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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

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SLCTR Registration Number

SLCTR/2021/026


Date of Registration

12 Sep 2021

The date of last modification

Oct 15, 2021



Application Summary


Scientific Title of Trial

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


Public Title of Trial

VAT00008: A parallel-group, Phase III, multi-stage, modified double-blind, Placebo-Controlled, multi-armed study to assess the efficacy, safety, and immunogenicity of two SARS-CoV-2 Adjuvanted Recombinant Protein Vaccines (monovalent- CoV2 preS dTM-AS03 (D614) and bivalent CoV2 preS dTM-AS03 (D614 + B.1.351)) for prevention against COVID-19 in adults 18 years of age and older.


Disease or Health Condition(s) Studied

COVID-19


Scientific Acronym

VAT00008


Public Acronym

VAT00008


Brief title

Efficacy and safety of Monovalent and Bivalent Recombinant Protein Vaccines against COVID-19 in adults who are 18 years of age and older.


Universal Trial Number

U1111-1264-3238


Any other number(s) assigned to the trial and issuing authority

Clinicaltrials.gov : NCT04904549


Trial Details


What is the research question being addressed?

What is the clinical efficacy and safety of SARS-CoV-2 adjuvanted recombinant protein vaccine (monovalent) consisting of a stabilized prefusion trimer of the SARS-CoV-2 S protein in prevention of symptomatic COVID-19 infection?


Type of study

Interventional


Study design

Allocation

Randomized controlled trial


Masking

Double blinded : Participants, Investigators, Healthcare providers, Outcome assessors


Control

Placebo


Assignment

Parallel


Purpose

Treatment


Study Phase

Phase 3


Intervention(s) planned

Study Setting National Institute of Infectious Diseases The National Hospital Sri Lanka Colombo North Teaching Hospital

This will be a Phase III, randomized, modified double-blind, placebo-controlled, multi-stage, multi-center, multi-country study 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 with 2 stages. 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 as shown below.

  1. In Stage 1, the AS03 adjuvanted monovalent vaccine with the prefusion S protein from the prototype (D614) variant will be evaluated against a placebo control.
  2. In Stage 2, the AS03 adjuvanted bivalent vaccine with the prefusion S protein from the prototype and South African variant (D614 + B.1.351) will be assessed against a placebo control.

This study will first be initiated globally including Sri Lanka with stage 01, where participants will be randomized in a 1:1 ratio to receive 2 injections 21 days apart of either CoV2 preS dTM-AS03 (D614) or Placebo. The availability of the bivalent vaccine for Stage 2 is scheduled for September 2021 while the monovalent vaccine (Stage 1) is scheduled to start in May 2021. It is expected to complete recruitment of Stage 1 by the middle of August 2021 and therefore do not anticipate any significant overlap in enrollment between the two stages.

In stage 01, total of 8000 participants will be randomized, out of which 6400 will be SARS-CoV-2 naïves and 1600 will be SARS-CoV-2 non naïves. In stage 02, total of 10, 715 participants will be randomized, out of which 8572 will be SARS-CoV-2 naïves and 2143 will be SARS-CoV-2 non naïves.

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. Participants will be randomized using an Interactive Response Technology (IRT).

Study interventions

Investigational medicinal product 1 (Stage 1): CoV2 preS dTM-AS03 (D614) • Form: Solution and emulsion for injection • Composition: prefusion S delta TM COVID-19 antigen D614 strain (10 ?g) and AS03 adjuvant that is an oil-in-water emulsion containing squalene (10.69 milligrams), DL-?- tocopherol (11.86 milligrams) and polysorbate 80 (4.86 milligrams) • Route of administration: Intramuscular (IM) • Frequency: 2 injections administered 21 days apart.

Investigational medicinal product 2 (Stage 2): CoV2 preS dTM-AS03 (D614 + B.1.351) • Form: Solution and emulsion for injection • Composition: prefusion S delta TM COVID-19 antigen D614 + B.1.351 (5 ?g D614 antigen +5 ?g B.1.351 antigen) and AS03 adjuvant that is an oil-in-water emulsion containing squalene (10.69 milligrams), DL-?-tocopherol (11.86 milligrams) and polysorbate 80 (4.86 milligrams) • Route of administration: Intramuscular (IM) • Frequency: 2 injections administered 21 days apart.

Placebo • Form- Liquid • Composition- 0.9% normal saline • Route of administration: Intramuscular (IM) • Frequency: 2 injections administered 21 days apart.

All participants will receive two injections (via intramuscular administration) given 21 days apart, followed by a 12-month safety follow up. 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 any symptoms of COVID-19-like illness. Study duration for each participant would be 365 days post-last injection (ie, approximately 386 days total).

Blinding Participants, outcome assessors, investigators, laboratory personnel, sponsor, study staff, those administering the study intervention will remain blinded throughout the study. Those preparing the study interventions will be unblinded.


