Clinical Trial Results:
Randomized, Double-Blind and Active-Controlled Study in Children and Adolescents Aged 3–17 Years to Assess the Safety and Immunogenicity of Abbott’s Candidate Quadrivalent Influenza Vaccine and its Non-Inferiority versus Trivalent Influenza Vaccine
Summary
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EudraCT number |
2015-005482-23 |
Trial protocol |
DE FI EE HU LT |
Global end of trial date |
14 Apr 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
28 Oct 2017
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First version publication date |
28 Oct 2017
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
INFQ3002
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Abbott Biologicals B.V.
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Sponsor organisation address |
C.J. van Houtenlaan 36, Weesp, Netherlands, NL-1381 CP
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Public contact |
Public Affairs Manager, Abbott Products Operations AG, hind.ounis@abbott.com
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Scientific contact |
Global Clinical Director, Abbott Healthcare Products B.V., serge.vandewitte@abbott.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001782-PIP01-15 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
14 Apr 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
14 Apr 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
14 Apr 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To demonstrate in a population of children and adolescents 3 to 17 years of age the non-inferiority of quadrivalent influenza vaccine (QIV) with respect to post-vaccination geometric mean Hemagglutination Inhibition (HI) antibody titers against the shared strains compared with the trivalent influenza vaccines (TIV) with either the B-strain of the Victoria lineage (TIV[Vic]) or the B-strain of the Yamagata lineage (TIV[Yam]).
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Protection of trial subjects |
The study was conducted in compliance with Good Clinical Practice and the applicable national regulations so as to ensure that the rights, safety, and well-being of the participating study subjects were protected consistent with the ethical principles that have their origin in the Declaration of Helsinki.
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Background therapy |
Children and adolescents aged ≥ 9 years were considered primed subjects as well as those aged < 9 years who had received ≥ two doses of a seasonal influenza vaccine at least one month apart; children aged < 9 years who had not previously received ≥ two doses of a seasonal influenza vaccine at least one month apart were considered unprimed. Primed subjects were required to attend two clinic visits, while unprimed subjects were required to attend three clinical visits. | ||
Evidence for comparator |
The candidate vaccine in this study, QIV, was compared against TIV(Vic) and TIV(Yam). For all vaccines, the active drug substance consisted of approximately 15 micrograms (μg) of hemagglutinin (HA) antigen of each of the three or four viral strains recommended by the World Health Organization and Committee for Medicinal Products for Human Use for the strains recommended for the northern hemisphere 2016/2017 season. These comprised: • an A/California/7/2009 (H1N1)pdm09-like virus; referred to as the A(H1N1) strain. • an A/Hong Kong/4801/2014 (H3N2)-like virus; referred to as the A(H3N2) strain. • a B/Brisbane/60/2008-like virus; referred to as the B-Victoria strain. • a B/Phuket/3073/2013-like virus; referred to as the B-Yamagata strain. The B/Brisbane/60/2008-like virus (TIV[Vic]) was the recommended B-strain for the marketed TIV formulation (Influvac®). | ||
Actual start date of recruitment |
02 Sep 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Poland: 229
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Country: Number of subjects enrolled |
Estonia: 127
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Country: Number of subjects enrolled |
Finland: 450
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Country: Number of subjects enrolled |
Germany: 80
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Country: Number of subjects enrolled |
Hungary: 184
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Country: Number of subjects enrolled |
Lithuania: 130
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Worldwide total number of subjects |
1200
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EEA total number of subjects |
1200
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
978
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Adolescents (12-17 years) |
222
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Twenty eight study centres in six countries (Estonia, Finland, Germany, Hungary, Lithuania, and Poland) screened and enrolled subjects. The first subject entered the study on 02 September 2016 and the last subject completed the last visit on 14 April 2017. | ||||||||||||||||||||||||
Pre-assignment
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Screening details |
A total of 1,223 subjects provided informed consent and were screened for eligibility. Of these, 23 subjects failed screening and 1,200 subjects were vaccinated. Allocation was stratified 2:1 by age group: 3 to 8 years and 9 to 17 years, and in both age groups, subjects were randomly assigned to receive QIV, TIV(Vic) and TIV(Yam) in a 1:1:1 ratio. | ||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | ||||||||||||||||||||||||
Blinding implementation details |
All syringes were identical in appearance and packaged in the correct proportions to ensure desired dosages were used and that blinding was maintained.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Quadrivalent Influenza Vaccine | ||||||||||||||||||||||||
Arm description |
Primed subjects received a single dose of QIV on Day 1 and unprimed subjects received two doses of QIV (Day 1 and Day 29). Each dose contained approximately 15 μg HA antigen per virus strain, given intramuscularly in the deltoid muscle of the upper arm. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Quadrivalent Influenza Vaccine
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Investigational medicinal product code |
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Other name |
QIV, Influvac® Tetra
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Pharmaceutical forms |
Suspension for injection in pre-filled syringe
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Routes of administration |
Intramuscular use
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Dosage and administration details |
Primed subjects: single dose of 0.5 milliliters (mL) QIV administered by intramuscular injection on Day 1 (Visit 1).
