FLUAD vs. FLUZONE HD Influenza Vaccine in Residents of Long Term Care

Study Overview
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Brief Summary
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Adjuvanted flu vaccine, Fluad, is not immunologically inferior to HD influenza vaccine in older persons living in long-term care.

Detailed Description
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As the primary endpoint, this trial is be using pre- to post-vaccine changes in HAI titers to compare seroconversion rates and post-vaccination HAI titers to calculate the ratio of the geometric mean titers in the two treatment groups. HAI is an in vitro bioassay that determines a subject's serum levels of anti-influenza antibodies. The FDA uses this as a standard immunogenicity assay for licensure. The trial will follow guidelines set out in the FDA guidance document discussing non-inferiority immunogenicity studies. As additional methods to assess immunogenicity, an assessment of anti-NA by performing NA inhibition assays (NAI) and SVN assays will be added. A recent trial supported the use of NAI and SVN assays as a correlate for protection in a trial of geriatric subjects. A healthy human challenge model showed that NAI is more predictive of protection and reduced disease than HAI In the large HD vaccine clinical efficacy trial (n=31,989) one third of subjects also had immunogenicity data that allowed looking for correlations of immune assays with protection. Their conclusions were that HAI and other immune assays are potential correlates of influenza vaccine protection in older adults, and that the protective thresholds for the HAI assay in the elderly appear consistent with those previously described for younger adults, provided the assay virus matches the circulating virus. Significance Data compiled by CDC in 2011-2012 showed that there were 1,383,700 residents in NHs. Also about 4,742,500 patients received services from home health agencies, and 1,244,500 patients received services from hospices, collectively accounting for much of the frailest in the US. Overall, these provider sectors served over 8 million people annually (2013). This study will focus on residents in NHs but the findings of this study are highly relevant to persons frail enough to require such services in all of settings where the vast majority are at least 65 years old and thus appropriate for Fluad or HD, influenza vaccines licensed for this age group. The SD influenza vaccine has diminished efficacy in the older population with the more debilitated LTC residents being among the worst responders yet with the highest mortality. Deaths due to pneumonia and influenza and chronic lung disease were 20 times higher among NH residents compared to community residents. The current availability of two vaccines specifically for the elderly that both appear to work better than SD vaccine begs the question: is the newer and less-costly Fluad vaccine non-inferior or even superior to HD vaccine? The proposed study aims to initially address non-inferiority using immunologic endpoints as this is feasible in the clinical trial R01 grant structure and a critical first step to obtain head-to-head data from the same trial, cohort and vaccine years. This proposed study itself may provide direct guidance on vaccine usage or inform a future trial assessing actual superiority should that be appropriate based on the results of this study. HD vaccine is increasingly used by older Americans despite its greater cost over the SD vaccine and no preferential recommendation by the Advisory Committee on Immunization Practices (ACIP), the CDC committee responsible for making the vaccine recommendations for the U.S. A finding of non-inferiority in the primary endpoint would provide a strong rationale to consider using Fluad over HD that could result in some cost avoidance across large long-term care system in the U.S. The trial is not powered for a superiority analysis but in a non-inferiority trial if the findings are substantial enough they may show superiority. In the normal seasonal setting, influenza strains drift antigenically and therefore vary from year to year. The CDC's prediction many months before the vaccination season sets the composition for the next season's vaccine, but does not always correctly anticipate the exact strain match that eventually actually circulates. There are Medicare claims data and modeling in the NH population that there is a significant increase in death and hospitalization in bad match over good match years particularly when A/H3N2 predominates. In those mismatched years in particular, heterologous immunity or immunity to other non-exact match strains becomes much more important if the vaccine is going to provide any benefit that season. Fluad is an adjuvanted vaccine that has been shown to have a more broad-based or heterologous immunity than SD vaccine that is not adjuvanted. HD is also not adjuvanted. Broad based immunity is especially desirable for A/H3N2 immunity as that has had 4 different circulating strains in the last 5 years while circulating A/H1N1 has been the same for 5 years; i.e., vaccine mismatch is more likely with the A/H3N2 circulating strain. A/H3N2 is associated with the majority of influenza hospitalizations and death among the elderly.

