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Clinical Trial Results:
A Combined Phase II/III, Observer-Blind, Randomized, Multi-center Study to Evaluate Safety, Tolerability and Immunogenicity of Trivalent Subunit Influenza Vaccines, Produced Either in Mammalian Cell Culture or in Embryonated Hen Eggs (Fluvirin®), in Healthy Children and Adolescents Aged 3-17 Years

Summary
EudraCT number	2007-001534-13
Trial protocol	HU LT FI IT
Global end of trial date	17 Jul 2008

Results information
Results version number	v2(current)
This version publication date	28 Jul 2016
First version publication date	04 Dec 2014
Other versions	v1 (removed from public view)
Version creation reason	Correction of full data set Required for the re-QC project because of the EudraCT system glitch and possible updates to results may be required. Moreover, a change in system user for this study is necessary.

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

V58P12

ISRCTN number

US NCT number

NCT00645411

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Vaccines

Sponsor organisation address

Via Fiorentina, 1, Siena, Italy, 53100

Public contact

Posting Director, Novartis Vaccines, RegistryContactVaccinesUS@novartis.com

Scientific contact

Posting Director, Novartis Vaccines, 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

30 Mar 2009

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

17 Jul 2008

Was the trial ended prematurely?

Main objective of the trial

Co-Primary: To demonstrate non-inferiority of the post-vaccination (Day 50) hemagglutination inhibition (HI) geometric mean titer (GMT) of the cell culture-derived influenza vaccine to the corresponding GMT of the egg-derived influenza vaccine for all three strains after two doses administered four weeks apart to a subset of children 3-8 years of age (Cohort 3, immunogenicity subset). To demonstrate non-inferiority of the percentages of subjects achieving seroconversion or significant increase in antibody titer at Day 50 following administration of the cell culture-derived influenza vaccine to the corresponding percentages of subjects following administration of the egg-derived influenza vaccine for all three strains after two doses administered four weeks apart to a subset of children 3-8 years of age (Cohort 3, immunogenicity subset).

Protection of trial subjects

Study vaccines were not administered to individuals with known hypersensitivity to any component of the vaccines. An oral temperature ≥38.0°C (≥100.4°F) or serious active infection was a reason for delaying vaccination. Standard immunization practices were observed and care was taken to administer the injection intramuscularly. As with all injectable vaccines, appropriate medical treatment and supervision was readily available in case of rare anaphylactic reactions following administration of the study vaccine. Epinephrine 1:1000 and diphenhydramine was available in case of any anaphylactic reactions. Care was taken to ensure that the vaccine is not injected into a blood vessel.

Background therapy

Evidence for comparator

Actual start date of recruitment

08 Oct 2007

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Finland: 632

Country: Number of subjects enrolled

Italy: 149

Country: Number of subjects enrolled

Lithuania: 248

Country: Number of subjects enrolled

Hungary: 575

Country: Number of subjects enrolled

Croatia: 109

Country: Number of subjects enrolled

Romania: 3

Country: Number of subjects enrolled

United States: 1888

Worldwide total number of subjects

3604

EEA total number of subjects

1716

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)

3017

Adolescents (12-17 years)

587

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants were enrolled from 14 sites in Finland, 16 in the US, 9 in Croatia, 5 in Italy, 6 in Lithuania, 2 in Romania, 8 in Hungary.

Screening details

All subjects enrolled were included in the trial.

Period 1 title

Overall Trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Cohort 1+2 cTIV (9-17 years)

Arm description

All subjects aged 9-17 years received one 0.5 mL IM injection, of Cell Culture-derived trivalent influenza vaccine.

Arm type

Experimental

Investigational medicinal product name

Cell culture-derived trivalent influenza vaccine

Investigational medicinal product code

Other name

cTIV, Optaflu

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Vaccination consisted of one 0.5 mL dose for Cohorts 1 and 2 and two 0.5 mL doses administered four weeks apart for Cohort 3; all injections were administered IM in the deltoid muscle, preferably of the non-dominant arm.

Cohort 1+2 eTIV (9-17 years)

Arm description

All subjects aged 9-17 years received one 0.5 mL injection, of egg -derived trivalent influenza vaccine.

Arm type

Active comparator

Investigational medicinal product name

Egg-derived trivalent influenza vaccine

Investigational medicinal product code

Other name

eTIV, Fluvirin

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Cohort 3 cTIV (3-8 years)

Arm description

All subjects aged 3-8 years received two 0.5 mL injections, administered four weeks apart, of Cell Culture-derived trivalent influenza vaccine.

Arm type

Experimental

Investigational medicinal product name

Cell culture-derived trivalent influenza vaccine

Investigational medicinal product code

Other name

cTIV, Optaflu

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Cohort 3 eTIV (3-8 Years)

Arm description

All subjects aged 3-8 years received two 0.5 mL injections, administered four weeks apart of egg - derived trivalent influenza vaccine.

Arm type

Active comparator

Investigational medicinal product name

Egg-derived trivalent influenza vaccine

Investigational medicinal product code

Other name

eTIV, Fluvirin

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Number of subjects in period 1	Cohort 1+2 cTIV (9-17 years)	Cohort 1+2 eTIV (9-17 years)	Cohort 3 cTIV (3-8 years)	Cohort 3 eTIV (3-8 Years)
Started	656	318	1608	1022
Completed	643	312	1457	919
Not completed	13	6	151	103
Consent withdrawn by subject	2	1	19	21
Unable to classify	-	-	3	4
Adverse event	-	-	-	2
Inappropriate enrolment	-	-	4	1
Lost to follow-up	10	5	124	75
Protocol deviation	1	-	1	-

Baseline characteristics

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Reporting group title

Cohort 1+2 cTIV (9-17 years)

Reporting group description

All subjects aged 9-17 years received one 0.5 mL IM injection, of Cell Culture-derived trivalent influenza vaccine.

Reporting group title

Cohort 1+2 eTIV (9-17 years)

Reporting group description

All subjects aged 9-17 years received one 0.5 mL injection, of egg -derived trivalent influenza vaccine.

Reporting group title

Cohort 3 cTIV (3-8 years)

Reporting group description

All subjects aged 3-8 years received two 0.5 mL injections, administered four weeks apart, of Cell Culture-derived trivalent influenza vaccine.

Reporting group title

Cohort 3 eTIV (3-8 Years)

Reporting group description

All subjects aged 3-8 years received two 0.5 mL injections, administered four weeks apart of egg - derived trivalent influenza vaccine.

Reporting group values	Cohort 1+2 cTIV (9-17 years)	Cohort 1+2 eTIV (9-17 years)	Cohort 3 cTIV (3-8 years)	Cohort 3 eTIV (3-8 Years)	Total
Number of subjects	656	318	1608	1022	3604
Age categorical
Units: Subjects
In utero					0
Preterm newborn infants (gestational age < 37 wks)					0
Newborns (0-27 days)					0
Infants and toddlers (28 days-23 months)					0
Children (2-11 years)					0
Adolescents (12-17 years)					0
Adults (18-64 years)					0
From 65-84 years					0
85 years and over					0
Age continuous
Units: years
arithmetic mean (standard deviation)	12.6 ( 2.6 )	12.6 ( 2.5 )	5.5 ( 1.7 )	5.4 ( 1.7 )	-
Gender categorical
Units: Subjects
Female	304	154	795	494	1747
Male	352	164	813	528	1857

End points

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Reporting group title

Cohort 1+2 cTIV (9-17 years)

Reporting group description

All subjects aged 9-17 years received one 0.5 mL IM injection, of Cell Culture-derived trivalent influenza vaccine.

