Safety and Immunogenicity of Two Doses of H5N1 Influenza Vaccine in Children

Study Overview
=================
Brief Summary
-----------------
Evaluate Safety, Tolerability and Immune response of adjuvanted H5N1 cell culture derived influenza vaccine in children.

Official Title
-----------------
A Phase II, Randomized, Observer-Blind, Multi-Center, Study to Evaluate Safety, Tolerability and Immunogenicity of an Adjuvanted Cell Culture-Derived H5N1 Subunit Influenza Virus Vaccine at Two Different Formulations in Healthy Pediatric Subjects.

Conditions
-----------------
Pandemic H5N1 Influenza

Intervention / Treatment
-----------------
* Biological: Adjuvanted H5N1 pandemic influenza vaccine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy pediatric subjects 6 months to 17 years of age, Individuals' parent(s) or legal guardian(s) willing to provide written informed consent, Individuals in good health, Individuals/Individuals' parent(s)/legal guardian(s) willing to allow for serum samples to be stored beyond the study period, Individuals willing to provide informed assent (where applicable). Exclusion Criteria: Individuals' parent(s)/legal guardian(s) not able to understand and follow study procedures, History of any significant illness, History of any chronic medical condition or progressive disease, Presence of medically significant cancer, Known or suspected impairment/alteration of immune function, Presence of any progressive or severe neurologic disorder, Presence of any bleeding disorders or conditions that prolongs bleeding time, History of allergy to vaccine components, Receipt of any other investigational product within 30 days prior to entry into the study, History of previous H5N1 vaccination, Receipt of any other type of seasonal vaccination within 2 months prior to entry into the study, Receipt of any other vaccine within 2 weeks prior to entry into the study, Body temperature ≥38°C (≥100.4° F) and/or acute illness within 3 days of intended study vaccination, Pregnant or breast feeding, Females of childbearing potential refusing to use acceptable method of birth control, Body mass index (BMI) ≥ 35 kg/m2, History of drug or alcohol abuse, Any planned surgery during study period, Individuals conducting the study and their immediate family members, Individuals with behavioral or cognitive impairment or psychiatric diseases, Individuals diagnosed with any growth disorders.

