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Clinical Trial Results:
A Multi-center, Phase III, Randomized, Observer Blind Study to Evaluate the Safety, Tolerability, and Immunogenicity of a Trivalent Subunit Inactivated Influenza Vaccine (Agriflu™) in Healthy Children and Adolescents 3 to 17 Years of Age.

Summary
EudraCT number	2014-004498-17
Trial protocol	Outside EU/EEA
Global end of trial date	29 Sep 2011

Results information
Results version number	v2(current)
This version publication date	29 Jul 2016
First version publication date	06 Mar 2015
Other versions	v1 (removed from public view)
Version creation reason	Correction of full data set Required for the re-QC because of EudraCT system glitch as possible updates to results are required. Moreover, the study is now transferred to another primary user.

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

V71_18

ISRCTN number

US NCT number

NCT01209780

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Vaccines and Diagnostics, Inc

Sponsor organisation address

Via Fiorentina 1, Siena, Italy, 53100

Public contact

Novartis Vaccines and Diagnostics, Novartis Vaccines and Diagnostics, RegistryContactVaccinesUS@novartis.com

Scientific contact

Novartis Vaccines and Diagnostics, Novartis Vaccines and Diagnostics, RegistryContactVaccinesUS@novartis.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

07 Feb 2012

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

29 Sep 2011

Was the trial ended prematurely?

Main objective of the trial

To demonstrate the non-inferiority of the HI antibody responses of Agriflu for the three influenza strains when compared to US licensed trivalent inactivated influenza vaccines (controls) 21 days after last vaccination in children ages 3 to 8 years as measured by: ▫differences in percentage of subjects achieving seroconversion ▫ vaccines ratio of post-vaccination geometric mean titers (GMT)

Protection of trial subjects

This trial was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with Good Clinical Practices (GCPs) and the applicable regulatory requirement (s) for the country in which the trial was conducted, Good Clinical Practice (GCP) according to International Conference on Harmonisation (ICH) guidelines, and applicable Standard Operating Procedures (SOPs).

Background therapy

Not Applicable

Evidence for comparator

Not Applicable

Actual start date of recruitment

30 Sep 2010

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

6 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Panama: 77

Country: Number of subjects enrolled

Philippines: 2092

Country: Number of subjects enrolled

Colombia: 635

Worldwide total number of subjects

2804

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

2060

Adolescents (12-17 years)

744

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted in 13 centers across 4 countries: Mexico, Colombia, Panama and Philippines.

Screening details

Subjects in each age group were randomly assigned (2:1) to receive either Agriflu (thimerosal-free formulation) or Fluvirin (as comparator for 4 to 17 years) or Fluzone (as comparator for children 3 to 4 years, since Fluvirin is not approved below 4 years of age).

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

TIV (3-8Yrs)

Arm description

The group consisted of naive (who have never received influenza vaccination or had received only one influenza vaccine dose in the same season) and non-naive subjects (who had a record of previous influenza vaccination). The non-naive subjects received one dose and naive subjects received two doses of investigational Trivalent Inactivated Influenza Vaccine (TIV).

Arm type

Experimental

Investigational medicinal product name

Trivalent Subunit Inactivated Influenza Vaccine (TIV)

Investigational medicinal product code

Other name

Agrippal

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Each dose 0.5 mL of injectable solution was administered intramuscularly.

Control (3-8 Yrs)

Arm description

The group [control (4-8 years) + control (3-<4 years)] consisted of naive (who have never received influenza vaccination or had received only one influenza vaccine dose in the same season) and non-naive subjects (who had a record of previous influenza vaccination). Subjects (4-<9 years) received Trivalent Inactivated Subunit Influenza Vaccine (TIVf) and subjects (3-<4 years) received comparator TIV. The non-naive subjects received one dose and naive subjects received two doses of control vaccine.

Arm type

Active comparator

Investigational medicinal product name

Trivalent Inactivated Subunit Influenza Vaccine (TIV)

Investigational medicinal product code

Other name

Fluzone

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Each dose 0.5 mL of injectable solution was administered intramuscularly.

Investigational medicinal product name

Trivalent Inactivated Subunit Influenza Vaccine (TIVf)

Investigational medicinal product code

Other name

Fluvirin

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Each dose 0.5 mL of injectable solution was administered intramuscularly.

TIV (9-17 Yrs)

Arm description

All subjects in this group were non-naive and received one dose of investigational TIV.

Arm type

Experimental

Investigational medicinal product name

Trivalent Subunit Inactivated Influenza Vaccine (TIV)

Investigational medicinal product code

Other name

Agrippal

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Each dose 0.5 mL of injectable solution was administered intramuscularly.

Control (9-17 yrs)

Arm description

All subjects in this group were non-naive and received one dose of US licensed control vaccine TIVf.

Arm type

Active comparator

Investigational medicinal product name

Trivalent Inactivated Subunit Influenza Vaccine(TIVf)

Investigational medicinal product code

Other name

Fluvirin

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Each dose 0.5 mL of injectable solution was administered intramuscularly.