Reporting group title

Cohort 1+2 eTIV (9-17 years)

Reporting group description

All subjects aged 9-17 years received one 0.5 mL injection, of egg -derived trivalent influenza vaccine.

Reporting group title

Cohort 3 cTIV (3-8 years)

Reporting group description

All subjects aged 3-8 years received two 0.5 mL injections, administered four weeks apart, of Cell Culture-derived trivalent influenza vaccine.

Reporting group title

Cohort 3 eTIV (3-8 Years)

Reporting group description

All subjects aged 3-8 years received two 0.5 mL injections, administered four weeks apart of egg - derived trivalent influenza vaccine.

Subject analysis set title

cTIV- Safety

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects with at least one vaccination and who provided some postvaccination safety data.

Subject analysis set title

eTIV - Safety

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects with at least one vaccination and who provided some postvaccination safety data.

Subject analysis set title

Cohort 1 cTIV- (9-17 Years)- PPS

Subject analysis set type

Per protocol

Subject analysis set description

All subjects in the Modified Intention To Treat (MITT) population who received all doses of vaccine correctly, who provided evaluable serum samples at the relevant time points and who had no major protocol violations as defined prior to unblinding.

Subject analysis set title

Cohort 1 eTIV- (9-17 Years)- PPS

Subject analysis set type

Per protocol

Subject analysis set description

All subjects in the MITT population who received all doses of vaccine correctly, who provided evaluable serum samples at the relevant time points and who had no major protocol violations as defined prior to unblinding.

Subject analysis set title

cTIV - PPS

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

eTIV - PPS

Subject analysis set type

Per protocol

Subject analysis set description

Primary: 1) Non-inferiority of the Cell Culture-derived Vaccine to the Egg-derived Vaccine in 3-8 Years Old Children in Post Vaccination Geometric Mean Titers

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End point title

1) Non-inferiority of the Cell Culture-derived Vaccine to the Egg-derived Vaccine in 3-8 Years Old Children in Post Vaccination Geometric Mean Titers ^[1]

End point description

To demonstrate non-inferiority of the post vaccination hemagglutination inhibition (HI) geometric mean titer (GMT) of the cell culture-derived influenza (cTIV) vaccine to the corresponding GMT of the egg-derived (eTIV_f) influenza vaccine, for all three strains, after two injections administered four weeks apart to a subset of children 3-8 years of age. GMTs were evaluated using two assays, HI egg derived antigen assay and HI cell derived antigen assay. The analysis was performed on the per-protocol dataset

End point type

Primary

End point timeframe

Day 50 post vaccination

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: There were no statistical analysis done to this endpoint.

End point values	Cohort 3 cTIV (3-8 years)	Cohort 3 eTIV (3-8 Years)
Number of subjects analysed	524	513
Units: Titers
geometric mean (confidence interval 95%)
A/H1N1 (egg derived antigen assay)	407 (358 to 462)	477 (419 to 542)
A/H3N2 (egg derived antigen assay)	768 (666 to 885)	1293 (1121 to 1491)
B (egg derived antigen assay)	25 (21 to 29)	44 (38 to 51)
A/H1N1 (cell derived antigen assay) (N=522,513)	563 (501 to 634)	610 (542 to 686)
A/H3N2 (cell derived antigen assay) (N=522,513)	858 (744 to 990)	1329 (1152 to 1533)
B (cell derived antigen assay) (N=522,513)	53 (46 to 62)	62 (53 to 72)

A/H1N1-Egg derived antigen assay

Statistical analysis description

Non-inferiority of cTIV to eTIV against A/H1N1 influenza strain as measured by HI egg-derived antigen assay

Comparison groups

Cohort 3 cTIV (3-8 years) v Cohort 3 eTIV (3-8 Years)

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[2]

Method

ANOVA

Parameter type

Ratio of GMTs

Point estimate

0.85

Confidence interval

level

95%

sides

2-sided

lower limit

0.72

upper limit

1.01

Notes
[2] - Cell derived vaccine was considered non-inferior to egg-derived vaccine in post vaccination HI GMTs if, for all three influenza strains, the lower limit of the two-sided 95% confidence interval (CI) for day 50 ratio of GMTs (cTIV/eTIV) was >0.667.

A/H3N2-Egg derived antigen assay

Statistical analysis description

Non-inferiority of cTIV to eTIV against A/H3N2 influenza strain as measured by HI egg-derived antigen assay.

Comparison groups

Cohort 3 cTIV (3-8 years) v Cohort 3 eTIV (3-8 Years)

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

Method

ANOVA

Parameter type

Ratio of GMTs

Point estimate

0.59

Confidence interval

level

95%

sides

2-sided

lower limit

0.49

upper limit

0.72

Notes
[3] - Cell derived vaccine was considered non-inferior to egg-derived vaccine in post vaccination HI GMTs if, for all three influenza strains, the lower limit of the two-sided 95% confidence interval (CI) for day 50 ratio of GMTs (cTIV/eTIV) was >0.667.

B-Egg derived antigen assay

Statistical analysis description

Non-inferiority of cTIV to eTIV against influenza B strain as measured by HI egg-derived antigen assay.

Comparison groups

Cohort 3 cTIV (3-8 years) v Cohort 3 eTIV (3-8 Years)

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[4]

Method

ANOVA

Parameter type

Ratio of GMTs

Point estimate

0.56

Confidence interval

level

95%

sides

2-sided

lower limit

0.46

upper limit

0.68

Notes
[4] - Cell derived vaccine was considered non-inferior to egg-derived vaccine in post vaccination HI GMTs if, for all three influenza strains, the lower limit of the two-sided 95% confidence interval (CI) for day 50 ratio of GMTs (cTIV/eTIV) was >0.667.

A/H1N1-Cell derived antigen assay

Statistical analysis description

Non-inferiority of cTIV to eTIV against A/H1N1 influenza strain as measured by HI cell-derived antigen assay.

Comparison groups

Cohort 3 cTIV (3-8 years) v Cohort 3 eTIV (3-8 Years)

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[5]

Method

ANOVA

Parameter type

Ratio of GMTs

Point estimate

0.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.79

upper limit

1.08

Notes
[5] - Cell derived vaccine was considered non-inferior to egg-derived vaccine in post vaccination HI GMTs if, for all three influenza strains, the lower limit of the two-sided 95% confidence interval (CI) for day 50 ratio of GMTs (cTIV/eTIV) was >0.667.

A/H3N1-Cell derived antigen assay

Statistical analysis description

Non-inferiority of cTIV to eTIV against A/H3N2 influenza strain as measured by HI cell-derived antigen assay.

Comparison groups

Cohort 3 cTIV (3-8 years) v Cohort 3 eTIV (3-8 Years)

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[6]

Method

ANOVA

Parameter type

Ratio of GMTs

Point estimate

0.65

Confidence interval

level

95%

sides

2-sided

lower limit

0.54

upper limit

0.78

Notes
[6] - Cell derived vaccine (cTIV ) was considered non-inferior to egg-derived vaccine (eTIV) in post vaccination HI GMTs if, for all three influenza strains, the lower limit of the two-sided 95% confidence interval (CI) for day 50 ratio of GMTs (cTIV/eTIV) was >0.667.

