Safety and Immunogenicity of MF59C.1 Adjuvanted Trivalent Subunit Influenza Vaccine in Elderly Subjects

Study Overview
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Brief Summary
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The present phase III study aims to evaluate the safety and immunogenicity of MF59-adjuvanted subunit seasonal influenza vaccine and to evaluate the consistency in the manufacturing process of three consecutive lots of MF59-adjuvanted subunit seasonal influenza vaccine with respect to immunogenicity in subjects aged 65 years and older. The active comparator non-adjuvanted seasonal influenza vaccine is approved for use in this age group in the United States and will be used to provide a comparative assessment for immunogenicity and safety.

Official Title
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A Phase III, Randomized, Controlled, Observer-Blind, Multicenter Study to Evaluate the Safety and Immunogenicity and the Consistency of Three Consecutive Lots of a MF59C.1 Adjuvanted Trivalent Subunit Influenza Vaccine in Elderly Subjects Aged 65 Years and Older

Conditions
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Influenza

Intervention / Treatment
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* Biological: MF59 adjuvanted trivalent subunit influenza vaccine (aTIV)
* Biological: Non-adjuvanted trivalent subunit influenza vaccine (TIV)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females subjects aged ≥65 years at day of vaccination who are willing and able to comply to study procedures. Exclusion Criteria: Individuals with behavioral or cognitive impairment or a psychiatric condition or with a history of any illness that,in the opinion of the investigator, would have interfered with the subject's ability to participate in the study. Individuals who were not able to comprehend and/or follow all required study procedures for the whole period of the study. Known or suspected impairment/alteration of immune function. Individuals with a known bleeding diathesis. History of Guillain-Barré syndrome. Individuals with history of allergy to vaccine components and/or a history of any anaphylaxis, serious vaccine reactions or hypersensitivity to influenza viral proteins, egg proteins (including ovalbumin), polymyxin, neomycin, betapropiolactone, thimerosal/ sodium ethylmercurothiosalicylate/ mercury and nonylphenolethoxylate/ nonoxynol-9 (spermicide). Receipt of another investigational agent within 30 days prior to enrollment in the study or before completion of the safety follow-up period in another study. Individuals who had received any other vaccines within 2 weeks for inactivated vaccines or 4 weeks for live vaccines prior to enrollment in this study or who had planned to receive any vaccine within 3 weeks from the study vaccine. Individuals who had received vaccination against seasonal influenza in the previous 6 months. Individuals with oral temperature ≥38.0°C (≥100.4°F) on day of study vaccination. Individuals with history of substance or alcohol abuse within the past 2 years. Individuals providing consent who did not consent to the retention of their serum samples after study completion. Elective surgery or hospitalization planned to occur during the treatment phase or during the follow-up phase that, according to the opinion of the investigator, might have poses additional risk to the subject. Subjects from whom blood could not be drawn at visit 1.

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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Accepts Healthy Volunteers

