Monovalent H5N1 Vaccine GSK1557484A in Children 6 Months to < 18 Years of Age

Phase 3

Completed

Conditions: Influenza
Influenza Vaccines

Interventions: Biological: Influenza A (H5N1) Virus monovalent vaccine
Biological: Saline placebo

Registration Number: NCT01310413

Lead Sponsor: GlaxoSmithKline

Brief Summary: This study will assess safety and immunogenicity of GSK Biologicals' H5N1 flu candidate vaccine GSK1557484A in children 6 months to \< 18 years of age.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 842

Inclusion Criteria

A male or female child >= 6 months and < 18 years of age at the time of first vaccination.
Written informed consent obtained from the subject's parent/guardian.
Documentation of assent for children 9 to < 18 years of age (or as deemed mandatory by local practice).
Satisfactory baseline medical assessment by history and physical examination
Parent/guardian and subject access to a consistent means of telephone contact, land line or mobile, but NOT a pay phone or other multiple-user device.
Parents/guardians and subjects who the investigator believes understand the requirements of the protocol and can and will comply with them.
Female subjects of non-childbearing potential may be enrolled in the study.
Female subjects of childbearing potential must
- have practiced adequate contraception for 30 days prior to vaccination, and
- have a negative pregnancy test on the day of each vaccination, and
- have agreed to continue adequate contraception for 2 months after completion of the vaccination series.