B-Cell derived antigen assay

Statistical analysis description

Non-inferiority of cTIV to eTIV against A/H1N1 influenza strain as measured by HI cell-derived antigen assay

Comparison groups

Cohort 3 cTIV (3-8 years) v Cohort 3 eTIV (3-8 Years)

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[7]

Method

ANOVA

Parameter type

Ratio of GMTs

Point estimate

0.87

Confidence interval

level

95%

sides

2-sided

lower limit

0.71

upper limit

1.06

Notes
[7] - Cell derived vaccine was considered non-inferior to egg-derived vaccine in post vaccination HI GMTs if, for all three influenza strains, the lower limit of the two-sided 95% confidence interval (CI) for day 50 ratio of GMTs (cTIV/eTIV) was >0.667.

Primary: 2) Non-inferiority of the Cell Culture-derived Vaccine to the Egg-derived Vaccine in 3-8 Years Old Children in the Percentage of Subjects Achieving Seroconversion or Significant Increase in Antibody Titers

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End point title

2) Non-inferiority of the Cell Culture-derived Vaccine to the Egg-derived Vaccine in 3-8 Years Old Children in the Percentage of Subjects Achieving Seroconversion or Significant Increase in Antibody Titers ^[8]

End point description

To demonstrate non-inferiority of the cell culture-derived influenza (cTIV) vaccine to the egg-derived (eTIV_f) influenza vaccine in the percentage of subjects achieving seroconversion or significant increase in antibody titer post vaccination, for all three strains, after two injections administered four weeks apart in children 3-8 years of age. Seroconversion rate was evaluated using two assays- HI egg derived antigen assay and HI cell derived antigen assay. The analysis was performed on the per-protocol dataset

End point type

Primary

End point timeframe

Day 50 post vaccination

Notes
[8] - 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: There were no statistical analysis done to this endpoint.

End point values	Cohort 3 cTIV (3-8 years)	Cohort 3 eTIV (3-8 Years)
Number of subjects analysed	524	513
Units: Percentage
number (confidence interval 95%)
A/H1N1 (egg derived antigen assay)	94 (92 to 96)	96 (94 to 97)
A/H3N2 (egg derived antigen assay)	77 (73 to 81)	86 (82 to 89)
B (egg derived antigen assay)	38 (34 to 42)	53 (49 to 58)
A/H1N1 (cell derived antigen assay) (N=522,513)	96 (93 to 97)	96 (94 to 98)
A/H3N2 (cell derived antigen assay) (N=522,513)	80 (76 to 83)	85 (82 to 88)
B (cell derived antigen assay) (N=522,513)	58 (54 to 63)	58 (54 to 63)

A/H1N1-Egg derived antigen assay

Statistical analysis description

Non-inferiority of cTIV to eTIV against A/H1N1 influenza strain as measured by HI egg-derived antigen assay.

Comparison groups

Cohort 3 cTIV (3-8 years) v Cohort 3 eTIV (3-8 Years)

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[9]

Method

Binomial or Miettinen & Nurimen Method

Parameter type

Difference in % (cTIV minus eTIV)

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-4

upper limit

Notes
[9] - cTIV was considered non-inferior to eTIV in terms of the percentages of subjects achieving seroconversion or significant increase in antibody titer at day 50 if for all three strains, the lower limit of the two-sided 95% CI around the differences in the percentages of subjects achieving seroconversion and significant increase (cTIV minus eTIV) was >-10%.

A/H3N2-Egg derived antigen assay

Statistical analysis description

Non-inferiority of cTIV to eTIV against A/H3N2 influenza strain as measured by HI egg-derived antigen assay.

Comparison groups

Cohort 3 cTIV (3-8 years) v Cohort 3 eTIV (3-8 Years)

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[10]

Method

Binomial or Miettinen & Nurimen Method

Parameter type

Difference in % (cTIV minus eTIV):

Point estimate

-9

Confidence interval

level

95%

sides

2-sided

lower limit

-13

upper limit

-4

Notes
[10] - cTIV was considered non-inferior to eTIV in terms of the percentages of subjects achieving seroconversion or significant increase in antibody titer at day 50 if for all three strains, the lower limit of the two-sided 95% CI around the differences in the percentages of subjects achieving seroconversion and significant increase (cTIV minus eTIV) was >-10%.

B-Egg derived antigen assay

Statistical analysis description

Non-inferiority of cTIV to eTIV against influenza B strain as measured by HI egg-derived antigen assay.

Comparison groups

Cohort 3 cTIV (3-8 years) v Cohort 3 eTIV (3-8 Years)

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[11]

Method

Binomial or Miettinen & Nurimen method

Parameter type

Difference in % (cTIV minus eTIV):

Point estimate

-15

Confidence interval

level

95%

sides

2-sided

lower limit

-21

upper limit

-9

Notes
[11] - cTIV was considered non-inferior to eTIV in terms of the percentages of subjects achieving seroconversion or significant increase in antibody titer at day 50 if for all three strains, the lower limit of the two-sided 95% CI around the differences in the percentages of subjects achieving seroconversion and significant increase (cTIV minus eTIV) was >-10%.

A/H1N1-Cell derived antigen assay

Statistical analysis description

Non-inferiority of cTIV to eTIV against A/H1N1 influenza strain as measured by HI cell-derived antigen assay.

Comparison groups

Cohort 3 cTIV (3-8 years) v Cohort 3 eTIV (3-8 Years)

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[12]

Method

Binominal or Miettinen &Nurimen method

Parameter type

Difference in % (cTIV minus eTIV

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-3

upper limit

Notes
[12] - cTIV was considered non-inferior to eTIV in terms of the percentages of subjects achieving seroconversion or significant increase in antibody titer at day 50 if for all three strains, the lower limit of the two-sided 95% CI around the differences in the percentages of subjects achieving seroconversion and significant increase (cTIV minus eTIV) was >-10%.

A/H3N2-Cell derived antigen assay

Statistical analysis description

Non-inferiority of cTIV to eTIV against A/H3N2 influenza strain as measured by HI cell-derived antigen assay.

Comparison groups

Cohort 3 cTIV (3-8 years) v Cohort 3 eTIV (3-8 Years)

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[13]

Method

Binominal or Miettinen &Nurimen method

Parameter type

Difference in % (cTIV minus eTIV)

Point estimate

-5

Confidence interval

level

95%

sides

2-sided

lower limit

-9.5

upper limit

Notes
[13] - cTIV was considered non-inferior to eTIV_f in terms of the percentages of subjects achieving seroconversion or significant increase in antibody titer at day 50 if for all three strains, the lower limit of the two-sided 95% CI around the differences in the percentages of subjects achieving seroconversion and significant increase (cTIV minus eTIV) was >-10%.

B-Cell derived antigen assay

Statistical analysis description

Non-inferiority of cTIV to eTIV against B influenza strain as measured by HI cell-derived antigen assay.

Comparison groups

Cohort 3 cTIV (3-8 years) v Cohort 3 eTIV (3-8 Years)

Number of subjects included in analysis

1037

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[14]

Method

Binominal or Miettinen &Nurimen method

Parameter type

Difference in % (cTIV minus eTIV)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-6

upper limit

Notes
[14] - cTIV was considered non-inferior to eTIV_f in terms of the percentages of subjects achieving seroconversion or significant increase in antibody titer at day 50 if for all three strains, the lower limit of the two-sided 95% CI around the differences in the percentages of subjects achieving seroconversion and significant increase (cTIV minus eTIV) was >-10%.

Secondary: 3) Geometric Mean Titers After 1 Dose of the Cell Culture-derived or the Egg- derived Influenza Vaccine in 9-17 Years Old Children and Adolescents

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End point title

3) Geometric Mean Titers After 1 Dose of the Cell Culture-derived or the Egg- derived Influenza Vaccine in 9-17 Years Old Children and Adolescents

End point description

To evaluate immunogenicity in terms of Geometric Mean Titers (GMTs) in children 9-17 years of age after one injection of either cTIV vaccine or eTIV_f. GMTs were evaluated using two assays, HI egg derived antigen assay and HI cell derived antigen assay. The analysis was performed on the per-protocol dataset.

