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Clinical Trial Results:
A Randomized, Single-blind, Dose-Ranging Study to Evaluate Immunogenicity, Safety and Tolerability of Different Formulations of Adjuvanted and non-Adjuvanted Egg-derived, Inactivated Novel Swine Origin A/H1N1 Monovalent Subunit Influenza Virus Vaccine in Healthy Subjects from 6 Months to 17 Years of Age

Summary
EudraCT number	2009-013672-45
Trial protocol	NL DE BE
Global end of trial date	01 Jul 2011

Results information
Results version number	v2(current)
This version publication date	28 Jul 2016
First version publication date	07 Jan 2015
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

V111_03

ISRCTN number

US NCT number

NCT00971542

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Vaccines and Diagnostics S.r.l

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)

Yes

EMA paediatric investigation plan number(s)

EMEA-000599-PIP01-09

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 Oct 2011

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

01 Jul 2011

Was the trial ended prematurely?

Main objective of the trial

To identify the preferred vaccine formulation (with and without MF59), dosage (of antigen and adjuvant) and schedule (one or two administrations) of the egg-derived H1N1sw monovalent vaccine in healthy adults based on CHMP criteria and pairwise statistical comparisons for immunogenicity, and safety & tolerability.

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

05 Sep 2009

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy, Regulatory reason, Scientific research

Long term follow-up duration

18 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 31

Country: Number of subjects enrolled

Belgium: 201

Country: Number of subjects enrolled

Germany: 178

Country: Number of subjects enrolled

Chile: 208

Country: Number of subjects enrolled

Dominican Republic: 66

Worldwide total number of subjects

684

EEA total number of subjects

410

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)

236

Children (2-11 years)

353

Adolescents (12-17 years)

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 ten sites in Germany, two sites in Belgium, one site in the Netherlands, two sites in the Dominican Republic, two sites in Chile.

Screening details

All subjects enrolled were included in the trial.

Period 1 title

Per arm in the overall period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Single blind

Roles blinded

Subject

Are arms mutually exclusive

Yes

Cohort 1 (3.75_Half MF59)

Arm description

Subjects aged 9 to 17 years received 2 doses of H1N1 vaccine (3.75mcg HA + half MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an adjuvanted trivalent influenza vaccine (aTIV).

Arm type

Experimental

Investigational medicinal product name

Focetria

Investigational medicinal product code

N/A

Other name

N/A

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Vaccination consisted of two 0.25mLdoses of H1N1 vaccine (3.75mcg HA + half MF59) administered 3 weeks apart followed by one dose of 0.5mL booster vaccination with aTIV; all injections were administered IM.

Cohort 1 (7.5_Full MF59)

Arm description

Subjects aged 9 to 17 years received 2 doses of H1N1 vaccine (7.5mcg HA + full MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an adjuvanted trivalent influenza vaccine (aTIV).

Arm type

Experimental

Investigational medicinal product name

Focetria

Investigational medicinal product code

N/A

Other name

N/A

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Vaccination consisted of two 0.5mLdoses of H1N1 vaccine (7.5mcg HA + full MF59) administered 3 weeks apart followed by one dose of 0.5mL booster vaccination with aTIV; all injections were administered IM.

Cohort 2 (3.75_Half MF59)

Arm description

Subjects aged 3 to 8 years received 2 doses of H1N1 vaccine (3.75mcg HA + half MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Arm type

Experimental

Investigational medicinal product name

Focetria

Investigational medicinal product code

N/A

Other name

N/A

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Cohort 2 (7.5_Full MF59)

Arm description

Subjects aged 3 to 8 years received 2 doses of H1N1 vaccine (7.5mcg HA + full MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Arm type

Experimental

Investigational medicinal product name

Focetria

Investigational medicinal product code

N/A

Other name

N/A

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Vaccination consisted of two 0.5mL doses of H1N1 vaccine (7.5mcg HA + full MF59) administered 3 weeks apart followed by one dose of 0.5mL booster seasonal vaccination with aTIV; all injections were administered IM

Cohort 2 (15_No MF59)

Arm description

Subjects aged 3 to 8 years received 2 doses of H1N1 vaccine (15mcg HA + no MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Arm type

