A Phase 1/2 Safety and Immunogenicity Trial of COVID-19 Vaccine COVIVAC
Condition: COVID-19 Disease; SARS Pneumonia; Pneumonia, Viral; COVID-19 Vaccine
MeSH terms: COVID-19; Pneumonia; Pneumonia, Viral
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      This prospective, single-center, randomized, placebo-controlled, observer-blind Phase 1/2
      study includes two separate parts.

      Part 1 is a first-in-human, Phase 1 study designed to evaluate the safety, tolerability and
      immunogenicity of the COVIVAC vaccine at three different dose levels (1, 3, and 10 µg)
      without adjuvant, and at one dose level (1 µg) with the adjuvant CpG 1018, in a total of 120
      subjects aged 18-59 years.

      In Part 2 of this combined Phase 1/2 study, 300 adults aged 18-75 years will be randomized
      (2:5:5) to placebo, or one of two selected formulations of COVIVAC being evaluated in Phase 1
    

Detailed description: 
      This prospective, single-center, randomized, placebo-controlled, observer-blind Phase 1/2
      study includes two separate parts.

      Part 1 is a first-in-human, Phase 1 study designed to evaluate the safety, tolerability and
      immunogenicity of the COVIVAC vaccine at three different dose levels (1, 3, and 10 µg)
      without adjuvant, and at one dose level (1 µg) with the adjuvant CpG 1018, in a total of 120
      subjects aged 18-59 years.

      An interim analysis of Phase 1 data conducted after the last subject last visit for V6 (D57)
      will serve as the basis for decisions about down selection and advancing to Part 2 of the
      study (Phase 2). Down selection and advancement to Part 2 (Phase 2) will be based on the
      following parameters:

        -  Post-dose 2 immunogenicity results at the aggregate treatment level

           o A threshold immune response at Visit 5 (D43) will be required: the observed
           seroresponse rate in a treatment group (defined as the percentage of subjects with at
           least a 4-fold rise from baseline in 80% neutralizing antibody titers) will need to be
           ≥52% at the LL of the 95% CI for that treatment (vaccine formulation) to be considered
           for advancement to Phase 2.

        -  Post-dose 1 and post dose 2 safety results including all solicited and unsolicited
           adverse events, serious adverse events, and clinical laboratory results.

      The following process will be followed for the decision about down selection and advancing to
      Part 2 (Phase 2):

        -  The DSMB will review the unblinded safety data and provide a recommendation to the
           Sponsor on whether the safety profile is acceptable for advancing a formulation to Phase
           2.

        -  The Sponsor will review the DSMB recommendation in conjunction with the immunogenicity
           data and select two formulations to advance to Phase 2.

           o If multiple formulations achieve the threshold immune response (as well as have an
           adequate safety and tolerability profile per the DSMB), the Sponsor will select two
           formulations to advance to Phase 2 based on consideration of such factors as the
           relative functional immunogenicity of these formulations, opportunity for dose sparing,
           and opportunity to limit cost and possible supply constraints associated with use of the
           CpG adjuvant.

        -  The selection and recommendation to advance to Phase 2 along with the interim report
           will be jointly reviewed by NIHE's IRB and MoH prior to Phase 2 enrollment.

      In Part 2 of this combined Phase 1/2 study, 300 adults aged 18-75 years will be randomized
      (2:5:5) to placebo, or one of two selected formulations of COVIVAC being evaluated in Phase
      1. At least one-third of the subjects in Phase 2 will be aged ≥60 years to ensure that
      adequate safety and immune data will be available from older and elderly adults to inform the
      selection of the COVIVAC formulation to advance to Phase 3 studies. The Phase 2 cohort will
      follow the same visit schedule, and undergo the same procedures and assessments, as in Phase
      1. In addition, as exploratory objectives, the anti-NDV HN IgG response will be assessed at
      V1, V3, V5, and V8 in all subjects, and 36 subjects (equally distributed between the two age
      strata) will be randomly selected in a 1:1:1 ratio to provide additional blood at V1, V5 and
      V7 to be used to isolate peripheral blood mononuclear cells (PBMCs) for assessment of
      T-cell-mediated immunity (CMI).

      An interim analysis of Phase 2 data (combined with immunogenicity and safety data generated
      for the placebo group and two selected COVIVAC formulations from Phase 1) will be conducted
      after the last subject of the Phase 2 cohort completes V6 (D57) as the basis for selecting
      the optimal formulation of COVIVAC to advance to Phase 3 studies. As was the case for the
      Phase 1 interim analysis at the same timepoint, the data generated will include unblinded
      post-dose 1 and dose 2 safety results for review by the DSMB, and immunogenicity results
      aggregated by treatment group for review by the Sponsor. The DSMB will consider all
      accumulated safety data from both phases of the study prior to making any recommendation to
      the Sponsor that it not advance a formulation based on safety concerns. The Sponsor will
      ultimately select the formulation to advance to Phase 3 that, in addition to having been
      judged by the DSMB to have an adequate safety and tolerability profile, is optimal based on
      relative functional immunogenicity and other programmatic considerations such as those noted
      above.
    

Intervention name(s): COVIVAC; Phosphate-buffered saline
Intervention type(s): Biological; Biological
Intervention description(s): COVIVAC vaccine, manufactured by IVAC with or without adjuvant CpG1018 for prevention of COVID-19; Phosphate buffer solution (pH 7.2), manufactured by IVAC
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: In Phase 1 is dose escalation design, eligible participants will be randomized to received study vaccine or placebo from low dose to higher dose and later to the formulation with CpG adjuvant. In phase 2, eligible participants will received 2 selected doses (from phase 1) or placebo.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: COVID-19; COVIVAC; COVID-19 disease; SARS-CoV-2; COVID-19 vaccine