Clinical Study to Evaluate the Efficacy, Safety and Immunogenicity of QIVc in Subjects ≥2 to <18 Years of Age

Study Overview
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Brief Summary
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This Phase 3/4, randomized, observer-blind, multi-center study, stratified study evaluated the immune (antibody) response, efficacy and safety of a cell-derived quadrivalent subunit influenza virus vaccine (Seqirus QIVc) in comparison with a non-influenza comparator, meningococcal serogroup A, C, W-135, and Y (Menveo®, GlaxoSmithKline Biologicals, S.A.) in healthy pediatric subjects ≥2 Years to <18 Years of Age

Detailed Description
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This Phase 3/4, randomized, observer-blind, multi-center, stratified study evaluated the efficacy, safety, and immunogenicity of a cell-derived quadrivalent subunit influenza virus vaccine (Seqirus QIVc) compared to a non-influenza comparator vaccine in healthy male and female participants between 2 to <18 years of age. A total of 4514 children/teens were randomized, receiving either QIVc or the non-influenza comparator vaccine. The comparator was (meningococcal [Groups A, C, W-135, and Y] oligosaccharide diphtheria CRM197 conjugate vaccine [Men ACWY]). Randomized enrollment was stratified in a 1:1 ratio via an Interactive Response Technology (IRT) system which assigned the participants into two age cohorts: 2 to <9 years of age and 9 to <18 years of age. Subjects between 2 to <9 years of age were further stratified by previous influenza vaccine status (previously vaccinated or not previously vaccinated).

Official Title
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A Phase III/IV, Stratified, Randomized, Observer Blind, Multicenter Clinical Study to Evaluate the Efficacy, Safety and Immunogenicity of a Cell-Based Quadrivalent Subunit Influenza Virus Vaccine Compared to Non-Influenza Comparator Vaccine in Subjects ≥2 to <18 Years of Age

Conditions
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Influenza, Human

Intervention / Treatment
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* Biological: QIVc
* Biological: Non-influenza Comparator Vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ≥2 to <18 years of age on the day of the first study vaccination Subject's parent(s) or legal guardian(s) who was/were able to give informed consent/dissent after the nature of the study had been explained in accordance with the practices described in the study and according to local regulatory requirements If the subject was of an age where, according to local regulations, informed assent was required, he/she must have provided assent to participate in the study Subject/subject's parent(s) or legal guardian(s) was/were able to comply with study procedures and was/were available for follow-up; and Subject was in generally good health as per the investigator's medical judgment Exclusion Criteria: Clinical signs of fever and/or an oral temperature of ≥100.4°F (38.0°C) within 3 days prior to vaccination; A known history of any anaphylaxis, serious vaccine reactions or hypersensitivity to any of the vaccine components described in the Investigator's Brochure, or had any of the contraindications listed in the package insert of the comparator vaccine; A history of Guillain-Barré syndrome or other de-myelinating diseases such as encephalomyelitis and transverse myelitis; Female subject of childbearing potential (ie, post onset of menarche and before natural or induced menopause), sexually active, and who did not use any acceptable contraceptive methods for at least 2 months prior to study entry and who did not intend to use any acceptable contraceptive methods throughout subject participation (acceptable contraceptive methods included: abstinence; hormonal contraceptive [such as oral, injection, transdermal patch, implant]; diaphragm with spermicide; tubal occlusion device; intrauterine device [IUD]; tubal ligation; male partner using condom; or male partner having been vasectomized); Pregnant or breast feeding female; Subject and/or subject's parent/guardians who were not able to comprehend or follow all required study procedures for the entire period of the study; Received prior Meningococcal ACWY vaccination that conflicted with national recommendations or local practices for the timing of the primary or the booster vaccination; Received influenza vaccination or had documented influenza disease in the last 6 months; Known or suspected congenital or acquired immunodeficiency; or received immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, within the preceding 6 months; or systemic corticosteroid therapy (prednisone or equivalent) at any dose for more than 2 consecutive weeks (14 days) within the past 3 months. Topical, inhaled and intra-nasal corticosteroids were permitted. Intermittent use (1 dose in 30 days) of intra-articular corticosteroids was also permitted; Administration of immunoglobulin and/or any blood products within the 3 months preceding vaccination, or administration was planned during the study; Participated in any clinical study with another investigational product within 30 days prior to first study visit or intended to participate in another clinical study at any time during the conduct of this study. Concomitant participation in an observational study (not involving drugs, vaccines, or medical devices) was acceptable; Medical conditions or treatments contraindicating IM vaccination due to increased risk of bleeding. These included known bleeding disorders (such as thrombocytopenia), or treatment with anticoagulants (such as warfarin) in the 3 weeks preceding vaccination. Antiplatelet agents such as low-dose aspirin, ticlopidine (Ticlid) and clopidogrel (Plavix) were permitted; Evidence or history (within the previous 12 months) of drug or alcohol abuse; Study personnel or immediate family members (brother, sister, child, parent), the spouse of study personnel or individuals who were financially or emotionally dependent on study staff; Participated in this study in a prior season, if applicable; or Any clinical condition that, in the opinion of the investigator, may have interfered with the results of the study or pose additional risk to the subject due to participation in the study.

