Study of Monovalent and Bivalent Recombinant Protein Vaccines Against COVID-19 in Adults 18 Years of Age and Older (VAT00008)

• ClinicalTrials.gov Identifier: NCT04904549
• Recruitment Status: Active, not recruiting
• First Posted: May 27, 2021
• Last Update Posted: January 4, 2023
• Sponsor: Sanofi Pasteur, a Sanofi Company
• Information provided by (Responsible Party): Sanofi ( Sanofi Pasteur, a Sanofi Company )

Tracking Information

• First Submitted Date: May 26, 2021
• First Posted Date: May 27, 2021
• Last Update Posted Date: January 4, 2023
• Actual Study Start Date: May 26, 2021
• Estimated Primary Completion Date: January 31, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 15, 2022)

• Occurrences of symptomatic COVID-19 [ Time Frame: From ≥ 14 days after the second injection to Day 387 ]
  Symptomatic COVID-19 is defined as virologically-confirmed SARS-CoV-2 infection accompanied by protocol-defined COVID-19-like illness.
• Presence of solicited injection site or systemic reactions (collected in the reactogenicity subset) [ Time Frame: Within 7 days after vaccination ]
  Injection site reactions: injection site pain, erythema and swelling. Systemic reactions: fever, headache, malaise, myalgia, arthralgia and chills.
• Presence of non-serious unsolicited adverse events (collected in the reactogenicity subset) [ Time Frame: Within 21 days after vaccination ]
  Adverse events other than solicited reactions.
• Presence of immediate adverse events [ Time Frame: Within 30 minutes after vaccination ]
  Immediate adverse events include unsolicited injection site and systemic adverse events occurring within 30 minutes after injection.
• Presence of medically attended adverse events [ Time Frame: From Day 1 to Day 387 ]
  Medically attended adverse events will be assessed throughout the study.
• Presence of serious adverse events [ Time Frame: From Day 1 to Day 387 ]
  Serious adverse events will be assessed throughout the study.
• Presence of adverse events of special interest [ Time Frame: From Day 1 to Day 387 ]
  Adverse events of special interest will be assessed throughout the study.
• Presence of virologically-confirmed SARS-CoV-2 infections and/or symptomatic COVID-19 [ Time Frame: From Day 1 to Day 387 ]
  Percentage of participants with positive result for SARSCoV-2 infection by Nucleic Acid Amplification Test (NAAT) on at least one respiratory sample accompanied or not by protocol-defined clinical COVID-19 symptoms.

Original Primary Outcome Measures (submitted: May 26, 2021)

• Occurrences of symptomatic COVID-19 [ Time Frame: From ≥ 14 days after the second injection to Day 387 ]
  Symptomatic COVID-19 is defined as virologically-confirmed SARS-CoV-2 infection accompanied by protocol-defined COVID-19-like illness.
• Presence of solicited injection site or systemic reactions [ Time Frame: Within 7 days after vaccination ]
  Injection site reactions: injection site pain, erythema and swelling. Systemic reactions: fever, headache, malaise, myalgia, arthralgia and chills.
• Presence of non-serious unsolicited adverse events [ Time Frame: Within 21 days after vaccination ]
  Adverse events other than solicited reactions.
• Presence of immediate adverse events [ Time Frame: Within 30 minutes after vaccination ]
  Immediate adverse events include unsolicited injection site and systemic adverse events occurring within 30 minutes after injection.
• Presence of medically attended adverse events [ Time Frame: From Day 1 to Day 387 ]
  Medically attended adverse events will be assessed throughout the study.
• Presence of serious adverse events [ Time Frame: From Day 1 to Day 387 ]
  Serious adverse events will be assessed throughout the study.
• Presence of adverse events of special interest [ Time Frame: From Day 1 to Day 387 ]
  Adverse events of special interest will be assessed throughout the study.
• Presence of virologically-confirmed SARS-CoV-2 infections and/or symptomatic COVID-19 [ Time Frame: From Day 1 to Day 387 ]
  Percentage of participants with positive result for SARS-CoV-2 infection by Nucleic Acid Amplification Test (NAAT) on at least one respiratory sample accompanied or not by protocol-defined clinical COVID-19 symptoms.