Unprimed subjects: two single doses of 0.5 mL of QIV administered by intramuscular injection on Day 1 (Visit 1) and on Day 29 (Visit 2).
The HA content of the QIV batch was as follows:
• A/California/7/2009 (H1N1)pdm09-like strain (A/California/7/2009, X-181) (14.4 µg HA/dose).
• A/Hong Kong/4801/2014 (H3N2)-like strain (A/Hong Kong/4801/2014, X-263B) (18.6 µg HA/dose).
• B/Brisbane/60/2008-like strain (B/Brisbane/60/2008, wild type) (16.2 µg HA/dose).
• B/Phuket/3073/2013-like strain (B/Phuket/3073/2013, wild type) (17.5 µg HA/dose).
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Arm title
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Trivalent Influenza Vaccine (Victoria) | ||||||||||||||||||||||||
Arm description |
Primed subjects received a single dose of TIV(Vic) on Day 1 and unprimed subjects received two doses of TIV(Vic) (Day 1 and Day 29). Each dose contained approximately 15 μg HA antigen per virus strain, given intramuscularly in the deltoid muscle of the upper arm. | ||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||
Investigational medicinal product name |
Trivalent Influenza Vaccine (Victoria)
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Investigational medicinal product code |
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Other name |
TIV(Vic), Influvac®
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Pharmaceutical forms |
Suspension for injection in pre-filled syringe
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Routes of administration |
Intramuscular use
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Dosage and administration details |
Primed subjects: single dose of 0.5 mL TIV(Vic) administered by intramuscular injection on Day 1 (Visit 1).
Unprimed subjects: two single doses of 0.5 mL of TIV(Vic) administered by intramuscular injection on Day 1 (Visit 1) and on Day 29 (Visit 2).
The HA content of the TIV(Vic) batch was as follows:
• A/California/7/2009 (H1N1)pdm09-like strain (A/California/7/2009, X-181) (14.7 µg HA/dose).
• A/Hong Kong/4801/2014 (H3N2)-like strain (A/Hong Kong/4801/2014, X-263B) (18.8 µg HA/dose).
• B/Brisbane/60/2008-like strain (B/Brisbane/60/2008, wild type) (15.6 µg HA/dose).
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Arm title
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Trivalent Influenza Vaccine (Yamagata) | ||||||||||||||||||||||||
Arm description |
Primed subjects received a single dose of TIV(Yam) on Day 1 and unprimed subjects received two doses of TIV(Yam) (Day 1 and Day 29). Each dose contained approximately 15 μg HA antigen per virus strain, given intramuscularly in the deltoid muscle of the upper arm. | ||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||
Investigational medicinal product name |
Trivalent Influenza Vaccine (Yamagata)
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Investigational medicinal product code |
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Other name |
TIV(Yam)
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Pharmaceutical forms |
Suspension for injection in pre-filled syringe
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Routes of administration |
Intramuscular use
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Dosage and administration details |
Primed subjects: single dose of 0.5 mL TIV(Yam) administered by intramuscular injection on Day 1 (Visit 1).