Number of subjects in period 1	TIV (3-8Yrs)	Control (3-8 Yrs)	TIV (9-17 Yrs)	Control (9-17 yrs)
Started	1042	533	817	412
Completed	1016	511	807	407
Not completed	26	22	10	5
Consent withdrawn by subject	9	3	1	-
Adverse Event	-	1	-	-
Inappropriate enrollment	-	2	-	1
Lost to follow-up	17	15	9	4
Protocol deviation	-	1	-	-

Baseline characteristics

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Reporting group title

TIV (3-8Yrs)

Reporting group description

Reporting group title

Control (3-8 Yrs)

Reporting group description

Reporting group title

TIV (9-17 Yrs)

Reporting group description

All subjects in this group were non-naive and received one dose of investigational TIV.

Reporting group title

Control (9-17 yrs)

Reporting group description

All subjects in this group were non-naive and received one dose of US licensed control vaccine TIVf.

Reporting group values	TIV (3-8Yrs)	Control (3-8 Yrs)	TIV (9-17 Yrs)	Control (9-17 yrs)	Total
Number of subjects	1042	533	817	412	2804
Age categorical
Units: Subjects
In utero	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0
Children (2-11 years)	1042	533	314	171	2060
Adolescents (12-17 years)	0	0	503	241	744
Adults (18-64 years)	0	0	0	0	0
From 65-84 years	0	0	0	0	0
85 years and over	0	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	5.6 ( 1.6 )	5.6 ( 1.6 )	12.4 ( 2.4 )	12.3 ( 2.3 )	-
Gender categorical
Units: Subjects
Female	517	269	398	215	1399
Male	525	264	419	197	1405

End points

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Reporting group title

TIV (3-8Yrs)

Reporting group description

Reporting group title

Control (3-8 Yrs)

Reporting group description

Reporting group title

TIV (9-17 Yrs)

Reporting group description

All subjects in this group were non-naive and received one dose of investigational TIV.

Reporting group title

Control (9-17 yrs)

Reporting group description

All subjects in this group were non-naive and received one dose of US licensed control vaccine TIVf.

Subject analysis set title

All Enrolled Population

Subject analysis set type

Intention-to-treat

Subject analysis set description

All subjects who have been enrolled.

Subject analysis set title

Immunogenicity Per Protocol (PP) Population

Subject analysis set type

Per protocol

Subject analysis set description

All subjects in the Full Analysis Set/MITT population who: ▫ correctly received all study vaccinations ▫ provided evaluable serum samples at the relevant time points, and ▫ had no major protocol violation as defined prior to unblinding A major violation is defined (prior to analysis) as a protocol deviation that was considered to have a significant impact on the immunogenicity result of the subject.

Subject analysis set title

Safety population

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects in the Exposed population who provided post vaccination safety data.

Subject analysis set title

Control (3-8 Years)

Subject analysis set type

Per protocol

Subject analysis set description

The group [control (4-8 years) + control (3 to<4 years)] consisted of naive (who have never received influenza vaccination or had received only one influenza vaccine dose in the same season) and non-naive subjects (who had a record of previous influenza vaccination).Subjects (4-<9 years) received TIVf and subjects (3-<4 years) received comparator TIV. The non-naive subjects received one dose and naive subjects received two doses of vaccine. All subjects in the Full Analysis Set/MITT population who: ▫ correctly received all study vaccinations ▫ provided evaluable serum samples at the relevant time points, and ▫ had no major protocol violation as defined prior to unblinding A major violation is defined (prior to analysis) as a protocol deviation that was considered to have a significant impact on the immunogenicity result of the subject.

Subject analysis set title

Control (3 to < 4Years)

Subject analysis set type

Per protocol

Subject analysis set description

The group consisted of naive (who have never received influenza vaccination or had received only one influenza vaccine dose in the same season) and non-naive subjects (who had a record of previous influenza vaccination. The non-naive subjects received one dose and non-naive subjects received two doses of US licensed control vaccine- comparator TIV.

Primary: Comparison of Antibody Responses of Investigational TIV to Control Vaccine in Terms of the Percentage of Subjects Achieving Seroconversion.

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End point title

Comparison of Antibody Responses of Investigational TIV to Control Vaccine in Terms of the Percentage of Subjects Achieving Seroconversion. ^[1]

End point description

The non-inferiority of the antibody responses of investigational TIV compared to control TIV assessed in terms of the percentage of subjects achieving seroconversion, against the three homologous vaccine strains, in children 3 to 8 years of age, at 21 days after last vaccination. Seroconversion was defined as a pre-vaccination HI titer <1:10 and post-vaccination HI titer ≥1:40 or as a pre-vaccination HI titer ≥1:10 and at minimum four-fold rise in post-vaccination antibody titer. Analysis was done on per protocol population.

End point type

Primary

End point timeframe

Day 22 for non-naive/Day 50 for naive subjects

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: No statistical analyses for this end point.

