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Title Page / Headers
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3 to 5
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Date and version changed to Version 5.0 dated 08 September 2021
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Protocol updated from version 3.0 to version 4.0. Then updated again from version 4.0 to version 5.0. Since version 4.0 was not used in the study, Amendment number remains at Amendment #1 for version 5.0.
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Document History and Overall Rationale for the Protocol Update; Appendix 10.8 (Protocol Amendment/Update History)
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3 to 5
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Revised document history
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Added rationale for major changes from version 4.0 to version 5.0 (kept changes from version 3.0 to version 4.0 in the table too)
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Moved rationale for changes for version 2.0 to version 3.0 from Document History section to Appendix 10.8
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Updates due to change in version, per Common Protocol Template instructions.
Since version 4.0 was not used in the study, kept changes from versions 3.0 to version 4.0 for Investigators.
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Title Page
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3 to 4
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Revised as shown below:
Medical Monitor name Responsible Medical Officer (RMO) and pharmacovigilance (PV) representative names and contact information are provided in the Operating Guidelines.
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Per recent Common Protocol Template changes.
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Synopsis: Rationale / Section 2 / Section 2.2
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3 to 4
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Johns Hopkins text changed to more general statement.
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To eliminate need to keep updating cases/deaths between document versions and across documents.
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Throughout
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3 to 4
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Greek strain/variant naming conventions added.
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To align with the World Health Organization naming convention of COVID-19 variants (see https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/).
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Throughout
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3 to 4
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At mention of VAT00002:
Added text for booster study and added “Original Cohort of VAT0002”
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Study VAT00002 has been amended to include supplemental Phase III booster cohorts. Initial portion of study (“Original Cohort of VAT00002”, Phase II) is ongoing.
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Synopsis: Rationale / Section 2.2 / Section 4.2
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3 to 4
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Nonclinical Studies text added for bivalent vaccine data.
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Additional data added at time of this protocol update, in line with text in the Investigator’s Brochure update.
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Objectives: Synopsis and Table 3.1
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3 to 4
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Add secondary efficacy objectives #11 and #12, with accompanying endpoints:
#11:
“To assess the durability of vaccine efficacy post-crossover in all participants and by prior SARS-CoV-2 infection (naïve and non-naïve).”
#12:
“To assess the durability of vaccine efficacy post-crossover, in participants who are SARS-CoV-2 naïve.”
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Additional objectives related to crossover design added to assess the long-term vaccine efficacy in all participants including in those vaccinated through crossover.
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Objectives: Synopsis and Table 3.1
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3 to 4
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Added secondary immunogenicity objective #5:
#5:
To describe the neutralizing antibody profile at D01, D22, D43, D78, D134, D202, D292, and D387 in each study group for participants aged 18‑25 years in the Random Immunogenicity Subcohort.
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Additional objective added to analyze immunogenicity data in younger adults (18-25 years). This age-group is the comparator group for pediatric population and the data generated will support pediatric development plan.
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Objectives: Synopsis and Table 3.1
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3 to 4
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Added secondary safety objective #2:
“To assess the safety of the CoV2 preS dTM-AS03 vaccines compared to placebo in participants aged 18‑25 years throughout the study.”
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Additional objective added to analyze safety data in younger adults (18-25 years). This age-group is the comparator group for pediatric population and the data generated will support the pediatric development plan.
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Table 3.1 only
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3 to 4
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Exploratory efficacy objectives #9 and #10 added, with accompanying endpoints:
#9:
“To describe in each group the occurrence of events that may be classified as Long COVID syndrome.”
#10:
“To assess impact of vaccination on asymptomatic SARS-CoV-2 NAAT positivity at the time of the crossover set of vaccinations in naïve participants.”
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#9: Additional exploratory efficacy objective to assess occurrence of Long COVID syndrome.
#10: Additional exploratory efficacy objective related to crossover design added.
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Countries: Synopsis and Table 4.1
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3 to 4 and 4 to 5
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Updated countries:
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Stage 1: United States, Honduras, Japan, Colombia, Kenya, Uganda, India, Ghana, Nepal, Sri Lanka
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Stage 2: Colombia, Kenya, Uganda, India, Ghana, Nigeria, Nepal, Sri Lanka, and others TBD
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Known and anticipated countries at the time of this amendment.