Ages Eligible for Study
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Minimum Age: 2 Years
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: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase 3/4
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: QIVc (≥2 years to <18 Years of Age)<br>Cell-derived Seasonal Quadrivalent Influenza Vaccine | Biological: QIVc<br>* Cell-derived Quadrivalent Influenza Vaccine for intramuscular use containing each of the 2 influenza type A strains and each of the 2 influenza type B strains<br>* Other names: Flucelvax Quadrivalent;|
| Active Comparator: Non-Influenza Comparator Vaccine<br>Non-Influenza Comparator Vaccine | Biological: Non-influenza Comparator Vaccine<br>* Non-influenza comparator vaccine for intramuscular use<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Efficacy: First Occurrence of Either RT-PCR- or Culture-confirmed Influenza (Time-to-event Analyses) Due to Any Influenza Type A or B Strain Regardless of Antigenic Match to the Strains Selected for the Seasonal Vaccine in Subjects ≥2 to <18 Years | The primary efficacy endpoint was defined as the time from the last study vaccination to the onset of the first occurrence of either RT-PCR- or culture-confirmed influenza (time-to-event analyses) due to any influenza Type A or B strain regardless of antigenic match to the strains selected for the seasonal vaccine, that occurred more than 14 days after the last vaccination until the end of the influenza season. Dataset Used: FAS-Efficacy = All subjects in the All Enrolled Set who received at least one dose of study vaccine and were evaluated for efficacy from 14 days after the last vaccination. The success criterion used for this primary objective was as follows: The efficacy of the QIVc was demonstrated if the lower limit (LL) of the 2-sided 95% confidence interval (CI) for VE was above 20%. | Day 14 to Day 180 or until the end of the influenza season, whichever is longer | 
| Co-Primary: First Occurrence of Either RT-PCR- or Culture-confirmed Influenza (Time-to-event Analyses) Due to Any Influenza Type A or B Strain Regardless of Antigenic Match to the Strains Selected for the Seasonal Vaccine in Subjects ≥3 to <18 Years | The co-primary efficacy endpoint: was defined as the time from the last study vaccination to the onset of the first occurrence of either RT-PCR- or culture-confirmed influenza (time-to-event analyses) due to any influenza Type A or B strain regardless of antigenic match to the strains selected for the seasonal vaccine, that occurred more than 14 days after the last vaccination until the end of the influenza season.Absolute vaccine efficacy of QIVc by first occurrence RT-PCR or culture confirmed influenza, due to any influenza Type A and B strain in subjects ≥3 years to <18 years of age | Day 14 to Day 180 or until the end of the influenza season, whichever is longer | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary Efficacy #1: First Occurrence of Either RT-PCR- or Culture-confirmed Influenza Due to Any Influenza Type A or B Strain Regardless of Antigenic Match to the Strains Selected for the Seasonal Vaccine | The endpoint was defined as the time from the last study vaccination to the onset of the first occurrence of either RT-PCR- or culture-confirmed influenza due to any influenza Type A or B strain regardless of antigenic match to the strains selected for the seasonal vaccine, that occurred more than 14 days after the last vaccination until the end of the influenza season in subjects 2 to <18 years, 2 to <9 years, 4 to <18 years, and 9 to <18 years. Dataset used: FAS Efficacy = All subjects in the All Enrolled Set who received at least one dose of study vaccine and were evaluated for efficacy from 14 days after the last vaccination. | Day 14 to Day 180 or until the end of the influenza season, whichever is longer. | 