Ages Eligible for Study
-----------------
Minimum Age: 6 Months
Maximum Age: 17 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: aH5N1c-High dose<br> | Biological: Adjuvanted H5N1 pandemic influenza vaccine<br>* Comparison of two doses of aH5N1c vaccine<br>|
| Experimental: aH5N1c-Low dose<br> | Biological: Adjuvanted H5N1 pandemic influenza vaccine<br>* Comparison of two doses of aH5N1c vaccine<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentages Of Subjects Aged 6 to <36 Months, Achieving Hemagglutination Inhibition (HI) Titers ≥40 Against A/H5N1 Strain | The optimal aH5N1c vaccine formulation was evaluated in terms of percentages of subjects aged 6 to <36 months, achieving HI titers ≥40 against homologous A/H5N1 strain, three weeks after second vaccination with either low dose or high dose of aH5N1c vaccine, according to the Center for Biologics Evaluation and Research (CBER) criterion. As there is no CBER criteria defined for children, immunogenicity was evaluated using CBER criterion applicable for adults (18-64 years). CBER criterion is met if the lower limit of the two-sided 95% confidence interval (CI) for the percentages of subjects achieving HI titer ≥40 meets or exceeds 70%. | Three weeks after 2nd vaccination (day 43) | 
| The Percentages Of Subjects Aged 3 to <9 Years, Achieving HI Titers ≥40 Against A/H5N1 Strain | The optimal aH5N1c vaccine formulation was evaluated in terms of percentages of subjects aged 3 to <9 years, achieving HI titers ≥40 against homologous A/H5N1 strain, three weeks after second vaccination with either low dose or high dose of aH5N1c vaccine, according to the CBER criterion. As there is no CBER criteria defined for children, immunogenicity was evaluated using CBER criterion applicable for adults (18-64 years). CBER criterion is met if the lower limit of the two-sided 95% CI for the percentages of subjects achieving HI titer ≥40 meets or exceeds 70%. | Three weeks after 2nd vaccination (day 43) | 
| The Percentages Of Subjects Aged 9 to <18 Years, Achieving HI Titers ≥40 Against A/H5N1 Strain | The optimal aH5N1c vaccine formulation was evaluated in terms of percentages of subjects aged 9 to <18 years, achieving HI titers ≥40 against homologous A/H5N1 strain, three weeks after second vaccination with either low dose or high dose of aH5N1c vaccine, according to the CBER criterion. As there is no CBER criteria defined for children, immunogenicity was evaluated using CBER criterion applicable for adults (18-64 years). CBER criterion is met if the lower limit of the two-sided 95% CI for the percentages of subjects achieving HI titer ≥40 meets or exceeds 70%. | Three weeks after 2nd vaccination (day 43) | 
| The Percentages Of Subjects Aged 6 to <36 Months, Achieving Seroconversion Against A/H5N1 Strain | Immunogenicity was measured in terms of the percentages of subjects aged 6 to <36 months, achieving seroconversion or significant increase in HI titer against the vaccine strain, three weeks after receiving two injections of low dose or high dose of aH5N1c vaccine according to the CBER criteria. Seroconversion is defined as the percentages of subjects with a prevaccination HI titer <10, a postvaccination titer ≥40; or in subjects with prevaccination HI titer ≥10, and a minimum four-fold rise in postvaccination HI antibody titer. CBER criterion is met if the lower limit of the two-sided 95% CI for the percentages of subjects achieving seroconversion for HI antibody titer meets or exceeds 40%. | Three weeks after 2nd vaccination (day 43) | 
| The Percentages Of Subjects Aged 3 to <9 Years, Achieving Seroconversion Against A/H5N1 Strain | Immunogenicity was measured in terms of the percentages of subjects aged 3 to <9 years, achieving seroconversion or significant increase in HI titer against the vaccine strain, three weeks after receiving two injections of low dose or high dose of aH5N1c vaccine according to the CBER criteria. Seroconversion is defined as the percentages of subjects with a prevaccination HI titer <10, a postvaccination titer ≥40; or subjects with prevaccination HI titer ≥10, and a minimum four-fold rise in postvaccination HI antibody titer. CBER criterion is met if the lower limit of the two-sided 95% CI for the percentages of subjects achieving seroconversion for HI antibody titer meets or exceeds 40%. | Three weeks after 2nd vaccination (day 43) | 
| The Percentages Of Subjects Aged 9 to <18 Years, Achieving Seroconversion Against A/H5N1 Strain | Immunogenicity was measured in terms of the percentages of subjects aged 9 to <18 years, achieving seroconversion or significant increase in HI titer against the vaccine strain, three weeks after receiving two injections of low dose or high dose of aH5N1c vaccine according to the CBER criteria. Seroconversion is defined as the percentages of subjects with a prevaccination HI titer <10, a postvaccination titer ≥40; or in subjects with prevaccination HI titer ≥10, and a minimum four-fold rise in postvaccination HI antibody titer. CBER criterion is met if the lower limit of the two-sided 95% CI for the percentages of subjects achieving seroconversion for HI antibody titer meets or exceeds 40%. | Three weeks after 2nd vaccination (day 43) | 
| Number of Subjects (6 Month - <6 Years) Reporting Solicited Local and Systemic Adverse Events, After Any Vaccination | Safety was assessed using the number of subjects who reported solicited local and systemic adverse events following vaccination with either low or high dose of aH5N1c vaccine. | From day 1 through day 7 after each vaccination. | 
| Number of Subjects (≥6 Years - 17 Years) Reporting Solicited Local and Systemic Adverse Events, After Any Vaccination | Safety was assessed using the number of subjects who reported solicited local and systemic adverse events following vaccination with either low or high dose of aH5N1c vaccine. | From day 1 through day 7 after any vaccination. | 
| Number of Subjects Reporting Unsolicited Adverse Events After Any Vaccination | Safety was assessed using the number of subjects who reported any unsolicited adverse events, adverse events possibly or probably related to study vaccine, serious adverse events (SAEs), new onset of chronic diseases (NOCDs), medically attended AEs, AEs of special interest (AESIs), AEs leading to withdrawal from study following vaccination with either low or high dose of aH5N1c vaccine. | Any unsolicited AEs - day 1 through day 22 after any vaccination; SAEs, NOCDs. medically attended AEs, AESIs, AEs leading to study withdrawal- day 1 to day 387 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Ratios Against A/H5N1 Strain Following 2-Dose Vaccination Schedule Of Either Low Dose Or High Dose AH5N1c Vaccine in Subjects Aged 6 to <36 Months. | Immunogenicity was measured as the geometric mean ratio (GMR). The ratio of postvaccination to prevaccination HI GMTs, 3 weeks after first vaccination, 3 weeks after second vaccination and 12 months after second vaccination with either low dose or high dose of aH5N1c in subjects aged 6 to <36 months is reported. The criterion is met according to the European Committee for Medicinal Products for Human Use (CHMP) criteria if the geometric mean increase GMR (day 43/day 1) in HI antibody titer is >2.5. As no CHMP criteria are established for the pediatric population, criteria given for subjects 18-60 years of age were applied. | Day 1, day 22, day 43 and day 387 | 
| Geometric Mean Ratios Against A/H5N1 Strain Following 2-Dose Vaccination Schedule Of Either Low Dose Or High Dose AH5N1c Vaccine in Subjects Aged 3 to <9 Years. | Immunogenicity was measured as geometric mean ratio (GMR). The ratio of postvaccination to prevaccination HI GMTs, 3 weeks after first vaccination, 3 weeks after second vaccination and 12 months after second vaccination with either low dose or high dose of aH5N1c in subjects aged 3 to <9 years is reported. As no CHMP criteria are established for the pediatric population, criteria given for subjects 18-60 years of age were applied. The criterion is met according to the European Committee for Medicinal Products for Human Use (CHMP) criteria if the geometric mean increase GMR (day 43/day 1) in HI antibody titer is >2.5. | Day 1, day 22, day 43 and day 387 | 
| Geometric Mean Ratios Against A/H5N1 Strain Following 2-Dose Vaccination Schedule Of Either Low Dose Or High Dose AH5N1c Vaccine in Subjects Aged 9 to <18 Years. | Immunogenicity was measured as the geometric mean ratio (GMR). The ratio of postvaccination to prevaccination HI GMTs, 3 weeks after first vaccination, 3 weeks after second vaccination and 12 months after second vaccination with either low dose or high dose of aH5N1c in subjects aged 9 to <18 years is reported. As no CHMP criteria are established for the pediatric population, criteria given for subjects 18-60 years of age were applied. The criterion is met according to the European Committee for Medicinal Products for Human Use (CHMP) criteria if the geometric mean increase GMR (day 43/day 1) in HI antibody titer is >2.5. | Day 1, day 22, day 43 and day 387 | 
| Percentages Of Subjects Aged 6 to <36 Months, With HI Titers ≥40 Against A/H5N1 Strain | Immunogenicity was assessed in terms of percentage of subjects aged 6 to <36 months, achieving HI titers ≥40, 3 weeks after first vaccination, 3 weeks after second vaccination and 12 months after second vaccination of either low dose or high dose of aH5N1c according to the CHMP criterion. European Licensure (CHMP) criterion is met if the percentage of subjects achieving (at day 43) HI titers ≥40 is >70%. | Day 1, day 22, day 43 and day 387. | 
| Percentages Of Subjects Aged 3 to <9 Years, With HI Titers ≥40 Against A/H5N1 Strain | Immunogenicity was assessed in terms of percentage of subjects aged 3 to <9 years, achieving HI titers ≥40, 3 weeks after first vaccination, 3 weeks after second vaccination and 12 months after second vaccination of either low dose or high dose of aH5N1c according to the CHMP criterion. European Licensure (CHMP) criterion is met if the percentage of subjects achieving (at day 43) HI titers ≥40 is >70%. | Day 1, day 22, day 43 and day 387. | 
| Percentages Of Subjects Aged 9 to <18 Years, With HI Titers ≥40 Against A/H5N1 Strain | Immunogenicity was assessed in terms of percentage of subjects aged 9 to <18 years, achieving HI titers ≥40, 3 weeks after first vaccination, 3 weeks after second vaccination and 12 months after second vaccination of either low dose or high dose of aH5N1c according to the CHMP criterion. European Licensure (CHMP) criterion is met if the percentage of subjects achieving (at day 43) HI titers ≥40 is >70%. | Day 1, day 22, day 43 and day 387. | 
| The Percentages Of Subjects Aged 6 to <36 Months, Achieving Seroconversion Against A/H5N1 Strain | Immunogenicity was assessed in terms of percentages of subjects aged 6 to <36 months achieving seroconversion in HI titers, 3 weeks after first vaccination, 3 weeks after second vaccination and 12 months after second vaccination of either low dose or high dose aH5N1c vaccine according to the CHMP criterion. Seroconversion is defined as the percentages of subjects with a prevaccination HI titer <10, a postvaccination titer ≥40; or in subjects with prevaccination HI titer ≥10, and a minimum four-fold rise in postvaccination HI antibody titer. The criterion is met according to the European (CHMP) guideline if the percentage of subjects achieving seroconversion (at day 43) is >40%. | Day 22, day 43 and day 387 | 
| The Percentages Of Subjects Aged 3 to <9 Years, Achieving Seroconversion Against A/H5N1 Strain | Immunogenicity was assessed in terms of percentages of subjects aged 3 to <9 years achieving seroconversion in HI titers, 3 weeks after first vaccination, 3 weeks after second vaccination and 12 months after second vaccination of either low dose or high dose aH5N1c vaccine according to the CHMP criterion. Seroconversion is defined as the percentages of subjects with a prevaccination HI titer <10, a postvaccination titer ≥40; or in subjects with prevaccination HI titer ≥10, and a minimum four-fold rise in postvaccination HI antibody titer. The criterion is met according to the European (CHMP) guideline if the percentage of subjects achieving seroconversion (at day 43) is >40%. | Day 22, day 43 and day 387 | 
| The Percentages Of Subjects Aged 9 to <18 Years, Achieving Seroconversion Against A/H5N1 Strain | Immunogenicity was assessed in terms of percentages of subjects aged 9 to <18 years achieving seroconversion in HI titers, 3 weeks after first vaccination, 3 weeks after second vaccination and 12 months after second vaccination of either low dose or high dose aH5N1c vaccine according to the CHMP criterion. Seroconversion is defined as the percentages of subjects with a prevaccination HI titer <10, a postvaccination titer ≥40; or in subjects with prevaccination HI titer ≥10, and a minimum four-fold rise in postvaccination HI antibody titer. The criterion is met according to the European (CHMP) guideline if the percentage of subjects achieving seroconversion (at day 43) is >40%. | Day 22, day 43 and day 387 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Influenza, Pandemic, H5N1, Children