Unprimed subjects: two single doses of 0.5 mL of TIV(Yam) administered by intramuscular injection on Day 1 (Visit 1) and on Day 29 (Visit 2).
The HA content of the TIV(Yam) batch was as follows:
• A/California/7/2009 (H1N1)pdm09-like strain (A/California/7/2009, X-181) (15.2 µg HA/dose).
• A/Hong Kong/4801/2014 (H3N2)-like strain (A/Hong Kong/4801/2014, X-263B) (20.0 µg HA/dose).
• B/Phuket/3073/2013-like strain (B/Phuket/3073/2013, wild type) (16.1 µg HA/dose).
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Baseline characteristics reporting groups
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Reporting group title |
Quadrivalent Influenza Vaccine
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Reporting group description |
Primed subjects received a single dose of QIV on Day 1 and unprimed subjects received two doses of QIV (Day 1 and Day 29). Each dose contained approximately 15 μg HA antigen per virus strain, given intramuscularly in the deltoid muscle of the upper arm. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Trivalent Influenza Vaccine (Victoria)
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Reporting group description |
Primed subjects received a single dose of TIV(Vic) on Day 1 and unprimed subjects received two doses of TIV(Vic) (Day 1 and Day 29). Each dose contained approximately 15 μg HA antigen per virus strain, given intramuscularly in the deltoid muscle of the upper arm. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Trivalent Influenza Vaccine (Yamagata)
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Reporting group description |
Primed subjects received a single dose of TIV(Yam) on Day 1 and unprimed subjects received two doses of TIV(Yam) (Day 1 and Day 29). Each dose contained approximately 15 μg HA antigen per virus strain, given intramuscularly in the deltoid muscle of the upper arm. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Quadrivalent Influenza Vaccine
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Reporting group description |
Primed subjects received a single dose of QIV on Day 1 and unprimed subjects received two doses of QIV (Day 1 and Day 29). Each dose contained approximately 15 μg HA antigen per virus strain, given intramuscularly in the deltoid muscle of the upper arm. | ||
Reporting group title |
Trivalent Influenza Vaccine (Victoria)
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Reporting group description |
Primed subjects received a single dose of TIV(Vic) on Day 1 and unprimed subjects received two doses of TIV(Vic) (Day 1 and Day 29). Each dose contained approximately 15 μg HA antigen per virus strain, given intramuscularly in the deltoid muscle of the upper arm. | ||
Reporting group title |
Trivalent Influenza Vaccine (Yamagata)
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Reporting group description |
Primed subjects received a single dose of TIV(Yam) on Day 1 and unprimed subjects received two doses of TIV(Yam) (Day 1 and Day 29). Each dose contained approximately 15 μg HA antigen per virus strain, given intramuscularly in the deltoid muscle of the upper arm. | ||
Subject analysis set title |
Trivalent Influenza Vaccine (Pooled)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Primed subjects received a single dose of TIV on Day 1 and unprimed subjects received two doses of TIV (Day 1 and Day 29). Each dose contained approximately 15 μg HA antigen per virus strain, given intramuscularly in the deltoid muscle of the upper arm. For each A strain, the HI, VN and NI titer data of the two trivalent formulations, TIV(Vic) and TIV(Yam), were pooled. Reactogenicity data of the two trivalent formulations was also pooled.
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End point title |
Post-vaccination geometric HI antibody titers against A(H1N1) strain [1] | ||||||||||||
End point description |
Non-inferiority of QIV was assessed with respect to post-vaccination geometric mean HI antibody titers against the shared strains compared with TIV(Vic) and TIV(Yam) groups; results are reported for HI titers against the A(H1N1) strain. Population for analysis was the per-protocol sample, defined through blind data review and comprised of all subjects who were included in the full analysis sample and did not present any major protocol violations.
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End point type |
Primary
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End point timeframe |
The HI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
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Notes [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: For each A strain, the HI titer data of the two trivalent formulations, TIV(Vic) and TIV(Yam), were pooled. |
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Statistical analysis title |
A(H1N1) strain non-inferiority analysis | ||||||||||||
Statistical analysis description |
Non-inferiority was analyzed by calculating for each of the two A-strains and each of the two B-strains a two-sided 95% confidence interval (CI) for adjusted geometric mean ratios (GMRs) for the TIV versus QIV comparison, using an analysis of variance (ANOVA) model for the log transformed titers at Day 29/Day 57 with age group, center and priming status included as covariates in the model.