Exclusion Criteria

Medical history of physician-confirmed infection with an H5N1 virus.
Previous vaccination at any time with an H5N1 vaccine.
Use of any investigational or non-registered product other than the study vaccine within 30 days preceding the first dose of study vaccine/product, or planned use during the study period.
Presence of significant acute or chronic, uncontrolled medical or psychiatric illness.
Presence of neurological or psychiatric diagnoses which, although stable, are deemed by the investigator to render the potential subject or parent/guardian unable/unlikely to provide accurate safety reports.
Evidence of current subject or parent/guardian substance abuse, including alcohol, by medical history.
Presence of a temperature >= 38.0ºC by any method, or acute symptoms greater than "mild" severity on the scheduled date of first dose.
Diagnosed with cancer, or treatment for cancer, within 3 years.
Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination.
Receipt of systemic glucocorticoids within 1 month prior to first dose of test article or any other cytotoxic or immunosuppressive drug within 6 months prior to first dose of test article. Receipt of any immunoglobulins and/or any blood products within 3 months of first test article administration or planned administration of any of these products during the study period.
Any significant disorder of coagulation or treatment with warfarin derivatives or heparin.
An acute evolving neurological disorder or history of Guillain-Barré syndrome within 6 weeks of receipt of seasonal influenza vaccine.
Administration of an inactivated seasonal influenza vaccine within 14 days, or of a live, attenuated seasonal influenza vaccine within 30 days before the first test article dose, or of any other vaccine(s) not foreseen by the study protocol within 30 days before the first test article dose.
Planned administration of any vaccine(s) not foreseen by the study protocol through completion of the "Day 42" visit.
Any known or suspected allergy to any constituent of influenza vaccines or history of severe reaction to any previous influenza vaccination.
Known pregnancy, or a positive urine pregnancy test result prior to each test article dose.
Lactating or nursing.
Child in care.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Influenza A (H5N1) Virus monovalent vaccine 9-<18Y Group	Influenza A (H5N1) Virus monovalent vaccine	Subjects aged at enrolment between 9 and 18 years, 18 years excluded, received 2 doses of Influenza A (H5N1) Virus monovalent vaccine (GSK1557484A vaccine or GSK Biologicals' monovalent A/Indonesia/5/2005 (H5N1) vaccine adjuvanted) at Days 0 and 21. Influenza A (H5N1) Virus monovalent vaccine was administered intramuscularly, Dose 1 in the deltoid region of the non-dominant arm (or left arm if dominance was not yet identified) and Dose 2 in the deltoid region of the dominant arm (or right arm).
Placebo 3-<9Y Group	Saline placebo	Subjects aged at enrolment between 3 and 9 years, 9 years excluded, received 2 doses of saline placebo at Days 0 and 21. The saline placebo was administered intramuscularly, Dose 1 in the deltoid region of the non-dominant arm (or left arm if dominance was not yet identified) and Dose 2 in the deltoid region of the dominant arm (or right arm).
Influenza A (H5N1) adjuvanted 6-<36M Group	Influenza A (H5N1) Virus monovalent vaccine	Subjects aged at enrolment between 3 and 36 months, 36 months excluded, received 2 doses of Influenza A (H5N1) Virus monovalent vaccine (GSK1557484A vaccine or GSK Biologicals' monovalent A/Indonesia/5/2005 (H5N1) vaccine adjuvanted) at Days 0 and 21. Influenza A (H5N1) Virus monovalent vaccine was administered intramuscularly. For children aged up to 12 months, 12 months excluded (\< 12 months), Dose 1 was administered in the left anterolateral thigh and Dose 2 in the right anterolateral thigh. For children older than (\>=) 12 months, Dose 1 was administered in the deltoid region of the non-dominant arm (or left arm if dominance was not yet identified) and Dose 2 in the deltoid region of the dominant arm (or right arm).
Influenza A (H5N1) Virus monovalent vaccine 3-<9Y Group	Influenza A (H5N1) Virus monovalent vaccine	Subjects aged at enrolment between 3 and 9 years, 9 years excluded, received 2 doses of Influenza A (H5N1) Virus monovalent vaccine (GSK1557484A vaccine or GSK Biologicals' monovalent A/Indonesia/5/2005 (H5N1) vaccine adjuvanted) at Days 0 and 21. Influenza A (H5N1) Virus monovalent vaccine was administered intramuscularly, Dose 1 in the deltoid region of the non-dominant arm (or left arm if dominance was not yet identified) and Dose 2 in the deltoid region of the dominant arm (or right arm).
Placebo 6-<36M Group	Saline placebo	Subjects aged at enrolment between 3 and 36 months, 36 months excluded, received 2 doses of saline placebo at Days 0 and 21. The saline placebo was administered intramuscularly. For children aged up to 12 months, 12 months excluded (\< 12 months), Dose 1 was administered in the left anterolateral thigh and Dose 2 in the right anterolateral thigh. For children older than (\>=) 12 months, Dose 1 was administered in the deltoid region of the non-dominant arm (or left arm if dominance was not yet identified) and Dose 2 in the deltoid region of the dominant arm (or right arm).
Placebo 9-<18Y Group	Saline placebo	Subjects aged at enrolment between 9 and 18 years, 18 years excluded, received 2 doses of saline placebo at Days 0 and 21. The saline placebo was administered intramuscularly, Dose 1 in the deltoid region of the non-dominant arm (or left arm if dominance was not yet identified) and Dose 2 in the deltoid region of the dominant arm (or right arm).
Placebo/Influenza A (H5N1) adjuvanted Group	Influenza A (H5N1) Virus monovalent vaccine	Subjects in this group were those who were administered the saline placebo solution in the Blinded Phase of the study (either in the Placebo 6-\<36M, Placebo 3-\<9Y or Placebo 9-\<18Y Group). These were subjects aged at enrolment between 6 months and 18 years, 18 years excluded, who had received 2 doses of saline placebo at Days 0 and 21 in the Blinded Phase of the study, as per described in the descriptions of the Placebo 6-\<36M, Placebo 3-\<9Y and Placebo 9-\<18Y groups. After consenting to participating to the Unblinded Phase of the study, these subjects received in addition 2 doses of Influenza A (H5N1) Virus monovalent vaccine at Days 385 (Day U0) and Day 385 + 21 days (Day U21). Influenza A (H5N1) Virus monovalent vaccine was administered intramuscularly. Dose 1 of was administered in the deltoid region of the non-dominant arm and Dose 2 in the deltoid region of the dominant arm.

Primary Outcome Measures

Name	Time	Method
Number of Subjects Seroprotected for Haemagglutination Inhibition (HI) Antibody Titers Against the H5N1 A/Indonesia Virus Strain.	At Day 42.	A seroprotected subject against the a/Indonesia/5/2005 (A/INDO) virus strain was defined as a subject with H5N1 reciprocal haemagglutination inhibition (HI) antibody titers greater than or equal to (\>=) the seroprotection cut-off of 1:40.