End point type

Secondary

End point timeframe

Day 29 post vaccination

End point values	Cohort 1 cTIV- (9-17 Years)- PPS	Cohort 1 eTIV- (9-17 Years)- PPS
Number of subjects analysed	142	144
Units: Titers
geometric mean (confidence interval 95%)
Baseline (A/H1N1) egg derived antigen assay	55 (42 to 72)	78 (60 to 101)
Day 29 (A/H1N1) egg derived antigen assay	879 (728 to 1062)	1107 (918 to 1334)
Baseline (A/H3N2) egg derived antigen assay	121 (94 to 155)	151 (118 to 193)
Day 29 (A/H3N2) egg derived antigen assay	706 (607 to 821)	1857 (1598 to 2157)
Baseline (B) Egg derived antigen assay	9.65 (8.2 to 11)	9.92 (8.45 to 12)
Day 29 (B) egg derived antigen assay	58 (48 to 71)	105 (86 to 129)
Baseline(A/H1N1)Cell derived assay	70 (53 to 92)	90 (69 to 119)
Day 29 (A/H1N1) cell derived antigen assay	1076 (886 to 1307)	1296 (1069 to 1571)
Baseline(A/H3N2)cell derived assay(N=141,144)	125 (98 to 158)	144 (114 to 182)
Day 29 (A/H3N2) cell derived antigen assay	676 (585 to 783)	1651 (1429 to 1908)
Baseline(B)cell derived assay(N=141,144)	22 (18 to 27)	25 (21 to 30)
Day 29 (B) cell derived antigen assay	136 (113 to 163)	186 (155 to 222)

No statistical analyses for this end point

Secondary: 4) Geometric Mean Ratio After 1 Dose of the Cell Culture-derived or the Egg-derived Influenza Vaccine in 9-17 Year-old Children and Adolescents.

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End point title

4) Geometric Mean Ratio After 1 Dose of the Cell Culture-derived or the Egg-derived Influenza Vaccine in 9-17 Year-old Children and Adolescents.

End point description

Immunogenicity was evaluated in terms of Geometric Mean Ratio (GMRs) in 9-17 year-old children and adolescents after one injection of either cTIV vaccine or eTIV. The criterion is met according to European (CHMP) guideline if the mean geometric increase GMR (day29/day1) in HI antibody titer is >2.5. The analysis was performed on the per-protocol dataset.

End point type

Secondary

End point timeframe

Day 29 post vaccination

End point values	Cohort 1 cTIV- (9-17 Years)- PPS	Cohort 1 eTIV- (9-17 Years)- PPS
Number of subjects analysed	142	144
Units: Ratio
geometric mean (confidence interval 95%)
Day 29 (A/H1N1)egg derived antigen assay	16 (12 to 21)	14 (11 to 19)
Day 29 (A/H3N2) egg derived antigen assay	5.84 (4.43 to 7.7)	12 (9.33 to 16)
Day 29 (B) egg derived antigen assay	6.03 (4.77 to 7.62)	11 (8.43 to 13)
Day29(A/H1N1)cell derived antigen assay(N=141,144)	15 (12 to 21)	14 (11 to 19)
Day29(A/H3N2)cell derived antigen assay(N=141,144)	5.45 (4.21 to 7.06)	11 (8.87 to 15)
Day29(B) cell derived antigen assay(N=141,144)	6.15 (4.96 to 7.63)	7.37 (5.96 to 9.12)

No statistical analyses for this end point

Secondary: 5) Percentage of 9-17 Year-old Children and Adolescents Achieving HI Titers ≥40 After 1 Dose of the Cell Culture-derived or the Egg-derived Influenza Vaccine

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End point title

5) Percentage of 9-17 Year-old Children and Adolescents Achieving HI Titers ≥40 After 1 Dose of the Cell Culture-derived or the Egg-derived Influenza Vaccine

End point description

To evaluate immunogenicity in terms of percentage of 9-17 year-old children and adolescents achieving HI titers ≥40, after one injection of either the cTIV vaccine or the eTIV_f vaccine. This criterion is met according to European (CHMP) guideline if the percentage of subjects achieving HI titers ≥40 is >70% and 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%. The analysis was performed on PPS

End point type

Secondary

End point timeframe

Day 29 post vaccination

End point values	Cohort 1 cTIV- (9-17 Years)- PPS	Cohort 1 eTIV- (9-17 Years)- PPS
Number of subjects analysed	142	144
Units: Percentage
number (confidence interval 95%)
Prevaccination(A/H1N1)egg derived antigen assay	65 (57 to 73)	75 (67 to 82)
Day 29 (A/H1N1) egg derived antigen assay	99 (96 to 100)	99 (95 to 100)
Prevaccination(A/H3N2) egg derived antigen assay	82 (74 to 88)	86 (79 to 91)
Day 29 (A/H3N2) egg derived antigen assay	100 (97 to 100)	100 (97 to 100)
Prevaccination(B)egg derived antigen assay	17 (11 to 24)	13 (8 to 19)
Day 29 (B) egg derived antigen assay	75 (67 to 82)	84 (77 to 90)
Prevaccination(H1N1)cell derived assay(N=141,144)	67 (59 to 75)	78 (71 to 85)
Day 29 (A/H1N1)cell derived antigen assay	99 (96 to 100)	98 (94 to 100)
Prevaccination (H3N2)cell derived assay(N=141,144)	83 (76 to 89)	86 (79 to 91)
Day 29 (A/H3N2) cell derived antigen assay	100 (97 to 100)	100 (97 to 100)
Prevaccination (B) cell derived assay(N=141,144)	40 (32 to 49)	47 (38 to 55)
Day 29 (B) cell derived antigen assay	95 (90 to 98)	94 (89 to 98)

No statistical analyses for this end point

Secondary: 6) Percentage of 9-17 Year-old Children and Adolescents With Seroconversion or Significant Increase After 1 Dose of the Cell Culture-derived or the Egg-derived Influenza Vaccine

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End point title

6) Percentage of 9-17 Year-old Children and Adolescents With Seroconversion or Significant Increase After 1 Dose of the Cell Culture-derived or the Egg-derived Influenza Vaccine

End point description

Seroconversion or significant increase as per CHMP criteria is defined as percentage of subjects with a pre vaccination HI titer <10 to a post vaccination titer ≥40 or a pre vaccination HI titer ≥10 and a ≥4-fold increase in post vaccination HI antibody titer. According to the CHMP criteria, the percentage of subjects achieving seroconversion or significant increase should be >40%. According to the CBER criteria, the lower bound of the two-sided 95% CI for the percentage of subjects achieving seroconversion/significant increase should be ≥40%.