Experimental

Investigational medicinal product name

15_no MF59

Investigational medicinal product code

N/A

Other name

N/A

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Vaccination consisted of two 0.5mLdoses of H1N1 vaccine administered 3 weeks apart followed by one dose of 0.5mL booster vaccination with aTIV; all injections were administered IM

Cohort 3 (3.75_Half MF59)

Arm description

Subjects aged 12 to 35 months received 2 doses of H1N1 vaccine (3.75mcg HA + half MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Arm type

Experimental

Investigational medicinal product name

Focetria

Investigational medicinal product code

N/A

Other name

N/A

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Cohort 3 (7.5Full MF59)

Arm description

Subjects aged 12 to 35 months received 2 doses of H1N1 vaccine (7.5mcg HA + full MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Arm type

Experimental

Investigational medicinal product name

Focetria

Investigational medicinal product code

N/A

Other name

N/A

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Cohort 3 (15_No MF59)

Arm description

Subjects aged 12 to 35 months received 2 doses of H1N1 vaccine (1.5mcg HA + no MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Arm type

Experimental

Investigational medicinal product name

15_no MF59

Investigational medicinal product code

N/A

Other name

N/A

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Vaccination consisted of two 0.5mLdoses of H1N1 vaccine (15mcg HA + no MF59) administered 3 weeks apart followed by one dose of 0.5mL booster vaccination with aTIV; all injections were administered IM

Cohort 4 (3.75_Half MF59)

Arm description

Subjects aged 6 to 11 months received 2 doses of H1N1 vaccine (3.75mcg HA + half MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Arm type

Experimental

Investigational medicinal product name

Focetria

Investigational medicinal product code

N/A

Other name

N/A

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Vaccination consisted of two 0.25mLdoses of H1N1 vaccine (3.75mcg HA + half MF59) administered 3 weeks apart followed by one dose of 0.25mL booster vaccination with aTIV; all injections were administered IM.

Cohort 4 (7.5_Full MF59)

Arm description

Subjects aged 6 to 11 months received 2 doses of H1N1 vaccine (7.5mcg HA + full MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Arm type

Experimental

Investigational medicinal product name

Focetria

Investigational medicinal product code

N/A

Other name

N/A

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Vaccination consisted of two 0.5mLdoses of H1N1 vaccine (7.5mcg HA + full MF59) administered 3 weeks apart followed by one dose of 0.25mL booster vaccination with aTIV; all injections were administered IM.

Number of subjects in period 1	Cohort 1 (3.75_Half MF59)	Cohort 1 (7.5_Full MF59)	Cohort 2 (3.75_Half MF59)	Cohort 2 (7.5_Full MF59)	Cohort 2 (15_No MF59)	Cohort 3 (3.75_Half MF59)	Cohort 3 (7.5Full MF59)	Cohort 3 (15_No MF59)	Cohort 4 (3.75_Half MF59)	Cohort 4 (7.5_Full MF59)
Started	79	80	78	78	39	75	73	37	72	73
Completed	26	27	48	51	25	52	57	28	47	47
Not completed	53	53	30	27	14	23	16	9	25	26
Consent withdrawn by subject	6	6	7	5	6	10	10	2	4	11
Adverse Event	-	-	-	-	-	1	-	-	-	-
Administrative Reason	43	43	19	20	8	3	2	1	6	5
Adverse Events	-	-	-	-	-	-	-	-	2	1
Lost to follow-up	3	3	3	2	-	8	4	3	2	1
Unable to Classify	-	-	-	-	-	1	-	3	11	7
Protocol deviation	1	1	1	-	-	-	-	-	-	1

Baseline characteristics

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Reporting group title

Cohort 1 (3.75_Half MF59)

Reporting group description

Reporting group title

Cohort 1 (7.5_Full MF59)

Reporting group description

Reporting group title

Cohort 2 (3.75_Half MF59)

Reporting group description

Subjects aged 3 to 8 years received 2 doses of H1N1 vaccine (3.75mcg HA + half MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group title

Cohort 2 (7.5_Full MF59)

Reporting group description

Subjects aged 3 to 8 years received 2 doses of H1N1 vaccine (7.5mcg HA + full MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group title

Cohort 2 (15_No MF59)

Reporting group description

Subjects aged 3 to 8 years received 2 doses of H1N1 vaccine (15mcg HA + no MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group title

Cohort 3 (3.75_Half MF59)