Secondary Outcome Measures

Name	Time	Method
Vaccine Response Rate (VRR) for Microneutralization (MN) Antibodies Against the H5N1 A/Indonesia and H5N1 A/Vietnam Virus Strains.	At Day 42	VRR for MN was defined as as the incidence rate of vaccinees with a 4-fold increase in post vaccination reciprocal titer relative to Day 0.
Number of Seroconverted Subjects for Haemagglutination Inhibition (HI) Antibodies Against the H5N1 A/Indonesia Virus Strain.	At Day 385	A subject seroconverted for HI antibodies against the H5N1 A/Indonesia virus strain (A/INDO) was defined as a vaccinee with either a pre-vaccination titer less than (\<) 1:10 and a post-vaccination titer higher than or equal to (\>=) 1:40, or with a pre-vaccination titer \>= 1:10 and at least a 4-fold increase in post-vaccination titer.
Geometric Mean Increase (GMI) for Haemagglutination Inhibition (HI) Antibodies Against the H5N1 A/Indonesia Virus Strain.	At Day 385.	GMI also known as the seroconversion factor (SCF) or geometric mean fold rise (GMFR) was defined as the geometric mean of the within-subject ratios of the post-vaccination reciprocal HI titer to the pre-vaccination reciprocal HI titer for the vaccine virus.
Number of Subjects Seroprotected as Regards Haemagglutination Inhibition (HI) Antibody Titers Against the H5N1 A/Indonesia Virus Strain.	At Day 0 and Day 182	A seroprotected subject against the a/Indonesia/5/2005 (A/INDO) virus strain was defined as a subject with H5N1 reciprocal haemagglutination inhibition (HI) antibody titers greater than or equal to (\>=) the seroprotection cut-off of 1:40. As the analyses were performed and disclosed stepwise - i.e. as soon as a study phase was completed - several releases of the CTRS (result summaries) were published. To generate an integrated Clinical Study Report, one set of domain datasets covering all analyses was used and the Adapted ATP cohort for immunogenicity has been defined. As a consequence, some of the data previously disclosed and based on ATP cohort for immunogenicity at Day 42, Day 182 and Day 385 have been replaced in this summary with data generated with the Adapted ATP cohort for immunogenicity.
Number of Subjects Reporting Solicited Local Symptoms.	During the 7-day (Days U0-U6) post-vaccination periods post Doses 1 and 2 of vaccine/placebo, across doses (Year 2)	Solicited local symptoms assessed were pain and swelling. "Any" was defined as any occurrence of the specified solicited local symptom reported, regardless of intensity. Grade 3 pain was defined as pain that prevented normal activity. Grade 3 redness and swelling were defined as redness/swelling above 100 millimeter (mm).
Haemagglutination Inhibition (HI) Antibody Titers Against the H5N1 A/Indonesia Virus Strain	At Day 42.	HI antibody titers against the H5N1 A/Indonesia virus strain (A/INDO) were expressed as geometric mean titers (GMTs). The cut-off of the assay was the seropositivity cut-off of higher than or equal to (\>=) 1:10. As the analyses were performed and disclosed stepwise - i.e. as soon as a study phase was completed - several releases of the CTRS (result summaries) were published. To generate an integrated Clinical Study Report, one set of domain datasets covering all analyses was used and the Adapted ATP cohort for immunogenicity has been defined. As a consequence, some of the data previously disclosed and based on ATP cohort for immunogenicity at Day 42, Day 182 and Day 385 have been replaced in this summary with data generated with the Adapted ATP cohort for immunogenicity.
Number of Subjects of Less Than 6 Years of Age Reporting Solicited General Symptoms.	During the 7-day (Days U0-U6) post-vaccination periods post Doses 1 and 2 of vaccine/placebo, across doses (Year 2)	Solicited general symptoms assessed in subjects of less than 6 years of age were drowsiness, irritability/fussiness, loss of appetite and fever \[axillary temperature (T) higher than or equal to (\>=) 38.0 degrees Celsius (°C)\]. "Any" was defined as any occurrence of the specified solicited general symptom reported, regardless of intensity or relationship to vaccination. Grade 3 was defined as a general symptom that prevented normal activity. Related was defined as a general symptom assessed by the investigator as causally related to the study vaccination. Any fever was defined as axillary temperature above 38.0 degrees Celsius (°C). Grade 3 fever was axillary temperature \>=39.0°C.
