An Efficacy Study of GlaxoSmithKline (GSK) Biologicals' Candidate Influenza Vaccine GSK2321138A in Children

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the efficacy, immunogenicity and safety of GSK Biologicals' influenza candidate vaccine GSK2321138A when compared to non-influenza vaccine comparators in children 6 to 35 months of age. Recruitment will encompass at least 4 independent cohorts: a first cohort in the Northern Hemisphere (2011-2012), a second cohort in subtropical countries (2012), third cohort in the Northern Hemisphere (2012-2013) and a fourth cohort and additional independent cohorts possibly in NH countries (end 2013) and subtropical countries (beginning 2014).

Official Title
-----------------
An Efficacy Study of GSK Biologicals' Quadrivalent Influenza Vaccine GSK2321138A (FLU D-QIV) When Administered in Children

Conditions
-----------------
Influenza

Intervention / Treatment
-----------------
* Biological: Quadrivalent seasonal influenza vaccine(Flu D-QIV) GSK2321138A
* Biological: Havrix Junior
* Biological: Prevenar 13
* Biological: Varivax/ProVarivax
* Biological: Varilrix


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects who the investigator believes that their parents/Legally Acceptable Representative (LARs) can and will comply with the requirements of the protocol. A male or female between, and including, 6 and 35 months of age at the time of first vaccination; children are eligible regardless of history of influenza vaccination. Written informed consent obtained from the parent(s) /LAR(s) of the subject. Subjects in stable health as determined by medical history and clinical examination before entering into the study. Exclusion Criteria: Participation in a previous FLU-D-QIV-004 study (115345) cohort. Child in care. Use of any investigational or non-registered product other than the study vaccines within 30 days preceding the first dose of study vaccine, or planned use during the study period. Prior receipt of any influenza vaccine within 6 months preceding the first dose of study vaccine, or planned use of such vaccines during the study period. Children with underlying illness who are at risk of complications of influenza and for whom yearly (seasonal) influenza vaccination is recommended in their respective country. Any confirmed or suspected immunosuppressive or immunodeficient condition (including HIV), based on medical history and physical examination. Chronic administration of immunosuppressants or other immune modifying drugs within six months prior to the first vaccine dose. Inhaled and topical steroids are allowed. Administration of immunoglobulins and/ or any blood products within 3 months preceding the first dose of study vaccine or planned administration during the study period. Any known or suspected allergy to any constituent of influenza vaccines, non-influenza vaccine comparators and latex; a history of anaphylactic-type reaction to consumption of eggs; or a history of severe adverse reaction to a previous vaccination. Any contraindication to intramuscular injection. Acute disease and/or fever at the time of enrolment. Any other condition which, in the opinion of the Investigator, prevents the subject from participating in the study. Additional criteria for children ≥ 12 months of age: Prior receipt of any licensed varicella vaccine* or any licensed hepatitis A vaccine or planned use of these vaccines during the study period. Other routine registered childhood vaccinations are permitted. * For countries with varicella vaccine administered as 2-dose schedule, prior receipt of a single dose of a varicella vaccine is allowed if administered at least 2 weeks before the first study vaccination. Any history of hepatitis A or varicella diseases. Additional criteria for children 6 - 11 months of age in countries without universal mass vaccination recommendation for pneumococcal vaccine: Prior receipt of any pneumococcal conjugated vaccine or planned use of this vaccine during the study period. Other routine registered childhood vaccinations are permitted.

Ages Eligible for Study
-----------------
Minimum Age: 6 Months
Maximum Age: 35 Months