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: aTIV<br>Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3). | Biological: MF59 adjuvanted trivalent subunit influenza vaccine (aTIV)<br>* one dose 0.5 mL administered IM in the deltoid muscle of (preferably) the non-dominant arm<br>* Other names: Fluad;|
| Experimental: Licensed TIV<br>Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV). | Biological: Non-adjuvanted trivalent subunit influenza vaccine (TIV)<br>* one 0.5 mL dose administered IM in the deltoid muscle of (preferably) the non-dominant arm<br>* Other names: Agriflu;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Titers in Subjects After Receiving One Dose of Lot 1 or Lot 2 or Lot 3 of aTIV | Immunologic equivalence of 3 consecutive production lots of aTIV (Lot 1, Lot 2 and Lot 3), was assessed in terms of Hemagglutination Inhibition (HI) Geometric Mean Titers (GMTs) in subjects, at three weeks after vaccination, against each vaccine strain. | Day 22 post vaccination | 
| Comparison of aTIV Versus TIV in Terms of Geometric Mean Titers (GMTs) Against Homologous Strains - PPS | The non-inferiority of HI antibody responses of aTIV compared to TIV assessed in terms of post vaccination GMTs at three weeks after vaccination against the three homologous vaccine strains. | Day 22 post vaccination | 
| Comparison of aTIV Versus TIV in Terms of Percentage of Subjects Achieving Seroconversion Against Homologous Strains-PPS | The non-inferiority of HI antibody responses of aTIV compared to TIV assessed in terms of percentage of subjects achieving seroconversion at three weeks after vaccination against the three homologous vaccine strains. Seroconversion defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10. | Day 22 post vaccination | 
| Comparison of aTIV Versus TIV in Terms of GMTs Against Homologous Strains-Full Analysis Set (FAS) | The superiority of HI antibody responses of aTIV compared to TIV assessed in terms of post vaccination GMTs at three weeks after vaccination against the three homologous vaccine strains. | Day 22 post vaccination | 
| Comparison of aTIV Versus TIV in Terms of Percentage of Subjects Achieving Seroconversion Against Homologous Strains-FAS | The superiority of HI antibody responses of aTIV compared to TIV assessed in terms of percentage of subjects achieving seroconversion at three weeks after vaccination against the three homologous vaccine strains. Seroconversion defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10. | Day 22 post vaccination | 
| Percentage of Subjects With HI Titers ≥40 Against Homologous Strains | The percentage of subjects demonstrating HI titers ≥40, in overall group and in subjects with pre-defined co-morbidities (high risk group), against homologous strains, three weeks after vaccination with aTIV or TIV. | Day 22 post vaccination | 
| Percentage of Subjects Achieving Seroconversion in HI Titers, Against Homologous Strains | The percentage of subjects achieving seroconversion in HI titers from baseline, in overall group and in subjects with pre-defined co-morbidities (high risk group), against homologous strains, three weeks after vaccination with aTIV or TIV. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10. | Day 22 post vaccination | 
| Geometric Mean Ratio (GMR) of Post- Versus Pre-vaccination HI Titers Against Homologous Strains | The GMR of post-vaccination versus pre-vaccination HI titers (day 22/day 1) in overall group and in subjects with pre-defined co-morbidities (high risk group), against homologous strains, three weeks after vaccination with aTIV or TIV. | Day 22 post vaccination | 
| Percentage of Subjects With HI Titers ≥40 Against Heterologous Strains | The percentage of subjects demonstrating HI titers ≥40, in overall group and in subjects with pre-defined co-morbidities (high risk group), against heterologous strains, three weeks after vaccination with aTIV or TIV. | Day 22 post vaccination | 
| Geometric Mean Ratio (GMR) of Post- Versus Pre-vaccination HI Titers, Against Heterologous Strains | The GMR of post-vaccination versus pre-vaccination HI titers (day 22/day 1) in overall group and in subjects with pre-defined co-morbidities (high risk group), against heterologous strains, three weeks after vaccination with aTIV or TIV. | Day 22 post vaccination | 
| Percentage of Subjects Achieving Seroconversion in HI Titers, Against Heterologous Strains | The percentage of subjects achieving seroconversion in HI titers from baseline, in overall group and in subjects with pre-defined co-morbidities (high risk group), against heterologous strains, three weeks after vaccination with aTIV or TIV. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10. | Day 22 post vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of aTIV Versus TIV in High Risk Group in Terms of GMTs Against Homologous Strains-PPS | The non-inferiority of HI antibody responses of ATIV compared to TIV, in subjects with pre-defined co-morbidities (high risk subjects), was assessed in terms of post vaccination GMTs at three weeks after vaccination against the three homologous vaccine strains. | Day 22 post vaccination | 
