Study to Evaluate the Efficacy, Safety and Immunogenicity of Influenza Vaccine in Healthy Subjects (Aged 6 to <72 Months) Versus Control Vaccines

Study Overview
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Brief Summary
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This study will evaluate the efficacy, safety and immunogenicity of one or two 0.25 mL or 0.5 mL intramuscular injections of an adjuvanted influenza vaccine compared with non-influenza and non-adjuvanted influenza control vaccines in subjects 6 to <72 months of age.

Official Title
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A Phase III, Randomized, Observer-blind, Controlled, Multi-center Clinical Trial to Evaluate the Efficacy, Safety and Immunogenicity of One and Two Intramuscular Doses of Influenza Vaccine Versus Control Vaccines in Healthy Subject Aged 6 to <72 Months

Conditions
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Influenza, Human

Intervention / Treatment
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* Biological: Adjuvanted trivalent inactivated subunit influenza vaccine
* Biological: Non-adjuvanted trivalent inactivated subunit influenza vaccine or non-adjuvanted trivalent inactivated split influenza vaccine
* Biological: Meningococcal C conjugate vaccine or tick-borne encephalitis vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children whose parents/legal guardians have given written informed consent prior to study entry: a) aged 6 to <72 months (Part I and II of the study; influenza seasons 2007/2008 and 2008/2009) b) aged 6 to <36 months (Part III of the study; influenza season 2009/2010) In good health as determined by: a) medical history, b) physical examination, c) clinical judgment of the investigator Exclusion criteria: Administration of licensed vaccines (including H1N1sw vaccines) within 14 days (for inactivated vaccines) or 28 days (for live vaccines) prior to enrollment in this study. Routine vaccines, according to local recommendations, or any other vaccines not foreseen in the protocol could be given after the active trial phase (i.e., 21 days after last vaccination) has been concluded. Receipt of another investigational vaccine or any investigational agent within 30 days prior to enrollment in the study or before completion of the safety follow-up period in another study, whichever is longer, and participation in another clinical trial during the present study. Experience of a severe acute infectious disease in the month prior to study start or experience of a mild acute infection disease in the week prior the study start (untreated common cold is acceptable). The severity of the infectious disease occurred will be based on the investigator's judgment. Any severe acute respiratory disease and infection requiring systemic antibiotic or antiviral therapy ongoing or resolved within 2 days prior to study start. Experience an axillary temperature equal to or greater than 37.8°C (rectal temperature equal to or greater than 38.3°C) within the 2 days before enrollment. Any serious disease in the opinion of the investigator including, for example: a) cancer, b) autoimmune disease (including rheumatoid arthritis under immunosuppressive therapy), c) insulin dependent diabetes mellitus, d) chronic pulmonary disease, asthma under inhalative therapy only is acceptable, e) acute or progressive hepatic disease, f) acute or progressive renal disease. Known or suspected impairment/alteration of immune function, for example, resulting from: a) receipt of immunosuppressive therapy (corticosteroid -except topical or inhaled steroids- or cancer chemotherapy), b) receipt of immunostimulants, c) receipt of parenteral immunoglobulin preparation, blood products, and/or plasma derivatives within the past 90 days and for the full length of the study, d) high risk for developing an immunocompromising disease (suspected or known HIV infection or HIV-related disease). Bleeding diathesis. History