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: D-QIV<br>Subjects received 1 or 2 doses of candidate influenza Influsplit™ Tetra vaccine (GSK2321138A). | Biological: Quadrivalent seasonal influenza vaccine(Flu D-QIV) GSK2321138A<br>* Intramuscular injection<br>|
| Active Comparator: Control<br>In function of their age and D-QIV-vaccine status, subjects received Prevenar 13® or Havrix® Junior and possibly a varicella vaccine (Varilrix® or Varivax/ProVarivax ®). | Biological: Havrix Junior<br>* Intramuscular injection administered to subjects aged 12 months or older<br>Biological: Prevenar 13<br>* Intramuscular injection administered to subjects less than 12 months of age<br>Biological: Varivax/ProVarivax<br>* Intramuscular injection administered to subjects more than 12 months of age<br>Biological: Varilrix<br>* Subcutaneous injection administered to subjects more than 12 months of age<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Moderate to Severe RT-PCR Confirmed Influenza. | Attack rate (AR) was defined as the number/percentage of subjects with at least 1 RT-PCR confirmed influenza event. | During the surveillance period (approximately 6 to 8 months) | 
| Number of Subjects With RT-PCR Confirmed Influenza of Any Severity. | Attack rate (AR) was defined as the number/percentage of subjects with at least 1 RT-PCR confirmed influenza event. | During the surveillance period (approximately 6 to 8 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With First Occurrence of Lower Respiratory Illness (LRI) With RT-PCR Confirmed Influenza. | Attack rate (AR) was defined as the number/percentage of subjects with at least 1 RT-PCR confirmed influenza event. | At any time starting 7 days before the onset of LRI and ending 7 days after end of LRI during the surveillance period (approximately 6 to 8 months) | 
| Number of Subjects With First Occurrence of Culture-confirmed Moderate to Severe Influenza A and/or B Disease Due to Antigenically-matching Influenza Strains. | Attack rate (AR) was defined as the number/percentage of subjects with at least 1 RT-PCR confirmed influenza event. | During the surveillance period (approximately 6 to 8 months) | 
| Number of Subjects With First Occurrence of Culture-confirmed Influenza A and/or B Disease of Any Severity Due to Antigenically-matching Influenza Strains | Attack rate (AR) was defined as the number/percentage of subjects with at least 1 RT-PCR confirmed influenza event. | During the surveillance period (approximately 6 to 8 months) | 
| Number of Subjects With First Occurrence of Culture-confirmed Moderate to Severe Influenza A and/or B Disease Due to Any Seasonal Influenza Strain. | Attack rate (AR) was defined as the number/percentage of subjects with at least 1 RT-PCR confirmed influenza event. | During the surveillance period (approximately 6 to 8 months) | 
| Number of Subjects With First Occurrence of Culture-confirmed Influenza A and/or B Disease of Any Severity Due to Any Seasonal Influenza Strain. | Attack rate (AR) was defined as the number/percentage of subjects with at least 1 RT-PCR confirmed influenza event. | During the surveillance period (approximately 6 to 8 months) | 
| Number of Subjects With First Occurrence of Acute Otitis Media (AOM) With RT-PCR Confirmed Influenza A and/or B Infection Due to Any Seasonal Influenza Strain. | Attack rate (AR) was defined as the number/percentage of subjects with at least 1 RT-PCR confirmed influenza event. | At any time starting 7 days before the onset of LRI and ending 7 days after end of LRI during the surveillance period (approximately 6 to 8 months) | 
| Number of Subjects With First Occurrence of RT-PCR Confirmed Severe Influenza A and/or B Due to Any Seasonal Influenza Strain. | Attack rate (AR) was defined as the number/percentage of subjects with at least 1 RT-PCR confirmed influenza event. | During the surveillance period (approximately 6 to 8 months) | 
| Humoral Immune Response in Terms of Haemagglutination-inhibition (HI) Antibody Titres Against Each of Four Vaccine Strains Contained in the D-QIV (in Immuno Subcohort of Subjects Only) | Titers were expressed as geometric mean antibody titers (GMTs). The vaccine strains assessed were A/California/7/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 (Victoria) and B/Brisbane/3/2007 (Yamagata). PRE= Pre-vaccination at Day 0; POST = Post-vaccination 1 at Day 28 for primed subjects or post-vaccination 2 at Day 56 for unprimed subjects | At Days 0 and 28/56 | 
| Number of Seropositive Subjects for HI Antibodies Against Each of the 4 Influenza Strains Contained in the D-QIV Vaccine (in Immuno Subcohort of Subjects Only) | A seropositive subject was a subject whose HI antibody titer was greater than or equal to the assay cut-off value of 1:10. The vaccine strains assessed were A/California/7/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 (Victoria) and B/Brisbane/3/2007 (Yamagata). PRE= Pre-vaccination at Day 0; POST = Post-vaccination 1 at Day 28 for primed subjects or post-vaccination 2 at Day 56 for unprimed subjects. | At Day 0 and Day 28/56 | 