Current Secondary Outcome Measures (submitted: July 15, 2022)

• Occurrences of SARS-CoV-2 infection [ Time Frame: From ≥ 14 days after the second injection to Day 387 ]
  SARS-CoV-2 infection is defined as a serologically-confirmed SARS-CoV-2 infection or virologically-confirmed SARS-CoV-2 infection.
• Occurrence of severe COVID-19 [ Time Frame: From ≥ 14 days after the second injection to Day 387 ]
• Occurrences of asymptomatic SARS-CoV-2 infection [ Time Frame: From Day 1 to Day 387 ]
  Asymptomatic SARS-CoV-2 infection is defined as SARS-CoV-2 infection, with no reported COVID-19-like illness episodes between enrollment and 14 days after the timepoint at which SARS-CoV-2 infection is ascertained.
• Number of days with positive NAAT [ Time Frame: From Day 1 to Day 387 ]
• Viral copies/mL in respiratory samples [ Time Frame: From Day 1 to Day 387 ]
• Occurrences of positive NAAT in respiratory samples at each follow-up timepoint during symptomatic COVID-19 [ Time Frame: From Day 1 to Day 387 ]
• Occurrences of CDC-defined COVID-19 [ Time Frame: From Day 1 to Day 387 ]
  Virologically-confirmed SARS-CoV-2 infection with at least one of CDC-defined clinical symptoms.
• Occurrences of hospitalized COVID-19 [ Time Frame: From Day 1 to Day 387 ]
  Hospitalized COVID-19 is defined as an episode of symptomatic COVID-19 that requires inpatient hospitalization.
• Occurrences of symptomatic COVID-19 with severity of moderate COVID-19 or worse. [ Time Frame: From Day 1 to Day 387 ]
  Composite endpoint of at least one of moderate or severe COVID-19.
• Neutralizing antibody titer [ Time Frame: Day 1, Day 22, Day 43, Day 78, Day 134, Day 202, Day 292, and Day 387 ]
• Responders, as determined by neutralizing antibody titers [ Time Frame: Day 1, Day 22, Day 43, Day 78, Day 134, Day 202, Day 292, and Day 387 ]
  Responders are defined as participants who had baseline values below lower limit of quantification (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
• Neutralizing antibody titer fold-rise post-vaccination at all pre-defined time points [ Time Frame: Day 1, Day 22, Day 43, Day 78, Day 134, Day 202, Day 292, and Day 387 ]
  Fold-rise in antibody neutralization titer post-vaccination relative to Day 1.
• 2-fold rise and 4-fold-rise in neutralization antibody titer at all pre-defined time points [ Time Frame: Day 1, Day 22, Day 43, Day 78, Day 134, Day 202, Day 292, and Day 387 ]
  Fold-rise in antibody neutralization titer post-vaccination relative to Day 1.
• Severity of symptoms associated with symptomatic COVID-19 episode [ Time Frame: From Day 1 to Day 387 ]
• Occurrences of COVID-19 in each severity rating [ Time Frame: From Day 1 to Day 387 ]
  COVID-19 severity score based on the ordinal scale of clinical assessment (7-point ordinal scale)
• Death associated with COVID-19 [ Time Frame: From Day 1 to day 387 ]

Original Secondary Outcome Measures (submitted: May 26, 2021)

