Safety and Efficacy of H1N1 Vaccines in Children Aged 6 Months to Less Than 10 Years of Age

Phase 3

Completed

Conditions: Influenza

Interventions: Biological: GSK Biologicals' investigational vaccine GSK2340273A (alternative formulations)
Biological: GSK Biologicals' investigational vaccine GSK2340274A (alternative formulations)
Biological: Placebo

Registration Number: NCT01051661

Lead Sponsor: GlaxoSmithKline

Brief Summary: The purpose of this study is to characterize the safety and efficacy of GSK Biologicals' H1N1 flu candidate vaccines GSK2340274A and GSK2340273A in children 6 months to less than 10 years of age.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 6154

Inclusion Criteria

Male or female children 6 months to less than 10 years of age at the time of the first vaccination. "Less than 10 years of age" implies inclusion of children who have not reached their 10th birthday as of Day 0, the day of first vaccine dose under this protocol.
Written informed consent obtained from the subject's parent(s)/legally acceptable representative(s) (LAR(s)); written informed assent obtained from the subject if appropriate pre local requirements).
Stable health status as defined by absence of a health event satisfying the definition of a SAE, or a change in an ongoing drug therapy due to therapeutic failure or symptoms of drug toxicity, within 1 month prior to enrolment.
Parent(s)/LAR(s) available and accessible for active surveillance contacts.
Parent(s)/LAR(s) and (if age-appropriate, subjects) who, in the investigator's opinion, can and will comply with the requirements of the protocol as documented by signature on the informed consent document.
Female subjects of non-childbearing potential (pre-menarche) may be enrolled in the study.