of hypersensitivity to any component of the study medication or chemically related substances. History of any anaphylaxis, serious vaccine reactions, or allergy to eggs, egg products or any other vaccine component. Laboratory confirmed influenza disease. History of neurological disorder or seizures (febrile seizures allowed). Received any influenza vaccine. Major surgery planned during the study period. Any condition which, in the opinion of the investigator, might interfere with the evaluation of the study objectives, e.g., planned travel or relocation of residence that would interfere with completion of study.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 71 Months

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: TIV-adj<br>Adjuvanted trivalent inactivated subunit influenza vaccine | Biological: Adjuvanted trivalent inactivated subunit influenza vaccine<br>* Either two intramuscular (IM) injections of half dose or one IM injection of full dose, depending on age of subject, were administered in the deltoid muscle preferably of the non-dominant arm.<br>* Other names: Fluad;|
| Active Comparator: Flu-control<br>Non-adjuvanted trivalent inactivated subunit influenza vaccine or non-adjuvanted trivalent inactivated split influenza vaccine | Biological: Non-adjuvanted trivalent inactivated subunit influenza vaccine or non-adjuvanted trivalent inactivated split influenza vaccine<br>* For both vaccines, either two intramuscular (IM) injections of half dose or one IM injection of full dose, depending on age of subject, were administered in the deltoid muscle preferably of the non-dominant arm.<br>* Other names: 2) Influsplit SSW;|
| Sham Comparator: Non-flu Control<br>Novartis meningococcal C conjugate vaccine or tick-borne encephalitis vaccine | Biological: Meningococcal C conjugate vaccine or tick-borne encephalitis vaccine<br>* Meningococcal vaccine: two IM injections Tick-borne encephalitis vaccine: two IM injections<br>* Other names: 2. Encepur Children;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects (Unprimed) 6 to <36 Months Age With Local and Systemic Reactions After Any Vaccination for All Seasons, Comparison of Adjuvanted Trivalent Influenza Vaccine (aTIV) and Flu Vaccine Control. | Safety was assessed in terms of number of subjects experiencing each of the local and systemic reactions within 7-days after any vaccination for all seasons, comparison of adjuvanted Trivalent influenza vaccine (aTIV) and flu vaccine control. | 7 days post-vaccination | 
| Percentage of Subjects (Unprimed) Aged 6 to <36 Months With Virus-Confirmed Influenza, Comparison of aTIV and Non-flu Vaccine Control (Men C/TBE Vaccine) | Virus-confirmed influenza illnesses were assessed and compared between the adjuvanted influenza vaccine (TIV-adj) and non-influenza vaccines (Non-flu control) in 6 to <36 month unprimed subjects for Absolute Efficacy. This primary endpoint is only for homologous strains. | 3 weeks after 2nd vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects (Unprimed) of 6 to <72 Months Age With Local and Systemic Reactions After Any Vaccination | Safety was assessed as the number of subjects aged 6 to <72 months who reported solicited local or systemic adverse events after any vaccination with TIV-adj for all seasons. | 7 days post-vaccination | 
| Number of Subjects (Unprimed) With Unsolicited Adverse Events Reported After Any Vaccination | Number of subjects aged 6 to <36 months and in the overall age cohort (unprimed children aged 6 to <72 months) experiencing each of the unsolicited adverse events (AEs) throughout the study | Study day 1 to Study day 181 | 
| Percentage of Subjects (Unprimed) Aged 6 to <72 Months With Virus-Confirmed Influenza, Comparison of aTIV to Non-flu Vaccine Control and Flu-vaccine Control (Matched Strains) | Virus-confirmed influenza illnesses were assessed and compared between the adjuvanted influenza vaccine (TIV-adj) and non-influenza vaccines (Non-flu control) in subjects aged 6 to <72 months (unprimed) for Absolute Efficacy. For Relative efficacy, the comparison was made between adjuvanted influenza vaccine (TIV-adj) and flu vaccine control. | 3 weeks after 2nd vaccination | 