End point type

Secondary

End point timeframe

Day 29 post vaccination

End point values	Cohort 1 cTIV- (9-17 Years)- PPS	Cohort 1 eTIV- (9-17 Years)- PPS
Number of subjects analysed	142	144
Units: Percentage
number (confidence interval 95%)
Day 29 (A/H1N1) egg derived antigen assay	77 (70 to 84)	77 (69 to 84)
Day 29 (A/H3N2) egg derived antigen assay	56 (48 to 65)	77 (69 to 84)
Day 29 (B) egg derived antigen assay	56 (48 to 65)	71 (63 to 78)
Day29(A/H1N1)cell derived antigen assay(N=141,144)	74 (66 to 81)	74 (66 to 81)
Day29(A/H3N2)cell derived antigen assay(N=141,144)	52 (44 to 61)	78 (70 to 84)
Day29(B)cell derived antigen assay (N=141,144)	63 (55 to 71)	69 (61 to 76)

No statistical analyses for this end point

Secondary: 7) Geometric Mean Titers After Two Doses of the Cell Derived or the Egg Derived Vaccine in 3-8 Year-old Children

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End point title

7) Geometric Mean Titers After Two Doses of the Cell Derived or the Egg Derived Vaccine in 3-8 Year-old Children ^[15]

End point description

To evaluate immunogenicity in terms of Geometric Mean Titers (GMTs) in children 3-8 years of age after two doses of either cTIV vaccine or eTIV, administered 4 weeks apart. The analysis was performed on the per-protocol dataset.

End point type

Secondary

End point timeframe

Day 29 and Day 50 post vaccination

Notes
[15] - 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: There were no statistical analysis done to this endpoint.

End point values	Cohort 3 cTIV (3-8 years)	Cohort 3 eTIV (3-8 Years)
Number of subjects analysed	524	513
Units: Titers
geometric mean (confidence interval 95%)
Baseline (A/H1N1) egg derived antigen assay	16 (14 to 18)	15 (13 to 17)
Day29(A/H1N1)egg derived antigen assay(N=515,507)	152 (124 to 186)	157 (128 to 192)
Day50(A/H1N1)egg derived antigen assay	407 (358 to 462)	477 (419 to 542)
Baseline (A/H3N2) egg derived antigen assay	68 (58 to 80)	74 (63 to 87)
Day29(A/H3N2)egg derived antigen assay(N=515,507)	584 (478 to 713)	1075 (880 to 1312)
Day50(A/H3N2)egg derived antigen assay	768 (666 to 885)	1293 (1121 to 1491)
Baseline (B) egg derived antigen assay	6.16 (5.86 to 6.48)	6.24 (5.93 to 6.56)
Day29(B) egg derived antigen assay (N=515,507)	19 (16 to 22)	27 (23 to 33)
Day 50 (B) egg derived antigen assay	25 (21 to 29)	44 (38 to 51)
Baseline (A/H1N1) cell derived antigen assay	19 (16 to 22)	17 (14 to 19)
Day 29 (A/H1N1) cell derived antigen assay	234 (194 to 283)	192 (159 to 232)
Day50(A/H1N1)cell derived antigen assay(N=522,513)	563 (501 to 634)	610 (542 to 686)
Baseline (A/H3N2) cell derived antigen assay	75 (64 to 88)	85 (72 to 99)
Day 29 (A/H3N2) cell derived antigen assay	653 (536 to 795)	1099 (903 to 1339)
Day50(A/H3N2)cell derived antigen assay(N=522,513)	858 (744 to 990)	1329 (1152 to 1533)
Baseline (B) cell derived antigen assay	8.22 (7.59 to 8.9)	8.72 (8.05 to 9.45)
Day 29 (B) cell derived antigen assay	29 (24 to 36)	36 (30 to 44)
Day50 (B) cell derived antigen assay(N=522,513)	53 (46 to 62)	62 (53 to 72)

No statistical analyses for this end point

Secondary: 8) Geometric Mean Ratio After Two Doses of the Cell-derived or the Egg-derived Vaccine in 3-8 Year-old Children

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End point title

8) Geometric Mean Ratio After Two Doses of the Cell-derived or the Egg-derived Vaccine in 3-8 Year-old Children ^[16]

End point description

To evaluate immunogenicity in terms of Geometric Mean Ratio (GMR) in children 3-8 years of age after two doses of either the cTIV vaccine or the eTIV vaccine, administered 4 weeks apart according to the CHMP criteria. The criterion is met according to the European (CHMP) guideline if the mean geometric increase(GMR day 29/day 1 and GMR day 50/day 1) in HI antibody titer is >2.5 The analysis was performed on the per-protocol dataset.

End point type

Secondary

End point timeframe

Day 29 and Day 50 post vaccination

Notes
[16] - 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: There were no statistical analysis done to this endpoint.

End point values	Cohort 3 cTIV (3-8 years)	Cohort 3 eTIV (3-8 Years)
Number of subjects analysed	524	513
Units: Ratios
number (confidence interval 95%)
Day29 (A/H1N1)egg derived antigen assay(N=515,507)	9.58 (8.37 to 11)	11 (9.36 to 12)
Day 50 (A/H1N1) egg derived antigen assay	25 (23 to 28)	33 (29 to 36)
Day29 (A/H3N2)egg derived antigen assay(N=515,507)	8.65 (7.4 to 10)	15 (13 to 17)
Day 50 (A/H3N2) egg derived antigen assay	11 (9.84 to 13)	17 (15 to 20)
Day 29 (B) egg derived assay (N=515,507)	3.04 (2.59 to 3.57)	4.36 (3.71 to 5.12)
Day 50 (B) egg derived antigen assay	3.99 (3.49 to 4.57)	7.04 (6.15 to 8.07)
Day 29 (A/H1N1) cell derived antigen assay	13 (11 to 14)	12 (10 to 13)
Day50(A/H1N1)cell derived antigen assay(N=522,513)	30 (27 to 34)	37 (33 to 42)
Day 29 (A/H3N2) cell derived antigen assay	8.73 (7.54 to 10)	13 (11 to 15)
Day50(A/H3N2)cell derived antigen assay(N=522,513)	12 (10 to 13)	16 (14 to 18)
Day 29 (B) cell derived antigen assay	3.59 (3.08 to 4.19)	4.14 (3.55 to 4.82)
Day 50 (B) cell derived antigen assay(N=522,513)	6.5 (5.75 to 7.34)	7.06 (6.24 to 7.99)

No statistical analyses for this end point

Secondary: 9) Percentage of 3-8 Year-old Children Achieving HI Titers ≥ 40 After Two Doses of the Cell Culture Derived or the Egg Derived Influenza Vaccine.

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End point title

9) Percentage of 3-8 Year-old Children Achieving HI Titers ≥ 40 After Two Doses of the Cell Culture Derived or the Egg Derived Influenza Vaccine. ^[17]

End point description

To evaluate immunogenicity in terms of HI titers ≥40, in children 3-8 years of age after two doses of either cTIV vaccine or eTIV_f vaccine, administered 4 weeks apart. The criterion is met according to European (CHMP) guideline if the percentage of subjects achieving HI titers ≥40 is >70% and according to the US (CBER) guideline if the lower bound of the two sided 95%CI for percentage of subjects achieving HI titers ≥40 is ≥70%. The analysis was performed on the per-protocol dataset.

End point type

Secondary

End point timeframe

Day 29 and Day 50 post vaccination

Notes
[17] - 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: There were no statistical analysis done to this endpoint.