Haemagglutination Inhibition (HI) Antibody Titers Against the H5N1 A/Indonesia Virus Strain.	At Day 0 and Day 385	HI antibody titers against the H5N1 A/Indonesia virus strain (A/INDO) were expressed as geometric mean titers (GMTs). The cut-off of the assay was the seropositivity cut-off of higher than or equal to (\>=) 1:10. As the analyses were performed and disclosed stepwise - i.e. as soon as a study phase was completed - several releases of the CTRS (result summaries) were published. To generate an integrated Clinical Study Report, one set of domain datasets covering all analyses was used and the Adapted ATP cohort for immunogenicity has been defined. As a consequence, some of the data previously disclosed and based on ATP cohort for immunogenicity at Day 42, Day 182 and Day 385 have been replaced in this summary with data generated with the Adapted ATP cohort for immunogenicity.
Number of Subjects Seroprotected for Haemagglutination Inhibition (HI) Antibody Titers Against the H5N1 A/Indonesia Virus Strain.	At Day 0 and Day 385	A seroprotected subject against the a/Indonesia/5/2005 (A/INDO) virus strain was defined as a subject with H5N1 reciprocal haemagglutination inhibition (HI) antibody titers greater than or equal to (\>=) the seroprotection cut-off of 1:40. As the analyses were performed and disclosed stepwise - i.e. as soon as a study phase was completed - several releases of the CTRS (result summaries) were published. To generate an integrated Clinical Study Report, one set of domain datasets covering all analyses was used and the Adapted ATP cohort for immunogenicity has been defined. As a consequence, some of the data previously disclosed and based on ATP cohort for immunogenicity at Day 42, Day 182 and Day 385 have been replaced in this summary with data generated with the Adapted ATP cohort for immunogenicity.
Number of Subjects Seropositive for Microneutralization (MN) Antibodies Against the H5N1 A/Indonesia Virus Strain.	At Days 0 and 42
Number of Subjects With Any Potential Immune-Mediated Diseases (pIMDs)	From Day U0 to Day U385	Potential immune-mediated diseases (pIMDs) were defined as a subset of adverse events that included both clearly autoimmune diseases and also other inflammatory and/or neurologic disorders which might or might not have an autoimmune aetiology. "Any pIMD" was defined as at least one pIMD experienced by the study subject.
Number of Subjects With Normal and Abnormal Haematological Parameters Assessed With Respect to Haematocrit (Hcr) and Haemoglobin (Hgb)	From Day 0 up to Day 385	Subjects were categorized according to their results at pre-vaccination (PRE), Day 42, Day 182 and Day 385 which were normal, above normal, below the normal ranges or unknown.
Microneutralization (MN) Antibody Titers Against the H5N1 A/Indonesia and H5N1 A/Vietnam Virus Strains.	At Days 0, 42, 182 and 385	MN HI antibody titers against the H5N1 A/Indonesia (A/INDO) and H5N1 A/Vietnam (A/VIET) virus strains were expressed as geometric mean titers (GMTs). The cut-off of the assay was the seropositivity cut-off of higher than or equal to (\>=) 1:28.
Number of Subjects With Medically-attended Adverse Events (MAEs)	From Day U0 up to Day U385	MAEs were defined as adverse events with medically-attended visits that were not routine visits for physical examination or vaccination. Any MAE was defined as atleast 1 MAE experienced.
Number of Subjects With Normal and Abnormal Haematological Parameters Assessed With Respect to Lymphocytes (LYM) and Monocytes (MON)	From Day 0 up to Day 385	Subjects were categorized according to their results at pre-vaccination (PRE), Day 42, Day 182 and Day 385 which were normal, above normal, below the normal ranges or unknown.