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Comparison groups |
Quadrivalent Influenza Vaccine v Trivalent Influenza Vaccine (Pooled)
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Number of subjects included in analysis |
1162
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [2] | ||||||||||||
Method |
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Parameter type |
Adjusted GMR | ||||||||||||
Point estimate |
1.1
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.98 | ||||||||||||
upper limit |
1.3 | ||||||||||||
Notes [2] - The non-inferiority margin was set at 1.5. Non-inferiority of QIV to TIV would be concluded if, for all four strains, the upper limit of the 95% CI fell below 1.5. |
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End point title |
Post-vaccination geometric HI antibody titers against A(H3N2) strain [3] | ||||||||||||
End point description |
Non-inferiority of QIV was assessed with respect to post-vaccination geometric mean HI antibody titers against the shared strains compared with TIV(Vic) and TIV(Yam) groups; results are reported for HI titers against the A(H3N2) strain. Population for analysis was the per-protocol sample, defined through blind data review and comprised of all subjects who were included in the full analysis sample and did not present any major protocol violations.
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End point type |
Primary
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End point timeframe |
The HI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
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Notes [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: For each A strain, the HI titer data of the two trivalent formulations, TIV(Vic) and TIV(Yam), were pooled. |
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Statistical analysis title |
A(H3N2) strain non-inferiority analysis | ||||||||||||
Statistical analysis description |
Non-inferiority was analyzed by calculating for each of the two A-strains and each of the two B-strains a two-sided 95% CI for adjusted GMRs for the TIV versus QIV comparison, using an ANOVA model for the log transformed titers at Day 29/Day 57 with age group, center and priming status included as covariates in the model.
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Comparison groups |
Quadrivalent Influenza Vaccine v Trivalent Influenza Vaccine (Pooled)
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Number of subjects included in analysis |
1162
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [4] | ||||||||||||
Method |
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Parameter type |
Adjusted GMR | ||||||||||||
Point estimate |
1
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.9 | ||||||||||||
upper limit |
1.19 | ||||||||||||
Notes [4] - The non-inferiority margin was set at 1.5. Non-inferiority of QIV to TIV would be concluded if, for all four strains, the upper limit of the 95% CI fell below 1.5. |
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End point title |
Post-vaccination geometric HI antibody titers against B-Victoria strain | ||||||||||||||||
End point description |
Non-inferiority of QIV was assessed with respect to post-vaccination geometric mean HI antibody titers against the shared strains compared with TIV(Vic) and TIV(Yam) groups; results are reported for HI titers against the B-Victoria strain. Population for analysis was the per-protocol sample, defined through blind data review and comprised of all subjects who were included in the full analysis sample and did not present any major protocol violations.
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End point type |
Primary
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End point timeframe |
The HI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
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Statistical analysis title |
B-Victoria strain non-inferiority analysis | ||||||||||||||||
Statistical analysis description |
Non-inferiority was analyzed by calculating for each of the two A-strains and each of the two B-strains a two-sided 95% CI for adjusted GMRs for the TIV versus QIV comparison, using an ANOVA model for the log transformed titers at Day 29/Day 57 with age group, center and priming status included as covariates in the model.
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Comparison groups |
Quadrivalent Influenza Vaccine v Trivalent Influenza Vaccine (Victoria)
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Number of subjects included in analysis |
781
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [5] | ||||||||||||||||
Method |
ANOVA | ||||||||||||||||
Parameter type |
Adjusted GMR | ||||||||||||||||
Point estimate |
1.2
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
0.98 | ||||||||||||||||
upper limit |
1.46 | ||||||||||||||||
Notes [5] - The non-inferiority margin was set at 1.5. Non-inferiority of QIV to TIV would be concluded if, for all four strains, the upper limit of the 95% CI fell below 1.5. |
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End point title |
Post-vaccination geometric HI antibody titers against B-Yamagata strain | ||||||||||||||||
End point description |
Non-inferiority of QIV was assessed with respect to post-vaccination geometric mean HI antibody titers against the shared strains compared with TIV(Vic) and TIV(Yam) groups; results are reported for HI titers against the B-Yamagata strain. Population for analysis was the per-protocol sample, defined through blind data review and comprised of all subjects who were included in the full analysis sample and did not present any major protocol violations.