| Secondary Efficacy #2: First Occurrence of RT-PCR-confirmed Influenza Due to Any Influenza Type A or B Strain Regardless of Antigenic Match to the Strains Selected for the Seasonal Vaccine | The endpoint was defined as the time from the last study vaccination to the onset of the first occurrence of RT-PCR-confirmed influenza due to any influenza Type A or B strain regardless of antigenic match to the strains selected for the seasonal vaccine, that occurred more than 14 days after the last vaccination until the end of the influenza season in subjects 2 to <18 years, 2 to <9 years, 4 to <18 years, and 9 to <18 years Dataset used: FAS Efficacy - All subjects in the All Enrolled Set who received at least one dose of study vaccine and were evaluated for efficacy from 14 days after the last vaccination. | Day 14 to Day 180 or until the end of the influenza season, whichever is longer. | 
| Secondary Efficacy #3: First Occurrence of Culture-confirmed Influenza Due to Any Influenza Type A or B Strain Regardless of Antigenic Match to the Strains Selected for the Seasonal Vaccine | The secondary endpoint was defined as the time from the last study vaccination to the onset of the first occurrence of culture-confirmed influenza due to any influenza Type A or B strain regardless of antigenic match to the strains selected for the seasonal vaccine, that occurred more than 14 days after the last vaccination until the end of the influenza season in subjects 2 to <18 years, 2 to <9 years, 4 to <18 years, and 9 to <18 years. Dataset used: FAS Efficacy | Day 14 to Day 180 or until the end of the influenza season, whichever is longer. | 
| Secondary Efficacy #4: First Occurrence of Culture-confirmed Influenza Due to Influenza Type A or B Strain Antigenically Matched to the Strains Selected for the Seasonal Vaccine | The endpoint was defined as the time from the last study vaccination to the onset of the first occurrence of culture-confirmed influenza due to influenza Type A or B strain antigenically matched to the strains selected for the seasonal vaccine, that occurred more than 14 days after the last vaccination until the end of the influenza season in subjects 2 to <18 years, 2 to <9 years, 4 to <18 years, and 9 to <18 years. | Day 14 to Day 180 or until the end of the influenza season, whichever is longer. | 
| Secondary Immunogenicity: Geometric Mean Titers for 4 Influenza Strains (HI Assay) | Immunogenicity was characterized by HI assay 3 weeks after the last vaccination in a subset of subjects 2 to <9 years of age enrolled in Season 2 (n=432) and Season 3 (n=319) who were immunized and had immunogenicity data at the assessed timepoints (FAS Immunogenicity). Immunogenicity was assessed at baseline (Day 1; all subjects in immunogenicity subset), at Day 22 (all previously vaccinated subjects receiving a single dose of the study vaccine), and at Days 29 and 50 (all not previously vaccinated subjects receiving 2 doses) for all 4 influenza strains using the HI assay. | Day 1 (all subjects), Day 22 (all previously vaccinated subjects) or Day 29 and Day 50 (all not previously vaccinated subjects receiving 2 doses) | 
| ISecondary Immunogenicity: Percentage of Subjects Achieving Seroconversion for 4 Influenza Strains (HI Assay) | Immunogenicity was characterized by HI assay 3 weeks after the last vaccination in a subset of subjects 2 to <9 years of age enrolled in Season 2 (n=432) and Season 3 (n=319) who were immunized and had immunogenicity data at the assessed timepoints (FAS Immunogenicity). Immunogenicity was assessed at baseline (Day 1; all subjects in immunogenicity subset), at Day 22 (all previously vaccinated subjects receiving a single dose of the study vaccine), and at Days 29 and 50 (all not previously vaccinated subjects receiving 2 doses) for all 4 influenza strains using the HI assay. Seroconversion was defined as: either a prevaccination HI titer <1:10 and a postvaccination HI titer ≥1:40 or a prevaccination HI titer ≥1:10 and a ≥4 fold increase in postvaccination HI titer) Dataset used: FAS Immunogenicity = All subjects in the All Enrolled Set who received at least one dose of study vaccine and provided evaluable serum samples at both baseline and after the last vaccination. | Day 22 (all previously vaccinated subjects) or Day 29 and Day 50 (all not previously vaccinated subjects) | 