| Percentage of Subjects (Unprimed) Aged 6 to <72 Months With Virus-Confirmed Influenza, Comparison of aTIV to Non-flu Vaccine Control and Flu Vaccine Control (Any Strains). | Virus-confirmed influenza illnesses (regardless of antigenic match to those contained in the vaccine) were assessed and compared between the adjuvanted influenza vaccine (TIV-adj) and non-influenza vaccines (Non-flu control) in subjects aged 6 to <72 months (unprimed) for Absolute Efficacy. For Relative efficacy, the comparison was made between adjuvanted influenza vaccine (TIV-adj) and flu vaccine control. | 3 weeks after 2nd vaccination | 
| Number of Subjects (Unprimed) With Influenza Like Illnesses (ILIs) in the 6 to <72 Months Age Cohort for Combined Seasons 2007/08 and 2008/09 | Virus-confirmed influenza illnesses were assessed and trivalent adjuvanted influenza vaccine (TIV-adj) was compared with Non-flu control vaccine and Flu-control vaccine in 6 to <72 month old subjects for Influenza like illnesses for seasons 2007/08 and 2008/09. | 3 weeks after 2nd vaccination | 
| Number of Subjects With Influenza Like Illnesses (ILIs) in the 6 to <36 Months and in Overall Age Cohort (Unprimed Subjects Aged 6 to <72 Months) for Combined Seasons 2007/08 and 2008/09 | Virus-confirmed influenza illnesses were assessed and trivalent adjuvanted influenza vaccine (TIV-adj) was compared with Non-flu control vaccine and Flu-control vaccine for Influenza like illnesses for seasons 2007/08 and 2008/09. | 3 weeks after 2nd vaccination | 
| Loss of Days of Usual Activity (Job, School, Day Care, Household/Family/Community Activities) Due to Influenza Like Illness (ILI) in Subjects in Aged 6 to <72 and 6 to <36 Months and in Direct Caregivers Living in the Household. | Virus-confirmed influenza illnesses were assessed and trivalent adjuvanted influenza vaccine (TIV-adj) was compared with Non-flu control vaccine and Flu-control vaccine for Influenza like illnesses for seasons 2007/08 and 2008/09. | 3 weeks after 2nd vaccination | 
| Number of Events of Influenza Like Illness for Combined Seasons 2007/08 and 2008/09. | The number of events of Influenza like Illness reported by subjects aged 6 to <72 months was assessed for combined seasons 2007/08 and 2008/09 | 3 weeks after 2nd vaccination | 
| Immunogenicity of aTIV, Compared to Flu and Non-Flu-control, in Terms of GMRs, in Unprimed Subjects Aged 6 to <36 Months or Season 2008/09 (Homologous and Heterologous Strains) | The immunogenicity was assessed in terms of Geometric mean titer ratios (GMRs) of study day 29/study day 1, study day 50/study day 1, study day 181/study day 1 were evaluated. The criteria for evaluation is GMR >2.5 | On study days 1, 29, 50 and 181 | 
| Immunogenicity of aTIV, Compared to Flu and Non-Flu-control, in Terms of Geometric Mean Titers (GMTs), in Unprimed Subjects Aged 6 to <36 Months for Season 2008/09 (Homologous and Heterologous Strains) | Immunogenicity was analyzed in terms of Geometric Mean Titers (GMTs) as measured by hemagglutination inhibition (HI) assay. For each strain and each vaccine group, least squares GMTs, associated 2-sided 95% confidence interval were determined for all time points. Superiority analysis: GMT-TIV-adj/GMT-Flu-control >1 should be elicited to show that GMT-TIV-adj is superior to GMT-Flu-control | On study days 1, 29, 50 and 181 | 
| Percentage (95% CI) of Unprimed Subjects Aged 6 to <36 Months With HI Titer ≥1:40 in Season 2008/09 HI Assay(Homologous and Heterologous Strains) | Percentage of subjects achieving seroprotection (i.e., with HI titer ≥1:40) at study day 1, study day 29, study day 50 and a study day 181 and associated 95% CI. The lower bound of the two-sided 95% CI for the percentage of subjects achieving an HI antibody titer ≥1:40 should meet or exceed 70%. | On study days 1, 29, 50, 181 | 
