Immunogenicity of High-dose Inactivated, Split-virion Influenza Vaccine Versus Standard Fluzone Vaccine in the Elderly

Study Overview
=================
Brief Summary
-----------------
Compared to young adults, the elderly mount a lower antibody response to vaccination. Thus, improvement of the immune response to influenza vaccination in this age group, which is at higher risk for influenza-related morbidity and mortality, represents an important unmet need. Primary Objectives: Immunogenicity: To demonstrate lot consistency of the Fluzone High Dose (Fluzone HD) manufacturing process through evaluation of the immune responses elicited by three different lots. To demonstrate the superiority of Fluzone HD vaccine compared to standard-dose Fluzone® vaccine. Secondary Objectives: Immunogenicity: To describe the seroprotection of Fluzone HD compared to that of standard dose Fluzone® vaccine. Safety: To describe the safety profile of Fluzone HD, in terms of solicited -, unsolicited adverse and serious adverse events post-vaccination. To describe clinical information on some additional defined criteria during the six months following vaccination.

Official Title
-----------------
Phase III Lot Consistency, Immunogenicity and Safety Study of Three Lots of Fluzone High Dose Vaccine Compared With One Lot of Standard Fluzone® in Adults ≥ 65 Years of Age.

Conditions
-----------------
Orthomyxoviridae Infection, Influenza, Myxovirus Infection

Intervention / Treatment
-----------------
* Biological: High-Dose Inactivated, Split-Virion Influenza Vaccine
* Biological: High-Dose Inactivated, Split-Virion Influenza Vaccine
* Biological: High-Dose Inactivated, Split-Virion Influenza Vaccine
* Biological: Inactivated, Split-Virion Influenza Vaccine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Aged ≥ 65 years on the day of vaccination. Informed consent form signed. Medically stable. (Subjects may have underlying chronic conditions such as hypertension, diabetes, ischemic heart disease, or hypothyroidism, as long as their symptoms/signs are controlled. If they are on medication for a condition, the medication dose must have been stable for at least 3 weeks preceding vaccination.) Able to attend all scheduled visits and to comply with all trial procedures. Exclusion Criteria: Systemic hypersensitivity to eggs, chicken proteins, or any of the vaccine components, or a history of a life-threatening reaction to the standard-dose Fluzone® vaccine or a vaccine containing any of the same substances. Congenital or history of acquired immunodeficiency, or immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within the preceding six months. Systemic corticosteroid therapy, as follows: Continuous use with a dosage equivalent to > 15 mg/day of oral prednisone for 90 days preceding vaccination. Sporadic use with a dosage equivalent to > 40 mg/day of oral prednisone for > 14 consecutive days in the 90 days preceding vaccination. Note:Use of topical or inhalant corticosteroids is acceptable. Neoplastic disease or any hematologic malignancy (except localized skin or prostate cancer that is stable at the time of vaccination in the absence of therapy, as well as subjects who have a history of neoplastic disease and who have been disease-free for ≥ 5 years). Current alcohol abuse or drug addiction that in the opinion of the investigator may interfere with the subject's ability to comply with trial procedures. Receipt of blood or blood-derived products in the past three months. Participation in a trial of a high-dose influenza vaccine in the past 12 months. Receipt of influenza vaccine in the past six months. Receipt of any other vaccine in the past four weeks. Planned receipt of any other vaccine in the four weeks following the trial vaccination. Participation in another clinical trial in the past four weeks. Planned participation in another clinical trial during the present trial period. Note:Concomitant participation in an observational trial (not involving drugs, vaccines, or medical devices) is acceptable. Thrombocytopenia or bleeding disorder contraindicating intramuscular (IM) vaccination. History of Guillain-Barré syndrome. Subject deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized without his/her consent. An acute febrile illness (oral temperature ≥ 99.5ºF [≥ 37.5ºC]) within 24 hours prior to vaccination. If this contraindication exists, vaccination will be deferred until the participant has been afebrile for at least 24 hours. Signs and symptoms of an acute infectious respiratory illness. If this exists, vaccination will be deferred until the symptoms resolve.

Ages Eligible for Study
-----------------
Minimum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study Group 1<br>Participants will receive the High-Dose Inactivated, Split-Virion Influenza Vaccine Lot 1 | Biological: High-Dose Inactivated, Split-Virion Influenza Vaccine<br>* 0.5 mL, IM<br>* Other names: Fluzone® High-Dose;|
| Experimental: Study Group 2<br>Participants will receive the High-Dose Inactivated, Split-Virion Influenza Vaccine Lot 2 | Biological: High-Dose Inactivated, Split-Virion Influenza Vaccine<br>* 0.5 mL, IM<br>* Other names: Fluzone® High-Dose;|
| Experimental: Study Group 3<br>Participants will receive the High-Dose Inactivated, Split-Virion Influenza Vaccine Lot 3 | Biological: High-Dose Inactivated, Split-Virion Influenza Vaccine<br>* 0.5 mL, IM<br>* Other names: Fluzone® High-Dose;|
| Active Comparator: Group 4<br>Participants will receive the Standard Fluzone® vaccine | Biological: Inactivated, Split-Virion Influenza Vaccine<br>* 0.5 mL, IM<br>* Other names: Fluzone® 2006-2007 formulation;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Titers (GMTs) of Hemagglutination Inhibition Antibody Titers Pre- and Post-vaccination With Fluzone® High Dose or Standard Fluzone® Vaccines. | Antibodies against each of three Influenza antigens (virus) in Fluzone® High-Dose and Standard Fluzone® vaccines (A/H1N1 New-Caledonia; A/H3N2 Wisconsin; and B Malaysia) were determined by the Hemagglutination inhibition assay method. | Day 0 and Day 28 Post-vaccination | 
| Percentage of Participants With Seroconversion Post-vaccination With Fluzone® High-Dose or Standard Fluzone® Vaccines. | Seroconversion was defined as a Hemagglutination Inhibition Antibody Titers of Titer ≥40 (1/dil) on Day 28 if pre-vaccination (Day 0) titer <10 (1/dil); or a four-fold increase of titer on Day 28, if pre-vaccination (Day 0) titer is ≥10 (1/dil) for each of the three Influenza vaccine antigens (A/H1N1 New-Caledonia; A/H3N2 Wisconsin; and B Malaysia). | Day 28 Post-vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Seroprotection Pre- and Post-Vaccination With Fluzone® High-Dose or Standard Fluzone® Vaccines. | Seroprotection was defined as a Hemagglutination Inhibition Titers of at least 40 (≥ 1:40) for each of the Influenza vaccine antigens (A/H1N1 New-Caledonia; A/H3N2 Wisconsin; and B Malaysia) pre- or post-vaccination with Fluzone® High-Dose or Standard Fluzone® vaccines. | Day 0 and Day 28 Post-vaccination | 
| Percentage of Participants Reporting Solicited Injection Site and Systemic Reactions After Fluzone® High-Dose or Standard Fluzone® Vaccination | The occurrence, time to onset, number of days of occurrence, and severity of solicited injection site reactions: Injection Site Pain, Erythema, and Swelling; Solicited systemic reactions: Fever (temperature), Headache, Malaise, and Myalgia were collected. | Day 0 to Day 7 Post-vaccination | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Influenza, Orthomyxoviruses, Inactivated Split-virion influenza vaccine, Adults