| Comparison of HI Antibody Responses of aTIV Versus TIV, in High Risk Group in Terms of Percentage of Subjects Achieving Seroconversion Against Homologous Strains-PPS | The non-inferiority of HI antibody responses of ATIV compared to TIV, in subjects with pre-defined co-morbidities (high risk group), assessed in terms of percentage of subjects achieving seroconversion at three weeks after vaccination against the homologous vaccine strains. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10. | Day 22 post vaccination | 
| Comparison of aTIV Versus TIV in High Risk Group in Terms of GMTs Against Homologous Strains-FAS | The superiority of HI antibody responses of aTIV compared to TIV, in subjects with predefined co-morbidities (high risk group) assessed in terms of post vaccination GMTs at three weeks after vaccination against the three homologous vaccine strains. | Day 22 post vaccination | 
| Comparison of HI Antibody Responses of aTIV Versus TIV, in High Risk Group in Terms of Percentage of Subjects Achieving Seroconversion Against Homologous Strains-FAS | The superiority of HI antibody responses of aTIV compared to TIV, in subjects with pre-defined co-morbidities (high risk group), assessed in terms of percentage of subjects achieving seroconversion at three weeks after vaccination against the homologous vaccine strains. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10. | Day 22 postvaccination | 
| Comparison of aTIV Versus TIV in Terms of GMTs Against Heterologous Strains-PPS | The non-inferiority of HI antibody responses of aTIV compared to TIV against the heterologous vaccine strains, in overall group and in subjects with pre-defined co-morbidities (high risk subjects), was assessed in terms of post vaccination GMTs at three weeks after vaccination . | Day 22 post vaccination | 
| Comparison of aTIV Versus TIV in Terms of GMTs Against Heterologous Strains-FAS | The superiority of HI antibody responses of aTIV compared to TIV against the heterologous vaccine strains, in overall group and in subjects with pre-defined co-morbidities (high risk subjects), was assessed in terms of post vaccination GMTs at three weeks after vaccination. | Day 22 post vaccination | 
| Comparison of HI Antibody Responses of aTIV Versus TIV, in Terms of Percentage of Subjects Achieving Seroconversion Against Heterologous Strains-PPS | The non-inferiority of HI antibody responses of aTIV compared to TIV against the heterologous strains, in overall group and in subjects with pre-defined co-morbidities (high risk group), assessed in terms of percentage of subjects achieving seroconversion at three weeks after vaccination. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10. | Day 22 postvaccination | 
| Comparison of aTIV Versus TIV in Terms of Percentage of Subjects Achieving Seroconversion Against Heterologous Strains-FAS | The superiority of HI antibody responses of aTIV compared to TIV against the heterologous vaccine strains, in overall group and in subjects with pre-defined co-morbidities (high risk subjects), was assessed in terms of percentage of subjects achieving seroconversion, at three weeks after vaccination. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10. | Day 22 post vaccination | 
| Persistence of GMTs Against Homologous and Heterologous Strains | The GMTs against homologous and heterologous strains, persisting in subjects at six months (day 181) and one year (day 366) after vaccination with either aTIV or TIV. | Day 181, Day 366 post vaccination | 
| Percentage of Subjects With Seroconversion Upto One Year After Vaccination, Against Homologous and Heterologous Strains | The percentage of subjects demonstrating seroconversion in HI titers against homologous and heterologous strains, at six months (day 181) and one year (day 366) after vaccination with either aTIV or TIV. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10. | Day 181, Day 366 post vaccination | 
| Number of Subjects Reporting Influenza Like Illness (ILI) Across Vaccine Groups | The number of subjects reporting ILI from three weeks after vaccination to up to one year in aTIV group compared to TIV group, by country. | Day 22 through Day 366 post vaccination | 
| Number of High Risk Subjects With Exacerbation of Preexisting Chronic Disease, Across Vaccine Groups | The number of high risk subjects reporting exacerbation of preexisting chronic conditions (i.e.congestive heart failure, Chronic Obstructive Pulmonary disease (COPD), asthma, hepatic disease, renal insufficiency, and neurological/neuromuscular or metabolic disorders including diabetes mellitus) in aTIV group compared to TIV group. | Day 1 through Day 366 post vaccination | 
| Number of Subjects Reporting Healthcare Utilization Across Vaccine Groups | The number of subjects with emergency room visits, unscheduled physician visits, and hospitalizations due to community acquired influenza or pneumonia, cardiopulmonary disease, cardiac disease, respiratory or pulmonary disease,in aTIV group compared to TIV group. | Day 1 through Day 366 post vaccination | 
| All Cause Mortality Rate, Across Vaccine Groups | The all-cause mortality rate (excluding injury)reported in aTIV group compared to TIV group, by country. | Day 1 through Day 366 post vaccination | 
| Number of Subjects Reporting Solicited Adverse Events Following Vaccination | The number of subjects reporting solicited local and systemic adverse events and other adverse events in aTIV group compared to TIV group. | Day 1 through Day 7 post vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Elderly, Influenza, Immunogenicity, Safety, Adjuvant, Adjuvanted, Adjuvants, Vaccines