Influenza Clinical Trial
Official title:
Phase I Study of the Safety and Immunogenicity of a Novel H5N1 Influenza Vaccine in Healthy Adults Age 18-49
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.
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.
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Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention
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