| Protocol No: | ECCT/21/06/10 | 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 |
| 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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| 7 | Objectives Summary. Secondary Immunogenicity: To describe the neutralizing antibody profile at D01 and at 21 days and 6 months after last crossover injection in the placebo group and booster injection in each study group for participants in the Random Immunogenicity Sub-cohort. Endpoints for secondary immunogenicity objective: Endpoints for secondary immunogenicity objective: Neutralizing antibody titers will be measured in participants for each study group against the D614G and B.1.351 variants: 1. Individual serum neutralizing titer at each pre-defined time point 2. Individual serum neutralization titer fold-rise post vaccination relative to D01 at each pre-defined time point 3. 2-fold rise and 4-fold-rise in serum neutralization titer [post/pre] (fold rise ≥ 2 and ≥ 4) at each pre-defined post-vaccination timepoint 4. Responders, defined as participants who had baseline values below LLOQ with quantifiable neutralization titer above assay LLOQ at each pre-defined post-vaccination time point and participants with baseline values above LLOQ with a 4-fold increase in neutralizing antibody Secondary Safety:1. To describe the frequency and spectrum of disease in episodes of symptomatic COVID-19 in SARSCoV-2 non-naïve adults after the crossover or booster vaccinations with the CoV2 preSdTMAS03 vaccines. Endpoints (Secondary safety) 1. Endpoints for secondary safety objective #1: For SARS-CoV-2 non-naïve participants in the study: a. Severity of symptoms associated with symptomatic COVID-19 episode b. Occurrences of hospitalized COVID-19 c. Occurrence of severe COVID-19 d. Occurrences of COVID-19 in each severity rating on the 7-point ordinal scale e. Death associated with COVID-19 2. To assess the safety of the CoV2 preS dTM-AS03 vaccines after the crossover or booster vaccinations 2. Endpoints for secondary safety objective #2: For all participants in the study: a. Presence of unsolicited injection site and systemic AEs reported in the 30 minutes after each vaccination b. Presence of non-serious unsolicited AEs reported up to 21 days after the booster vaccination c. Presence of MAAEs throughout the study d. Presence of SAEs throughout the study e. Presence of AESIs throughout the study |
| 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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| 7 | Summary Specific aim This Phase III study will assess efficacy, safety, and immunogenicity of two COVID-19 vaccines in adults 18 years of age and older, in two stages. Hypothesis 1: The Stage 1 vaccine (CoV2 preS dTM-AS03 monovalent (D614) vaccine) will be safe and provide protection against COVID-19 in naïve adults and elderly population older than 18 years of age. Hypothesis 2: The Stage 2 vaccine (CoV2 preS dTM-AS03 bivalent (D614 + B.1.351) vaccine) will be safe and provide protection against COVID-19 in naïve adults and elderly population older than 18 years of age. Research procedures: This study will consist of eight in-person visits and three crossover visits beside illness visits. There will be weekly safety telephone calls to monitor for adverse events and COVID-19 symptoms. There will be two vaccinations in visits 1 & 2 and two vaccinations in the crossover for placebo participants. A total of eleven whole blood samples will be drawn. Study population and age range: The study will be conducted in adults 18 years of age and older with stratification by 2 age groups: 18-59 years of age and 60 years and older. Current proposed amendment from protocol version 5.0 to 8.0 A group that oversees the study (study oversight group) reviewed interim analyses of the Stage 1 and Stage 2 results from the initial parts of this study. The study oversight group recommended to continue with a Crossover and Booster part of the study. For the Crossover, those who got the placebo in the initial part of the study will be offered the choice of receiving the monovalent D614 vaccine that was tested in Stage 1 of the study or getting an authorized/approved vaccine (outside of the study). Whether the participant gets the study vaccine or an authorized/approved vaccine outside of the study, this will be considered the participant’s “primary vaccination series”. For the Booster part of the study, participants who have received a primary vaccination series will get a booster dose of a study vaccine. The booster dose is intended to “boost” the immune system to create more antibodies to maintain 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 an antigen different COVID-19 virus variant called B.1.351 (beta variant). This vaccine is called “monovalent beta booster vaccine”. It was tested in another Sanofi study called VAT00002. Early results from VAT00002 showed that the booster injection increased antibody levels more than getting only the primary vaccination (either from the Sanofi study vaccine or a vaccine from another company) and did not show any safety