End point values	Cohort 3 cTIV (3-8 years)	Cohort 3 eTIV (3-8 Years)
Number of subjects analysed	524	513
Units: Percentage
number (confidence interval 95%)
Prevaccination (A/H1N1) egg derived antigen assay	35 (30 to 39)	31 (27 to 35)
Day29(A/H1N1)egg derived antigen assay (N=515,507)	72 (68 to 76)	68 (64 to 72)
Day 50 (A/H1N1) egg derived antigen assay	96 (94 to 98)	97 (95 to 98)
Prevaccination (A/H3N2) egg derived antigen assay	67 (62 to 71)	70 (66 to 74)
Day29(A/H3N2)egg derived antigen assay(N=515,507)	87 (84 to 90)	85 (82 to 88)
Day50 (A/H3N2) egg derived antigen assay	96 (94 to 98)	94 (91 to 96)
Prevaccination (B) egg derived antigen assay	4 (3 to 7)	4 (3 to 6)
Day 29 (B) egg derived antigen assay (N=515,507)	35 (30 to 39)	40 (36 to 45)
Day 50 (B) egg derived antigen assay	40 (35 to 44)	55 (51 to 95)
Prevaccination (A/H1N1) cell derived antigen assay	36 (32 to 40)	33 (29 to 38)
Day 29 (A/H1N1) cell derived antigen assay	82 (78 to 85)	76 (72 to 80)
Day50(A/H1N1)cell derived antigen assay(N=522,513)	98 (97 to 99)	98 (96 to 99)
Prevaccination (A/H3N2) cell derived antigen assay	71 (67 to 75)	75 (71 to 79)
Day 29 (A/H3N2) cell derived antigen assay	89 (86 to 92)	85 (82 to 88)
Day50(A/H3N2)cell derived antigen assay(N=522,513)	98 (96 to 99)	93 (91 to 95)
Prevaccination (B) cell derived antigen assay	11 (8 to 14)	12 (10 to 16)
Day 29 (B) cell derived antigen assay	43 (39 to 47)	45 (40 to 49)
Day 50 (B) cell derived antigen assay (N=522,513)	60 (56 to 65)	62 (57 to 66)

No statistical analyses for this end point

Secondary: 10) Percentage of 3-8 Year-old Children Achieving Seroconversion or Significant Increase in HI Titers After Two Doses of the Cell Culture-derived or the Egg-derived Influenza Vaccine.

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End point title

10) Percentage of 3-8 Year-old Children Achieving Seroconversion or Significant Increase in HI Titers After Two Doses of the Cell Culture-derived or the Egg-derived Influenza Vaccine. ^[18]

End point description

Seroconversion or significant increase as per CHMP criteria is defined as percentage of subjects with a pre vaccination HI titer <10 to a post vaccination titer ≥40 or a prevaccination HI titer ≥10 and a ≥4-fold increase in post vaccination HI antibody titer. According to the CHMP criteria, the percentage of subjects achieving seroconversion or significant increase should be >40%. According to the CBER criteria, the lower bound of the two-sided 95% CI for the percentage of subjects achieving seroconversion/significant increase should be ≥40%. The analysis was performed on the per-protocol dataset.

End point type

Secondary

End point timeframe

Day 29 and Day 50 post vaccination

Notes
[18] - 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: There were no statistical analysis done to this endpoint.

End point values	Cohort 3 cTIV (3-8 years)	Cohort 3 eTIV (3-8 Years)
Number of subjects analysed	524	513
Units: Percentage
number (confidence interval 95%)
Day29(A/H1N1) egg derived antigen assay(N=515,507)	70 (66 to 74)	67 (63 to 72)
Day 50 (H1N1) egg derived antigen assay	94 (92 to 96)	96 (94 to 97)
Day29(A/H3N2) egg derived antigen assay(N=515,507)	65 (61 to 70)	78 (74 to 81)
Day 50 (A/H3N2) egg derived antigen assay	77 (73 to 81)	86 (82 to 89)
Day29(B) egg derived antigen assay(N=515,507)	33 (29 to 37)	38 (34 to 43)
Day 50 (B) egg derived antigen assay	38 (34 to 42)	53 (49 to 58)
Day 29 (A/H1N1) cell derived antigen assay	79 (75 to 83)	75 (70 to 78)
Day50(A/H1N1)cell derived antigen assay(N=522,513)	96 (93 to 97)	96 (94 to 98)
Day 29 (A/H3N2) cell derived antigen assay	70 (66 to 74)	76 (72 to 80)
Day50(A/H3N2)cell derived antigen assay(N=522,513)	80 (76 to 83)	85 (82 to 88)
Day 29 (B) cell derived antigen assay	40 (36 to 44)	41 (37 to 45)
Day 50(B)cell derived antigen assay(N=522,513)	58 (54 to 63)	58 (54 to 63)

No statistical analyses for this end point

Secondary: 11) Number of 9-17 Year-old Children and Adolescents Reporting Local and Systemic Reactions After 1 Dose of the Cell Culture-derived or the Egg-derived Influenza Vaccine

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End point title

11) Number of 9-17 Year-old Children and Adolescents Reporting Local and Systemic Reactions After 1 Dose of the Cell Culture-derived or the Egg-derived Influenza Vaccine ^[19]

End point description

To evaluate safety and tolerability in terms of number of 9-17 year-old children and adolescents (cohorts 1 and 2)reporting local and systemic reactions following of one injection of the cTIV or the eTIV vaccine .

End point type

Secondary

End point timeframe

Up to 7 days after vaccination

Notes
[19] - 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: There were no statistical analysis done to this endpoint.

End point values	Cohort 1+2 cTIV (9-17 years)	Cohort 1+2 eTIV (9-17 years)
Number of subjects analysed	652	316
Units: Participants
Any Local	276	141
Injection site pain	220	120
Injection site erythema	91	45
Injection site induration	44	28
Injection site ecchymosis	34	10
Injection site swelling	32	17
Any Systemic	188	95
Chills	26	13
Malaise	60	34
Myalgia	99	59
Arthralgia	27	17
Headache	92	44
Sweating	14	3
Fatigue	57	41
Fever (≥38C) (N=651,316)	5	3
Any Other	44	37
Stayed at home (N=649,316)	9	10
Analgesic Medication Used	42	31

No statistical analyses for this end point

Secondary: 12) Number of 3-8 Year-old Children Reporting Local and Systemic Reactions After One and Two Doses of the Cell Culture-derived or Egg-derived Influenza Vaccine.

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End point title

12) Number of 3-8 Year-old Children Reporting Local and Systemic Reactions After One and Two Doses of the Cell Culture-derived or Egg-derived Influenza Vaccine. ^[20]

End point description

To evaluate the safety and tolerability of the cTIV and the eTIV_f influenza vaccines in 3-8 year-old children terms of number of participants reporting local and systemic reactions after each vaccination.

End point type

Secondary

End point timeframe

Up to 7 days after each vaccination

Notes
[20] - 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: There were no statistical analysis done to this endpoint.

End point values	Cohort 3 cTIV (3-8 years)	Cohort 3 eTIV (3-8 Years)
Number of subjects analysed	1599	1013
Units: Participants
number (not applicable)
Injection site pain	653	398
Injection site erythema	337	206
Injection site induration	141	84
Injection site ecchymosis	144	99
Injection site swelling	119	85
Chills	70	68
Malaise	156	117
Myalgia	202	119
Arthralgia	65	28
Headache	182	144
Sweating	47	28
Fatigue	210	170
Fever (≥ 38C)	75	60
Oral temp; 38 to <38.9 C (N=1598,1013)	48	43
Oral temp; 39 to < 40 C (N=1598,1013)	16	15
Oral temp; ≥ 40 C (N=1598,1013)	6	1
Stayed at home (N=1586, 1004))	77	63
Analgesic Medication Used	221	148

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Throughout the study period (Day 1-181 for Cohorts 1 and 2, and Day 1-209 for cohort 3)

Adverse event reporting additional description

Solicited AEs - day 1 through day 7 after vaccination. All AEs- day 1 through day 29 ( cohort 1&2); day 1 through day 50 (cohort 3). SAEs, onset of chronic illness, and AEs that lead to withdrawal from the study and associated concomitant medications-day 29 to day 181 (cohort 1&2); day 50 through day 209 (cohort 3)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

11.1

Reporting group title

Cohort 1 & 2 cTIV (9-17 years)

Reporting group description

All subjects aged 9-17 years received one 0.5 mL IM injection, of Cell Culture-derived trivalent influenza vaccine.