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Throughout
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3 to 4
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Blinded Crossover text/tables added
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Description of blinded crossover design including additional study visits and procedures was added throughout the protocol.
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Throughout
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4 to 5
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Overall sample size reduced for each stage
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The assumed incidence rate for the study was revised based on monitoring available epidemiological data in the public domain in VAT08 countries. The assumed incidence rate over 2 months was increased from 1.25% to 2.25% which reduces the sample size of the study and for each stage. This decreases the proposed sample size of the study from 37 430 to 21 046.
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Throughout
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4 to 5
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For Stage 2:
Reactogenicity subset sample size reduced to match Stage 1
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Despite reducing sample size of the study, kept subsets as-is for Stage 1. This maintains the proposed number of 2000 participants in each intervention arm to provide reactogenicity data.
Reduced Reactogenicity subset and Random Immunogenicity subset sample size for Stage 2 to be consistent with Stage 1 as Stage 2 sample size is similar to Stage 1.
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Throughout
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4 to 5
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For Stage 2:
Random Immunogenicity subset sample size reduced to match Stage 1
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Throughout
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4 to 5
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Cap for participants who are SARS-CoV-2 non-naive at baseline changed from a “maximum of approximately 20%” to “30%”
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This reflects the observed increase in SARS-CoV-2 seropositivity rates in the study and decreases the number of screen failures while maintaining sufficient number of SARS-CoV-2 naïve adults for demonstration of the primary objective.
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Throughout
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4 to 5
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Target recruitment enrollment for older adults (≥ 60 years of age) changed from “at least 40%” to “approximately 40%”
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The target to recruit older participants in the study is maintained; however, as there is widespread global COVID-19 vaccination campaigns with prioritization of vaccination of older adults, recruitment and retention of older adults in the trial is unlikely to be higher than 40% of the entire study population.
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Throughout
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4 to 5
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Within the age group of 18-59 years, the study target for recruitment of participants with high-risk medical conditions for COVID‑19 changed from “35%” (and “at least 35%”) to “approximately 35%”.
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This modification has been made to be consistent with the wording through the document stating that the recruitment targets are approximates.
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Analysis Sets: Synopsis Table and Section 9.3
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3 to 4
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Added bullet for Modified Full Analysis Set post-dose 1 and post-dose 2 text:
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(Section 9.3 only) Post-dose 1: “Participant discontinued from study before 14 days after the first injection”
(Synopsis and Section 9.3) Post-dose 2: “Participant discontinued from study before 14 days after the second injection”
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Definition of mFAS-PD1 and mFAS-PD2 revised to match revised SAP text. Events accrued only after D14 post-vaccination will be evaluated for the efficacy endpoints and therefore participants censored prior to 14 days post-vaccination will not be included in the modified FAS.
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Synopsis
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3 to 4
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Added for key secondary endpoints:
“Hypothesis testing for key secondary objectives will be conducted if both of the following conditions are met:
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The primary objective is demonstrated
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22 severe cases and 162 infections are collected
If both of the criteria are met, the hypothesis testing of the key secondary endpoints will be done in the same timeframe as the efficacy analysis for the primary endpoint.
If either criteria are not met, hypothesis testing for the key secondary endpoints will be performed with final data available in comparison to a placebo control, (ie, at the time of the analysis with data prior to the cross-over) if at least a minimum of 11 severe events or 70 infections are collected.”
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Added details of the strategy of hypothesis testing of the 2 key secondary endpoints with consideration of the crossover process to clarify scenarios considering the criteria of hypothesis testing and the timing of planned analyses prior to cross-over.
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Table 1.4: Schedule of Activities
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3 to 4
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For V04 – V08:
Changed Time window to “+/-14 days”
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If the crossover visit is scheduled 2 weeks prior to an original visit schedule (Initial V04 through V08 only), the 2 visits will be combined so no additional visit will be performed. If the crossover visit is scheduled 2 weeks after an original visit scheduled (Initial V04 through V08 only), minimal visit procedures necessary for vaccinating the participant will be undertaken without collection of additional blood samples.