End point values	TIV (3-8Yrs)	Control (3-8 Yrs)
Number of subjects analysed	918	468
Units: Percentage of Subjects
number (confidence interval 95%)
H1N1 strain (N=916,467)	95 (93 to 96)	94 (91 to 96)
H3N2 strain (N=917,468)	78 (75 to 80)	87 (84 to 90)
B strain	87 (84 to 89)	85 (82 to 89)

TIV(3-8 Yrs) vs Control(3-8 Yrs): A/H1N1

Statistical analysis description

Non-inferiority of investigational TIV to control TIV against A/H1N1 influenza strain considering the two non-inferiority immunogenicity end-points for three influenza strains, a sample size of 1500 subjects (1000 in TIV and 500 in comparator) with a vaccine ratio of 2:1 was sufficient to reject the null hypotheses for the primary objective with a power of 81.82%.

Comparison groups

TIV (3-8Yrs) v Control (3-8 Yrs)

Number of subjects included in analysis

1386

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[2]

Method

Chi-squared

Parameter type

Control minus TIV

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-4

upper limit

Notes
[2] - Investigational TIV was to be considered non-inferior to the control TIV if two-sided 95% CI on the difference between the seroconversion rates, at 21 days after last vaccination, does not exceed 10% points assuming that the true unknown rates of subjects with seroconversion for A/H1N1, A/H3N2 & B after 1 or 2 doses of TIV would be in the range of 83.5% to 74% & for comparator would be in the range of 85.5% to 71.5% using one-sided testing with an α = 0.025, power was estimated to be 92.5%.

TIV(3-8 Yrs) vs Control(3-8 Yrs): A/H3N2

Statistical analysis description

Non-inferiority of investigational TIV to the control TIV against A/H3N2 strain considering the two non-inferiority immunogenicity end-points for three influenza strains, a sample size of 1500 subjects (1000 in TIV and 500 in comparator) with a vaccine ratio of 2:1 was sufficient to reject the null hypotheses for the primary objective with a power of 81.82%.

Comparison groups

TIV (3-8Yrs) v Control (3-8 Yrs)

Number of subjects included in analysis

1386

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

Method

Chi-squared

Parameter type

Control minus TIV

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Notes
[3] - Investigational TIV was to be considered non-inferior to the control TIV if two-sided 95% CI on the difference between the seroconversion rates, at 21 days after last vaccination, does not exceed 10% points assuming that the true unknown rates of subjects with seroconversion for A/H1N1, A/H3N2 & B after 1 or 2 doses of TIV would be in the range of 83.5% to 74% & for comparator would be in the range of 85.5% to 71.5% using one-sided testing with an α = 0.025, power was estimated to be 92.5%.

TIV(3-8 Yrs) vs Control(3-8 Yrs):B Strain

Statistical analysis description

Non-inferiority of investigational TIV to the control TIV against B influenza strain considering the two non-inferiority immunogenicity end-points for three influenza strains, a sample size of 1500 subjects (1000 in TIV and 500 in comparator) with a vaccine ratio of 2:1 was sufficient to reject the null hypotheses for the primary objective with a power of 81.82%.

Comparison groups

TIV (3-8Yrs) v Control (3-8 Yrs)

Number of subjects included in analysis

1386

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[4]

Method

Chi-squared

Parameter type

Control minus TIV

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-5

upper limit

Notes
[4] - Investigational TIV was to be considered non-inferior to the control TIV if two-sided 95% CI on the difference between the seroconversion rates, at 21 days after last vaccination, does not exceed 10% points assuming that the true unknown rates of subjects with seroconversion for A/H1N1, A/H3N2 & B after 1 or 2 doses of TIV would be in the range of 83.5% to 74% & for comparator would be in the range of 85.5% to 71.5% using one-sided testing with an α = 0.025, power was estimated to be 92.5%.

Primary: Comparison of Antibody Responses of Investigational TIV to Control Vaccine in Terms of Post Vaccination Geometric Mean Titers (GMTs)

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End point title

Comparison of Antibody Responses of Investigational TIV to Control Vaccine in Terms of Post Vaccination Geometric Mean Titers (GMTs) ^[5]

End point description

The non-inferiority of the antibody responses of investigational TIV compared to control vaccine assessed in terms of post vaccination GMTs, at 21 days after last vaccination against the three homologous vaccine strains in children aged 3 to 8 years. Analysis was performed on the per protocol population.

End point type

Primary

End point timeframe

Day 22 for non-naive/Day 50 for naive subjects

Notes
[5] - 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: No statistical analyses for this end point.

End point values	TIV (3-8Yrs)	Control (3-8 Yrs)
Number of subjects analysed	918	468
Units: Titers
geometric mean (confidence interval 95%)
Baseline (H1N1 strain, N=917,467)	26 (22 to 31)	28 (25 to 31)
Day 22 or Day 50 (H1N1 strain, N=917,468)	1157 (1052 to 1272)	1501 (1283 to 1756)
Baseline (H3N2 strain)	142 (127 to 158)	150 (129 to 175)
Day 22 or Day 50 (H3N2 strain, N=917,468)	1385 (1300 to 1475)	2032 (1843 to 2240)
Baseline (B strain)	12 (11 to 13)	13 (12 to 14)
Day 22 or Day 50 (B strain)	208 (193 to 224)	195 (174 to 217)

TIV(3-8 Yrs) vs Control(3-8 Yrs): A/H1N1 Strain

Statistical analysis description

Non-inferiority of investigational TIV to licensed control TIV against A/H1N1 influenza strain considering the two non-inferiority immunogenicity end-points for three influenza strains, a sample size of 1500 subjects (1000 in TIV and 500 in comparator) with a vaccine ratio of 2:1 was sufficient to reject the null hypotheses for the primary objective with a power of 81.82%.

