A Study to Evaluate the Efficacy of GSK Biologicals' Influenza Vaccine in Children

Study Overview
=================
Brief Summary
-----------------
This study is designed to test the efficacy of an investigational influenza vaccine, in children compared to Havrix®, a licensed Hepatitis A virus vaccine. This study will also evaluate the immunogenicity and safety of the investigational vaccine.

Official Title
-----------------
Efficacy Study of GSK Biologicals' Quadrivalent Influenza Vaccine, GSK2282512A, (FLU Q-QIV) When Administered in Children

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

Intervention / Treatment
-----------------
* Biological: FluLaval® Quadrivalent
* Biological: Havrix™


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects who the investigator believes that they and/or their parent(s) or legally acceptable representative(s) can and will comply with the requirements of the protocol. A male or female child aged between 3 and 8 years inclusive at the time of the first vaccination; children are eligible regardless of history of administration of influenza vaccine in a previous season. However, subjects who have received any seasonal or pandemic influenza vaccine within 6 months preceding the first dose of study vaccine will not be enrolled. Written informed consent obtained from the subject/from the parent(s)/legally acceptable representative(s) of the subject. Written assent obtained from the subject if/as required by local regulations. Subjects in stable health as determined by investigator's clinical examination and assessment of subjects' medical history. Access to a consistent means of telephone contact Exclusion Criteria: Child in care. Use of an investigational or non-registered product other than the study vaccines within 30 days before study vaccination or planned use during study period. Routine registered childhood vaccinations are permitted. Prior receipt of any seasonal or pandemic influenza vaccine within 6 months preceding the first dose of study vaccine, or planned use of such vaccines during the study period. Prior receipt of more than one dose of a licensed hepatitis A vaccine, with the first dose administered at >=12 months of age. Chronic administration of immunosuppressants or other immune-modifying drugs within 6 months prior to the first vaccine dose. Administration of immunoglobulins and/or any blood products within the 3 months preceding the first dose of study vaccine or planned administration during the study period. History of Guillain-Barre syndrome within 6 weeks of receipt of prior influenza virus vaccine. Any known or suspected allergy to any constituent of influenza vaccines ; a history of anaphylactic-type reaction to constituent of vaccine; or a history of severe adverse reaction to a previous influenza vaccine. Fever at the time of enrolment. Acute disease at the time of enrolment. Any significant disorder of coagulation or treatment with Coumadin derivatives or heparin. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination. Ongoing aspirin therapy. Any other condition which, in the opinion of the Investigator, prevents the subject from participating in the study.