| Number of Seroconverted Subjects for HI Antibodies Against Each of the 4 Influenza Strains Contained in the D-QIV Vaccine (in Immuno Subcohort of Subjects Only) | Seroconversion rate (SCR) was defined as the number of subjects who have either a pre-vaccination reciprocal HI titer < 1:10 and a post-vaccination reciprocal titer ≥ 1:40, or a pre-vaccination reciprocal HI titer ≥ 10 and at least a 4 fold increase in post vaccination reciprocal titer against the vaccine virus. PRE= Pre-vaccination at Day 0; POST = Post-vaccination 1 at Day 28 for primed subjects or post-vaccination 2 at Day 56 for unprimed subjects | At Day 28/56 (POST) | 
| Mean Geometric Increase (MGI) for HI Antibody Titer Against Each of the 4 Vaccine Influenza Strains Contained in the D-QIV Vaccine (in Immuno Subcohort of Subjects Only). | MGI also known as the seroconversion factor [SCF] was defined as the fold increase in serum HI GMTs post vaccination compared to pre-vaccination (Day 0). The vaccine strains assessed were A/California/7/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 (Victoria) and B/Brisbane/3/2007 (Yamagata). POST = Post-vaccination 1 at Day 28 for primed subjects or post-vaccination 2 at Day 56 for unprimed subjects. | At Day 28/56 (POST) | 
| Number of Seroprotected Subjects for HI Antibodies Against Each of the 4 Influenza Strains Contained in the D-QIV Vaccine (in Immuno Subcohort of Subjects Only) | Seroprotection rate (SPR) was defined as the number of subjects with H1N1 reciprocal HI titers ≥ 1:40 against the tested vaccine virus.The vaccine strains assessed were A/California/7/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 (Victoria) and B/Brisbane/3/2007 (Yamagata). PRE= Pre-vaccination at Day 0; POST = Post-vaccination 1 at Day 28 for primed subjects or post-vaccination 2 at Day 56 for unprimed subjects | At Day 0 and Day 28/56 | 
| Number of Subjects Reporting Any and Grade 3 Solicited Local Symptoms. | Solicited local symptoms assessed were pain, redness and swelling. Any was defined as any solicited local symptom reported irrespective of intensity. Grade 3 pain was defined as pain that resulted crying when limb was moved/ spontaneously painful. Grade 3 redness and swelling was greater than 50 millimeters (mm) i.e. >50mm. | During the 7-day post-vaccination period (Days 0-6 for Dose 1, Days 28-34 for Dose 2) | 
| Number of Subjects Reporting Any, Grade 3 and Related Solicited General Symptoms. | Solicited general symptoms assessed were Drowsiness, Irritability/fussiness, Loss of appetite and Temperature (Axillary). Any was defined as any general symptom reported irrespective of intensity or relationship to vaccination. Grade 3 was defined as symptoms that prevented normal activity. Related was defined as general symptom assessed by the investigator to have a causal relationship to vaccination. | During the 7-day post-vaccination period (Days 0-6 for Dose 1, Days 28-34 for Dose 2) | 
| Duration of Solicited Local Symptoms | Duration was defined as number of days with any grade of local symptoms. | During the 7-day post-vaccination period (Days 0-6 for Dose 1, Days 28-34 for Dose 2) | 
| Duration of Solicited General Symptoms | Duration was defined as number of days with any grade of general symptoms. | During the 7-day post-vaccination period (Days 0-6 for Dose 1, Days 28-34 for Dose 2) | 
| Number of Subjects Reporting Any, Grade 3 and Related Unsolicited Adverse Events (AEs) | Unsolicited AE covers any AE 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. Grade 3 was an event that prevented normal activities and related was defined as an unsolicited AE assessed by the investigator to be causally related to the study vaccination. | During the 28-day (Days 0-27) post-vaccination period | 
| Number of Subjects Reporting Any, Grade 3 and Related AEs With Medically Attended Visits (MAVs) | MAVs were defined as AEs with a medically-attended visit i.e. prompting emergency room (ER) visits, hospitalizations or physician visits and that were not routine visits for physical examination or vaccination. Any MAV was defined as at least one MAV experienced. Grade 3 was defined as MAVs that prevented normal activities and related was defined as MAVs assessed by the investigator to be causally related to the study vaccination. | During the entire study period (approximately 6- 8 months per subject) | 
| Number of Subjects Reporting Any, Grade 3 and Related Potential Immune-mediated Diseases (pIMDs). | pIMDs are a subset of adverse events (AEs) that include both clearly autoimmune diseases and also other inflammatory and/or neurologic disorders which may or may not have an autoimmune etiology. Grade 3 = pIMDs that prevented normal activities. Related = symptom assed by the investigator as causally related to the study vaccination. | During the entire study period (approximately 6- 8 months per subject) | 
| Number of Subjects Reporting Any and Related Serious Adverse Events (SAEs). | SAEs assessed include medical occurrences that results in death, are life threatening, require hospitalization or prolongation of hospitalization, results in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subjects. Related = symptom assessed by the investigator as causally related to the study vaccination. | During the entire study period (approximately 6- 8 months per subject) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Vaccine, Seasonal Flu, Efficacy, Children