Study of the Safety and Immunogenicity of a Novel H5N1 Influenza Vaccine in Healthy Adults Age 18-49
Condition: Influenza
MeSH terms: Influenza, Human; Influenza in Birds
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to test an investigational vaccine known as "VAX161C." An
      "investigational" vaccine is one that is not licensed for commercial use in the by the United
      States (US) by the US Food and Drug Administration (FDA). VAX161C is a vaccine for the
      influenza A virus subtype H5N1 avian influenza virus (bird flu). In this study, the subject
      will receive the VAX161C vaccine at one of six doses to see which dose is the best. VaxInnate
      wants to find out how safe these doses of vaccines are and how well they are tolerated by
      people who receive them. To measure how effective each type of the vaccine is, VaxInnate will
      test the ability of the body to develop an immune response, which means how the body
      recognizes and defends itself against the influenza virus.
    

Detailed description: 
      SAFETY ASSESSMENTS AND REPORTING Immediate Complaints Immediate complaints are vaccination
      symptoms that are solicited and observed for two hours (+30 minutes) after vaccination on Day
      0 and vaccination on Day 21. Solicited immediate complaints will be grouped as local
      (injection site) complaints and general complaints (Appendix A: Solicited Local and General
      Vaccination Reactogenicity Symptoms). Solicited local (injection site) complaints include
      redness (erythema), swelling or induration, pain, bruising and solicited general complaints
      will include fever, headache, fatigue, joint pain, muscle aches, shivering (chills), and
      increased sweating. Each of these local and general complaints will be graded for severity
      using the guidelines provided in Appendix B: Local Reactogenicity Toxicity Grading Scale and
      Appendix C: General Reactogenicity Toxicity Grading Scale. The data will be reported as
      "immediate complaints" and presumed to be related to the investigational product. These
      findings should NOT be additionally recorded as AEs unless they meet the criteria set forth
      in Section 8.3. Any other symptom offered by study subjects at 2 hours (+30 minutes) after
      each vaccination will be recorded under the AE section of the CRF.

      Vaccine Reactogenicity The same sets of local and general complaints, complaints reasonably
      anticipated to occur as a result of receipt of the investigational product are included in
      the Reactogenicity Memory Aid and listed in Appendix A: Solicited Local and General
      Vaccination Reactogenicity Symptoms. These will be solicited by study staff in conjunction
      with review of the Memory Aid during the 7 days following vaccinations on Day 0 and 21. The
      severity will be graded using the grading scales provided in Appendix B: Local Reactogenicity
      Toxicity Grading Scale and Appendix C: General Reactogenicity Toxicity Grading Scale and all
      findings recorded in the CRFs. Symptoms from the Reactogenicity Memory Aid will be reported
      as "reactogenicity" and presumed to be related to the investigational product. These
      complaints should NOT be additionally recorded as AEs unless they meet the criteria set forth
      in Section 8.3. Definitions used to grade reactogenicity severity will be included on the
      Reactogenicity Memory Aid form.

      Safety Oversight VaxInnate VaxInnate is the study Sponsor. Sponsor responsibilities will
      include the creation and oversight of protocol development, submission of the Investigational
      New Drug (IND) application to the FDA, monitoring and ensuring Good Clinical Practice (GCP)
      conduct of the study, and the submission of annual and final study reports to the FDA.

      Safety Monitoring Committee (SMC) The SMC will consist of 3 independent medical monitors not
      associated with study. The Principal Investigator(s), VaxInnate Medical Monitor, and the Data
      Manager will provide information to the SMC. The SMC will assess the safety information after
      each part of the study to determine if it is safe to escalate to the next dose level. The SMC
      meetings will be convened after the safety data for both doses has been collected for
      subjects enrolled in part 1 and later for part 2. The SMC will review the safety data and
      make a recommendation on continuing on to the next part of the study. The safety data and the
      SMC's recommendations will be forwarded to CBER for their review and agreement. The SMC will
      also meet on an ad hoc basis to review adverse events or other safety related issues. If a
      safety issue occurs that would halt the study (Section 4.5), the IRB and FDA will be
      notified.

      ANALYTICAL AND STATISTICAL ANALYSIS PLAN Data Entry and Management Subject
      screening/enrollment will be documented using an electronic master subject log. This log will
      capture the following information: subject number; initials; date screen/enroll; and, reason
      for not enrolling.

      In this study and in VAX161B, CRFs utilizing Smart Pen TM, a digital pen technology, will be
      used to gather originally-captured data. Therefore, the CRFs will serve as the source
      documentation for all protocol procedures and assessments, except for concomitant
      medications, adverse events, and all "Symptom Assessments" obtained from subject-completed
      memory aids (MEMA CRF). For these required procedures and assessments, the collected data
      will be recorded onto logs or memory aids as source documentation. This data will then be
      transcribed onto the CRF by the study staff. Health Decisions' electronic data management
      system will be used to create, modify, maintain, archive, retrieve, and transmit study data.

      The Investigator remains responsible for the accuracy and adequacy of all data entered onto
      the CRFs. Data will be monitored as described in section 10.1. Under direction of the
      clinical monitor, CRFs will be source document verified, as appropriate and further
      processed. Upon further data processing, queries may be generated and sent to the
      Investigator for clarification or correction. The Investigator will address any queries and
      resolutions verified by the clinical monitor.