Ages Eligible for Study
-----------------
Minimum Age: 3 Years
Maximum Age: 8 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FluLaval® Quadrivalent Group<br>Subjects between 3 and 8 years of age at the time of first vaccination received, if primed, 1 dose of FluLaval® Quadrivalent vaccine at Day 0 and, if unprimed, 2 doses of FluLaval® Quadrivalent vaccine at Days 0 and 28. The vaccine was administered intramuscularly in the deltoid muscle of the non-dominant arm. | Biological: FluLaval® Quadrivalent<br>* One intramuscular dose for primed subjects. Two intramuscular doses for unprimed subjects.<br>* Other names: Quadrivalent seasonal influenza vaccine GSK2282512A;|
| Active Comparator: Havrix Group<br>Subjects between 3 and 8 years of age at the time of first vaccination received, if primed, 1 dose of Havrix™ vaccine at Day 0 and, if unprimed, 2 doses of Havrix™ vaccine at Days 0 and 28. The vaccine was administered intramuscularly in the deltoid muscle of the non-dominant arm. | Biological: Havrix™<br>* Two intramuscular doses for primed subjects. Three intramuscular doses for unprimed subjects.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Reporting at Least One Confirmed Occurrence of Influenza A or B. | To confirm influenza A and/or B disease, a positive reverse transcriptase polymerase chain reaction (RT-PCR) result for influenza A or B virus from a nose and throat swab obtained concurrently with an influenza like illness (ILI) was required. ILI was defined as the presence of an oral or axillary temperature ≥ 37.8 degrees Celsius (°C) in the presence of at least one of the following symptoms on the same day: cough, sore throat, runny nose or nasal congestion. | From Day 14 to Day 180 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Reporting at Least One Moderate to Severe Occurrence of Influenza A or B. | To confirm influenza A and/or B disease moderate to severe cases, a positive RT-PCR result for influenza A or B virus from a nose and throat swab obtained concurrently with an ILI was required. Moderate to severe influenza was defined as RT-PCR-confirmed ILI with: Fever >39°C, and/or at least one of the following manifestations, Physician-verified shortness of breath, pulmonary congestion, pneumonia, bronchiolitis, bronchitis, wheezing, croup, or acute otitis media, and/or one of the following, Physician-diagnosed serious extra-pulmonary complication of influenza, including myositis, encephalitis, seizure, or myocarditis | From Day 14 to Day 180 | 
| Number of Subjects Reporting at Least One Culture Confirmed Occurrence of Influenza A or B Due to Antigenically Matched Strain. | To confirm influenza A and/or B disease due to antigenically matched strain, a positive reverse transcriptase polymerase chain reaction (RT-PCR) result for influenza A or B virus from a nose and throat swab obtained concurrently with an influenza like illness (ILI) was required. ILI was defined as the presence of an oral or axillary temperature ≥ 37.8 degrees Celsius (°C) in the presence of at least one of the following symptoms on the same day: cough, sore throat, runny nose or nasal congestion. | From Day 14 to Day 180 | 
| Number of Subjects Reporting at Least One Culture Confirmed Occurrence of Influenza A or B Due to Any Strain. | To confirm influenza A and/or B disease due to any strain, a positive reverse transcriptase polymerase chain reaction (RT-PCR) result for influenza A or B virus from a nose and throat swab obtained concurrently with an influenza like illness (ILI) was required. ILI was defined as the presence of an oral or axillary temperature ≥ 37.8 degrees Celsius (°C) in the presence of at least one of the following symptoms on the same day: cough, sore throat, runny nose or nasal congestion. | From Day 14 to Day 180 | 
| Titers for Serum Hemagglutination Inhibition (HI) Antibodies Against 4 Strains of Influenza Disease. | Titers are presented as geometric mean titers (GMTs). The reference cut-off value was the seropositivity cut-off of 1:10. The 4 influenza strains assessed were the Flu A/California/7/09 (H1N1), Flu A/Victoria/210/09 (H3N2), FluB/Brisbane/60/08 (Victoria) and Flu B/Florida/4/06 (Yamagata). | At Day 0 [PRE] and 28 days post vaccination (Day 28 for primed subjects and day 56 for unprimed subjects) [POST] | 
| Number of Seroconverted Subjects Against 4 Strains of Influenza Disease. | A seroconverted subject was defined as a vaccinated subject who had either a pre-vaccination titer < 1:10 and a post-vaccination titer ≥ 1:40 or a pre-vaccination titer ≥ 1:10 and at least a four-fold increase in post-vaccination titer. The 4 influenza strains assessed were the Flu A/California/7/09 (H1N1), Flu A/Victoria/210/09 (H3N2), FluB/Brisbane/60/08 (Victoria) and Flu B/Florida/4/06 (Yamagata). | At 28 days post vaccination (Day 28 for primed subjects and day 56 for unprimed subjects) [POST] | 
| Number of Seroprotected Subjects Against 4 Strains of Influenza Disease. | A seroprotected subject was defined as a vaccinated subject who had a serum HI titer ≥ 1:40. The 4 influenza strains assessed were the Flu A/California/7/09 (H1N1), Flu A/Victoria/210/09 (H3N2), FluB/Brisbane/60/08 (Victoria) and Flu B/Florida/4/06 (Yamagata). | At Day 0 [PRE] and 28 days post vaccination (Day 28 for primed subjects and day 56 for unprimed subjects) [POST] | 
| Seroconversion Factor for Hemagglutination Inhibition (HI) Antibodies Against 4 Strains of Influenza Disease. | The seroconversion factor (SCF) was defined as the fold increase in serum Hemagglutination Inhibition (HI) geometric mean titers (GMTs) post vaccination compared to Day 0. The 4 influenza strains assessed were the Flu A/California/7/09 (H1N1), Flu A/Victoria/210/09 (H3N2), FluB/Brisbane/60/08 (Victoria) and Flu B/Florida/4/06 (Yamagata). | At 28 days post vaccination (Day 28 for primed subjects and day 56 for unprimed subjects) [POST] | 