Reporting group description

Subjects aged 12 to 35 months received 2 doses of H1N1 vaccine (3.75mcg HA + half MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group title

Cohort 3 (7.5Full MF59)

Reporting group description

Subjects aged 12 to 35 months received 2 doses of H1N1 vaccine (7.5mcg HA + full MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group title

Cohort 3 (15_No MF59)

Reporting group description

Subjects aged 12 to 35 months received 2 doses of H1N1 vaccine (1.5mcg HA + no MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group title

Cohort 4 (3.75_Half MF59)

Reporting group description

Subjects aged 6 to 11 months received 2 doses of H1N1 vaccine (3.75mcg HA + half MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group title

Cohort 4 (7.5_Full MF59)

Reporting group description

Subjects aged 6 to 11 months received 2 doses of H1N1 vaccine (7.5mcg HA + full MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group values	Cohort 1 (3.75_Half MF59)	Cohort 1 (7.5_Full MF59)	Cohort 2 (3.75_Half MF59)	Cohort 2 (7.5_Full MF59)	Cohort 2 (15_No MF59)	Cohort 3 (3.75_Half MF59)	Cohort 3 (7.5Full MF59)	Cohort 3 (15_No MF59)	Cohort 4 (3.75_Half MF59)	Cohort 4 (7.5_Full MF59)	Total
Number of subjects	79	80	78	78	39	75	73	37	72	73	684
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: months
arithmetic mean (standard deviation)	155.3 ( 30.6 )	156.4 ( 29.1 )	69.4 ( 21.3 )	71.8 ( 19.7 )	67.3 ( 21.2 )	24 ( 7.4 )	23.9 ( 6.4 )	25.1 ( 6.4 )	8.8 ( 1.3 )	8.3 ( 1.4 )	-
Gender categorical
Units: Subjects
Female	38	39	39	44	14	40	42	17	36	35	344
Male	41	41	39	34	25	35	31	20	36	38	340

End points

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Reporting group title

Cohort 1 (3.75_Half MF59)

Reporting group description

Reporting group title

Cohort 1 (7.5_Full MF59)

Reporting group description

Reporting group title

Cohort 2 (3.75_Half MF59)

Reporting group description

Subjects aged 3 to 8 years received 2 doses of H1N1 vaccine (3.75mcg HA + half MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group title

Cohort 2 (7.5_Full MF59)

Reporting group description

Subjects aged 3 to 8 years received 2 doses of H1N1 vaccine (7.5mcg HA + full MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group title

Cohort 2 (15_No MF59)

Reporting group description

Subjects aged 3 to 8 years received 2 doses of H1N1 vaccine (15mcg HA + no MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group title

Cohort 3 (3.75_Half MF59)

Reporting group description

Subjects aged 12 to 35 months received 2 doses of H1N1 vaccine (3.75mcg HA + half MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group title

Cohort 3 (7.5Full MF59)

Reporting group description

Subjects aged 12 to 35 months received 2 doses of H1N1 vaccine (7.5mcg HA + full MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group title

Cohort 3 (15_No MF59)

Reporting group description

Subjects aged 12 to 35 months received 2 doses of H1N1 vaccine (1.5mcg HA + no MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group title

Cohort 4 (3.75_Half MF59)

Reporting group description

Subjects aged 6 to 11 months received 2 doses of H1N1 vaccine (3.75mcg HA + half MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group title

Cohort 4 (7.5_Full MF59)

Reporting group description

Subjects aged 6 to 11 months received 2 doses of H1N1 vaccine (7.5mcg HA + full MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Subject analysis set title

Per protocol set- Day 43 All Cohorts (3.75_Half MF59)

Subject analysis set type

Per protocol

Subject analysis set description

All subjects who received all the relevant doses of vaccine correctly and provided evaluable serum samples at relevant time points (day 43) and who had no major protocol violations as pre-specified in the analysis plan

Subject analysis set title

Per protocol set- Day 43 All Cohorts (7.5_Full MF59)

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Per Protocol Set-Day 43 ALL Cohorts (15_No MF59)

Subject analysis set type

Per protocol

Subject analysis set description

Primary: Percentage of subjects achieving seroconversion against A/H1N1 Strain as measured by hemagglutination inhibition assay