Comparison groups

TIV (3-8Yrs) v Control (3-8 Yrs)

Number of subjects included in analysis

1386

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[6]

Method

ANOVA

Parameter type

Ratio of GMTs Control:TIV

Point estimate

1.32

Confidence interval

level

95%

sides

2-sided

lower limit

1.11

upper limit

1.56

Notes
[6] - Investigational TIV was to be considered non-inferior to control TIV, if for all three strains, the upper bound of the two-sided 95% CI on the ratio of the GMTs at 21 days after last vaccination does not exceed 1.5. Assuming standard deviation (SD) for the log transformed titer for strains A/H1N1, A/H3N2 & B at 21 days after 1 or 2 doses of TIV/comparator was in range of 0.91 to 0.65,the power for one-sided testing with an α = 0.025 was estimated to be 88.45% for non-inferiority GMT ratio.

TIV(3-8 Yrs) vs Control(3-8 Yrs): A/H3N2 Strain

Statistical analysis description

Non-inferiority of investigational TIV to licensed control TIV against A/H3N2 influenza strain considering the two non-inferiority immunogenicity end-points for three influenza strains, a sample size of 1500 subjects (1000 in TIV and 500 in comparator) with a vaccine ratio of 2:1 was sufficient to reject the null hypotheses for the primary objective with a power of 81.82%.

Comparison groups

TIV (3-8Yrs) v Control (3-8 Yrs)

Number of subjects included in analysis

1386

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[7]

Method

ANOVA

Parameter type

Ratio of GMTs Control: TIV

Point estimate

1.48

Confidence interval

level

95%

sides

2-sided

lower limit

1.34

upper limit

1.64

Notes
[7] - Investigational TIV was to be considered non-inferior to control TIV, if for all three strains, the upper bound of the two-sided 95% CI on the ratio of the GMTs at 21 days after last vaccination does not exceed 1.5. Assuming standard deviation (SD) for the log transformed titer for strains A/H1N1, A/H3N2 & B at 21 days after 1 or 2 doses of TIV/comparator was in range of 0.91 to 0.65,the power for one-sided testing with an α = 0.025 was estimated to be 88.45% for non-inferiority GMT ratio.

TIV(3-8 Yrs) vs Control(3-8 Yrs): B Strain

Statistical analysis description

Non-inferiority of investigational TIV to licensed control TIV against B influenza strain. Considering the two non-inferiority immunogenicity end-points for three influenza strains, a sample size of 1500 subjects (1000 in TIV and 500 in comparator) with a vaccine ratio of 2:1 was sufficient to reject the null hypotheses for the primary objective with a power of 81.82%.

Comparison groups

Control (3-8 Yrs) v TIV (3-8Yrs)

Number of subjects included in analysis

1386

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[8]

Method

Parameter type

Ratio of GMTs Control: TIV

Point estimate

0.95

Confidence interval

level

95%

sides

2-sided

lower limit

0.85

upper limit

1.07

Notes
[8] - Investigational TIV was to be considered non-inferior to control TIV, if for all three strains, the upper bound of the two-sided 95% CI on the ratio of the GMTs at 21 days after last vaccination does not exceed 1.5. Assuming standard deviation (SD) for the log transformed titer for strains A/H1N1, A/H3N2 & B at 21 days after 1 or 2 doses of TIV/comparator was in range of 0.91 to 0.65,the power for one-sided testing with an α = 0.025 was estimated to be 88.45% for non-inferiority GMT ratio.

Secondary: Percentages of Subjects Achieving HI Titers ≥40 Following Vaccination With Investigational TIV or Control Vaccine.

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End point title

Percentages of Subjects Achieving HI Titers ≥40 Following Vaccination With Investigational TIV or Control Vaccine. ^[9]

End point description

The percentages of 3 to 8 year old subjects achieving HI titers ≥40 after receiving either one or two doses of investigational TIV or control vaccine, 21 days after last vaccination, are reported. This criterion according to the US (CBER) guideline is met if the lower bound of the two sided 95%CI for percentage of subjects achieving HI titers ≥40 is ≥70%. Analysis was performed on the per protocol population.

End point type

Secondary

End point timeframe

Day 22 for non-naive/Day 50 for naive 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: No statistical analyses for this end point.