Number of Subjects at Least 6 Years of Age Reporting Solicited General Symptoms.	During the 7-day (Days U0-U6) post-vaccination periods post Doses 1 and 2 of vaccine/placebo, across doses (Year 2)	Solicited general symptoms assessed in subjects of at least 6 years of age were fatigue, gastrointestinal symptoms, headache, joint pain at other location, muscle aches, shivering, sweating and fever \[axillary temperature (T) \>= 38.0 degrees Celsius (°C)\]. Gastrointestinal symptoms included nausea, vomiting, diaorrhea and/or abdominal pain. "Any" was defined as any occurrence of the specified solicited general symptom reported, regardless of intensity or relationship to vaccination. Grade 3 was defined as a general symptom that prevented normal activity. Related was defined as a general symptom assessed by the investigator as causally related to the study vaccination. Grade 3 fever was axillary temperature \>= 39.0°C.
Number of Subjects Reporting Pregnancies, and Outcomes of These Reported Pregnancies	From Day U0 to Day U385
Number of Subjects With Normal and Abnormal Haematological Parameters Assessed With Respect to Basophils (BAS) and Eosinophils (EOS)	From Day 0 up to Day 385	Subjects were categorized according to their results at pre-vaccination (PRE), Day 42, Day 182 and Day 385 which were normal, above normal, below the normal ranges or unknown.
Number of Subjects With Normal and Abnormal Haematological Parameters Assessed With Respect to Neutrophils (NEU) and Platelets (PLA)	From Day 0 up to Day 385	Subjects were categorized according to their results at pre-vaccination (PRE), Day 42, Day 182 and Day 385 which were normal, above normal, below the normal ranges or unknown.
Number of Subjects Reporting Any Unsolicited Adverse Events (AEs).	During the 42-day (Days U0-U41) post-vaccination period following Dose 1 of Influenza A (H5N1) Virus monovalent vaccine	An unsolicited AE was defined as any AE (i.e. any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product) 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 occurrence of any unsolicited symptom regardless of intensity grade or relation to vaccination. As the study is still ongoing and data per age group are not available, results are presented for the groups pooled by vaccine/placebo administered. This outcome measure will be amended when data by age group become available.
Number of Subjects With Normal and Abnormal Biochemical Parameters Assessed With Respect to Alanine Aminotransferase (ALAT) and Aspartate Aminotransferase (ASAT)	From Day 0 up to Day 385	Subjects were categorized according to their results at pre-vaccination (PRE), Day 42, Day 182 and Day 385 which were normal, above normal, below the normal ranges or unknown.
Number of Subjects With Normal and Abnormal Biochemical Parameters Assessed With Respect to Total Bilirubin (T-BIL) and Bilirubin Conjugated/Direct (BIL-C/D)	From Day 0 up to Day 385	Subjects were categorized according to their results at pre-vaccination (PRE), Day 42, Day 182 and Day 385 which were normal, above normal, below the normal ranges or unknown.
Number of Subjects With Normal and Abnormal Biochemical Parameters Assessed With Respect to Creatinine (CREA) and Blood Urea Nitrogen (BUN)	From Day 0 up to Day 385	Subjects were categorized according to their results at pre-vaccination (PRE), Day 42, Day 182 and Day 385 which were normal, above normal, below the normal ranges or unknown.
Number of Subjects With Normal and Abnormal Haematological Parameters Assessed With Respect to Red and White Blood Cells (RBC and WBC)	From Day 0 up to Day 385	Subjects were categorized according to their results at pre-vaccination (PRE), Day 42, Day 182 and Day 385 which were normal, above normal, below the normal ranges or unknown.
Number of Subjects Reporting Serious Adverse Events (SAEs)	From Day U0 up to Day U385	A SAE was defined as any untoward medical occurrence that: resulted in death, was life threatening, required hospitalization or prolongation of hospitalization, resulted in disability/incapacity or was a congenital anomaly/birth defect in the offspring of a study subject. Any was defined as occurrence of any symptom regardless of intensity grade or relation to vaccination and related was an event assessed by the investigator as causally related to the study vaccination.