Inclusion criteria

  1. Aged 18 years or older on the day of inclusion (Both male and female)
  2. For persons living with HIV, stable HIV infection determined by participant currently on antiretrovirals with CD4 count > 200/mm3
  3. Subjects who have had SARS-CoV-2 rapid sero-diagnostic test performed at the time of enrollment to detect presence of SARS-CoV-2 antibodies. Both sero positive and negative subjects will be enrolled however with restriction in sero-positive numbers as a target number of sero-negative subjects need to be enrolled.
  4. 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.
  5. A female participant is eligible to participate if she is not pregnant or breastfeeding and one of the following conditions applies: o 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 o 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. 6. Informed consent form has been signed and dated. 7. Able to attend all visits and to comply with all study procedures 8. Covered by health insurance, only if required by local, regional, or national regulations


Exclusion criteria

  1. 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
  2. Dementia or any other cognitive condition at a stage that could interfere with following the study procedures based on Investigator’s judgment.
  3. Self-reported thrombocytopenia, contraindicating intramuscular (IM) vaccination based on Investigator’s judgment.
  4. Bleeding disorder, or receipt of anticoagulants in the past 21 days preceding inclusion, contraindicating IM vaccination based on Investigator’s judgment.
  5. 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.
  6. 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.
  7. 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.
  8. Prior administration of a coronavirus vaccine (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2], SARS-CoV, Middle East Respiratory Syndrome [MERSCoV])
  9. Receipt of solid-organ or bone marrow transplants in the past 180 days
  10. Receipt of anti-cancer chemotherapy in the last 90 days
  11. 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.
  12. Deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily
  13. 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


Primary outcome(s)

1.

Occurrences of symptomatic COVID-19

[

Time Frame: From ? 14 days after the second injection to Day 387

]
2.

Presence of solicited injection site or systemic reactions (Injection site reactions: injection site pain, erythema and swelling. Systemic reactions: fever, headache, malaise, myalgia, arthralgia and chills).

[

Time Frame: Within 7 days after vaccination

]
3.

Presence of non-serious unsolicited adverse events

[

Time Frame: Within 21 days after vaccination

]
4.

Presence of immediate adverse events

[

Time Frame: Within 30 minutes after vaccination

]
5.

Presence of medically attended adverse events

[

Time Frame: From Day 1 to Day 387

]
6.

Presence of serious adverse events

[

Time Frame: From Day 1 to Day 387

]
7.

Presence of adverse events of special interest

[

Time Frame: From Day 1 to Day 387

]
8.

Presence of virologically-confirmed SARS-CoV-2 infections and/or symptomatic COVID-19

[

Time Frame: From Day 1 to Day 387

]

Secondary outcome(s)

1.

Occurrences of SARS-CoV-2 infection. SARS-CoV-2 infection is defined as a serologically-confirmed SARS-CoV-2 infection or virologically-confirmed SARS-CoV-2 infection.

[

Time Frame: From ? 14 days after the second injection to Day 387

]
2.

Occurrence of severe COVID-19 a. Severe COVID-19 is defined as COVID-19 with any one of the following: Any clinical signs of severe illness measured at least on 2 occasions separated by 30 minutes (saturation of oxygen [SpO2] ≤ 93% on room air (corrected for altitude), PaO2/FiO2 ˂ 300 mm Hg, RR ˃ 30 breaths per minute at rest, HR ˃ 125 beats per minute at rest) Supplemental oxygen administration for > 1 hour Use of invasive or non-invasive ventilation or Extracorporeal Membrane Oxygenation Clinical diagnosis of respiratory failure (ie, clinical need for one of the preceding therapies, but preceding therapies not able to be administered in setting of resource limitation) Significant acute renal, hepatic, or neurologic dysfunction Shock (defined by systolic blood pressure ˂ 90 mm Hg, or diastolic blood pressure ˂ 60 mm Hg or requiring vasopressors) Admission to an ICU Death

[

Time Frame: From ≥ 14 days after the second injection to Day 387

]
3.

Occurrences of asymptomatic SARS-CoV-2 infection. 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.

[

Time Frame: From Day 1 to Day 387

]
4.

Viral copies/mL in respiratory samples (Abbott RealTime SARS-CoV-2 assay will be used to quantize the viral burden in nasopharyngeal swabs and the anterior nasal swabs).

[

Time Frame: From Day 1 to Day 387

]
5.

Number of days with positive NAAT (Nucleic Acid Amplification Test using Abbott RealTime SARS-CoV-2 assay).

[

Time Frame: From Day 1 to Day 387

]
6.

Occurrences of positive NAAT in respiratory samples at each follow-up timepoint during symptomatic COVID-19.

[

Time Frame: From Day 1 to Day 387

]
7.

Occurrences of Centers for Disease Control and Prevention (CDC)-defined COVID-19. Virologically confirmed SARS-CoV-2 infection with at least one of CDC-defined clinical symptoms.

[

Time Frame: From Day 1 to Day 387

]
8.

Occurrences of hospitalized COVID-19. Hospitalized COVID-19 is defined as an episode of symptomatic COVID-19 that requires inpatient hospitalization.

[

Time Frame: From Day 1 to Day 387

]
9.