• Occurrences of SARS-CoV-2 infection [ Time Frame: From ≥ 14 days after the second injection to Day 387 ]
  SARS-CoV-2 infection is defined as a serologically-confirmed SARS-CoV-2 infection or virologically-confirmed SARS-CoV-2 infection.
• Occurrence of severe COVID-19 [ Time Frame: From ≥ 14 days after the second injection to Day 387 ]
• Occurrences of asymptomatic SARS-CoV-2 infection [ Time Frame: From Day 1 to Day 387 ]
  Asymptomatic SARS-CoV-2 infection is defined as SARS-CoV-2 infection, with no reported COVID-19-like illness episodes between enrollment and 14 days after the timepoint at which SARS-CoV-2 infection is ascertained.
• Viral copies/mL in respiratory samples [ Time Frame: From Day 1 to Day 387 ]
• Number of days with positive NAAT [ Time Frame: From Day 1 to Day 387 ]
• Occurrences of positive NAAT in respiratory samples at each follow-up timepoint during symptomatic COVID-19 [ Time Frame: From Day 1 to Day 387 ]
• Occurrences of Centers for Disease Control and Prevention (CDC)-defined COVID-19 [ Time Frame: From Day 1 to Day 387 ]
  Virologically-confirmed SARS-CoV-2 infection with at least one of CDC-defined clinical symptoms.
• Occurrences of hospitalized COVID-19 [ Time Frame: From Day 1 to Day 387 ]
  Hospitalized COVID-19 is defined as an episode of symptomatic COVID-19 that requires inpatient hospitalization.
• Occurrences of symptomatic COVID-19 with severity of moderate COVID-19 or worse. [ Time Frame: From Day 1 to Day 387 ]
  Composite endpoint of at least one of moderate or severe COVID-19.
• Neutralizing antibody titer [ Time Frame: Day 1, Day 22, Day 43, Day 78, Day 134, Day 202, Day 292, and Day 387 ]
• Responders, as determined by neutralizing antibody titers [ Time Frame: Day 1, Day 22, Day 43, Day 78, Day 134, Day 202, Day 292, and Day 387 ]
  Responders are defined as participants who had baseline values below lower limit of quantification (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
• Neutralizing antibody titer fold-rise post-vaccination at all pre-defined time points [ Time Frame: Day 1, Day 22, Day 43, Day 78, Day 134, Day 202, Day 292, and Day 387 ]
  Fold-rise in antibody neutralization titer post-vaccination relative to Day 1.
• 2-fold rise and 4-fold-rise in neutralization antibody titer at all pre-defined time points [ Time Frame: Day 1, Day 22, Day 43, Day 78, Day 134, Day 202, Day 292, and Day 387 ]
  Fold-rise in antibody neutralization titer post-vaccination relative to Day 1.
• Severity of symptoms associated with symptomatic COVID-19 episode [ Time Frame: From Day 1 to Day 387 ]
• Occurrences of COVID-19 in each severity rating [ Time Frame: From Day 1 to Day 387 ]
  COVID-19 severity score based on the ordinal scale of clinical assessment (7-point ordinal scale)
• Death associated with COVID-19 [ Time Frame: From Day 1 to day 387 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Monovalent and Bivalent Recombinant Protein Vaccines Against COVID-19 in Adults 18 Years of Age and Older
• Official 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 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

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.

A total of approximately 21 046 participants are planned to be enrolled (5080 per study intervention group in Stage 1 and 5443 per study intervention group in Stage 2).

Initial, double-blind, primary series study design is planned for 365 days post-last Initial injection (ie, approximately 386 days total) for each participant.

Based on decisions of the Study Oversight Group, 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.

Detailed Description

The duration of participation in the initial, double-blind, primary series design of the study will be approximately 365 days post-last 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.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

The study is designed to demonstrate clinical efficacy of each of the two SARS-CoV-2 adjuvanted recombinant protein vaccines (monovalent and bivalent). In Stage 1, the monovalent vaccine will be evaluated against a placebo control. In Stage 2, the bivalent vaccine will be assessed against a placebo control.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

For initial, double-blind, primary series design of study: participants, outcome assessors, Investigators, laboratory personnel, and sponsor trial staff are blinded to intervention group; and those preparing the study interventions are unblinded to vaccine assignment group.

For crossover / booster design of study (Stage 1 and Stage 2): unblinded

Primary Purpose: Prevention

• Condition: COVID-19

Intervention

• Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine (monovalent D614) (primary series)
  Pharmaceutical form: emulsion for injection. Route of administration: intramuscular injection
• Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine (bivalent D614 + B.1.351) (primary series)
  Pharmaceutical form: emulsion for injection. Route of administration: intramuscular injection.
• Biological: Placebo
  Pharmaceutical form: liquid. Route of administration: intramuscular administration.
• Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine (monovalent B.1.351) (booster dose) >= 4 months after last vaccination
  Pharmaceutical form: emulsion for injection. Route of administration: intramuscular injection.
• Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine(monovalent D614)(primary series)& SARS-CoV-2 adjuvanted recombinant protein vaccine(monovalent B.1.351)(booster dose)>=4 months after last vaccination
  Pharmaceutical form: emulsion for injection. Route of administration: intramuscular injection.

Study Arms

• Experimental: Stage 1: SARS-CoV-2 vaccine
  2 injections of monovalent SARS-CoV-2 vaccine at Day 1 and Day 22
  Interventions:

  • Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine (monovalent D614) (primary series)
  • Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine (monovalent B.1.351) (booster dose) >= 4 months after last vaccination
• Placebo Comparator: Stage 1: Placebo
  2 injections of placebo at Day 1 and Day 22
  Interventions:

  • Biological: Placebo
  • Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine(monovalent D614)(primary series)& SARS-CoV-2 adjuvanted recombinant protein vaccine(monovalent B.1.351)(booster dose)>=4 months after last vaccination
• Experimental: Stage 2: SARS-CoV-2 vaccine
  2 injections of bivalent SARS-CoV-2 vaccine at Day 1 and Day 22
  Interventions:

  • Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine (bivalent D614 + B.1.351) (primary series)
  • Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine (monovalent B.1.351) (booster dose) >= 4 months after last vaccination
• Placebo Comparator: Stage 2: Placebo
  2 injections of placebo at Day 1 and Day 22
  Interventions:

  • Biological: Placebo
  • Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine(monovalent D614)(primary series)& SARS-CoV-2 adjuvanted recombinant protein vaccine(monovalent B.1.351)(booster dose)>=4 months after last vaccination

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: July 22, 2022): 23726
• Original Estimated Enrollment (submitted: May 26, 2021): 37430
• Estimated Study Completion Date: January 31, 2025
• Estimated Primary Completion Date: January 31, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Aged 18 years or older on the day of inclusion.
• For persons living with human immunodeficiency virus (HIV), stable HIV infection determined by participant currently on antiretrovirals with CD4 count > 200/mm3.
• SARS-CoV-2 rapid serodiagnostic test performed at the time of enrollment to detect presence of SARS-CoV-2 antibodies.
• Does not intend to receive an authorized/approved COVID-19 vaccine despite encouragement by the Investigator to receive the authorized vaccine available to them at the time of enrollment.
• Informed consent form has been signed and dated
• Able to attend all visits and to comply with all study procedures
• Covered by health insurance, only if required by local, regional or national regulations

• A female participant is eligible to participate if she is not pregnant or breastfeeding and one of the following conditions applies:

  • is of non-childbearing potential. To be considered of non-childbearing potential, a female must be post-menopausal for at least 1 year or surgically sterile, or
  • is of childbearing potential and agrees to use an effective contraceptive method or abstinence from at least 4 weeks prior to the first study intervention administration until at least 12 weeks after the second study intervention administration.

A participant of childbearing potential must have a negative highly sensitive pregnancy test (urine or serum as required by local regulation) within 25 hours before any dose of study intervention.

Exclusion Criteria:

• Known systemic hypersensitivity to any of the vaccine components, or history of a life-threatening reaction to a vaccine containing any of the same substances.
• Dementia or any other cognitive condition at a stage that could interfere with following the study procedures based on Investigator?s judgment.
• Self-reported thrombocytopenia, contraindicating intramuscular (IM) vaccination based on Investigator?s judgment
• Bleeding disorder, or receipt of anticoagulants in the past 21 days preceding inclusion, contraindicating IM vaccination based on Investigator?s judgment.
• Unstable acute or chronic illness that in the opinion of the Investigator or designee poses additional risk as a result of participation or that could interfere with the study procedures.
• Moderate or severe acute illness/infection (according to investigator judgment) on the day of vaccination or febrile illness (temperature ? 38.0 C [? 100.4 F]). A prospective participant should not be included in the study until the condition has resolved or the febrile event has subsided.
• Receipt of any vaccine in the 30 days preceding or on the day of the first study vaccination or planned receipt of any vaccine between the first study vaccination and in the 30 days following the second study vaccination except for influenza vaccination, which may be received at any time in relation to study intervention.
• Prior administration of a coronavirus vaccine (SARS-CoV-2, SARS-CoV, Middle East Respiratory Syndrome).
• Receipt of solid-organ or bone marrow transplants in the past 180 days.
• Receipt of anti-cancer chemotherapy in the last 90 days.
• Deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily.
• Identified as an Investigator or employee of the Investigator or study center with direct involvement in the proposed study, or identified as an immediate family member (ie, parent, spouse, natural or adopted child) of the Investigator or employee with direct involvement in the proposed study.
• Participation at the time of study enrollment (or in the 30 days preceding the first study vaccination) or planned participation during the present study period in another clinical study investigating a vaccine, drug, medical device, or medical procedure.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Colombia, Ghana, Honduras, India, Japan, Kenya, Mexico, Nepal, Nigeria, Sri Lanka, Uganda, Ukraine, United States

Administrative Information

• NCT Number: NCT04904549
• Other Study ID Numbers: VAT00008; U1111-1264-3238 ( Registry Identifier: ICTRP )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

• Current Responsible Party: Sanofi ( Sanofi Pasteur, a Sanofi Company )
• Original Responsible Party: Same as current
• Current Study Sponsor: Sanofi Pasteur, a Sanofi Company
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Sanofi
• Verification Date: January 2023