End point values	TIV (3-8Yrs)	Control (3-8 Yrs)
Number of subjects analysed	918	468
Units: Percentages of Subjects
number (confidence interval 95%)
Baseline (H1N1strain, N=917,467)	49 (46 to 53)	48 (44 to 53)
Day 22 or Day 50 (H1N1 strain, N=917,468)	97 (95 to 98)	95 (93 to 97)
Baseline (H3N2 strain)	84 (81 to 86)	85 (82 to 88)
Day 22 or Day 50 (H3N2 strain, N=917,468)	100 (100 to 100)	100 (99 to 100)
Baseline (B strain)	23 (21 to 26)	26 (22 to 30)
Day 22 or Day 50 (B strain)	95 (93 to 96)	92 (90 to 95)

No statistical analyses for this end point

Secondary: Percentages of Subjects With Seroconversion in Antibody Titers Following Vaccination With Investigational TIV or Control Vaccine.

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End point title

Percentages of Subjects With Seroconversion in Antibody Titers Following Vaccination With Investigational TIV or Control Vaccine. ^[10]

End point description

The percentages of 3 to 8 years-old subjects achieving seroconversion in HI antibody titers after receiving either one or two doses of investigational TIV or control vaccine, at 21 days after last vaccination, are reported. This criterion, according to the US (CBER) guideline, is met if the lower limit of 95% CI of percentage of subjects achieving seroconversion or significant increase at day 22 and day 50 (21 days after last vaccination) is ≥40. Analysis was performed on the per protocol population.

End point type

Secondary

End point timeframe

Day 22 for non-naive/Day 50 for naive 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: No statistical analyses for this end point.

End point values	TIV (3-8Yrs)	Control (3-8 Yrs)
Number of subjects analysed	918	468
Units: Percentages of Subjects
number (confidence interval 95%)
H1N1 strain (N= 916,467)	95 (93 to 96)	94 (91 to 96)
H3N2 strain ( N= 917,468)	78 (75 to 80)	87 (84 to 90)
B strain	87 (84 to 89)	85 (82 to 89)

No statistical analyses for this end point

Secondary: Percentages of Vaccine-naive Children Achieving HI Titers ≥40 After Receiving Two Doses of Investigational TIV or Control Vaccine.

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End point title

Percentages of Vaccine-naive Children Achieving HI Titers ≥40 After Receiving Two Doses of Investigational TIV or Control Vaccine. ^[11]

End point description

The percentage of 3 to 8 years-old vaccine-naive subjects achieving HI titers ≥40, after receiving two doses of investigational TIV or control vaccine. The time frame of evaluation was 28 days after first (Day 29) and 21 days after second vaccine dose (Day 50). This criterion according to the US (CBER) guideline is met if the lower bound of the two sided 95%CI for percentage of subjects achieving HI titers ≥40 is ≥70%, for each vaccine strain. Analysis was performed on the per protocol population.

End point type

Secondary

End point timeframe

Day 29 and Day 50

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: No statistical analyses for this end point.

End point values	TIV (3-8Yrs)	Control (3-8 Yrs)
Number of subjects analysed	820	413
Units: Percentages of Subjects
number (confidence interval 95%)
Day 1 (H1N1 strain, N=819,412)	49 (46 to 53)	48 (43 to 53)
Day 29(H1N1 strain, N=819,413)	83 (80 to 86)	82 (78 to 86)
Day 50 (H1N1 strain, N= 819,413)	99 (98 to 100)	98 (96 to 99)
Day 1 (H3N2 strain)	88 (85 to 90)	90 (87 to 93)
Day 29 (H3N2 strain, N= 819, 413)	99 (98 to 100)	98 (96 to 99)
Day 50 (H3N2 strain, N= 819, 413)	100 (100 to 100)	100 (99 to 100)
Day 1(B strain)	25 (22 to 28)	26 (22 to 31)
Day 29(B strain, N= 820,412)	82 (79 to 84)	81 (77 to 85)
Day 50 (B strain)	98 (96 to 99)	94 (92 to 96)

No statistical analyses for this end point

Secondary: Percentages of Vaccine-naive Children Achieving Seroconversion in Antibody Titers, After Receiving Two Doses of Investigational TIV or Control Vaccine

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End point title

Percentages of Vaccine-naive Children Achieving Seroconversion in Antibody Titers, After Receiving Two Doses of Investigational TIV or Control Vaccine ^[12]

End point description

The percentages of 3 to 8 years-old vaccine naive children achieving seroconversion or significant increase in HI antibody titers after receiving two doses of investigational TIV or control vaccine, are reported. The time frame of evaluation was 28 days after first (Day 29) and 21 days after the second dose (Day 50). This criterion, according to the US (CBER) guideline, is met if the lower limit of 95% CI of percentage of subjects achieving seroconversion or significant increase at day 29 and day 50 is ≥40, for each vaccine strain. Analysis was performed on the per protocol population.

End point type

Secondary

End point timeframe

Day 29 and Day 50

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: No statistical analyses for this end point.

