and discontinuation from further vaccination.
Section 4.2
change
Updated rationale for development approach for variants, VAT00008, and VAT00002 Supplemental cohorts
Rationale for change
Development approach updated with data available at the time of this amendment.
change
Justification for the age range and study population: added paragraph for cases in VAT00008 Stage 1 and VAT00002 booster data surrounding participants ≥ 60 years
Rationale for change
Justification expanded incorporating updated information available at the time of this amendment
change
Text revised as below: The AS03 adjuvanted H7 recombinant protein vaccine was found to be well tolerated with an acceptable safety profile and led to robust immune responses.
Rationale for change
No need to state “safe”, there is no vaccine 100% safe, and in the text is already mentioned “well tolerated and with acceptable safety profile”, which was clear as-is.
Section 4.3
Change
Justification for Dose: Added VAT00002 Supplemental Cohort data
Rationale for change
Data added to support booster study design and booster study intervention of a beta booster at 5 µg antigen dose.
Change
Justification for crossover vaccination with CoV2 preS DTM-AS03 monovalent (D614) vaccine: Added subsection for justification of monovalent (D614) vaccine for crossover vaccination
Rationale for Change
Data added to support crossover design.
change
Justification for booster vaccination with CoV2 preS DTM-AS03 monovalent (B.1.351) vaccine:Revised subsection for justification of monovalent (B.1.351) vaccine for booster vaccination
Rationale for change
Data added to support booster design
Section 5.4
Change
Deleted text as shown in PROTOCOL SUMMARY OF CHANGES FROM v5 to v 8 dated 08 sep 2022 page 14
Rationale for change
To allow for assessment of naïve and nonnaïve participants to be done using the tests that will be used for analyses instead of the RDT.
Section 6.9
Changes
Revised text as shown below: Reportable medications/vaccinations will be collected in the CRF from the day of each Initial study vaccination only to the end of the solicited and unsolicited follow-up period after each Initial study vaccination in all participants, with the exception of influenza and COVID-19 vaccination which will be collected throughout the study in all participants. In addition, any medications used for COVID-19 treatment or prophylaxis (eg, SARS-CoV-2 antivirals, monoclonal or polyclonal antibodies or plasma) will be collected throughout the study in all participants.
Rationale for change
Reportable medications/vaccinations will be
collected in the CRF only after each Initial
study vaccination but not during crossover
vaccinations. Any medications used for
COVID-19 treatment or prophylaxis (eg,
SARS-CoV-2 antivirals, monoclonal or
polyclonal antibodies or plasma) have to be
collected will still be collected during
crossover.
Section 7.1.4 (Definitive Contraindication #8 for Crossover/Booster Design) and throughout
Change
Definitive Contraindication #8 and throughout: Previous text required at least 1 dose of primary vaccination. New text changed to require the complete primary series before booster vaccination.
Rationale for change
To ensure participants complete primary series before receiving the booster vaccination.
Section 7.1.4 (Definitive Contraindication #9 for Crossover/Booster Design)
Change
Included history of myocarditis and/or pericarditis prior to vaccination as definitive contraindication to further vaccination in the crossover/booster stage of the study.
Rationale for Change
Added as a definitive contraindication to ensure that participants with a history of myocarditis and/or pericarditis are excluded from further vaccination in the crossover/booster stage of the study. History of myocarditis and/or pericarditis were not added to exclusion criteria since the study has finished recruitment.
Table 8.1
Change
Added note as shown below: “†† BL1-BL3 samples for all US participants only will be tested in the D614G Pseudovirus neutralization assay at Monogram”
Rationale for Change
Separate notation added that testing all BL1- BL3 samples from US subjects only in the D614G PSVN at Monogram
Section 8.1.4.1: Assure COVID-19 IgG/IgM Rapid Test
Change
Added text: “Other local tests could be used if the Assure COVID-19 IgG/IgM Rapid Test is not allowed for use in the country where the study is conducted.
Rationale for Change
To give flexibility for countries where the Assure test is not allowed for use
Section 8.2.1.1
Change
Definition for COVID-19-like-illness: Previous text: • Fever (measured temperature > 100.4ºF OR 38.0ºC)
Revised text: • Fever (measured temperature ≥ 100.4ºF OR ≥ 38.0ºC)
Rationale for Change
Revised to “≥” to align with measurement used in the Case Report Forms and intensity grading scales
change
Reversed order of COVID-19 severity scale as shown below:
1) Death
2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation
3) Hospitalized, on non-invasive ventilation or high flow oxygen devices
4) Hospitalized, requiring supplemental oxygen
5) Hospitalized, not requiring supplemental oxygen – discharged but requiring ongoing medical care (COVID-19 related or otherwise)
6) Hospitalized, not requiring supplemental oxygen – discharged without ongoing medical care
7) Not hospitalized.
Rationale for change
Order reversed to match order of presentation in the blank Case Report Forms
Section 8.2.2.5
Change
Blood sampling revised as shown below: “SARS-CoV-2 binding antibodies will be measured using an electrochemiluminescence immunoassay (ECLIA) on blood samples BL0001-BL0003 and…”
Rationale for Change
Sample numbers changed from “BL0008” to “BL0003” to align with plan in Table 8.1
Section 8.4.6
Change
- Replaced previous references for myocarditis and pericarditis with reference to the Centers for Disease Control and Prevention (CDC) case definitions. - Relocated all case definition references to footnotes for readability.
Rationale for Change
The CDC case definitions for myocarditis and pericarditis were included as they are more specific than the Brighton Collaboration case definitions.
Section 9.5
Change
“Stage 1”, “Stage 2”, or “each stage” specified as appropriate for analysis sets.
Rationale for change
Text revised to align with efficacy objectives changes noted above
Section 10.1.5
Change
Added new subsection 10.1.5.2 Cardiac Adjudication Committee.
Rationale for change
Subsection added to reflect implementation of an external cardiac adjudication committee for assessment/confirmation of suspected cases of myocarditis and/or pericarditis to mitigate risk due to these events.
Section 10.5
Change
Included definitions for probable and confirmed cases of myocarditis, as well as acute pericarditis.
Rationale for Change
Text added to guide the investigator in the reporting of suspected cases of myocarditis and/or pericarditis.
Section 10.5 (Table 10.4)
Change
Table 10.4 List of potential immune-mediated diseases: Table replaced with an updated table; date updated in table title to “version: January-2022”
Rationale for Change
Updated for consideration of emerging possible immune-mediated pIMDs of interest in the context of COVID-19 vaccine safety monitoring
Table 10.6
Change
Bivalent Vaccine row: Data for 18-59 years changed from “75” to “750"
Rationale for change
Administrative error corrected.
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