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Section 4.2
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3 to 4
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Further rationale added for use of placebo
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To support the use of a placebo group in this study for vaccine efficacy evaluation and to reinforce the description of all measures set up to minimize risks related to placebo use, ie, encouraging participants to be vaccinated with an approved/authorized vaccine, no prohibition to receive approved/authorized vaccine during enrollment and at any time during the study, and access to the study vaccine for the placebo recipients.
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Table 6.1
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3 to 4
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Dose Form text updated and placeholder bivalent text replaced by actual text
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Description was not available at time of previous update. Updates made in line with current Investigator’s Brochure.
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Table 6.1
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3 to 4
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Bivalent CoV2 preS dTM-AS03 (D614 + B.1.351) Packaging and Labeling text updated (separate kits).
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Stage 2 will follow what was done for Stage 1.
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Section 6.2
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3 to 4
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List item #3 updated as shown below:
“The multi-dose vial of CoV2 preS dTM antigen, either monovalent or bivalent antigen, will be mixed with the multi-dose vial of the AS03 adjuvant at the site prior to administration. The vaccine formulation will be prepared in the CoV2 preS dTM antigen vials by adding an equal volume of AS03 adjuvant. Further details of the mixing protocol will be provided in the Operating Guidelines.”
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To include mixing for the bivalent vaccine used in Stage 2.
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Section 6.8
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3 to 4
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Updated from “Medical Monitor” to “RMO” as shown below:
However, in the event of an overdose, the Investigator should:
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Contact the
Medical Monitor RMO immediately.
Evaluate the participant to determine, in consultation with the Medical Monitor RMO, whether study intervention should be interrupted.
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To align with current Common Protocol Template changes.
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Section 7.1
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3 to 4
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Split out Temporary and Definitive contraindications into “Initial” and “Crossover” sections.
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To describe the different contraindications before (Initial) and after crossover.
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Section 7.1.4
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4 to 5
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Renumbered definitive contraindications for crossover
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To maintain consistency with numbering for contraindications that are the same between initial and crossover and to avoid the same numbering for 2 different items between initial and crossover.
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Section 9.5
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4 to 5
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Monitoring for Harm:
Changed the population used for harm monitoring from “FAS” to “SafAS”
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Changed to reflect change made in the SAP. Harm monitoring is safety analysis; it is more appropriate to use the safety population with treatment group as they actually received.
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Section 8.2.2.2 and 8.2.2.3
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3 to 4
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Previous testing Section 8.2.2.2 (SARS-CoV-2 Neutralizing Antibody Assessment [Sanofi Pasteur]) deleted and replaced by 2 new sections:
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Section 8.2.2.2: SARS-CoV-2 Pseudovirus Neutralization Assay (Nexelis)
Section 8.2.2.3: SARS-CoV-2 Virus Neutralization Assay (USG)
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Previous testing Section 8.2.2.2 (SARS-CoV-2 Neutralizing Antibody Assessment [Sanofi Pasteur]) deleted and replaced by 2 new sections:
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Section 8.2.2.2: SARS-CoV-2 Pseudovirus Neutralization Assay (Nexelis)
Section 8.2.2.3: SARS-CoV-2 Virus Neutralization Assay (USG)
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Section 8.10
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3 to 4
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Minor updates for leftover biological samples and use of data
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Minor updates for leftover biological samples and use of data
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Section 9.4.3.1
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3 to 4
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Added for key secondary endpoints:
“Hypothesis testing for key secondary objectives will be conducted when both of the following conditions are met:
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The primary objective is demonstrated
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22 severe cases and 162 infections are collected
The criteria of 22 severe COVID-19 and 162 SARS-CoV-2 infections are calculated based on 80% of power with assumed VEs (80% for VE against severe COVID-19 and 40% for VE against SARS-CoV-2 infection) and one-side alpha 0.0125.
If both of the criteria are met, the hypothesis testing of the key secondary endpoints will be done in the same timeframe as the efficacy analysis for the primary endpoint.
If either criteria are not met, hypothesis testing for the key secondary endpoints will be performed with final data available in comparison to a placebo control, (ie, at the time of the analysis with data prior to the cross-over) if at least a minimum of 11 severe events or 70 infections are collected. In this case, if only the minimum number of events are met for only one of the key secondary endpoints, the corresponding hypothesis testing will be performed without alpha splitting. If the minimum numbers of events are met for both key secondary endpoints, the Holm’s procedure will be applied for the testing of the 2 key secondary endpoints.
For planning of situation that not meeting the number of planned number of cases upon the availability of final data described above, a base case is planned for the minimum numbers of severe COVID-19 (11) and SARS-CoV-2 infections (70), which are calculated based on at least 70% of power and assumed VEs (90% for VE against severe COVID-19 and 50% for VE against SARS-CoV-2 infection) and one-side alpha 0.0125.”
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Added for key secondary endpoints:
“Hypothesis testing for key secondary objectives will be conducted when both of the following conditions are met:
-
The primary objective is demonstrated
-
22 severe cases and 162 infections are collected
The criteria of 22 severe COVID-19 and 162 SARS-CoV-2 infections are calculated based on 80% of power with assumed VEs (80% for VE against severe COVID-19 and 40% for VE against SARS-CoV-2 infection) and one-side alpha 0.0125.
If both of the criteria are met, the hypothesis testing of the key secondary endpoints will be done in the same timeframe as the efficacy analysis for the primary endpoint.
If either criteria are not met, hypothesis testing for the key secondary endpoints will be performed with final data available in comparison to a placebo control, (ie, at the time of the analysis with data prior to the cross-over) if at least a minimum of 11 severe events or 70 infections are collected. In this case, if only the minimum number of events are met for only one of the key secondary endpoints, the corresponding hypothesis testing will be performed without alpha splitting. If the minimum numbers of events are met for both key secondary endpoints, the Holm’s procedure will be applied for the testing of the 2 key secondary endpoints.
For planning of situation that not meeting the number of planned number of cases upon the availability of final data described above, a base case is planned for the minimum numbers of severe COVID-19 (11) and SARS-CoV-2 infections (70), which are calculated based on at least 70% of power and assumed VEs (90% for VE against severe COVID-19 and 50% for VE against SARS-CoV-2 infection) and one-side alpha 0.0125.”
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Section 9.5
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3 to 4
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Text added for Monitoring of Operational Futility:
“The DSMB monitors the study for operational futility. The objective is to monitor the projected number of treatment arm-pooled symptomatic COVID primary endpoints by each of a set of calendar dates to aid ascertainment of whether the study is on target to meet the study objective regarding the evaluation of VE.
The operational futility monitoring report is based on treatment-blinded data and is provided to the DSMB as well as to the Oversight Group and the Trial Leadership Group starting at the second data review DSMB meeting to be held in September 2021. The report will include the following:
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The enrollment rate
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The accrual rate of symptomatic COVID-19 cases for the primary efficacy endpoint
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The right censoring rate to date, including participants early terminated and received approved COVID-19 vaccine
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The mean projected number of treatment arm-pooled primary symptomatic COVID-19 endpoints in the mFAS-PD2 naive D01+D22 cohort, with a Wald 95% CI for the mean by each calendar date 15 October 2021, 15 December 2021, and 15 February 2022
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The estimated distribution of the total treatment arm-pooled number of primary symptomatic COVID-19 endpoints in the mFAS-PD2 naïve D01+D22 cohort, with corresponding power to reject H0: VE ≤ 30% using a 1-sided 0.025-level Wald test from a Cox model under the alternative hypotheses VE = 70%, 80%, and 90% by each calendar date 15 October 2021, 15 December 2021, and 15 February 2022.
The estimation procedures in (d) and (e) above will be conducted under each of the following 3 scenarios:
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The treatment arm-pooled symptomatic COVID-19 endpoint rate in (d) and (e) used for generating future data are based on a Bayesian model and the prior assumption that VE=70% (the design alternative)
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The treatment arm-pooled symptomatic COVID-19 endpoint rate in (d) and (e) used for generating future data are based on a Bayesian model and the prior assumption that VE= 30% (the null hypothesis)
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The treatment arm-pooled symptomatic COVID-19 endpoint rate in (d) and (e) used for generating future data is based on a Bayesian model and the prior assumption that the COVID-19 endpoint rate equals to the observed-to-date symptomatic COVID-19 endpoint rate.
The Bayesian model in (d) and (e) will be conditioned on the observed data to-date, more specifically, to-date data in (a), (b), and (c). Right censoring in (c) occurs due to a variety of events including early termination, unblinding for any reason and receipt authorized/approved COVID-19 vaccine.
While it is the primary responsibility of the Oversight Group with the Trial Leadership Group to make decisions regarding trial operations and modifications based on the monitoring of the treatment-blinded primary endpoints, given the resource issues involved, DSMB review is also needed because issues of scientific integrity are also involved. Upon request, the statisticians will provide the DSMB and the Oversight Group with additional information, as appropriate, for use in their consideration of whether to recommend early trial completion.
A full description of the operational futility statistical analysis is available in the Operational Futility Monitoring SAP.”
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Text added for Monitoring of Operational Futility:
“The DSMB monitors the study for operational futility. The objective is to monitor the projected number of treatment arm-pooled symptomatic COVID primary endpoints by each of a set of calendar dates to aid ascertainment of whether the study is on target to meet the study objective regarding the evaluation of VE.
The operational futility monitoring report is based on treatment-blinded data and is provided to the DSMB as well as to the Oversight Group and the Trial Leadership Group starting at the second data review DSMB meeting to be held in September 2021. The report will include the following:
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The enrollment rate
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The accrual rate of symptomatic COVID-19 cases for the primary efficacy endpoint
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The right censoring rate to date, including participants early terminated and received approved COVID-19 vaccine
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The mean projected number of treatment arm-pooled primary symptomatic COVID-19 endpoints in the mFAS-PD2 naive D01+D22 cohort, with a Wald 95% CI for the mean by each calendar date 15 October 2021, 15 December 2021, and 15 February 2022
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The estimated distribution of the total treatment arm-pooled number of primary symptomatic COVID-19 endpoints in the mFAS-PD2 naïve D01+D22 cohort, with corresponding power to reject H0: VE ≤ 30% using a 1-sided 0.025-level Wald test from a Cox model under the alternative hypotheses VE = 70%, 80%, and 90% by each calendar date 15 October 2021, 15 December 2021, and 15 February 2022.
The estimation procedures in (d) and (e) above will be conducted under each of the following 3 scenarios:
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The treatment arm-pooled symptomatic COVID-19 endpoint rate in (d) and (e) used for generating future data are based on a Bayesian model and the prior assumption that VE=70% (the design alternative)
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The treatment arm-pooled symptomatic COVID-19 endpoint rate in (d) and (e) used for generating future data are based on a Bayesian model and the prior assumption that VE= 30% (the null hypothesis)
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The treatment arm-pooled symptomatic COVID-19 endpoint rate in (d) and (e) used for generating future data is based on a Bayesian model and the prior assumption that the COVID-19 endpoint rate equals to the observed-to-date symptomatic COVID-19 endpoint rate.
The Bayesian model in (d) and (e) will be conditioned on the observed data to-date, more specifically, to-date data in (a), (b), and (c). Right censoring in (c) occurs due to a variety of events including early termination, unblinding for any reason and receipt authorized/approved COVID-19 vaccine.
While it is the primary responsibility of the Oversight Group with the Trial Leadership Group to make decisions regarding trial operations and modifications based on the monitoring of the treatment-blinded primary endpoints, given the resource issues involved, DSMB review is also needed because issues of scientific integrity are also involved. Upon request, the statisticians will provide the DSMB and the Oversight Group with additional information, as appropriate, for use in their consideration of whether to recommend early trial completion.
A full description of the operational futility statistical analysis is available in the Operational Futility Monitoring SAP.”
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Primary Efficacy: 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.
Primary Safety: To assess the safety of the CoV2 preS dTM-AS03 vaccines compared to placebo throughout the study
The study vaccine is developed by Sanofi Pasteur, a company that produces vaccines against other diseases such as diphtheria, tetanus, pertussis, meningitis and influenza.
The vaccine will be manufactured using the same technology as is used to make an influenza vaccine that is licensed in the US for the prevention of influenza in adults, marketed as Flublok®.
The study vaccines can prevent infection with SARS-CoV-2
The study vaccines can prevent severe COVID-19 illness and hospitalization