End point values	TIV (3-8Yrs)	Control (3-8 Yrs)
Number of subjects analysed	820	413
Units: Percentages of Subjects
number (confidence interval 95%)
Day 29 (H1N1 strain, N= 818,412)	82 (79 to 84)	81 (77 to 85)
Day 50 (H1N1 strain, N= 818,412)	98 (96 to 99)	96 (94 to 98)
Day 29 (H3N2 strain, N= 819,413)	74 (71 to 77)	87 (83 to 90)
Day 50 (H3N2 strain, N= 819,413)	78 (75 to 80)	87 (84 to 90)
Day 29 (B strain, N= 820,412)	74 (71 to 77)	73 (68 to 77)
Day 50 (B strain)	89 (87 to 91)	88 (85 to 91)

No statistical analyses for this end point

Secondary: Number of Subjects Reporting Solicited Adverse Events After Vaccination With Investigational TIV and Control Vaccine

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End point title

Number of Subjects Reporting Solicited Adverse Events After Vaccination With Investigational TIV and Control Vaccine

End point description

The number of 3-17 year old children with solicited local and systemic adverse events and other adverse events, after receiving either one or two doses of investigational TIV as compared to control vaccine are reported. Analysis was done on the safety set population.

End point type

Secondary

End point timeframe

Day 1 to 7 after vaccination

End point values	TIV (3-8Yrs)	Control (3-8 Yrs)	TIV (9-17 Yrs)	Control (9-17 yrs)
Number of subjects analysed	1037	531	817	412
Units: Number of Subjects
Any local	364	216	270	148
Injection site pain	363	215	268	146
Injection site ecchymosis	1	1	2	0
Injection site erythema	1	1	2	1
Injection site induration	10	6	5	6
Injection site swelling	11	11	6	3
Any systemic	262	161	193	94
Chills	37	20	38	8
Malaise	77	51	68	27
Myalgia	78	50	54	34
Arthralgia	41	20	26	12
Headache (N=1037,531,817,411)	101	52	93	38
Sweating	37	29	43	22
Fatigue	34	22	52	21
Fever (≥ 38°C)	116	68	39	12
Other	153	89	103	54
Analgesic/Antipyretic med.used(N=1032,531,816,412)	91	52	22	9
Stayed at home due to reaction(N=1019,524,809,411)	93	54	89	49

No statistical analyses for this end point

Secondary: Number of Subjects Reporting Unsolicited Adverse Events After Vaccination With Investigational TIV and Control Vaccine

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End point title

Number of Subjects Reporting Unsolicited Adverse Events After Vaccination With Investigational TIV and Control Vaccine

End point description

The number of 3-17 year old children reporting any unsolicited adverse event and any serious adverse event (SAE) after receiving either one or two doses of investigational TIV and control vaccine are reported. Analysis was done on the safety set population.

End point type

Secondary

End point timeframe

Day 1 to 180 (non-naive )/Day 1 to 209 (naive)

End point values	TIV (3-8Yrs)	Control (3-8 Yrs)	TIV (9-17 Yrs)	Control (9-17 yrs)
Number of subjects analysed	1039	531	817	412
Units: Number of Subjects
Any adverse event	395	194	101	58
At least possibly related adverse event	64	36	23	11
Serious adverse event	14	3	4	3
At least possibly related serious adverse event	1	0	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Throughout study

Adverse event reporting additional description

Solicited adverse events collected from Day 1-7 after each vaccination. Serious adverse events and other unsolicited adverse events were collected from Day 1-180 for non-naive and Day 1-209 for vaccine-naive subjects.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

TIV (3-8 Yrs)

Reporting group description

Reporting group title

Control (9-17 Yrs)

Reporting group description

All subjects received one dose of control vaccine (TIVf).

Reporting group title

TIV (9-17 Yrs)

Reporting group description

All subjects received one dose of investigational TIV.

Reporting group title

Control (3-8 Yrs)