Occurrences of symptomatic COVID-19 with severity of moderate COVID-19 or worse. Composite endpoint of at least one of moderate or severe COVID-19.

[

Time Frame: From Day 1 to Day 387

]
10.

Neutralizing antibody titer (SARS-CoV-2 neutralizing antibodies will be measured using a pseudovirus neutralization assay on blood samples).

[

Time Frame: Day 1, Day 22, Day 43, Day 78, Day 134, Day 202, Day 292, and Day 387

]
11.

Responders, as determined by neutralizing antibody titers. 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

[

Time Frame: Day 1, Day 22, Day 43, Day 78, Day 134, Day 202, Day 292, and Day 387

]
12.

Neutralizing antibody titer fold-rise post-vaccination at all pre-defined time points. Fold-rise in antibody neutralization titer post-vaccination relative to Day 1.

[

Time Frame: Day 1, Day 22, Day 43, Day 78, Day 134, Day 202, Day 292, and Day 387

]
13.

2-fold rise and 4-fold-rise in neutralization antibody titer at all pre-defined time points. Fold-rise in antibody neutralization titer post-vaccination relative to Day 1.

[

Time Frame: Day 1, Day 22, Day 43, Day 78, Day 134, Day 202, Day 292, and Day 387

]
14.

Severity of symptoms associated with symptomatic COVID-19 episode. The severity will be determined by the participants The COVID-19 severity scale is based on the ordinal scale of clinical assessment: 1) Not hospitalized 2) Hospitalized, not requiring supplemental oxygen – discharged without ongoing medical care 3) Hospitalized, not requiring supplemental oxygen – discharged but requiring ongoing medical care (COVID-19 related or otherwise) 4) Hospitalized, requiring supplemental oxygen 5) Hospitalized, on non-invasive ventilation or high flow oxygen devices 6) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation 7) Death 8) Severity scale COVID-19 symptoms (except for loss of taste and loss of smell) will be classified according to the following intensity scale: • Grade 1 • CRF: A type of AE that is usually transient and may require only minimal treatment or therapeutic intervention. The event does not generally interfere with usual activities of daily living. • DC: No interference with usual activities. • Grade 2 • CRF: A type of AE that is usually alleviated with additional therapeutic intervention. The event interferes with usual activities of daily living, causing discomfort but poses no significant or permanent risk of harm to the research participant. • DC: Some interference with usual activities. • Grade 3 • CRF: A type of AE that interrupts usual activities of daily living, or significantly affects clinical status, or may require intensive therapeutic intervention. • DC: Significant; prevents usual activities.

For sense of smell and sense of taste, the following grading will apply: • Grade 0 – sense of smell/sense of taste is the same as usual • Grade 1 – sense of smell/sense of taste is less than usual • Grade 2 – no sense of smell/sense of taste

[

Time Frame: From Day 1 to day 387

]
15.

Occurrences of COVID-19 in each severity rating. COVID-19 severity score based on the ordinal scale of clinical assessment (7-point ordinal scale)

[

Time Frame: From Day 1 to day 387

]
16.

Death associated with COVID-19

[

Time Frame: From Day 1 to day 387

]

Target number/sample size

1000 (500 in each arm)


Countries of recruitment

Japan, Mexico, Pakistan, Sri Lanka, United States


Anticipated start date

2021-09-13


Anticipated end date

2022-09-13


Date of first enrollment


Date of study completion


Recruitment status

Pending


Funding source

Sanofi Pasteur Inc. Discovery Drive, Swiftwater, PA 18370-0187, USA


Regulatory approvals

Approval number- CLTRI/2020/0049



State of Ethics Review Approval


Status

Approved


Date of Approval

2021-08-27


Approval number

16/21 (Conditional approval - only for stage 1 of the trial)


Details of Ethics Review Committee

Name: Ethics Review Committee, University of Sri Jayewardenepura
Institutional Address:ERC Office, Faculty of Medical Sciences, University of Sri Jayewardenepura, Gangodawila, Nugegoda
Telephone:011 2758000 Ext: 4075
Email: erc.fms.usjp@gmail.com

Contact & Sponsor Information


Contact person for Scientific Queries/Principal Investigator

Dr. Ananda Wijewickrama
Consultant Physician
National Institute of Infectious Diseases, Angoda – 10620, Sri Lanka

+94777559398

anandawijewickrama012@gmail.com

Contact Person for Public Queries

Dr. Ananda Wijewickrama
Consultant Physician
National Institute of Infectious Diseases, Angoda – 10620, Sri Lanka

+94777559398

anandawijewickrama012@gmail.com


Primary study sponsor/organization

Sanofi Pasteur Inc.
Sponsor
Discovery Drive, Swiftwater, PA 18370-0187, USA



Secondary study sponsor (If any)







Trial Completion details


Do the investigators plan to share identified individual clinical trial participant-level data (IPD)?

No


IPD sharing plan description


Study protocol available

No


Protocol version and date

Not Available


Protocol URL

Not Available


Results summary available

No


Date of posting results


Date of study completion


Final sample size


Date of first publication


Link to results


Brief summary of results