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End point type |
Primary
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End point timeframe |
The HI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
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Statistical analysis title |
B-Yamagata strain non-inferiority analysis | ||||||||||||||||
Statistical analysis description |
Non-inferiority was analyzed by calculating for each of the two A-strains and each of the two B-strains a two-sided 95% CI for adjusted GMRs for the TIV versus QIV comparison, using an ANOVA model for the log transformed titers at Day 29/Day 57 with age group, center and priming status included as covariates in the model.
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Comparison groups |
Quadrivalent Influenza Vaccine v Trivalent Influenza Vaccine (Yamagata)
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Number of subjects included in analysis |
769
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [6] | ||||||||||||||||
Method |
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Parameter type |
Adjusted GMR | ||||||||||||||||
Point estimate |
1
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
0.81 | ||||||||||||||||
upper limit |
1.19 | ||||||||||||||||
Notes [6] - The non-inferiority margin was set at 1.5. Non-inferiority of QIV to TIV would be concluded if, for all four strains, the upper limit of the 95% CI fell below 1.5. |
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End point title |
Post-vaccination geometric HI antibody titers against the alternate lineage B-strain (Victoria lineage) | ||||||||||||||||
End point description |
Superiority of QIV to TIV(Vic) and TIV(Yam) was assessed with respect to post-vaccination geometric HI antibody titers against the alternate lineage B-strain; results are reported for HI titers against the B-Victoria strain. Population for analysis was the full analysis sample and comprised of all subjects who were included in the safety sample and had post-vaccination primary efficacy data (i.e., HI titers).
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
The HI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
B-Victoria strain superiority analysis | ||||||||||||||||
Statistical analysis description |
Superiority was analyzed by calculating for each of the two A-strains and each of the two B-strains a two-sided 95% CI for adjusted GMRs for the TIV versus QIV comparison, using an ANOVA model for the log transformed titers at Day 29/Day 57 with age group, center and priming status included as covariates in the model.
|
||||||||||||||||
Comparison groups |
Trivalent Influenza Vaccine (Yamagata) v Quadrivalent Influenza Vaccine
|
||||||||||||||||
Number of subjects included in analysis |
785
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [7] | ||||||||||||||||
P-value |
< 0.0001 | ||||||||||||||||
Method |
ANOVA | ||||||||||||||||
Parameter type |
Adjusted GMR | ||||||||||||||||
Point estimate |
2.9
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
2.36 | ||||||||||||||||
upper limit |
3.64 | ||||||||||||||||
Notes [7] - Superiority of QIV to TIV against the alternate lineage B-strains would be concluded if for both strains: GMR > 1 and p-value <0.05. |
|
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End point title |
Post-vaccination geometric HI antibody titers against the alternate lineage B-strain (Yamagata lineage) | ||||||||||||||||
End point description |
Superiority of QIV to TIV(Vic) and TIV(Yam) was assessed with respect to post-vaccination geometric HI antibody titers against the alternate lineage B-strain; results are reported for HI titers against the B-Yamagata strain. Population for analysis was the full analysis sample and comprised of all subjects who were included in the safety sample and had post-vaccination primary efficacy data (i.e., HI titers).
|
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End point type |
Secondary
|
||||||||||||||||
End point timeframe |
The HI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
B-Yamagata strain superiority analysis | ||||||||||||||||
Statistical analysis description |
Superiority was analyzed by calculating for each of the two A-strains and each of the two B-strains a two-sided 95% CI for adjusted GMRs for the TIV versus QIV comparison, using an ANOVA model for the log transformed titers at Day 29/Day 57 with age group, center and priming status included as covariates in the model.