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End point title

Percentage of subjects achieving seroconversion against A/H1N1 Strain as measured by hemagglutination inhibition assay

End point description

1) Immunogenicity was measured in terms of percentage of subjects achieving seroconversion or significant increase in HI titer against the vaccine strain, weeks after receiving 2 doses of vaccination according to CHMP criterion. 2) Seroconversion is defined as HI ≥1:40 for subjects negative at baseline (day 1) [<1:10]; a minimum 4-fold increase in HI titer for subjects positive at baseline(day 1) [HI≥1:10]) on Day 22, Day 43, Day366 and Day 387 and percentage of subjects achieving seroconversion on Day 387 referring to pre-booster values. 3) There are no predefined CHMP criteria for the pediatric population however, the criterion is met if the percentage of subjects achieving seroconversion or atleast 4-fold increase in HI antibody (at day 43) is >40%.

End point type

Primary

End point timeframe

Day 43

End point values	Cohort 1 (3.75_Half MF59)	Cohort 1 (7.5_Full MF59)	Cohort 2 (3.75_Half MF59)	Cohort 2 (7.5_Full MF59)	Cohort 2 (15_No MF59)	Cohort 3 (3.75_Half MF59)	Cohort 3 (7.5Full MF59)	Cohort 3 (15_No MF59)	Cohort 4 (3.75_Half MF59)	Cohort 4 (7.5_Full MF59)
Number of subjects analysed	65	70	66	60	34	60	58	31	55	49
Units: Percentages of subjects
number (confidence interval 95%)	92 (83 to 97)	94 (86 to 98)	97 (89 to 100)	98 (91 to 100)	85 (69 to 95)	100 (94 to 100)	100 (94 to 100)	74 (55 to 88)	96 (87 to 100)	98 (89 to 100)

Immune response in Cohort 1

Comparison groups

Cohort 1 (7.5_Full MF59) v Cohort 1 (3.75_Half MF59)

Number of subjects included in analysis

135

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

ANOVA

Parameter type

Vaccine Group Ratios

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-7

upper limit

Immune response in Cohort 2

Comparison groups

Cohort 2 (3.75_Half MF59) v Cohort 2 (7.5_Full MF59)

Number of subjects included in analysis

126

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

ANOVA

Parameter type

Vaccine Group Ratios

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Immune response in Cohort 2

Comparison groups

Cohort 2 (3.75_Half MF59) v Cohort 2 (15_No MF59)

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

ANOVA

Parameter type

Vaccine Group Ratios

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Immune response in Cohort 2

Comparison groups

Cohort 2 (7.5_Full MF59) v Cohort 2 (15_No MF59)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

ANOVA

Parameter type

Vaccine Group Ratios

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Immune response in Cohort 3

Comparison groups

Cohort 3 (3.75_Half MF59) v Cohort 3 (7.5Full MF59)

Number of subjects included in analysis

118

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

ANOVA

Parameter type

Vaccine Group Ratios

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Immune response in Cohort 3

Comparison groups

Cohort 3 (3.75_Half MF59) v Cohort 3 (15_No MF59)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

ANOVA

Parameter type

Vaccine Group Ratios

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Immune response in Cohort 3

Comparison groups

Cohort 3 (7.5Full MF59) v Cohort 3 (15_No MF59)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

ANOVA

Parameter type

Vaccine Group Ratios

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Immune response in Cohort 4

Comparison groups

Cohort 4 (3.75_Half MF59) v Cohort 4 (7.5_Full MF59)

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

ANOVA

Parameter type

Vaccine Group Ratios

Point estimate

-2

Confidence interval

level

95%

sides

2-sided

lower limit

-8

upper limit

Primary: Percentage of subjects achieving HI titers ≥1:40 agianst A/H1N1 Strain.

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End point title

Percentage of subjects achieving HI titers ≥1:40 agianst A/H1N1 Strain.

End point description

Immunogenicity was measured in terms of percentage of subjects achieving HI titers ≥1:40 against A/H1N1 strain, 3 weeks after receiving 2 doses of vaccination according to CHMP criterion. There are no predefined CHMP criteria for the pediatric population however, the criterion is met if the percentage of subjects achieving HI antibody titer ≥1:40 is >70% (at day 43).

