Standard-dose Versus High-dose Flu Vaccine in Solid Organ Transplant.

Study Overview
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Brief Summary
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Influenza infection in recipients of solid organ transplants recipients while on maintenance immunosuppressant therapy is associated with increased morbidity and mortality. Although influenza vaccination is recommended in these high-risk patients, safety and immunogenicity of commercially available different strengths of influenza vaccine have not been established. The primary study objective is to determine the safety and immunogenicity of Fluzone and Fluzone High-Dose, with a secondary objective to determine the tolerability and efficacy of two different strengths of trivalent influenza vaccine (TIV, flu vaccine). Both vaccines are commercially available for use in the general population. Fluzone is approved for use in 6 months of age and older, and Fluzone High-Dose is approved for use in 65 years of age and older. This is an exploratory, open-label, parallel group, observer blinded, prospective study. All recipients of kidney, lung, heart transplants who attend for post-transplant follow-up, at least 30-days after transplantation at Inova Fairfax Hospital Transplant Center will be eligible for enrollment. Enrolled patients will be followed for three months (a total of 4 visits) following enrollment and randomization: day 0 (enrollment) and follow-up visits at weeks 1, 4, 8, and 12.

Detailed Description
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A potential strategy to enhance immune responses to influenza vaccine in this patient population could be to use different strengths of TIV. One of the pathways that can improve the immunogenicity of inactivated vaccines is to increase the dose of influenza antigens contained in the vaccine. Studies have demonstrated that increasing the dose of the influenza virus hemagglutinin for each of the commonly encountered viral strains beyond the conventional dose of 15 microgram for each strain is associated with dose-dependent increase in serum antibody titers. Influenza TIV is commercially available in two different strengths, Fluzone as well as Fluzone High-Dose, and it is valuable because of variable immunogenic potency of different strengths. Fluzone is approved for use in persons 6 months of age and older. High-dose Fluzone is approved for use in persons 65 years of age and older. The purpose of this exploratory study is to assess the safety, tolerability, and immunogenicity of these two commercially available different strengths of TIV in solid organ transplant recipients (kidney, heart and lung) in the period after 30 days after transplant procedure. We will evaluate the safety, tolerability (reactogenicity) and immunogenicity of two different strengths of commercially available TIV in a single center, cluster randomization, investigator blinded, study by enrolling patients in the post-transplant clinic at Inova Fairfax Hospital from: August 1, 2013 - March 31, 2014; and August 1, 2014 to March 31, 2015. Study protocol will remain active till December 31, 2016. All bio-specimens will be stored till December 31, 2016.

Official Title
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Phase IV, Pilot, Randomized, Investigator-blinded, Study to Evaluate the Reactogenicity and Immunogenicity of Standard-dose Versus High-dose Inactivated Influenza Vaccine After Kidney, Heart and Lung Transplantation.

Conditions
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Influenza, Human, Transplantation Infection

Intervention / Treatment
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* Biological: influenza trivalent inactive vaccine
* Biological: influenza trivalent inactive vaccine high dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All adults age ≥18 years of age following solid organ transplants (kidney, heart and lung) of all races and gender unless as specified in the exclusion criteria. At least 30 days after organ transplantation of kidney, heart, or lung. In good health as determined by a) medical history, b) physical examinations, c) clinical judgment of the investigator team. Informed consent will be obtained from all the subjects before enrollment into the study, after the nature of the study has been fully explained to the satisfaction of the participant. Non-English speaking persons will be included ONLY if consent can be obtained with the help of the translator or interpreter. Exclusion Criteria: Less than 30 days after transplantation procedure. Post operative complications of any type. Transplant organ dysfunction and/or under evaluation for possible infection. Recent acute transplant rejection and treatment for rejection for the past 30 days. Receiving another investigational drug or biologic for transplant. Previous history of allergic reaction to influenza vaccine, chicken egg or other unknown allergic reactions to flu vaccine or other vaccines. Acute ongoing respiratory illness. Bleeding diathesis or on anticoagulation therapy. Major surgery (pre-arranged) planned during the study period. Any condition that may preclude the participant from completion of study related activities; such as planned travel, or out of the state of residence and not able to return for follow-up visits or relocation of residence. Females of reproductive age unless proven to be urine HCG negative at the time of participation. Recent opportunistic infection, such as CMV, EBV, BK viral reactivation, or any other documented or laboratory confirmed opportunistic infection or on treatment for confirmed infection. Vulnerable subjects such as aged less than 18 years, pregnant women, nursing home residents or other institutionalized persons, students, employees, prisoners, and persons who may not be able to make independent decisions or is considered to have a cognitive impairment, or non-English speaking in the absence of a reliable interpreter or translator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High Dose Flu Vaccine<br>influenza trivalent inactive vaccine high dose. IM (intramuscular) injection one time administration | Biological: influenza trivalent inactive vaccine high dose<br>* one time IM injection of high dose influenza vaccine to measure immunogenicity, safety, and efficacy in organ transplant recipients<br>* Other names: Fluzone High Dose (R);|
| Active Comparator: Flu Vaccine<br>influenza trivalent inactive vaccine IM injection one time administration | Biological: influenza trivalent inactive vaccine<br>* one time IM injection of standard influenza vaccine to measure immunogenicity, safety, and efficacy in organ transplant recipients<br>* Other names: flu vaccine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Local Site Reactions | Evaluation of local and systemic reactions, use of analgesics or antipyretics. | Day 1 and weeks 1, 4, and 12 | 
| Measurement of Strain-specific Hemagglutination Inhibition (HI) Antibody Titers | Number of patients and percentage of subjects achieving hemagglutination inhibition (HI) titer≥40 | Week 1, 4, and 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All Cause ED Visits/Unscheduled Clinic Visits | All-cause outpatient/Emergency department visits during study follow-up (other than pre-specified post transplant follow-up visits). | day 1 - 3 months | 
| Number and Percentage of Subjects in Each Group Achieving Seroconversion for Each Strain | Number and percentage of subjects in each group achieving seroconversion (at least 4-fold increase in titers from baseline) for each any strain at weeks 4 and 12 | Week 4 and Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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kidney transplant, heart transplant, lung transplant, influenza vaccine