|
||||||||||||||||
Comparison groups |
Quadrivalent Influenza Vaccine v Trivalent Influenza Vaccine (Victoria)
|
||||||||||||||||
Number of subjects included in analysis |
795
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [8] | ||||||||||||||||
P-value |
< 0.0001 | ||||||||||||||||
Method |
ANOVA | ||||||||||||||||
Parameter type |
Adjusted GMR | ||||||||||||||||
Point estimate |
7.3
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
5.83 | ||||||||||||||||
upper limit |
9.03 | ||||||||||||||||
Notes [8] - Superiority of QIV to TIV against the alternate lineage B-strains would be concluded if for both strains: GMR > 1 and p-value <0.05. |
|
||||||||||||||||||||||
End point title |
Post-vaccination geometric mean fold increases in HI, Virus Neutralization (VN) and Neuraminidase Inhibition (NI) antibody titers against A(H1N1) strain [9] | |||||||||||||||||||||
End point description |
Characterization of the immunogenicity of each of the strains in QIV and TIV was assessed by deriving the geometric mean fold increase with respect to HI, VN and NI antibody titers; results are reported for antibody titers against the A(H1N1) strain. Population for analysis was the full analysis sample and comprised of all subjects who were included in the safety sample and had post-vaccination primary efficacy data (i.e., HI titers). Note: VN and NI titers were assessed only for a random subset of subjects (comprising of approximately 15% of the overall randomized population). n = Number of subjects with non-missing data.
|
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End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
The HI, VN and NI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
|
|||||||||||||||||||||
Notes [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: For each A strain, the HI, VN and NI titer data of the two trivalent formulations, TIV(Vic) and TIV(Yam), were pooled. |
||||||||||||||||||||||
|
||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||
End point title |
Post-vaccination geometric mean fold increases in HI, VN and NI antibody titers against A(H3N2) strain [10] | |||||||||||||||||||||
End point description |
Characterization of the immunogenicity of each of the strains in QIV and TIV was assessed by deriving the geometric mean fold increase with respect to HI, VN and NI antibody titers; results are reported for antibody titers against the A(H3N2) strain. Population for analysis was the full analysis sample and comprised of all subjects who were included in the safety sample and had post-vaccination primary efficacy data (i.e., HI titers). Note: VN and NI titers were assessed only for a random subset of subjects (comprising of approximately 15% of the overall randomized population). n = Number of subjects with non-missing data.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
The HI, VN and NI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
|
|||||||||||||||||||||
Notes [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: For each A strain, the HI, VN and NI titer data of the two trivalent formulations, TIV(Vic) and TIV(Yam), were pooled. |
||||||||||||||||||||||
|
||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||
End point title |
Post-vaccination geometric mean fold increases in HI, VN and NI antibody titers against B-Victoria strain | ||||||||||||||||||||||||||||
End point description |
Characterization of the immunogenicity of each of the strains in QIV and TIV was assessed by deriving the geometric mean fold increase with respect to HI, VN and NI antibody titers; results are reported for antibody titers against the B-Victoria strain. Population for analysis was the full analysis sample and comprised of all subjects who were included in the safety sample and had post-vaccination primary efficacy data (i.e., HI titers). Note: VN and NI titers were assessed only for a random subset of subjects (comprising of approximately 15% of the overall randomized population). n = Number of subjects with non-missing data.
|
||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||
End point timeframe |
The HI, VN and NI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
|
||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||
End point title |
Post-vaccination geometric mean fold increases in HI, VN and NI antibody titers against B-Yamagata strain | ||||||||||||||||||||||||||||
End point description |
Characterization of the immunogenicity of each of the strains in QIV and TIV was assessed by deriving the geometric mean fold increase with respect to HI, VN and NI antibody titers; results are reported for antibody titers against the B-Yamagata strain. Population for analysis was the full analysis sample and comprised of all subjects who were included in the safety sample and had post-vaccination primary efficacy data (i.e., HI titers). Note: VN and NI titers were assessed only for a random subset of subjects (comprising of approximately 15% of the overall randomized population). n = Number of subjects with non-missing data.