Reporting group title

Cohort 1 & 2 eTIV (9-17 years)

Reporting group description

All subjects aged 9-17 years received one 0.5 mL injection, of egg -derived trivalent influenza vaccine.

Reporting group title

Cohort 3 cTIV(3-8 years)-First vaccination

Reporting group description

All subjects aged 3-8 years received two 0.5 mL injections, administered four weeks apart, of Cell Culture-derived trivalent influenza vaccine.

Reporting group title

Cohort 3 eTIV(3-8 years)-First vaccination

Reporting group description

All subjects aged 3-8 years received two 0.5 mL injections, administered four weeks apart of egg - derived trivalent influenza vaccine.

Reporting group title

Cohort 3 cTIV(3-8 years)-Second vaccination

Reporting group description

All subjects aged 3-8 years received two 0.5 mL injections, administered four weeks apart, of Cell Culture-derived trivalent influenza vaccine.

Reporting group title

Cohort 3 eTIV(3-8 years)-Second vaccination

Reporting group description

All subjects aged 3-8 years received two 0.5 mL injections, administered four weeks apart of egg - derived trivalent influenza vaccine.

Serious adverse events	Cohort 1 & 2 cTIV (9-17 years)	Cohort 1 & 2 eTIV (9-17 years)	Cohort 3 cTIV(3-8 years)-First vaccination	Cohort 3 eTIV(3-8 years)-First vaccination	Cohort 3 cTIV(3-8 years)-Second vaccination	Cohort 3 eTIV(3-8 years)-Second vaccination
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 652 (0.77%)	3 / 316 (0.95%)	2 / 1599 (0.13%)	0 / 1013 (0.00%)	7 / 1557 (0.45%)	5 / 977 (0.51%)
number of deaths (all causes)	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0
Investigations
Body height below normal
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 652 (0.15%)	0 / 316 (0.00%)	0 / 1599 (0.00%)	0 / 1013 (0.00%)	0 / 1557 (0.00%)	0 / 977 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Concussion
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 652 (0.00%)	0 / 316 (0.00%)	0 / 1599 (0.00%)	0 / 1013 (0.00%)	2 / 1557 (0.13%)	0 / 977 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Contusion
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 652 (0.00%)	0 / 316 (0.00%)	1 / 1599 (0.06%)	0 / 1013 (0.00%)	1 / 1557 (0.06%)	0 / 977 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye injury
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 652 (0.00%)	0 / 316 (0.00%)	0 / 1599 (0.00%)	0 / 1013 (0.00%)	1 / 1557 (0.06%)	0 / 977 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Thalassaemia beta
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 652 (0.00%)	0 / 316 (0.00%)	0 / 1599 (0.00%)	0 / 1013 (0.00%)	1 / 1557 (0.06%)	0 / 977 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Tonsillectomy
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 652 (0.00%)	0 / 316 (0.00%)	0 / 1599 (0.00%)	0 / 1013 (0.00%)	0 / 1557 (0.00%)	1 / 977 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Post procedural haemorrhage
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 652 (0.00%)	0 / 316 (0.00%)	0 / 1599 (0.00%)	0 / 1013 (0.00%)	0 / 1557 (0.00%)	1 / 977 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 652 (0.15%)	0 / 316 (0.00%)	0 / 1599 (0.00%)	0 / 1013 (0.00%)	0 / 1557 (0.00%)	0 / 977 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Appendix disorder
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 652 (0.15%)	0 / 316 (0.00%)	0 / 1599 (0.00%)	0 / 1013 (0.00%)	0 / 1557 (0.00%)	0 / 977 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Ovarian torsion
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 652 (0.00%)	1 / 316 (0.32%)	0 / 1599 (0.00%)	0 / 1013 (0.00%)	0 / 1557 (0.00%)	0 / 977 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Bronchitis chronic
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 652 (0.00%)	0 / 316 (0.00%)	0 / 1599 (0.00%)	0 / 1013 (0.00%)	0 / 1557 (0.00%)	1 / 977 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Major depression
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 652 (0.15%)	0 / 316 (0.00%)	0 / 1599 (0.00%)	0 / 1013 (0.00%)	0 / 1557 (0.00%)	0 / 977 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abscess limb
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 652 (0.00%)	0 / 316 (0.00%)	0 / 1599 (0.00%)	0 / 1013 (0.00%)	0 / 1557 (0.00%)	1 / 977 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 652 (0.00%)	0 / 316 (0.00%)	0 / 1599 (0.00%)	0 / 1013 (0.00%)	1 / 1557 (0.06%)	1 / 977 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infectious mononucleosis
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 652 (0.00%)	0 / 316 (0.00%)	1 / 1599 (0.06%)	0 / 1013 (0.00%)	0 / 1557 (0.00%)	0 / 977 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 652 (0.00%)	1 / 316 (0.32%)	0 / 1599 (0.00%)	0 / 1013 (0.00%)	0 / 1557 (0.00%)	0 / 977 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Otitis media chronic
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 652 (0.00%)	0 / 316 (0.00%)	0 / 1599 (0.00%)	0 / 1013 (0.00%)	0 / 1557 (0.00%)	1 / 977 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic abscess
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 652 (0.15%)	0 / 316 (0.00%)	0 / 1599 (0.00%)	0 / 1013 (0.00%)	0 / 1557 (0.00%)	0 / 977 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngotonsillitis
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 652 (0.00%)	0 / 316 (0.00%)	0 / 1599 (0.00%)	0 / 1013 (0.00%)	1 / 1557 (0.06%)	0 / 977 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 652 (0.00%)	1 / 316 (0.32%)	0 / 1599 (0.00%)	0 / 1013 (0.00%)	0 / 1557 (0.00%)	0 / 977 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection viral
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 652 (0.00%)	0 / 316 (0.00%)	0 / 1599 (0.00%)	0 / 1013 (0.00%)	1 / 1557 (0.06%)	0 / 977 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Streptococcal bacteraemia
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 652 (0.00%)	1 / 316 (0.32%)	0 / 1599 (0.00%)	0 / 1013 (0.00%)	0 / 1557 (0.00%)	0 / 977 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 652 (0.15%)	0 / 316 (0.00%)	0 / 1599 (0.00%)	0 / 1013 (0.00%)	0 / 1557 (0.00%)	0 / 977 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 652 (0.15%)	0 / 316 (0.00%)	0 / 1599 (0.00%)	0 / 1013 (0.00%)	0 / 1557 (0.00%)	0 / 977 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diabetes mellitus
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 652 (0.00%)	0 / 316 (0.00%)	0 / 1599 (0.00%)	0 / 1013 (0.00%)	1 / 1557 (0.06%)	0 / 977 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Cohort 1 & 2 cTIV (9-17 years)	Cohort 1 & 2 eTIV (9-17 years)	Cohort 3 cTIV(3-8 years)-First vaccination	Cohort 3 eTIV(3-8 years)-First vaccination	Cohort 3 cTIV(3-8 years)-Second vaccination	Cohort 3 eTIV(3-8 years)-Second vaccination
Total subjects affected by non serious adverse events
subjects affected / exposed	328 / 652 (50.31%)	168 / 316 (53.16%)	799 / 1599 (49.97%)	507 / 1013 (50.05%)	670 / 1557 (43.03%)	413 / 977 (42.27%)
Nervous system disorders
Headache
subjects affected / exposed	99 / 652 (15.18%)	47 / 316 (14.87%)	143 / 1599 (8.94%)	111 / 1013 (10.96%)	94 / 1557 (6.04%)	73 / 977 (7.47%)
occurrences all number	125	56	167	135	110	89
General disorders and administration site conditions
Fatigue
subjects affected / exposed	57 / 652 (8.74%)	41 / 316 (12.97%)	155 / 1599 (9.69%)	119 / 1013 (11.75%)	99 / 1557 (6.36%)	82 / 977 (8.39%)
occurrences all number	67	47	171	143	110	92
Injection site erythema
subjects affected / exposed	91 / 652 (13.96%)	45 / 316 (14.24%)	197 / 1599 (12.32%)	138 / 1013 (13.62%)	209 / 1557 (13.42%)	118 / 977 (12.08%)
occurrences all number	94	45	198	139	211	121
Injection site haemorrhage
subjects affected / exposed	34 / 652 (5.21%)	10 / 316 (3.16%)	98 / 1599 (6.13%)	60 / 1013 (5.92%)	52 / 1557 (3.34%)	43 / 977 (4.40%)
occurrences all number	37	11	106	67	58	51
Injection site induration
subjects affected / exposed	44 / 652 (6.75%)	28 / 316 (8.86%)	87 / 1599 (5.44%)	44 / 1013 (4.34%)	66 / 1557 (4.24%)	51 / 977 (5.22%)
occurrences all number	44	29	89	45	66	51
Injection site pain
subjects affected / exposed	220 / 652 (33.74%)	120 / 316 (37.97%)	451 / 1599 (28.21%)	251 / 1013 (24.78%)	421 / 1557 (27.04%)	266 / 977 (27.23%)
occurrences all number	227	122	462	261	430	278
Malaise
alternative assessment type: Non-systematic
subjects affected / exposed	60 / 652 (9.20%)	34 / 316 (10.76%)	103 / 1599 (6.44%)	78 / 1013 (7.70%)	76 / 1557 (4.88%)	50 / 977 (5.12%)
occurrences all number	68	41	118	85	86	56
Pyrexia
subjects affected / exposed	12 / 652 (1.84%)	5 / 316 (1.58%)	88 / 1599 (5.50%)	73 / 1013 (7.21%)	63 / 1557 (4.05%)	44 / 977 (4.50%)
occurrences all number	13	7	96	84	70	49
Respiratory, thoracic and mediastinal disorders
Cough
alternative assessment type: Non-systematic
subjects affected / exposed	10 / 652 (1.53%)	4 / 316 (1.27%)	124 / 1599 (7.75%)	75 / 1013 (7.40%)	70 / 1557 (4.50%)	51 / 977 (5.22%)
occurrences all number	10	4	130	87	75	52
Musculoskeletal and connective tissue disorders
Myalgia
subjects affected / exposed	99 / 652 (15.18%)	59 / 316 (18.67%)	141 / 1599 (8.82%)	76 / 1013 (7.50%)	100 / 1557 (6.42%)	67 / 977 (6.86%)
occurrences all number	107	67	150	88	28	22