Reporting group description

Serious adverse events	TIV (3-8 Yrs)	Control (9-17 Yrs)	TIV (9-17 Yrs)	Control (3-8 Yrs)
Total subjects affected by serious adverse events
subjects affected / exposed	14 / 1039 (1.35%)	3 / 412 (0.73%)	4 / 817 (0.49%)	3 / 531 (0.56%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0
Injury, poisoning and procedural complications
Road traffic accident
subjects affected / exposed	1 / 1039 (0.10%)	0 / 412 (0.00%)	0 / 817 (0.00%)	0 / 531 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Soft tissue injury
subjects affected / exposed	1 / 1039 (0.10%)	0 / 412 (0.00%)	0 / 817 (0.00%)	0 / 531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thermal burn
subjects affected / exposed	0 / 1039 (0.00%)	0 / 412 (0.00%)	0 / 817 (0.00%)	1 / 531 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury
subjects affected / exposed	1 / 1039 (0.10%)	0 / 412 (0.00%)	0 / 817 (0.00%)	0 / 531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Headache
subjects affected / exposed	0 / 1039 (0.00%)	0 / 412 (0.00%)	1 / 817 (0.12%)	0 / 531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	1 / 1039 (0.10%)	0 / 412 (0.00%)	1 / 817 (0.12%)	0 / 531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Suicide attempt
subjects affected / exposed	0 / 1039 (0.00%)	1 / 412 (0.24%)	0 / 817 (0.00%)	0 / 531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abscess
subjects affected / exposed	1 / 1039 (0.10%)	0 / 412 (0.00%)	0 / 817 (0.00%)	0 / 531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Amoebiasis
subjects affected / exposed	1 / 1039 (0.10%)	0 / 412 (0.00%)	0 / 817 (0.00%)	0 / 531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 1039 (0.00%)	1 / 412 (0.24%)	0 / 817 (0.00%)	0 / 531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ascariasis
subjects affected / exposed	1 / 1039 (0.10%)	0 / 412 (0.00%)	0 / 817 (0.00%)	0 / 531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	1 / 1039 (0.10%)	0 / 412 (0.00%)	0 / 817 (0.00%)	0 / 531 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 1039 (0.10%)	0 / 412 (0.00%)	0 / 817 (0.00%)	0 / 531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholera
subjects affected / exposed	1 / 1039 (0.10%)	0 / 412 (0.00%)	0 / 817 (0.00%)	0 / 531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dengue fever
subjects affected / exposed	1 / 1039 (0.10%)	1 / 412 (0.24%)	1 / 817 (0.12%)	0 / 531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 1039 (0.10%)	0 / 412 (0.00%)	0 / 817 (0.00%)	0 / 531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis bacterial
subjects affected / exposed	2 / 1039 (0.19%)	0 / 412 (0.00%)	0 / 817 (0.00%)	0 / 531 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 1039 (0.00%)	0 / 412 (0.00%)	0 / 817 (0.00%)	1 / 531 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Measles
subjects affected / exposed	1 / 1039 (0.10%)	0 / 412 (0.00%)	0 / 817 (0.00%)	0 / 531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 1039 (0.00%)	0 / 412 (0.00%)	1 / 817 (0.12%)	0 / 531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	2 / 1039 (0.19%)	0 / 412 (0.00%)	0 / 817 (0.00%)	0 / 531 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary Track Infection Bacterial
subjects affected / exposed	0 / 1039 (0.00%)	0 / 412 (0.00%)	1 / 817 (0.12%)	0 / 531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	TIV (3-8 Yrs)	Control (9-17 Yrs)	TIV (9-17 Yrs)	Control (3-8 Yrs)
Total subjects affected by non serious adverse events
subjects affected / exposed	586 / 1039 (56.40%)	179 / 412 (43.45%)	362 / 817 (44.31%)	309 / 531 (58.19%)
Nervous system disorders
Headache
subjects affected / exposed	106 / 1039 (10.20%)	39 / 412 (9.47%)	94 / 817 (11.51%)	54 / 531 (10.17%)
occurrences all number	130	44	115	63
General disorders and administration site conditions
Fatigue
subjects affected / exposed	34 / 1039 (3.27%)	21 / 412 (5.10%)	52 / 817 (6.36%)	22 / 531 (4.14%)
occurrences all number	37	27	60	26
Injection site pain
subjects affected / exposed	363 / 1039 (34.94%)	146 / 412 (35.44%)	268 / 817 (32.80%)	215 / 531 (40.49%)
occurrences all number	471	280	284	151
Malaise
subjects affected / exposed	77 / 1039 (7.41%)	27 / 412 (6.55%)	68 / 817 (8.32%)	52 / 531 (9.79%)
occurrences all number	89	32	74	61
Pyrexia
subjects affected / exposed	158 / 1039 (15.21%)	14 / 412 (3.40%)	43 / 817 (5.26%)	91 / 531 (17.14%)
occurrences all number	190	17	47	119
Skin and subcutaneous tissue disorders
Hyperhidrosis
subjects affected / exposed	37 / 1039 (3.56%)	22 / 412 (5.34%)	43 / 817 (5.26%)	29 / 531 (5.46%)
occurrences all number	41	27	47	41
Musculoskeletal and connective tissue disorders
Myalgia
subjects affected / exposed	79 / 1039 (7.60%)	34 / 412 (8.25%)	54 / 817 (6.61%)	51 / 531 (9.60%)
occurrences all number	89	37	61	62
Infections and infestations
Nasopharyngitis
subjects affected / exposed	88 / 1039 (8.47%)	11 / 412 (2.67%)	19 / 817 (2.33%)	39 / 531 (7.34%)
occurrences all number	101	11	19	49
Upper respiratory tract infection
subjects affected / exposed	99 / 1039 (9.53%)	7 / 412 (1.70%)	14 / 817 (1.71%)	42 / 531 (7.91%)
occurrences all number	118	7	14	45

More information

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Due to GCP non-compliance at the Mexico site, data of 312 subjects (3-8 year olds) enrolled from this site were excluded from the final immunogenicity and safety analysis.

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Clinical trials

Clinical Trial Results:
A Multi-center, Phase III, Randomized, Observer Blind Study to Evaluate the Safety, Tolerability, and Immunogenicity of a Trivalent Subunit Inactivated Influenza Vaccine (Agriflu™) in Healthy Children and Adolescents 3 to 17 Years of Age.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Comparison of Antibody Responses of Investigational TIV to Control Vaccine in Terms of the Percentage of Subjects Achieving Seroconversion.