Official Title
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Non-inferiority Study of Adjuvanted vs. High Dose Flu Vaccine in Residents of Long Term Care

Conditions
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Flu

Intervention / Treatment
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* Drug: Fluad Vaccine
* Drug: Fluzone HD Vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: > 65 years old Able to obtain consent from subject or legally authorized representative (subject to provide assent if cognitively/physically able to do so) Able to participate throughout the study period Exclusion Criteria: Recent illness (within 30 days) severe enough to require hospitalization or physician-directed outpatient pharmacotherapy Administration of immunomodulatory agents (e.g. oral corticosteroids except prednisone < 10 mg daily, cyclosporine, and biologics (DMARDS) for Rheumatologic/Dermatologic conditions) in the last 3 months Cancer requiring treatment in the past three years, except for non- melanoma skin cancers or cancers that have clearly been cured or carry an excellent prognosis including prostate cancer. Myocardial infarction, major heart surgery (i.e. valve replacement or bypass surgery), stroke, deep vein thrombosis or pulmonary embolus in the past 4 months Allergies or history of significant adverse reactions to any component of influenza vaccine including egg protein and latex or after a previous dose of any influenza vaccine. History of Guillian-Barré Syndrome within 6 weeks of a prior influenza vaccine.

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A non-inferiority randomized clinical trial to enroll 500 long term care (LTC) dwellers from at least one of 40 nursing homes sites in northern Ohio. Age 65 and older to receive either Fluad or HD vaccine at 1:1 ratio. Blood will be sampled pre- and post-vaccine and post-influenza season and coded for blinded laboratory analysis. Randomization by from randomizer.org software./RedCAP
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Fluad Vaccine<br>A single adjuvanted dose (AD) intramuscular injection | Drug: Fluad Vaccine<br>* single adjuvanted dose (AD) intramuscular injection<br>|
| Active Comparator: Fluzone Vaccine<br>A single high dose (HD) intramuscular injection | Drug: Fluzone HD Vaccine<br>* single high dose (HD) intramuscular injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-inferiority in overall hemagglutinin inhibition (HAI) titer and seroconversion rate between FLUAD and FLUZONE HD at 1 month post-vaccination will be determined. | HAI is an in vitro bioassay testing subjects' sera for specific anti-influenza antibodies to each strain in the vaccine. Seroconversion is 4-fold rise in antibody titer. The FDA uses this as the standard immunogenicity assay for licensure. The investigators will follow the guidelines set out in the FDA guidance document on non-inferiority immunogenicity studies for the analysis plan. | 1 month post vaccine administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-inferiority in overall neuraminidase inhibition (NAI) titer and seroconversion rate between FLUAD and FLUZONE HD at 1 month post-vaccination will be determined. | Neuraminidase inhibition (NAI) assays will be performed to measure anti-neuraminidase titers. Seroconversion is 4-fold rise in antibody titer. | 1 month post vaccine administration | 
| Non-inferiority in overall serum virus neutralization (SVN) assays titer and seroconversion rate between FLUAD and FLUZONE HD at 1 month post-vaccination will be determined. | Serum virus neutralization (SVN) assays will be performed to measure the ability of serum to inhibit influenza infecgtion. Seroconversion is 4-fold rise in serum titer of inhibitory activity. | 1 month post vaccine administration | 
| Heterologous immunity at 1 month post-vaccination will be compared between FLUAD and FLUZONE HD. | Hemagglutinin inhibition (HAI), neuraminidase inhibition (NAI) assays and serum virus neutralization (SVN) assays will be performed with heterologous A/H3N2 strains to determine if Fluad has an increased breadth of both B and T cell responses as would be predicted from an adjuvanted vaccine. | 1 month post vaccine administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Flu, Vaccine