End point type

Primary

End point timeframe

Day 1 and Day 43

End point values	Cohort 1 (3.75_Half MF59)	Cohort 1 (7.5_Full MF59)	Cohort 2 (3.75_Half MF59)	Cohort 2 (7.5_Full MF59)	Cohort 2 (15_No MF59)	Cohort 3 (3.75_Half MF59)	Cohort 3 (7.5Full MF59)	Cohort 3 (15_No MF59)	Cohort 4 (3.75_Half MF59)	Cohort 4 (7.5_Full MF59)
Number of subjects analysed	65	70	66	60	34	60	58	31	55	49
Units: Percentages of subjects
number (confidence interval 95%)
Day 1	14 (7 to 25)	17 (9 to 28)	12 (5 to 22)	18 (10 to 30)	24 (11 to 41)	18 (10 to 30)	24 (14 to 37)	26 (12 to 45)	22 (12 to 35)	22 (12 to 37)
Day 43	100 (94 to 100)	100 (95 to 100)	100 (95 to 100)	100 (94 to 100)	91 (76 to 98)	100 (94 to 100)	100 (94 to 100)	81 (63 to 93)	98 (90 to 100)	100 (93 to 100)

Immune response in Cohort 1

Statistical analysis description

The statistical significance for the differences in immune responses between vaccine groups on day 43 was calculated

Comparison groups

Cohort 1 (3.75_Half MF59) v Cohort 1 (7.5_Full MF59)

Number of subjects included in analysis

135

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

ANOVA

Parameter type

Vaccine Group Ratios

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Immune response in Cohort 2

Statistical analysis description

The statistical significance for the differences in immune responses between vaccine groups on day 43 was calculated

Comparison groups

Cohort 2 (3.75_Half MF59) v Cohort 2 (7.5_Full MF59)

Number of subjects included in analysis

126

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

ANOVA

Parameter type

Vaccine Group Ratios

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Immune response in Cohort 2

Comparison groups

Cohort 2 (3.75_Half MF59) v Cohort 2 (15_No MF59)

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

ANOVA

Parameter type

Vaccine Group Ratios

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Immune response in Cohort 2

Statistical analysis description

The statistical significance for the differences in immune responses between vaccine groups on day 43 was calculated

Comparison groups

Cohort 2 (7.5_Full MF59) v Cohort 2 (15_No MF59)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

ANOVA

Parameter type

Vaccine Group Ratios

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Immune response in Cohort 3

Statistical analysis description

The statistical significance for the differences in immune responses between vaccine groups on day 43 was calculated

Comparison groups

Cohort 3 (3.75_Half MF59) v Cohort 3 (7.5Full MF59)

Number of subjects included in analysis

118

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

ANOVA

Parameter type

Vaccine Group Ratios

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Immune response in Cohort 3

Statistical analysis description

The statistical significance for the differences in immune responses between vaccine groups on day 43 was calculated

Comparison groups

Cohort 3 (3.75_Half MF59) v Cohort 3 (15_No MF59)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

ANOVA

Parameter type

Vaccine Group Ratios

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Immune response in Cohort 3

Statistical analysis description

The statistical significance for the differences in immune responses between vaccine groups on day 43 was calculated

Comparison groups

Cohort 3 (7.5Full MF59) v Cohort 3 (15_No MF59)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

ANOVA

Parameter type

Vaccine Group Ratios

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Immune response in Cohort 4

Statistical analysis description

The statistical significance for the differences in immune responses between vaccine groups on day 43 was calculated

Comparison groups

Cohort 4 (3.75_Half MF59) v Cohort 4 (7.5_Full MF59)

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

ANOVA

Parameter type

Vaccine Group Ratios

Point estimate

-2

Confidence interval

level

95%

sides

2-sided

lower limit

-5

upper limit

Primary: Geometric mean Ratios against A/H1N1 strain following 2-dose vaccination schedule as determined by HI assay

Top of page

End point title

Geometric mean Ratios against A/H1N1 strain following 2-dose vaccination schedule as determined by HI assay

End point description

Immunogenicity was measured in terms of geometric mean ratios. The ratio of postvaccination to prevaccination HI GMTs, 3 weeks after second vaccination was reported. There are no predefined CHMP criteria for the pediatric population however, the criterion is met if the geometric mean ratio (day 43/day 1) in HI antibody titer is >2.5.