      The database will be "soft-locked" for analysis when all subjects' data have been entered and
      data queries have been resolved through Day 42 (± 2) and after immunogenicity samples have
      been tested.

      Data Analysis Additional details of the analysis will be provided in the Statistical Analysis
      Plan (SAP) and the Clinical Study Report (CSR). This plan will include details of handling
      missing data, and if applicable, unused and spurious data. Deviations from the SAP will be
      reported in the CSR. The SAP will be finalized before study completion. If there are any
      discrepancies between the protocol and the SAP, the SAP will take precedence.

      Sample Size and Power For the purpose of assessing the safety and immunogenicity of VAX161C
      vaccine a total of 250 subjects are divided into 6 dose groups in a ratio of 1:2:2:2:2:1.
      Groups of 50 subjects were chosen for the 2.5, 4, 6 and 8 µg doses, the anticipated safe and
      immunogenic dose range for VAX161C. Groups of 25 subjects were chosen for the 1 and 12 µg
      dose groups. Based on previous findings with similar vaccines, we anticipate that the 1 µg
      group will serve as the "placebo" group. The purpose of the 12 µg group is to assess the
      upper limit of safety and immunogenicity. The sample size for this study (50 subjects in each
      of the key vaccine doses and 25 subjects in the control (1 µg group) was selected to provide
      a robust initial safety database as well as some information on the dose-related immune
      response.

      Safety Analysis All subjects who receive at least one dose of vaccine will be considered
      enrolled and included in the post-dosing safety analysis (safety population). The safety
      outcome will be the occurrence of solicited complaints (identified in Section 8.2) during the
      seven days after receiving the vaccine. These symptoms will be collected from the memory aid
      and from the information collected at the clinic visits. All symptoms will be graded
      according to severity. Response to vaccine will be categorized as local (arm pain, redness,
      bruising, etc.) or systemic (headache, muscle aches, fatigue, etc.) symptoms. Local or
      systemic reactions between vaccine dose groups will be compared to the 1 µg group by
      two-sided Fisher's exact test. Laboratory tests such as WBC and LFTs collected before and
      after vaccination will also be analyzed looking for differences between pre- and
      post-vaccination and across vaccine formats. We will compare the types and severity of
      symptoms and laboratory results based on vaccine construct.

      Proportions for those reporting the endpoints in the vaccine groups will be calculated and
      analyzed using the upper boundary of a two-tailed 95% confidence interval (CI) to compare
      against the 1 µg group. In addition, the frequency and percent of subjects in each of the
      vaccine groups reporting each of the solicited complaints and laboratory findings will be
      tabulated and presented with 2-sided 95% confidence intervals. A chi-square test may be used
      to test whether the observed proportions differ from the expected proportions across dosage
      groups.

      Immune Response Analysis

      Sera collected at Screening, Days 21 (prior to vaccination0, 42 (±2) and 180 (±10) will be
      analyzed for determination of HAI, MN assay, serum anti-HA ELISA and serum anti-flagellin
      ELISA. The results of these determinations will be evaluated as follows:

        -  Calculation of the geometric mean of pre- and post-vaccination HAI, MN assay, anti-HA,
           and anti-flagellin serum antibody titers for each treatment group.

        -  Change from pre- to post-vaccination in geometric mean HAI, MN anti-HA, and
           anti-flagellin serum antibody titers for each treatment group

        -  Seroconversion rates based on HAI response defined as percentage of subjects having a
           pre-vaccination titer of < 1:10 and a post vaccination HI titer ≥ 1:40 or a
           pre-vaccination HI titer ≥ 1:10 and a minimum four-fold rise in post-vaccination HI
           antibody titer).

        -  Proportion of subjects with HAI, MN, anti-HA and anti-flagellin serum antibody titers
           before and after vaccination by treatment group.

      Statistical comparisons between the treatment groups will be provided. GMTs will be compared
      with one-way ANOVA of log10-transformed titers and reported as GMT ratios and 95% CIs,
      calculated on the log10 scale and transformed. Proportions of subjects that achieve
      seroconversion for each dose will be determined by two-sided Fisher's exact test. Exact CIs
      are reported for all proportional endpoints.

      Efficacy Analysis The current protocol is not designed to evaluate the efficacy of VAX161C.
      CLINICAL MONITORING AND ADMINISTRATION Disposition of Data A CRF will be provided for each
      enrolled study subject. Data collected through the completion of experimental procedures
      required by this protocol will be recorded in the subject's chart as source documentation.
      This data will then be transcribed onto the CRF by the study staff. All data entered into the
      CRFs will have source documentation in the form of laboratory print outs or entries into the
      subject's chart. The Investigator remains responsible for the accuracy and adequacy of all
      data entered on the CRFs. Under direction of the clinical monitor, CRFs will be source data
      verified and further processed. Upon further data processing, queries may be generated and
      sent to the Investigator for clarification or correction. The Investigator will address any
      queries and resolutions verified by the clinical monitor. Once all CRFs are completed and
      queries resolved, the subjects' CRFs may be locked.
    

Intervention name(s): VAX161C vaccine
Intervention type(s): Biological
Intervention description(s): Recombinant H5 influenza vaccine, VAX161C
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: H5N1 Influenza; H5N1 Influenza vaccine