Primary: Comparison of Antibody Responses of Investigational TIV to Control Vaccine in Terms of the Percentage of Subjects Achieving Seroconversion.

Primary: Comparison of Antibody Responses of Investigational TIV to Control Vaccine in Terms of Post Vaccination Geometric Mean Titers (GMTs)

Primary: Comparison of Antibody Responses of Investigational TIV to Control Vaccine in Terms of Post Vaccination Geometric Mean Titers (GMTs)

Secondary: Percentages of Subjects Achieving HI Titers ≥40 Following Vaccination With Investigational TIV or Control Vaccine.

Secondary: Percentages of Subjects Achieving HI Titers ≥40 Following Vaccination With Investigational TIV or Control Vaccine.

Secondary: Percentages of Subjects With Seroconversion in Antibody Titers Following Vaccination With Investigational TIV or Control Vaccine.

Secondary: Percentages of Subjects With Seroconversion in Antibody Titers Following Vaccination With Investigational TIV or Control Vaccine.

Secondary: Percentages of Vaccine-naive Children Achieving HI Titers ≥40 After Receiving Two Doses of Investigational TIV or Control Vaccine.

Secondary: Percentages of Vaccine-naive Children Achieving HI Titers ≥40 After Receiving Two Doses of Investigational TIV or Control Vaccine.

Secondary: Percentages of Vaccine-naive Children Achieving Seroconversion in Antibody Titers, After Receiving Two Doses of Investigational TIV or Control Vaccine

Secondary: Percentages of Vaccine-naive Children Achieving Seroconversion in Antibody Titers, After Receiving Two Doses of Investigational TIV or Control Vaccine

Secondary: Number of Subjects Reporting Solicited Adverse Events After Vaccination With Investigational TIV and Control Vaccine

Secondary: Number of Subjects Reporting Solicited Adverse Events After Vaccination With Investigational TIV and Control Vaccine

Secondary: Number of Subjects Reporting Unsolicited Adverse Events After Vaccination With Investigational TIV and Control Vaccine

Secondary: Number of Subjects Reporting Unsolicited Adverse Events After Vaccination With Investigational TIV and Control Vaccine

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
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Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A Multi-center, Phase III, Randomized, Observer Blind Study to Evaluate the Safety, Tolerability, and Immunogenicity of a Trivalent Subunit Inactivated Influenza Vaccine (Agriflu™) in Healthy Children and Adolescents 3 to 17 Years of Age.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Comparison of Antibody Responses of Investigational TIV to Control Vaccine in Terms of the Percentage of Subjects Achieving Seroconversion.

Primary: Comparison of Antibody Responses of Investigational TIV to Control Vaccine in Terms of the Percentage of Subjects Achieving Seroconversion.

Primary: Comparison of Antibody Responses of Investigational TIV to Control Vaccine in Terms of Post Vaccination Geometric Mean Titers (GMTs)

Primary: Comparison of Antibody Responses of Investigational TIV to Control Vaccine in Terms of Post Vaccination Geometric Mean Titers (GMTs)

Secondary: Percentages of Subjects Achieving HI Titers ≥40 Following Vaccination With Investigational TIV or Control Vaccine.

Secondary: Percentages of Subjects Achieving HI Titers ≥40 Following Vaccination With Investigational TIV or Control Vaccine.

Secondary: Percentages of Subjects With Seroconversion in Antibody Titers Following Vaccination With Investigational TIV or Control Vaccine.

Secondary: Percentages of Subjects With Seroconversion in Antibody Titers Following Vaccination With Investigational TIV or Control Vaccine.

Secondary: Percentages of Vaccine-naive Children Achieving HI Titers ≥40 After Receiving Two Doses of Investigational TIV or Control Vaccine.

Secondary: Percentages of Vaccine-naive Children Achieving HI Titers ≥40 After Receiving Two Doses of Investigational TIV or Control Vaccine.

Secondary: Percentages of Vaccine-naive Children Achieving Seroconversion in Antibody Titers, After Receiving Two Doses of Investigational TIV or Control Vaccine

Secondary: Percentages of Vaccine-naive Children Achieving Seroconversion in Antibody Titers, After Receiving Two Doses of Investigational TIV or Control Vaccine

Secondary: Number of Subjects Reporting Solicited Adverse Events After Vaccination With Investigational TIV and Control Vaccine

Secondary: Number of Subjects Reporting Solicited Adverse Events After Vaccination With Investigational TIV and Control Vaccine

Secondary: Number of Subjects Reporting Unsolicited Adverse Events After Vaccination With Investigational TIV and Control Vaccine

Secondary: Number of Subjects Reporting Unsolicited Adverse Events After Vaccination With Investigational TIV and Control Vaccine

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Multi-center, Phase III, Randomized, Observer Blind Study to Evaluate the Safety, Tolerability, and Immunogenicity of a Trivalent Subunit Inactivated Influenza Vaccine (Agriflu™) in Healthy Children and Adolescents 3 to 17 Years of Age.