concerns. There is no new consent form but we are adding an addendum (ICF addendum version 3.0) to the current consent form version 4.0. ICF Addendum v3.0 corresponds to protocol version 8.0 and does not replace the ICF v4.0. The two are intended to be used together to provide consent for the overall study and the booster/crossover procedures. Please note that ICF addendum versions 1.0 and 2.0 were not implemented at our site, so were not submitted to the KNH-UoN ERC. Addendum 1.0 corresponded to protocol version 6.0 and addendum 2.0 corresponded to protocol version 7.0. Our site is participating only in Stage 2 of the trial, so changes relevant only to Stage 1 participants and described in the first two ICF addendum versions are not applicable. The languages of communication will be English and Kiswahili. The English consent has been translated to Kiswahili and translation certificates are attached. There is only one consent form approved for use currently: version 4.0, dated 28-Sep-2021 |
| 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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| 7 | Brief Summary: The purpose of this Phase III study is to assess the efficacy, safety, and immunogenicity of two CoV2 preS dTM-AS03 vaccines (monovalent and bivalent) as part of primary series vaccinations in a multi-stage approach, as well as a booster injection of a CoV2 preS dTM-AS03 vaccine, in adults 18 years of age and older. Study Duration: Initial, double-blind, primary series study design planned for 365 days post-last Initial injection (ie, approximately 386 days total) for each participant. Based on decisions of the Study OG, Stage 1 and Stage 2 participants will be invited to participate in an unblinded Crossover / Booster study design with duration as follows: For participants who initially received vaccine: 12 months post-booster (ie, approximately 18 to 24 months) For participants who initially received placebo: ≥ 4 months post-last dose of the primary series + 12 months post-booster (ie, approximately 28 to 34 months) For participants who do not consent to continue in the unblinded Crossover / Booster part of the study, all study procedures will be stopped and participants will be discontinued from the study. Treatment Duration: Initial Injections(Protocol v 5.0): 2 injections of either CoV2 preS dTM-AS03 monovalent (D614) vaccine (Stage 1), CoV2 preS dTM-AS03 bivalent (D614 + B.1.351) vaccine (Stage 2), or placebo will be administered 21 days apart. Current protocol version 8.0 (Crossover) Crossover Injection(s) (Stage 1 and Stage 2): If initial injection was placebo, primary injection(s) of an authorized/approved vaccine outside of the study (interval of doses dependent on available vaccine and following local standard of care) or 2 primary series injections administered 21 days apart of CoV2 preS dTM-AS03 monovalent (D614) vaccine. Booster Injection (Stage 1 and Stage 2): A single injection of Sanofi’s investigational CoV2 preS dTM-AS03 monovalent (B.1.351) 5 µg antigen dose of booster vaccine ≥ 4 months post-last dose of the primary series. Planned Visit Frequency: The planned initial visits (protocol v5.0) includes 8 visits at D01, D22, D43, D78, D134, D202, D292, and D387. However, if participants do not agree to participate in the Crossover / Booster, all study procedures will be stopped, and participants will be discontinued from the study. For participants who agree to participate in the Crossover / Booster design, it will include: For those who initially received an investigational CoV2 preS dTM-AS03 vaccine: 3 blood sample visits i.e on the day of booster vaccination (pre-booster) and then 21 days and 6 months post-booster plus an Efficacy follow-up 12 months post-booster and a Safety follow-up phone call: 12 months post-booster. For those who initially received placebo and then receive an authorized vaccine (outside of the study) or Sanofi’s CoV2 preS dTM-AS03 monovalent (D614) vaccine (Stage 1) or CoV2 preS dTM-AS03 bivalent (D614+B.1.351)(Stage2) vaccines as primary series: 5 blood sample visits i.e on the day of first primary series vaccination (pre-vaccination 1)*, 21 days post-last dose of primary series*, day of the booster dose at ≥ 4 months post-last dose of primary series, 21 days post-booster, and 6 months post-booster • Efficacy follow-up: visit ≥ 4 months post-last dose of the primary series and phone call 12 months post-booster • Safety follow-up: visit ≥ 4 months post-last dose of the primary series and phone call 12 months post-booster * Note for those who receive authorized vaccine (outside of the study) as primary series (Crossover vaccination), no protocol deviation will be considered if the corresponding blood sample is missed. Summary of visits Participants who received the placebo initially will have a total of 6 inperson visits and 1remote visit. Participants who received vaccine initially will have a total of 3 visits and 1 remote visit
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Primary Safety: To assess the safety of the CoV2 preS dTM-AS03 vaccines compared to placebo throughout the study