|
||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||
End point timeframe |
The HI, VN and NI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
|
||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||
End point title |
Seroconversion rates based on HI, VN and NI antibody titers against A(H1N1) strain [11] | |||||||||||||||||||||
End point description |
Characterization of the immunogenicity of each of the strains in QIV and TIV was assessed by deriving the seroconversion rates with respect to HI, VN and NI antibody titers. Seroconversion (defined as becoming seropositive if seronegative at enrollment, or [at least] a 4-fold rise in titer if seropositive at enrollment) rates are presented as percentage of subjects and are reported for antibody titers against the A(H1N1) strain. Population for analysis was the full analysis sample and comprised of all subjects who were included in the safety sample and had post-vaccination primary efficacy data (i.e., HI titers). Note: VN and NI titers were assessed only for a random subset of subjects (comprising of approximately 15% of the overall randomized population). n = Number of subjects with non-missing data.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
The HI, VN and NI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
|
|||||||||||||||||||||
Notes [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: For each A strain, the HI, VN and NI titer data of the two trivalent formulations, TIV(Vic) and TIV(Yam), were pooled. |
||||||||||||||||||||||
|
||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||
End point title |
Seroconversion rates based on HI, VN and NI antibody titers against A(H3N2) strain [12] | |||||||||||||||||||||
End point description |
Characterization of the immunogenicity of each of the strains in QIV and TIV was assessed by deriving the seroconversion rates with respect to HI, VN and NI antibody titers. Seroconversion (defined as becoming seropositive if seronegative at enrollment, or [at least] a 4-fold rise in titer if seropositive at enrollment) rates are presented as percentage of subjects and are reported for antibody titers against the A(H3N2) strain. Population for analysis was the full analysis sample and comprised of all subjects who were included in the safety sample and had post-vaccination primary efficacy data (i.e., HI titers). Note: VN and NI titers were assessed only for a random subset of subjects (comprising of approximately 15% of the overall randomized population). n = Number of subjects with non-missing data.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
The HI, VN and NI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
|
|||||||||||||||||||||
Notes [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: For each A strain, the HI, VN and NI titer data of the two trivalent formulations, TIV(Vic) and TIV(Yam), were pooled. |
||||||||||||||||||||||
|
||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||
End point title |
Seroconversion rates based on HI, VN and NI antibody titers against B-Victoria strain | ||||||||||||||||||||||||||||
End point description |
Characterization of the immunogenicity of each of the strains in QIV and TIV was assessed by deriving the seroconversion rates with respect to HI, VN and NI antibody titers. Seroconversion (defined as becoming seropositive if seronegative at enrollment, or [at least] a 4-fold rise in titer if seropositive at enrollment) rates are presented as percentage of subjects and are reported for antibody titers against the B-Victoria strain. Population for analysis was the full analysis sample and comprised of all subjects who were included in the safety sample and had post-vaccination primary efficacy data (i.e., HI titers). Note: VN and NI titers were assessed only for a random subset of subjects (comprising of approximately 15% of the overall randomized population). n = Number of subjects with non-missing data.
|
||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||
End point timeframe |
The HI, VN and NI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
|
||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||
End point title |
Seroconversion rates based on HI, VN and NI antibody titers against B-Yamagata strain | ||||||||||||||||||||||||||||
End point description |
Characterization of the immunogenicity of each of the strains in QIV and TIV was assessed by deriving the seroconversion rates with respect to HI, VN and NI antibody titers. Seroconversion (defined as becoming seropositive if seronegative at enrollment, or [at least] a 4-fold rise in titer if seropositive at enrollment) rates are presented as percentage of subjects and are reported for antibody titers against the B-Yamagata strain. Population for analysis was the full analysis sample and comprised of all subjects who were included in the safety sample and had post-vaccination primary efficacy data (i.e., HI titers). Note: VN and NI titers were assessed only for a random subset of subjects (comprising of approximately 15% of the overall randomized population). n = Number of subjects with non-missing data.