| Haemagglutination Inhibition (HI) Antibody Titers Against Each of the 4 Vaccine Strains | HI antibody titres were expressed as Geometric mean titers (GMTs). The vaccine strains assessed were Flu A/California/7/2009 (H1N1), Flu A/Victoria/210/09 (H3N2), Flu B/Brisbane/60/08 (Victoria) and Flu B/Florida/4/06 (Yamagata). | On Day 0 and at least 6 months after first vaccination (Month 6) | 
| Number of Seroconverted Subjects for HI Antibody Titers Against Each of the 4 Vaccine Influenza Strains. | A seroconverted subject was defined as a vaccinated subject with either a pre-vaccination titer less than (<) 1:10 and a post-vaccination titer greater than or equal to (≥) 1:40, or a pre-vaccination titer ≥ 1:10 and at least a 4-fold increase in post-vaccination titer. The vaccine strains assessed were Flu A/California/7/09 (H1N1), Flu A/Victoria/210/09 (H3N2), FluB/Brisbane/60/08 (Victoria) and Flu B/Florida/4/06 (Yamagata). | At least 6 months after first vaccination (Month 6) | 
| Number of Seroprotected Subjects for HI Antibody Titers Against Each of the 4 Vaccine Influenza Strains. | A seroprotected subject was defined as a vaccinated subject with a serum HI titer greater than or equal to (≥) 1:40 that usually is accepted as indicating protection in adults. The vaccine strains assessed were Flu A/California/7/09 (H1N1), Flu A/Victoria/210/09 (H3N2), FluB/Brisbane/60/08 (Victoria) and Flu B/Florida/4/06 (Yamagata). | At Day 0 and at least 6 months after first vaccination (Month 6) | 
| Seroconversion Factors for HI Antibodies Against 4 Strains of Influenza Disease. | Seroconversion factors were defined as the fold increase in serum HI GMTs post-vaccination compared to Day 0. The 4 influenza strains assessed were the Flu A/California/7/09 (H1N1), Flu A/Victoria/210/09 (H3N2), FluB/Brisbane/60/08 (Victoria) and Flu B/Florida/4/06 (Yamagata). | At least 6 months after first vaccination (Month 6) | 
| Number of Subjects With Any, Grade 3 and Related Solicited Local Symptoms. | Assessed solicited local symptoms were pain, redness and swelling at the injection site. Any = Incidence of a particular symptom regardless of intensity grade. Grade 3 pain = Cried when limb was moved/spontaneously painful for subjects < 5 years of age or significant pain at rest that prevented normal, everyday activities for subjects ≥ 5 years of age. Grade 3 redness/swelling = Redness/swelling above 100 millimeters (mm) of the injection site. All solicited local symptoms were considered related to vaccination. | During the 7-day (Days 0-6) follow-up period after any vaccination | 
| Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms in Subjects Below 5 Years of Age. | Assessed solicited general symptoms were drowsiness, irritability, loss of appetite and temperature. Any = Occurrence of any solicited general symptom regardless of intensity grade and relation to vaccination. Any temperature = Axillary temperature ≥ 38.0 °C. Grade 3 Drowsiness = Drowsiness that prevented normal activity. Grade 3 Irritability = Crying that could not be comforted/prevented normal activity. Grade 3 Loss of appetite = not eating at all. Related = General symptom assessed by the investigator as causally related to the study vaccination. Grade 3 temperature = Axillary temperature ≥ 39.0°C. | During the 7-day (Days 0-6) follow-up period after any vaccination | 
| Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms in Subjects of 5 Years of Age and Above. | Assessed solicited general symptoms were fatigue, gastrointestinal symptoms (Gastro.), headache, joint pain at other location (Joint pain), muscle aches, shivering and temperature. Any = Occurrence of any solicited general symptom regardless of intensity grade or relation to vaccination. Any temperature = Axillary temperature ≥ 38.0 °C. Grade 3 symptom = Symptom that prevented normal activity. Related = Symptom assessed by the investigator as causally related to the vaccination. Grade 3 temperature = Axillary temperature ≥ 39.0°C. | During the 7-day (Days 0-6) follow-up period after any vaccination | 
| Number of Subjects With 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 = Any unsolicited AE regardless of intensity or relationship to vaccination. Grade 3 = Unsolicited AE that prevented normal activity. Related = Unsolicited AE assessed by the investigator as causally related to the vaccination. | During the 28-day (Days 0-27) follow-up period after vaccination | 
| Number of Subjects With Any and Related Medically Attended Adverse Events (MAEs). | MAEs were defined as AEs that resulted in medical attention (defined as hospitalization, an emergency room visit or a visit to or from medical personnel for any reason). Any = Any MAE regardless of intensity or relationship to vaccination. Related = MAE assessed by the investigator as causally related to the vaccination. | During the entire study period (Day 0 - Day 180) | 
| Number of Subjects With Any and Related Potential Immune-mediated Diseases (pIMDs). | pIMDs were defined as a subset of AEs that included both clearly autoimmune diseases (AID) and also other inflammatory and/or neurologic disorders which may or may not have an autoimmune etiology. Any = Any pIMD(s) regardless of intensity or relationship to vaccination. Related = pIMDs assessed by the investigator as causally related to the vaccination. | During the entire study period (Day 0 - Day 180) | 
| Number of Subjects With Any and Related 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. Any = Any SAE(s) regardless of intensity or relationship to vaccination. Related = SAEs assessed by the investigator as causally related to the vaccination. | During the entire study period (Day 0 - Day 180) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Influenza