End point type

Primary

End point timeframe

Day 1 and Day 43

End point values	Cohort 1 (3.75_Half MF59)	Cohort 1 (7.5_Full MF59)	Cohort 2 (3.75_Half MF59)	Cohort 2 (7.5_Full MF59)	Cohort 2 (15_No MF59)	Cohort 3 (3.75_Half MF59)	Cohort 3 (7.5Full MF59)	Cohort 3 (15_No MF59)	Cohort 4 (3.75_Half MF59)	Cohort 4 (7.5_Full MF59)
Number of subjects analysed	65	70	66	60	34	60	58	31	55	49
Units: Ratios
geometric mean (confidence interval 95%)
Day 43/Day 1	53 (34 to 84)	90 (58 to 142)	88 (56 to 138)	81 (50 to 132)	20 (11 to 35)	91 (51 to 162)	80 (44 to 146)	12 (6.43 to 21)	79 (44 to 142)	121 (66 to 225)

Immune response in Cohort 1

Statistical analysis description

The statistical significance for the differences in immune responses between vaccine groups on day 43 was calculated

Comparison groups

Cohort 1 (3.75_Half MF59) v Cohort 1 (7.5_Full MF59)

Number of subjects included in analysis

135

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

ANOVA

Parameter type

Vaccine Group Ratios

Point estimate

0.59

Confidence interval

level

95%

sides

2-sided

lower limit

0.38

upper limit

0.92

Immune response in Cohort 2

Statistical analysis description

The statistical significance for the differences in immune responses between vaccine groups on day 43 was calculated

Comparison groups

Cohort 2 (7.5_Full MF59) v Cohort 2 (3.75_Half MF59)

Number of subjects included in analysis

126

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

ANOVA

Parameter type

Vaccine Group Ratios

Point estimate

1.08

Confidence interval

level

95%

sides

2-sided

lower limit

0.67

upper limit

1.75

Immune response in Cohort 2

Statistical analysis description

The statistical significance for the differences in immune responses between vaccine groups on day 43 was calculated

Comparison groups

Cohort 2 (3.75_Half MF59) v Cohort 2 (15_No MF59)

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

ANOVA

Parameter type

Vaccine Group Ratios

Point estimate

4.41

Confidence interval

level

95%

sides

2-sided

lower limit

2.49

upper limit

7.81

Immune response in Cohort 2

Statistical analysis description

The statistical significance for the differences in immune responses between vaccine groups on day 43 was calculated

Comparison groups

Cohort 2 (7.5_Full MF59) v Cohort 2 (15_No MF59)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

ANOVA

Parameter type

Vaccine Group Ratios

Point estimate

4.08

Confidence interval

level

95%

sides

2-sided

lower limit

2.28

upper limit

7.31

Immune response in Cohort 3

Statistical analysis description

The statistical significance for the differences in immune responses between vaccine groups on day 43 was calculated

Comparison groups

Cohort 3 (3.75_Half MF59) v Cohort 3 (7.5Full MF59)

Number of subjects included in analysis

118

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

ANOVA

Parameter type

Vaccine Group Ratios

Point estimate

1.13

Confidence interval

level

95%

sides

2-sided

lower limit

0.71

upper limit

1.82

Immune response in Cohort 3

Statistical analysis description

The statistical significance for the differences in immune responses between vaccine groups on day 43 was calculated

Comparison groups

Cohort 3 (3.75_Half MF59) v Cohort 3 (15_No MF59)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

ANOVA

Parameter type

Vaccine Group Ratios

Point estimate

7.72

Confidence interval

level

95%

sides

2-sided

lower limit

4.35

upper limit

Immune response in Cohort 3

Statistical analysis description

The statistical significance for the differences in immune responses between vaccine groups on day 43 was calculated

Comparison groups

Cohort 3 (7.5Full MF59) v Cohort 3 (15_No MF59)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

ANOVA

Parameter type

Vaccine Group Ratios

Point estimate

6.81

Confidence interval

level

95%

sides

2-sided

lower limit

3.82

upper limit

Immune response in Cohort 4

Statistical analysis description

The statistical significance for the differences in immune responses between vaccine groups on day 43 was calculated

Comparison groups

Cohort 4 (3.75_Half MF59) v Cohort 4 (7.5_Full MF59)