|
||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||
End point timeframe |
The HI, VN and NI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
|
||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Proportion (percentage) of subjects with solicited systemic reactions [13] | |||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
A subject diary was used to record pre-specified systemic reactions occurring during the first 7 days after vaccination (solicited reactogenicity). Population for analysis was the safety sample and comprised of all subjects who were vaccinated and had at least one post-vaccination safety observation. Solicited systemic reactions were assessed only in children aged 3-5 years for the following categories: Irritability/fussiness, Drowsiness, Diarrhea/vomiting, and Loss of appetite; and only in children aged 6-17 years for: Headache, Fatigue/tiredness, Gastrointestinal symptoms, Myalgia/muscle pain, Arthralgia/joint pain, Malaise, and Shivering; Fever and Sweating were assessed for both age groups. Note: n = Number of subjects with non-missing data.
|
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End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Solicited events were recorded during the first 7 days after vaccination (up to Day 7).
|
|||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The reactogenicity data of the two trivalent formulations, TIV(Vic) and TIV(Yam), were pooled. |
||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||
End point title |
Proportion (percentage) of subjects with solicited local reactions [14] | |||||||||||||||||||||||||||
End point description |
A subject diary was used to record pre-specified injection site (local) reactions occurring during the first 7 days after vaccination (solicited reactogenicity).Population for analysis was the safety sample and comprised of all subjects who were vaccinated and had at least one post-vaccination safety observation. Note: n = Number of subjects with non-missing data.
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
Solicited events were recorded during the first 7 days after vaccination (up to Day 7).
|
|||||||||||||||||||||||||||
Notes [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The reactogenicity data of the two trivalent formulations, TIV(Vic) and TIV(Yam), were pooled. |
||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
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Adverse events information
|
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Timeframe for reporting adverse events |
For serious adverse events (SAEs): Day 1 up to end of safety follow-up period (up to Day 183). For non-serious adverse events (AEs): Day 1 up to Day 29 (primed subjects) or up to Day 57 (unprimed subjects).
|
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Adverse event reporting additional description |
All AEs are reported as treatment-emergent AEs during the immunization period plus safety follow-up period for SAEs and during the immunization period only for non-serious AEs. Population for analysis was the safety sample and comprised of all subjects who were vaccinated and had at least one post-vaccination safety observation.
|
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.0
|
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Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Trivalent Influenza Vaccine (Pooled)
|
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Reporting group description |
Primed subjects received a single dose of TIV on Day 1 and unprimed subjects received two doses of TIV (Day 1 and Day 29). Each dose contained approximately 15 μg HA antigen per virus strain, given intramuscularly in the deltoid muscle of the upper arm. The safety data of the subjects vaccinated with the two trivalent formulations, TIV(Vic) and TIV(Yam), were pooled. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Quadrivalent Influenza Vaccine
|
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Reporting group description |
Primed subjects received a single dose of QIV on Day 1 and unprimed subjects received two doses of QIV (Day 1 and Day 29). Each dose contained approximately 15 μg HA antigen per virus strain, given intramuscularly in the deltoid muscle of the upper arm. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 1% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
24 Mar 2016 |
The amendment was implemented to include feedback from the protocol review conducted by the centralized Voluntary Harmonization Procedure. Updates comprised:
• The person who was authorized and in the position to break the blinding in case of a serious adverse event (SAE) was specified.
• It was clarified that the use of prohibited medications did not affect the contraindications for the second study vaccination in unprimed subjects.
• Major protocol deviations, considered for the exclusion of subjects from the per protocol subject sample, were defined and specified.
• It was emphasized that all attempts to contact the subject/parent(s)/legally acceptable representative (LAR) of drop-outs after study vaccination had to be documented in the source documents.
• The reactogenicity grading scale for local solicited reactions was adapted for use in the pediatric populations.
• AE reporting methods were clarified, to state that all AEs, including those not considered related to the study vaccine, were to be reported.
• The analysis of safety was updated to state that all solicited local reactions were to be considered as related to the vaccine.
• The analysis of efficacy was updated to state that the serology data were to include serological baseline status.
• The benefit-risk considerations were updated to state that subjects who received TIV with the alternate B-strain lineage may have less benefit compared with those who received TIV with the recommended B-strain lineage or QIV with both B-strain lineages.
• The study assessments and flow chart were updated to state that parents/LARs should have been reminded to inform the study site in case of an SAE not treated at site. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |