Safety and Immunogenocity Study of GSK Biologicals' Pandemic Influenza (H1N1) Candidate Vaccine in Japanese Children

Study Overview
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Brief Summary
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The objective of this study is to evaluate the immunogenicity and safety of GSK Biologicals' investigational influenza vaccine GSK2340274A following one dose and following a second dose, using the same dosage as has been used in the H5N1 development program in Japanese children aged 10-17 years and an alternative dose in children aged 6 months to 9 years.

Official Title
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Safety and Immunogenicity Study of GSK Biologicals' Pandemic Influenza (H1N1) Candidate Vaccine (GSK2340274A) in Japanese Children Aged 6 Months to 17 Years

Conditions
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Influenza

Intervention / Treatment
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* Biological: GSK Biologicals' Pandemic influenza (H1N1) candidate vaccine (GSK2340274A)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who the investigator believes that their parent(s)/Legally Acceptable Representative(s) (LAR) can and will comply with the requirements of the protocol. Japanese children, male or female, aged between 6 months and 17 years at the time of the first study vaccination. Written informed consent obtained from the subject's parent(s) or LAR(s) of the subject. Whenever possible, an assent should also be obtained from the subject. Healthy children as established by medical history and clinical examination when entering into the study (Particular attention must be exercised when dealing with patients with bronchial asthma). Parent/LAR with access to a consistent means of telephone contact, land line or mobile, but NOT a pay phone or other multiple-user device. Female subjects of childbearing potential may be enrolled in the study, if the subject: has practiced adequate contraception for 30 days prior to vaccination, and has a negative pregnancy test on the day of vaccination, and has agreed to continue adequate contraception during the entire treatment period and for 2 months after completion of the vaccination series. Exclusion Criteria: Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine within 30 days preceding the first dose of the study vaccine or planned use during the study period. Clinically or virologically confirmed influenza infection from May 2009 to the day of enrolment. Previous administration of a novel [H1N1]v vaccine. Administration of any vaccines within 30 days before vaccination or planned administration within the first vaccination up to blood sampling at Day 42 and within 30 days prior to blood sampling at Day 182, with the exception of seasonal influenza vaccine. Administration of any seasonal influenza vaccine within 14 days before vaccination on Day 0, or planned administration within the first vaccination up to blood sampling at Day 42 and within 14 days prior to blood sampling at Day 182. Excessive underweight or excessive obesity. (Under or upper 2-fold standard deviation of weight distribution that are corresponding age group are used as reference). Chronic administration of immunosuppressants or other immune-modifying drugs within three months prior to enrolment in this study or planned administration during the study period. Acute disease and/or fever at the time of enrolment: Fever is defined as temperature >= 37.5°C on oral, axillary or tympanic setting, or >= 38.0°C on rectal setting. Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory infection) without fever may be enrolled at the discretion of the investigator. Any confirmed or suspected immunosuppressive or immunodeficient condition based on medical history and physical examination (no laboratory testing required). Acute or chronic, clinically-significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by medical history and physical examination. Administration of immunoglobulins and/or any blood products within the three months prior to the enrolment in this study, or planned during the study. Any known or suspected allergy to any constituent of influenza vaccines; a history of anaphylactic-type reaction to consumption of eggs; or a history of severe adverse reaction to a previous influenza vaccine. History of any neurological disorder including acute disseminated encephalomyelitis and Guillain-Barré syndrome, or convulsive seizures and epilepsy. Any significant disorder of coagulation or treatment with warfarin derivatives or heparin. Persons receiving individual doses of low molecular weight heparin are eligible if no such doses are given in the 24 hours before a study vaccination. Persons receiving prophylactic antiplatelet medications, e.g., low-dose acetylsalicylic acid, and without a clinically-apparent bleeding tendency, are eligible Any conditions which, in the opinion of the investigator, prevents the subject from participating to the study. Child in Care.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 17 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK2340274A_F1 6M-9Y GROUP<br>Healthy male or female Japanese children, between and including 6 months to 9 years of age, who received two doses of GSK2340274A vaccine (formulation 1), administered intramuscularly into the deltoid region of the arm (intramuscularly into the anterolateral part of the thigh for subjects below 12 months of age at the entry of the study), according to 0, 21-day schedule. Within this group, enrolment of subjects was stratified by age into two subgroups, from 6 to 35 months and from 3 to 9 years. | Biological: GSK Biologicals' Pandemic influenza (H1N1) candidate vaccine (GSK2340274A)<br>* Two intramuscular injections<br>|
| Experimental: GSK2340274A_F2 10Y-17Y GROUP<br>Healthy male or female Japanese children, between and including 10 to 17 years of age, who received two doses of GSK2340274A vaccine (formulation 2), administered intramuscularly into the deltoid region of the arm, according to 0, 21-day schedule. | Biological: GSK Biologicals' Pandemic influenza (H1N1) candidate vaccine (GSK2340274A)<br>* Two intramuscular injections<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Haemagglutination Inhibition (HI) Antibody Concentrations Above the Cut-off Value | The cut-off values for the humoral immune response in terms of vaccine H1N1 HI antibodies were equal to or above (≥) 1:10. The Flu strain assessed was A/California/7/2009 (H1N1)v-like virus (Flu A/CAL/7/09), in subjects aged between 6 months to 9 years and 10 to 17 years, following the Committee for Medicinal Products for Human Use (CHMP) and the Center for Biologics Evaluation and Research (CBER) guidance. | At Day 42 | 
| Titers for Serum HI Antibodies Against Flu A/CAL/7/09 Strain of Influenza Disease | Titers are presented as geometric mean titers (GMTs). The reference seropositivity cut-off value was ≥ 1:10. The Flu strain assessed was Flu A/CAL/7/09, in subjects aged between 6 months to 9 years and 10 to 17 years, following the CHMP and the CBER guidance. | At Day 42 | 
| Number of Seroconverted Subjects for HI Antibodies | Seroconversion (SCR) was defined as follows: For initially seronegative subjects, antibody titer ≥ 1:40 after vaccination; For initially seropositive subjects, antibody titer after vaccination ≥ 4 fold the pre-vaccination antibody titer. The Flu strain assessed was Flu A/CAL/7/09, in subjects aged between 6 months to 9 years and 10 to 17 years, following the CHMP and the CBER guidance. The CBER criterion was fulfilled if the lower 97.5% confidence interval for SCR was > 40%. The CHMP criterion was fulfilled if the point estimate for SCR was > 40%. | At Day 42 | 
| Number of Seroprotected Subjects for HI Antibodies | A seroprotected subject was defined as a vaccinated subject with a serum hemagglutination inhibition (HI) titer equal to or above (≥) 1:40. The Flu strain assessed was Flu A/CAL/7/09, in subjects aged between 6 months to 9 years and 10 to 17 years, following the CHMP and the CBER guidance. The CBER Criterion was fulfilled if the lower 97.5% confidence interval for seroprotection (SPR) was > 70%. The CHMP Criterion was fulfilled if the post-vaccination point estimate for SPR was > 70%. | At Day 42 | 
| Geometric Mean Fold Rise (GMFR) for HI Antibodies Against Flu A/CAL/7/09 Strain of Influenza Disease | GMFR, also called seroconversion factor (SCF), was defined as the fold increase in serum HI GMTs post-vaccination compared to pre-vaccination. The Flu strain assessed was Flu A/CAL/7/09, in subjects aged between 6 months to 9 years and 10 to 17 years, following the CHMP guidance. The CHMP Criterion was fulfilled if the point estimate for GMFR was > 2.5. | At Day 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With HI Antibody Concentrations Above the Cut-off Value | The cut-off values for the humoral immune response in terms of vaccine H1N1 HI antibodies were equal to or above (≥) 1:10. The Flu strain assessed was Flu A/CAL/7/09, in subjects aged between 6 months to 9 years and 10 to 17 years, following the CHMP and the CBER guidance. | At Days 0 and 21 | 
| Number of Subjects With HI Antibody Concentrations Above the Cut-off Value | The cut-off values for the humoral immune response in terms of vaccine H1N1 HI antibodies were equal to or above (≥) 1:10. The Flu strain assessed was Flu A/CAL/7/09, in subjects aged between 6 months to 9 years, following the CHMP and the CBER guidance. Note: Analyses based on 95% CI for 10-17 year age category at Day 42 were not performed. | At Days 0 and 42 | 
| Number of Subjects With HI Antibody Concentrations Above the Cut-off Value | The cut-off values for the humoral immune response in terms of vaccine H1N1 HI antibodies were equal to or above (≥) 1:10. The Flu strain assessed was Flu A/CAL/7/09, in subjects aged between 6 months to 9 years and 10 to 17 years, following the CHMP and the CBER guidance. | At Days 0 and 182 | 
| Titers for Serum HI Antibodies Against Flu A/CAL/7/09 Strain of Influenza Disease | Titers are presented as geometric mean titers (GMTs). The reference seropositivity cut-off value was ≥ 1:10. The Flu strain assessed was Flu A/CAL/7/09, in subjects aged between 6 months to 9 years and 10 to 17 years, following the CHMP and the CBER guidance. | At Days 0 and 21 | 
| Titers for Serum HI Antibodies Against Flu A/CAL/7/09 Strain of Influenza Disease | Titers are presented as geometric mean titers (GMTs). The reference seropositivity cut-off value was ≥ 1:10. The Flu strain assessed was Flu A/CAL/7/09, in subjects aged between 6 months to 9 years, following the CHMP and the CBER guidance. Note: Analyses based on 95% CI for 10-17 year age category at Day 42 were not performed. | At Days 0 and 42 | 
| Titers for Serum HI Antibodies Against Flu A/CAL/7/09 Strain of Influenza Disease | Titers are presented as geometric mean titers (GMTs). The reference seropositivity cut-off value was ≥ 1:10. The Flu strain assessed was Flu A/CAL/7/09, in subjects aged between 6 months to 9 years and 10 to 17 years, following the CHMP and the CBER guidance. | At Days 0 and 182 | 
| Number of Seroconverted Subjects for HI Antibodies | Seroconversion (SCR) was defined as follows: For initially seronegative subjects, antibody titer ≥ 1:40 after vaccination; For initially seropositive subjects, antibody titer after vaccination ≥ 4 fold the pre-vaccination antibody titer. The Flu strain assessed was Flu A/CAL/7/09, in subjects aged between 6 months to 9 years and 10 to 17 years, following the CHMP and the CBER guidance. The CHMP Criterion was fulfilled if the point estimate for SCR was > 40%. The CBER Criterion was fulfilled if the lower 97.5% confidence interval for SCR was > 40%. | At Day 21 | 
| Number of Seroconverted Subjects for HI Antibodies | Seroconversion (SCR) was defined as follows: For initially seronegative subjects, antibody titer ≥ 1:40 after vaccination; For initially seropositive subjects, antibody titer after vaccination ≥ 4 fold the pre-vaccination antibody titer. The Flu strain assessed was Flu A/CAL/7/09, in subjects aged between 6 months to 9 years, following the CHMP and the CBER guidance. The CHMP Criterion was fulfilled if the point estimate for SCR was > 40%. The CBER Criterion was fulfilled if the lower 97.5% confidence interval for SCR was > 40%. Note: Analyses based on 95% CI for 10-17 year age category at Day 42 were not performed. | At Day 42 | 
| Number of Seroconverted Subjects for HI Antibodies | Seroconversion (SCR) was defined as follows: For initially seronegative subjects, antibody titer ≥ 1:40 after vaccination; For initially seropositive subjects, antibody titer after vaccination ≥ 4 fold the pre-vaccination antibody titer. The Flu strain assessed was Flu A/CAL/7/09, in subjects aged between 6 months to 9 years and 10 to 17 years, following the CHMP and the CBER guidance. The CHMP Criterion was fulfilled if the point estimate for SCR was > 40%. The CBER Criterion was fulfilled if the lower 97.5% confidence interval for SCR was > 40%. | At Day 182 | 
| Number of Seroprotected Subjects for HI Antibodies | A seroprotected subject was defined as a vaccinated subject with a serum hemagglutination inhibition (HI) titer equal to or above (≥) 1:40. The Flu strain assessed was Flu A/CAL/7/09, in subjects aged between 6 months to 9 years and 10 to 17 years, following the CHMP and the CBER guidance. The CHMP Criterion was fulfilled if the post-vaccination point estimate for SPR was > 70%. The CBER Criterion was fulfilled if the lower 97.5% confidence interval for SPR was > 70%. | At Days 0 and 21 | 
| Number of Seroprotected Subjects for HI Antibodies | A seroprotected subject was defined as a vaccinated subject with a serum HI titer equal to or above (≥) 1:40. The Flu strain assessed was Flu A/CAL/7/09, in subjects aged between 6 months to 9 years, following the CHMP and the CBER guidance. The CHMP Criterion was fulfilled if the post-vaccination point estimate for SPR was > 70%. The CBER Criterion was fulfilled if the lower 97.5% confidence interval for SPR was > 70%. Note: Analyses based on 95% CI for 10-17 year age category at Day 42 were not performed. | At Days 0 and 42 | 
| Number of Seroprotected Subjects for HI Antibodies | A seroprotected subject was defined as a vaccinated subject with a serum HI titer equal to or above (≥) 1:40. The Flu strain assessed was Flu A/CAL/7/09, in subjects aged between 6 months to 9 years and 10 to 17 years, following the CHMP and the CBER guidance. The CHMP Criterion was fulfilled if the post-vaccination point estimate for SPR was > 70%. The CBER Criterion was fulfilled if the lower 97.5% confidence interval for SPR was > 70%. | At Days 0 and 182 | 
| Seroconversion Factor (SCF) for HI Antibodies Against Flu A/CAL/7/09 Strain of Influenza Disease | Seroconversion factor (SCF) was defined as the fold increase in serum HI GMTs post-vaccination compared to pre-vaccination. The Flu strain assessed was Flu A/CAL/7/09, in subjects aged between 6 months to 9 years and 10 to 17 years, following the CHMP guidance. The CHMP Criterion was fulfilled if the point estimate for SCF was > 2.5. | At Day 21 | 
| SCF for HI Antibodies Against Flu A/CAL/7/09 Strain of Influenza Disease | SCF was defined as the fold increase in serum HI GMTs post-vaccination compared to pre-vaccination. The Flu strain assessed was Flu A/CAL/7/09, in subjects aged between 6 months to 9 years, following the CHMP guidance. The CHMP Criterion was fulfilled if the point estimate for SCF was > 2.5. Note: Analyses based on 95% CI for 10-17 year age category at Day 42 were not performed. | At Day 42 | 
| SCF for HI Antibodies Against Flu A/CAL/7/09 Strain of Influenza Disease | SCF was defined as the fold increase in serum HI GMTs post-vaccination compared to pre-vaccination. The Flu strain assessed was Flu A/CAL/7/09, in subjects aged between 6 months to 9 years and 10 to 17 years, following the CHMP guidance. The CHMP Criterion was fulfilled if the point estimate for SCF was > 2.5. | At Day 182 | 
| Number of Subjects With Neutralizing Antibody Concentrations Above the Cut-off Value | The cut-off values for the humoral immune response in terms of vaccine neutralizing antibodies were equal to or above (≥) 1:8. The Flu strain assessed was Flu A/Neth/602/09 H1N1, in subjects aged between 6 months to 9 years and 10 to 17 years, following the CHMP and the CBER guidance. | At Days 0 and 21 | 
| Number of Subjects With Neutralizing Antibody Concentrations Above the Cut-off Value | The cut-off values for the humoral immune response in terms of vaccine neutralizing antibodies were equal to or above (≥) 1:8. The Flu strain assessed was Flu A/Neth/602/09 H1N1, in subjects aged between 6 months to 9 years and 10 to 17 years, following the CHMP and the CBER guidance. | At Days 0 and 42 | 
| Number of Subjects With Neutralizing Antibody Concentrations Above the Cut-off Value | The cut-off values for the humoral immune response in terms of vaccine neutralizing antibodies were equal to or above (≥) 1:8. The Flu strain assessed was Flu A/Neth/602/09 H1N1, in subjects aged between 6 months to 9 years and 10 to 17 years, following the CHMP and the CBER guidance. | At Days 0 and 182 | 
| Titers for Serum Neutralizing Antibodies Against Flu A/Neth/602/09 Strain of Influenza Disease | Titers are presented as geometric mean titers (GMTs). The reference seropositivity cut-off value was ≥ 1:8. The Flu strain assessed was Flu A/Neth/602/09 H1N1, in subjects aged between 6 months to 9 years and 10 to 17 years, following the CHMP and the CBER guidance. | At Days 0 and 21 | 
| Titers for Serum Neutralizing Antibodies Against Flu A/Neth/602/09 Strain of Influenza Disease | Titers are presented as geometric mean titers (GMTs). The reference seropositivity cut-off value was ≥ 1:8. The Flu strain assessed was Flu A/Neth/602/09 H1N1, in subjects aged between 6 months to 9 years and 10 to 17 years, following the CHMP and the CBER guidance. | At Days 0 and 42 | 
| Titers for Serum Neutralizing Antibodies Against Flu A/Neth/602/09 Strain of Influenza Disease | Titers are presented as geometric mean titers (GMTs). The reference seropositivity cut-off value was ≥ 1:8. The Flu strain assessed was Flu A/Neth/602/09 H1N1, in subjects aged between 6 months to 9 years and 10 to 17 years, following the CHMP and the CBER guidance. | At Days 0 and 182 | 
| Number of Subjects With Vaccine Response Rates (VRR) for Neutralizing Antibodies Against Flu A/Neth/602/09 H1N1 | VRR is defined as the number of vaccinees that have a 4-fold increase between pre- and post-vaccination titers. The Flu strain assessed was Flu A/Neth/602/09 H1N1, in subjects aged between 6 months to 9 years and 10 to 17 years, following the CHMP and the CBER guidance. | At Day 21 | 
| Number of Subjects With Vaccine Response Rates (VRR) for Neutralising Antibodies Against Flu A/Neth/602/09 H1N1 | VRR is defined as the number of vaccinees that have a 4-fold increase between pre- and post-vaccination titers. The Flu strain assessed was Flu A/Neth/602/09 H1N1, in subjects aged between 6 months to 9 years and 10 to 17 years, following the CHMP and the CBER guidance. | At Day 42 | 
| Number of Subjects With Vaccine Response Rates (VRR) for Neutralising Antibodies Against Flu A/Neth/602/09 H1N1 | VRR is defined as the number of vaccinees that have a 4-fold increase between pre- and post-vaccination titers. The Flu strain assessed was Flu A/Neth/602/09 H1N1, in subjects aged between 6 months to 9 years and 10 to 17 years, following the CHMP and the CBER guidance. | At Day 182 | 
| Number of Subjects With Any and Grade 3 Solicited Local Symptoms | Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain [child below (<) 6 years] = cried when limb was moved/spontaneously painful. Grade 3 pain [child equal to or above (≥) 6 years] = pain that prevented normal activity. Grade 3 redness/swelling = redness/swelling spreading beyond 100 millimeters (mm) of injection site. | During the 7-day (Days 0-6) post-vaccination period following each dose and across doses | 
| Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms | Assessed solicited general symptoms were drowsiness, irritability, loss of appetite, fever [defined as axillary temperature equal to or above (≥) 37.5 degrees Celsius (°C)]. Any = occurrence of any general symptoms regardless of their intensity grade or their relation to vaccination. Grade 3 symptom = symptom that prevented normal activity. Grade 3 loss of appetite = not eating at all. Grade 3 fever = fever ≥ 39.0 °C - ≤ 40.0°C. Related = symptom assessed by the investigator as causally related to the vaccination. | During the 7-day (Days 0-6) post-vaccination period following each dose and across doses | 
| Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms | Assessed solicited general symptoms were fatigue, gastrointestinal, headache, joint pain at other location, muscle aches, shivering, sweating, and fever [defined as axillary temperature equal to or above 37.5 degrees Celsius (°C)]. Any = occurrence of any general symptoms regardless of their intensity grade or their relation to vaccination. Grade 3 symptom = symptom that prevented normal activity. Grade 3 fever = fever ≥ 39.0°C - ≤ 40.0°C. Related symptom = symptom assessed by the investigator as causally related to the study vaccination. | During the 7-day (Days 0-6) post-vaccination period following each dose and across doses | 
| Number of Subjects With Any, Grade 3 and Related Unsolicited Adverse Events (AEs) | An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. Grade 3 AE = an AE which prevented normal, everyday activities. Related = AE assessed by the investigator as related to the vaccination. | Up to 84 days (Days 0-83) after the first vaccination | 
| Number of Subjects With Medically Attended Events (MAEs) | MAEs were defined as events for which the subject received medical attention defined as hospitalization, an emergency room visit, or a visit to or from medical personnel (medical doctor) for any reason. Any MAE(s) = occurrence of any MAE(s) regardless of intensity grade or relation to vaccination. Analysis of intensity and relationship to vaccination of MAEs was not performed. | During the entire study period (from Day 0 to Day 182) | 
| Number of Subjects With Potential Immune-Mediated Diseases (pIMDs) | Potential immune-mediated diseases (pIMDs) are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune aetiology. | During the entire study period (from Day 0 to Day 182) | 
| Number of Subjects With Serious Adverse Events (SAEs) | Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life-threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. | During the entire study period (from Day 0 to Day 182) | 
| Number of Subjects With Normal or Abnormal Biochemical Levels | Among biochemical parameters assessed were Alanine Amino Transferase (ALAT), Albumin, Alkaline Phosphatase (AP), Aspartate Amino Transferase (ASAT), Bilirubin, Bilirubin Conjugated/Direct, Cholesterol, Chloride, Creatinine, Creatine Phosphokinase (CK), Gamma-Glutamyl Transpeptidase (GGT), Potassium, Lactate dehydrogenase (LDH), Sodium, Protein, Urate/Uric acid and Blood Urea Nitrogen (BUN). Unknown = value unknown for the specified time point and laboratory parameter; Below = value below the laboratory reference range defined for the specified time point and laboratory parameter; Within = value within the laboratory reference range defined for the specified time point and laboratory parameter; Above = value above the laboratory reference range defined for the specified time point and laboratory parameter. | At Days 0, 7 and 42 | 
| Number of Subjects With Normal or Abnormal Values of Haematological Parameters | Among haematological parameters assessed were Basophils (Baso), Eosinophils (EOS), Hematocrit (HEM), Hemoglobin (Hgb), Lymphocytes (LYM), Monocytes (MON), Neutrophils (NEU), Platelets (PLA), Red Blood Cells (RBC) and White Blood Cells (WBC). Unknown = value unknown for the specified time point and laboratory parameter; Below = value below the laboratory reference range defined for the specified time point and laboratory parameter; Within = value within the laboratory reference range defined for the specified time point and laboratory parameter; Above = value above the laboratory reference range defined for the specified time point and laboratory parameter. | At Days 0, 7 and 42 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GSK Bio's influenza vaccine GSK2340274A, influenza infection