Exclusion Criteria

Previous vaccination with an A/California/7/2009 (H1N1)v-like virus vaccine.
Medical history of physician-confirmed infection with an A/California/7/2009 (H1N1)v-like virus.
Presence of evidence of substance abuse or of neurological or psychiatric diagnoses which, even if stable, are deemed by the investigator to render the potential subject or parent(s)/LAR(s) unable/unlikely to provide accurate safety reports.
Presence of a temperature ≥ 38.0ºC (≥ 100.4ºF) by any route or method, or acute symptoms greater than "mild" severity on the scheduled date of first vaccination. NOTE: The subject may be vaccinated at a later date, provided symptoms have resolved, vaccination occurs within the window specified by the protocol, and all other eligibility criteria continue to be satisfied.
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 (no laboratory testing required).
Receipt of systemic glucocorticoids within 1 month prior to study enrollment (first dose of study vaccine), or any other cytotoxic or immunosuppressive drug within 6 months of study enrollment. Topical, intra-articular or inhaled glucocorticoids are allowed.
Receipt of any immunoglobulins and/or any blood products within 6 months of study enrollment or planned administration of any of these products during the study period.
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.
An acute evolving neurological disorder or history of Guillain-Barré syndrome within 6 weeks of receipt of seasonal influenza vaccine.
Administration of any licensed live attenuated vaccine within 4 weeks before the first vaccination or of any licensed inactivated vaccine within 2 weeks before the first vaccination.
Planned administration of any vaccine not foreseen by the study protocol between Day 0 and Day 42. Routine childhood vaccinations are exempted if they cannot be delayed, but they must not be administered on the same day as the H1N1 vaccine candidate.
Planned use of a pandemic monovalent A/California/7/2009 (H1N1)v-like virus vaccine other than the study vaccines during the study period.
Planned administration of seasonal trivalent influenza vaccine during the 4 month period following Day 0.
Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine(s) within 30 days before the first dose of study vaccine, or planned use during the study period.
Any known or suspected allergy to any constituent of influenza vaccines (including egg proteins or mercurial preservatives); a history of anaphylactic-type reaction to consumption of eggs; or a history of severe adverse reaction to a previous influenza vaccine.
Child in care.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arepanrix 1D 3Y-10Y Group	Placebo	Subjects, male and female, aged 3 years (Y) to 10 years, received 1 dose (D) of the Arepanrix™ vaccine followed by 1 dose of saline placebo at a 21-day interval at a 21-day interval (Days 0 and 21). First doses were administered in the deltoid region of the non-dominant arm (or left arm if dominance is not yet identified). Second doses were administered at a 21-day interval in the deltoid region of the dominant arm (or right arm).
GSK2340273A 6M-3Y Group	GSK Biologicals' investigational vaccine GSK2340273A (alternative formulations)	Subjects, male and female, aged 6 months (M) to 3 years (Y), received 2 doses (D) of the GSK2340273A vaccine at a 21-day interval (Days 0 and 21). First doses were administered in the deltoid region of the non-dominant arm (or left arm if dominance is not yet identified) or, for children \<12 months of age, in the left anterolateral thigh. Second doses were administered at a 21-day interval in the deltoid region of the dominant arm (or right arm) or, for, children \<12 months of age, in the right anterolateral thigh.
Arepanrix 2D 3Y-10Y Group	GSK Biologicals' investigational vaccine GSK2340274A (alternative formulations)	Subjects, male and female, aged 3 years (Y) to 10 years, received 2 doses (D) of the Arepanrix™ vaccine at a 21-day interval (Days 0 and 21). First doses were administered in the deltoid region of the non-dominant arm (or left arm if dominance is not yet identified). Second doses were administered at a 21-day interval in the deltoid region of the dominant arm (or right arm).
Arepanrix 2D 6M-3Y Group	GSK Biologicals' investigational vaccine GSK2340274A (alternative formulations)	Subjects, male and female, aged 6 months (M) to 3 years (Y), received 2 doses (D) of the Arepanrix™ vaccine at a 21-day interval (Days 0 and 21). First doses were administered in the deltoid region of the non-dominant arm (or left arm if dominance is not yet identified) or, for children \<12 months of age, in the left anterolateral thigh. Second doses were administered at a 21-day interval in the deltoid region of the dominant arm (or right arm) or, for, children \<12 months of age, in the right anterolateral thigh.
Arepanrix 1D 6M-3Y Group	GSK Biologicals' investigational vaccine GSK2340274A (alternative formulations)	Subjects, male and female, aged 6 months (M) to 3 years (Y), received 1 dose (D) of the Arepanrix™ vaccine followed by 1 dose of saline placebo at a 21-day interval at a 21-day interval (Days 0 and 21). First doses were administered in the deltoid region of the non-dominant arm (or left arm if dominance is not yet identified) or, for children \<12 months of age, in the left anterolateral thigh. Second doses were administered at a 21-day interval in the deltoid region of the dominant arm (or right arm) or, for, children \<12 months of age, in the right anterolateral thigh.
Arepanrix 1D 3Y-10Y Group	GSK Biologicals' investigational vaccine GSK2340274A (alternative formulations)	Subjects, male and female, aged 3 years (Y) to 10 years, received 1 dose (D) of the Arepanrix™ vaccine followed by 1 dose of saline placebo at a 21-day interval at a 21-day interval (Days 0 and 21). First doses were administered in the deltoid region of the non-dominant arm (or left arm if dominance is not yet identified). Second doses were administered at a 21-day interval in the deltoid region of the dominant arm (or right arm).
GSK2340273A 3Y-10Y Group	GSK Biologicals' investigational vaccine GSK2340273A (alternative formulations)	Subjects, male and female, aged 3 years (Y) to 10 years, received 2 doses (D) of the GSK2340273A vaccine at a 21-day interval (Days 0 and 21). First doses were administered in the deltoid region of the non-dominant arm (or left arm if dominance is not yet identified). Second doses were administered at a 21-day interval in the deltoid region of the dominant arm (or right arm).
Arepanrix 1D 6M-3Y Group	Placebo	Subjects, male and female, aged 6 months (M) to 3 years (Y), received 1 dose (D) of the Arepanrix™ vaccine followed by 1 dose of saline placebo at a 21-day interval at a 21-day interval (Days 0 and 21). First doses were administered in the deltoid region of the non-dominant arm (or left arm if dominance is not yet identified) or, for children \<12 months of age, in the left anterolateral thigh. Second doses were administered at a 21-day interval in the deltoid region of the dominant arm (or right arm) or, for, children \<12 months of age, in the right anterolateral thigh.

Primary Outcome Measures

Name	Time	Method
Number of Subjects Reporting at Least One A/California Influenza Event	From 14 days after first vaccination until study conclusion on Day 385	The influenza virus presence was confirmed by quantitative reverse transcription polymerase chain reaction assay (RT-qPCR).