| Secondary Immunogenicity: Geometric Mean Ratio for 4 Influenza Strains (HI Assay) | Immunogenicity was characterized by HI assay 3 weeks after the last vaccination in a subset of subjects 2 to <9 years of age enrolled in Season 2 (n=432) and Season 3 (n=319) who were immunized and had immunogenicity data at the assessed timepoints (FAS Immunogenicity). Immunogenicity was assessed at baseline (Day 1; all subjects in immunogenicity subset), at Day 22 (all previously vaccinated subjects receiving a single dose of the study vaccine), and at Days 29 and 50 (all not previously vaccinated subjects receiving 2 doses) for all 4 influenza strains using the HI assay. Geometric mean ratios (GMRs) measure the ratio in immunogenicity titers within subject\ Dataset used: FAS Immunogenicity = All subjects in the All Enrolled Set who received at least one dose of study vaccine and provided evaluable serum samples at both baseline and after the last vaccination. | Day 22/Day 1 (all previously vaccinated subjects) or Day 29/Day 1 and Day 50/Day 1 (all not previously vaccinated subjects receiving 2 doses) | 
| Secondary Immunogenicity: Percentage of Subjects With HI Titer ≥1:40 for All 4 Influenza Strains (HI Assay) | Immunogenicity was characterized by HI assay 3 weeks after the last vaccination in a subset of subjects 2 to <9 years of age enrolled in Season 2 (n=432) and Season 3 (n=319) who were immunized and had immunogenicity data at the assessed timepoints (FAS Immunogenicity). Immunogenicity was assessed at baseline (Day 1; all subjects in immunogenicity subset), at Day 22 (all previously vaccinated subjects receiving a single dose of the study vaccine), and at Days 29 and 50 (all not previously vaccinated subjects receiving 2 doses) for all 4 influenza strains using the HI assay. The measures for assessing immunogenicity as determined by HI were as follows: Percentage of subjects with an HI titer ≥1:40 on Day 22 (all previously vaccinated subjects receiving a single vaccine dose) or Days 29 and 50 (all not previously vaccinated subjects receiving 2 doses) for all 4 influenza strains | Day 1 (all subjects), Day 22 (all previously vaccinated subjects receiving a single vaccine dose) or Days 29 and 50 (all not previously vaccinatedsubjects receiving 2 doses) | 
| Safety: Percentage of Subjects With Solicited Local and Systemic Adverse Events for 7 Days After Vaccination | The measures for assessing safety and tolerability were as follows: Percentage of subjects with solicited local and systemic adverse events (AEs) for 7 days after vaccination on Day 1 (for previously vaccinated subjects) or for 7 days after vaccination on Day 1 and Day 29 (for not previously vaccinated subjects) in the QIVc group and the non-influenza comparator vaccine group. Dataset used: Solicited Safety Set | days after vaccination on Day 1 (for previously vaccinated subjects) or for 7 days after vaccination on Day 1 and Day 29 (for not previously vaccinated subjects) | 
| Safety: Percentage of Subjects With Unsolicited AEs for 21 Days After Vaccination | The measures for assessing safety and tolerability were as follows: Percentage of subjects with unsolicited AEs assessed from Day 1 to Day 22 (for previously vaccinated subjects) or from Day 1 to Day 50 (for not previously vaccinated subjects) in the QIVc group and the non-influenza comparator vaccine group. Dataset used: Unsolicited Safety Set (Unsolicited Adverse Events) | Day 1 to Day 22 (for previously vaccinated subjects) or Day 1 to Day 50 (for not previously vaccinated subjects) | 
| Safety: Subjects With SAEs, AEs Leading to Withdrawal From Vaccination and/or the Study,(MAAEs) Within 30 Days of a 1st Occurrence, Post-ILI, and NOCDs Reported During Entire Study Participation or End of Flue Season, Whichever Was Longer | The measures for assessing safety and tolerability were as follows: Percentage of subjects with SAEs, AEs leading to withdrawal from vaccination and/or the study, Medically-Attended AEs (MAAEs) within 30 days after the first occurrence of an ILI, and New Onset of Chronic Diseases (NOCDs) reported during the subject's entire participation in the study (ie, from Day 1 to Day 181 [for previously vaccinated subjects] or from Day 1 to Day 209 [for not previously vaccinated subjects]), or until the end of influenza season, whichever was longer, and all medications associated with these events. Dataset used: Overall Safety Set | Day 1 to Day 181 (for previously vaccinated subjects) or to Day 209 (for not previously vaccinated subjects) | 

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