| Percentage (95% CI) of Unprimed Subjects Aged 6 to <36 Months With Seroconversion From Baseline, for Season 2008/09 (Homologous and Heterologous Strains) | HI assay was used for the analysis. Seroconversion is defined as negative pre-vaccination serum (<10)/ post-vaccination HI titer ≥1:40. Seroconversion is defined as either pre-vaccination HI titer <10 and a post-vaccination HI titer ≥1:40 or a prevaccination HI titer ≥10 and a minimum four-fold rise in post-vaccination HI antibody titer. The lower bound of the two-sided 95% confidence interval (CI) for the percentage of subjects achieving seroconversion for HI antibody should meet or exceed 40%. | On study days 1, 29, 50, 181 | 
| Immunogenicity of aTIV, Compared to Flu and Non-Flu-control, in Terms of GMTs, in Unprimed Subjects Aged 6 to <72 Months for Season 2008/09 (Homologous and Heterologous Strains) | Immunogenicity was analyzed in terms of Geometric Mean Titers (GMTs) as measured by hemagglutination inhibition (HI) assay. For each strain and each vaccine group, least squares GMTs, associated 2-sided 95% confidence interval were determined for all time points Superiority analysis: GMT-TIV-adj/GMT-Flu-control >1 and GMT-TIV-adj/GMT-Non Flu-control >1 should be elicited to show that GMT-TIV-adj is superior to GMT-Flu-control/Non Flu-control. | On study days 1, 29, 50 , 181 | 
| Immunogenicity of aTIV, Compared to Flu and Non-Flu-control, in Terms of GMRs, in Unprimed Subjects Aged 6 to <72 Months for Season 2008/09 (Homologous and Heterologous Strains) | Hemagglutination Inhibition (HI) assay was used for the analysis. Geometric mean titer ratios (GMRs) of study day 29/study day 1, study day 50/study day 1, study day 181/study day 1 were evaluated. The criteria for evaluation is GMR >2.5 | On study days 1, 29, 50, 181 | 
| Percentages of Subjects With HI Titers ≥ 1:40 in Unprimed Subjects 6 to <72 Months of Age for Season 2008/09 Homologous and Heterologous Strains | Hemagglutination Inhibition (HI) assay was used for the analysis. Percentage of subjects achieving seroprotection (i.e., with HI titer ≥1:40) at study day 1, study day 29, study day 50 and a study day 181 and associated 95% Confidence Intervals. The lower bound of the two-sided 95% CI for the percentage of subjects achieving an HI antibody titer ≥1:40 should meet or exceed 70%. | On study days 1, 29, 50, 181 | 
| Percentages of Subjects With Seroconversion and Vaccine Group Differences in Unprimed Subjects 6 to <72 Months of Age for Season 2008/09 (Homologous and Heterologous Strains) | HI assay was used for the analysis. Seroconversion is defined as negative pre-vaccination serum (<10)/ post-vaccination HI titer ≥1:40. Seroconversion is defined as either pre-vaccination HI titer <10 and a post-vaccination HI titer ≥1:40 or a prevaccination HI titer ≥10 and a minimum 4-fold rise in post-vaccination HI antibody titer. The lower bound of the two-sided 95% confidence interval (CI) for the percentage of subjects achieving seroconversion for HI antibody should meet or exceed 40%. | On study days 1, 29, 50, 181 | 
| Number of Subjects With Local and Systemic Reactions for Egg and Cell Derived Inactivated Novel Swine Origin A/H1N1 Subunit Influenza Vaccines After Each Vaccination for All Seasons |  | 7 days post-vaccination | 
| Indirect Protective Effect of Fluad (NH Composition 2007/2008), Compared to Non-flu Control and Flu Control, in Connection to Household-contact Persons Via a Questioning of the Parents About ILI of Persons Living in the Same Household as the Study Child |  | 3 weeks after 2nd vaccination | 
| Incidence Rate of the 2009-2010 H1N1 Swine Pandemic Caused by a Novel Influenza A (H1N1) Virus of Swine Origin in Unprimed Children Aged 6 to <36 and 6 to <72 Months |  | 3 weeks after 2nd vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Influenza, vaccine, children