Secondary Outcome Measures

Name	Time	Method
Number of Subjects Reporting at Least One Culture Confirmed A/California Influenza Event	From Day 0 until study conclusion on Day 385	The influenza virus presence was confirmed by a positive culture.
Number of Subjects With Protocol Specified Influenza-like Illness (ILI) Symptoms in All Reported ILI Cases	From Day 14 until study end at Day 385	Protocol specified ILI symptoms were: fever, muscle aches all over the body, cough, sore throat, runny or stuffy nose, short of breath, headache, vomiting, diarrhea, chills and fatigue. Analysis for the time frame Day 42 till Day 385 was not performed as planned per protocol.
Number of Seroconverted (SCR) Subjects for Flu A/CAL/7/09 (H1N1) Influenza Strain	At Day 385	Seroconversion was defined as: for initially seronegative subjects, antibody titer ≥ 1:40 after vaccination; and for initially seropositive subjects, antibody titer after vaccination ≥ 4 fold the pre-vaccination antibody titer.
Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms in Children Aged Between 6 to 10 Years	During the 7-day follow-up period (Day 0 - Day 6) after each dose and across doses	Assessed solicited general symptoms were fatigue, gastrointestinal symptoms (gastro.sympt.), headache, joint pain at other location, muscle aches, shivering, sweating and temperature \[defined as axillary temperature equal to or above (≥) 38.0 degrees Celsius (°C)\]. Any = Incidence of a particular symptom regardless of intensity grade or relationship to study vaccination. Grade 3 = symptom which prevented normal everyday activity. Grade 3 temperature = fever ≥ 39.0 °C. Related = symptom assessed by the investigator as related to the vaccination.
Number of Subjects With Any Unsolicited Adverse Events (AEs)	From Day 0 to Day 42	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.
Titers for Serum Hemagglutination Inhibition (HI) Antibodies Against Flu A/CAL/7/09 (H1N1) Influenza Strain	At Days 0 and 385	Titers are presented as geometric mean titers (GMTs).
Number of Subjects Reporting at Least One A/California Influenza Event	From Day 0 until study conclusion on Day 385	The influenza virus presence was confirmed by quantitative reverse transcription polymerase chain reaction assay (RT-qPCR).
Number of Subjects Reporting Any Potential Immune-mediated Diseases (pIMDs)	Up to Day 385	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.
Number of Subjects With at Least One Pneumonia Event	From Day 0 after first vaccination until study conclusion at Day 385	Pneumonia was confirmed by quantitative reverse transcription polymerase chain reaction assay (RT-qPCR).
Number of Subjects With Protocol Specified ILI Symptoms in RT-qPCR-confirmed A/California Influenza Cases	From Day 14 until study end at Day 385	Protocol specified ILI symptoms were: fever, muscle aches all over the body, cough, sore throat, runny or stuffy nose, short of breath, headache, vomiting, diarrhea, chills and fatigue. Analysis for the time frame Day 42 till Day 385 was not performed as planned per protocol.
Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms in Children Aged 6 Months to Less Than 6 Years	During the 7-day follow-up period (Day 0 - Day 6) after each dose and across doses	Assessed solicited general symptoms were drowsiness, irritability, loss of appetite and temperature \[defined as axillary temperature equal to or above (≥) 38.0 degrees Celsius (°C)\]. Any = occurrence of the symptom regardless of intensity grade. Grade 3 drowsiness = drowsiness which prevented normal everyday activity. Grade 3 irritability = crying that could not be comforted/ prevented normal activity. Grade 3 loss of appetite = not eating at all. Grade 3 temperature = fever ≥ 39.0 °C. Related = symptom assessed by the investigator as related to the vaccination.
Number of Seropositive Subjects for Hemagglutination Inhibition (HI) Antibodies Against Flu A/CAL/7/09 (H1N1) Influenza Strain	At Days 0 and 385	A seropositive subject was defined as a subject whose HI titers was greater than or equal to (≥) 1:10.
Number of Seroprotected (SPR) Subjects Against Flu A/CAL/7/09 (H1N1) Influenza Strain	At Days 0 and 385	A seroprotected subject was defined as a vaccinated subject with serum Hemagglutination Inhibition (HI) titer ≥ 1:40.
Seroconversion Factor for Hemagglutination Inhibition (HI) Antibodies Against Flu A/CAL/7/09 (H1N1) Influenza Strain	At Day 385	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.
Number of Subjects With Any and Grade 3 Solicited Local Symptoms	During the 7-day follow-up period (Day 0 - Day 6) after each dose and across doses	Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = pain that prevented normal activity. Grade 3 redness/swelling = redness/swelling spreading beyond 100 millimeters (mm) of injection site.
Number of Subjects With Any Medically-attended Adverse Events (MAEs)	Up to Day 385	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.
Number of Subjects With Serious Adverse Events (SAEs)	Up to Day 385	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.
Geometric Mean Antibody Titer Ratio Adjusted for Baseline Titers for Serum Hemagglutination Inhibition (HI) Antibodies Against Flu A/CAL/7/09 (H1N1)	At Day 42	The geometric mean titer ratio (GMT ratio) was defined as the ratio of geometric mean of the post-vaccination reciprocal HI titer between groups. The analysis was not performed for Day 182 and Day 385 as planned per protocol.
Titers for Serum Hemagglutination Inhibition (HI) Antibodies Against Flu A/CAL/7/09 (H1N1)	At Days 0 and 182	Titers are presented as geometric mean titers (GMTs).