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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.

None reported

http://www.ncbi.nlm.nih.gov/pubmed/22301476

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 1) Non-inferiority of the Cell Culture-derived Vaccine to the Egg-derived Vaccine in 3-8 Years Old Children in Post Vaccination Geometric Mean Titers

Primary: 1) Non-inferiority of the Cell Culture-derived Vaccine to the Egg-derived Vaccine in 3-8 Years Old Children in Post Vaccination Geometric Mean Titers

Primary: 2) Non-inferiority of the Cell Culture-derived Vaccine to the Egg-derived Vaccine in 3-8 Years Old Children in the Percentage of Subjects Achieving Seroconversion or Significant Increase in Antibody Titers

Primary: 2) Non-inferiority of the Cell Culture-derived Vaccine to the Egg-derived Vaccine in 3-8 Years Old Children in the Percentage of Subjects Achieving Seroconversion or Significant Increase in Antibody Titers

Secondary: 3) Geometric Mean Titers After 1 Dose of the Cell Culture-derived or the Egg- derived Influenza Vaccine in 9-17 Years Old Children and Adolescents

Secondary: 3) Geometric Mean Titers After 1 Dose of the Cell Culture-derived or the Egg- derived Influenza Vaccine in 9-17 Years Old Children and Adolescents

Secondary: 4) Geometric Mean Ratio After 1 Dose of the Cell Culture-derived or the Egg-derived Influenza Vaccine in 9-17 Year-old Children and Adolescents.

Secondary: 4) Geometric Mean Ratio After 1 Dose of the Cell Culture-derived or the Egg-derived Influenza Vaccine in 9-17 Year-old Children and Adolescents.

Secondary: 5) Percentage of 9-17 Year-old Children and Adolescents Achieving HI Titers ≥40 After 1 Dose of the Cell Culture-derived or the Egg-derived Influenza Vaccine

Secondary: 5) Percentage of 9-17 Year-old Children and Adolescents Achieving HI Titers ≥40 After 1 Dose of the Cell Culture-derived or the Egg-derived Influenza Vaccine

Secondary: 6) Percentage of 9-17 Year-old Children and Adolescents With Seroconversion or Significant Increase After 1 Dose of the Cell Culture-derived or the Egg-derived Influenza Vaccine

Secondary: 6) Percentage of 9-17 Year-old Children and Adolescents With Seroconversion or Significant Increase After 1 Dose of the Cell Culture-derived or the Egg-derived Influenza Vaccine

Secondary: 7) Geometric Mean Titers After Two Doses of the Cell Derived or the Egg Derived Vaccine in 3-8 Year-old Children

Secondary: 7) Geometric Mean Titers After Two Doses of the Cell Derived or the Egg Derived Vaccine in 3-8 Year-old Children

Secondary: 8) Geometric Mean Ratio After Two Doses of the Cell-derived or the Egg-derived Vaccine in 3-8 Year-old Children

Secondary: 8) Geometric Mean Ratio After Two Doses of the Cell-derived or the Egg-derived Vaccine in 3-8 Year-old Children

Secondary: 9) Percentage of 3-8 Year-old Children Achieving HI Titers ≥ 40 After Two Doses of the Cell Culture Derived or the Egg Derived Influenza Vaccine.

Secondary: 9) Percentage of 3-8 Year-old Children Achieving HI Titers ≥ 40 After Two Doses of the Cell Culture Derived or the Egg Derived Influenza Vaccine.

Secondary: 10) Percentage of 3-8 Year-old Children Achieving Seroconversion or Significant Increase in HI Titers After Two Doses of the Cell Culture-derived or the Egg-derived Influenza Vaccine.

Secondary: 10) Percentage of 3-8 Year-old Children Achieving Seroconversion or Significant Increase in HI Titers After Two Doses of the Cell Culture-derived or the Egg-derived Influenza Vaccine.

Secondary: 11) Number of 9-17 Year-old Children and Adolescents Reporting Local and Systemic Reactions After 1 Dose of the Cell Culture-derived or the Egg-derived Influenza Vaccine

Secondary: 11) Number of 9-17 Year-old Children and Adolescents Reporting Local and Systemic Reactions After 1 Dose of the Cell Culture-derived or the Egg-derived Influenza Vaccine

Secondary: 12) Number of 3-8 Year-old Children Reporting Local and Systemic Reactions After One and Two Doses of the Cell Culture-derived or Egg-derived Influenza Vaccine.

Secondary: 12) Number of 3-8 Year-old Children Reporting Local and Systemic Reactions After One and Two Doses of the Cell Culture-derived or Egg-derived Influenza Vaccine.

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

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