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

ANOVA

Parameter type

Vaccine Group Ratios

Point estimate

0.65

Confidence interval

level

95%

sides

2-sided

lower limit

0.32

upper limit

1.32

Primary: Number of Subjects Reporting Solicited Local and Systemic Adverse Events, After Primary Vaccination

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End point title

Number of Subjects Reporting Solicited Local and Systemic Adverse Events, After Primary Vaccination ^[1]

End point description

Safety was assessed as the number of subjects who reported solicited local and systemic adverse events, 3 weeks after the primary course with H1N1sw monovalent vaccine

End point type

Primary

End point timeframe

From day 1 through day 7 after any vaccination

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses for this end point

End point values	Cohort 1 (3.75_Half MF59)	Cohort 1 (7.5_Full MF59)	Cohort 2 (3.75_Half MF59)	Cohort 2 (7.5_Full MF59)	Cohort 2 (15_No MF59)	Cohort 3 (3.75_Half MF59)	Cohort 3 (7.5Full MF59)	Cohort 3 (15_No MF59)	Cohort 4 (3.75_Half MF59)	Cohort 4 (7.5_Full MF59)
Number of subjects analysed	79	80	78	77	39	75	73	37	72	73
Units: Number
Ecchymosis	7	6	7	8	4	8	7	2	3	2
Erythema	11	9	16	20	5	21	18	7	15	18
Induration	10	12	6	4	4	4	8	2	3	2
Swelling	7	7	3	8	3	3	2	1	2	1
Pain	42	48	29	40	10	0	0	0	0	0
Tenderness	0	0	0	0	0	26	25	8	11	18
Chills	2	3	3	3	4	0	0	0	0	0
Malaise	8	10	12	10	4	0	0	0	0	0
Myalgia	12	17	6	10	3	0	0	0	0	0
Arthralgia	4	5	3	6	3	0	0	0	0	0
Headache	16	14	7	15	1	0	0	0	0	0
Sweating	1	1	1	2	3	0	0	0	0	0
Fatigue	14	19	21	13	8	0	0	0	0	0
Nausea	3	4	9	4	1	0	0	0	0	0
Sleepiness	0	0	0	0	0	29	21	11	30	34
Diarrhea	0	0	0	0	0	18	15	9	21	23
Vomiting	0	0	0	0	0	7	4	4	10	11
Irritability	0	0	0	0	0	21	21	10	22	20
Change in eating	0	0	0	0	0	18	14	6	18	20
Shivering	0	0	0	0	0	8	7	4	6	5
Unusual Crying	0	0	0	0	0	23	21	9	26	24
Fever (≥38°C)	2	2	3	3	2	7	11	3	9	10
Temp (°C) ≥40.0°C	0	0	0	0	0	0	0	0	1	0
Stayed Home	3	3	4	6	3	11	8	2	8	8
Analg. Antipyr.	4	10	10	9	5	11	14	8	22	23

No statistical analyses for this end point

Primary: Number of Subjects Reporting Solicited Local and Systemic Adverse Events, After booster Vaccination

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End point title

Number of Subjects Reporting Solicited Local and Systemic Adverse Events, After booster Vaccination ^[2]

End point description

Safety was assessed as the number of subjects who reported solicited local and systemic adverse events following booster vaccination, 12 months (day 366) after the first dose of primary vaccination.

End point type

Primary

End point timeframe

From day 366 through day 373.

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses for this end point

End point values	Cohort 1 (3.75_Half MF59)	Cohort 1 (7.5_Full MF59)	Cohort 2 (3.75_Half MF59)	Cohort 2 (7.5_Full MF59)	Cohort 2 (15_No MF59)	Cohort 3 (3.75_Half MF59)	Cohort 3 (7.5Full MF59)	Cohort 3 (15_No MF59)	Cohort 4 (3.75_Half MF59)	Cohort 4 (7.5_Full MF59)
Number of subjects analysed	26	27	48	52	25	52	57	29	50	49
Units: Number
Ecchymosis	1	1	3	5	3	5	5	1	4	4
Erythema	5	5	17	15	6	20	16	3	14	15
Induration	6	5	9	14	3	16	10	2	9	12
Swelling	5	4	5	10	3	12	7	2	6	8
Pain	22	22	34	37	16	0	0	0	0	0
Tenderness	0	0	0	0	0	25	23	10	17	19
Chills	1	4	3	8	1	0	0	0	0	0
Malaise	7	4	8	9	2	0	0	0	0	0
Myalgia	10	11	9	16	2	0	0	0	0	0
Arthralgia	5	7	4	8	2	0	0	0	0	0
Headache	4	13	4	15	4	0	0	0	0	0
Sweating	2	7	3	3	0	0	0	0	0	0
Fatigue	7	7	10	10	3	0	0	0	0	0
Nausea	4	5	4	7	3	0	0	0	0	0
Sleepiness	0	0	0	0	0	7	5	4	8	13
Diarrhea	0	0	0	0	0	4	5	2	9	8
Vomiting	0	0	0	0	0	2	6	1	3	6
Irritability	0	0	0	0	0	13	12	5	14	17
Change in eating habits	0	0	0	0	0	5	3	4	10	13
Shivering	0	0	0	0	0	2	4	2	4	4
Unusual Crying	0	0	0	0	0	11	10	5	16	13
Fever (≥ 38C)	1	1	3	6	0	6	11	2	12	11
temperature(<38°C)	25	26	45	46	25	46	46	27	38	38
temperature ≥40°C	0	0	0	0	0	0	0	0	0	0
Stayed home	3	2	6	9	1	6	5	1	6	8
Anti./Ana. Med	1	6	6	8	4	13	14	4	15	20

No statistical analyses for this end point

Primary: Number of Subjects Reporting Unsolicited Adverse Events after primary and booster vaccination.

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End point title

Number of Subjects Reporting Unsolicited Adverse Events after primary and booster vaccination. ^[3]

End point description

Safety was assessed as the number of subjects who reported unsolicited adverse events after primary vaccination and following booster vaccination, 12 months (day 366) after the first dose of primary vaccination. For subjects aged <9 years of age at the time of booster received a second dose of seasonal vaccine on day 387. All AEs were collected from day 1 to day 43 after primary vaccination, from day 366 through day 387 after vaccination and day 387 to day 546 for subjects who receive second dose of seasonal vaccine.

End point type

Primary

End point timeframe

Day 1 through day 43, day 366 through day 387, day 387 through day 546.

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses for this end point

End point values	Cohort 1 (3.75_Half MF59)	Cohort 1 (7.5_Full MF59)	Cohort 2 (3.75_Half MF59)	Cohort 2 (7.5_Full MF59)	Cohort 2 (15_No MF59)	Cohort 3 (3.75_Half MF59)	Cohort 3 (7.5Full MF59)	Cohort 3 (15_No MF59)	Cohort 4 (3.75_Half MF59)	Cohort 4 (7.5_Full MF59)
Number of subjects analysed	79	80	77	77	39	75	73	37	72	73
Units: Number
Any AE (Primary Vaccination)	27	30	36	32	17	45	42	19	43	43
Atleast Possibly Related AEs (Primary Vaccination)	5	15	8	9	4	8	6	2	11	12
Any AE N=84,85,78,82,38,63,68,35,68,62	4	1	12	10	4	19	14	7	18	17
Atleast Possibly AEN=84,85,78,82,38,63,68,35,68,62	1	0	2	2	1	4	2	0	5	2
Any AE N= 26,27,48,51,25,52,57,28,47,47	0	0	0	0	0	0	0	0	0	0
Atleast Possibly AEN=26,27,48,51,25,52,57,28,47,47	0	0	0	0	0	0	0	0	0	0

No statistical analyses for this end point

Primary: Number of Subjects Reporting Unsolicited Adverse Events

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End point title

Number of Subjects Reporting Unsolicited Adverse Events ^[4]

End point description

Safety was assessed as the number of subjects who reported unsolicited adverse events. For subjects aged <9 years of age at the time of vaccination received a second dose of a seasonal vaccine on day 387. SAEs, new onset of chronic diseases, AEs leading to withdrawal from the study were collected from day 1 to day 546 following 2-dose vaccination H1N1sw monovalent vaccine

End point type

Primary

End point timeframe

All AEs, SAEs, NOCDs, AEs leading to withdrawal-were collected through day 1 to day 546

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses for this end point

End point values	Cohort 1 (3.75_Half MF59)	Cohort 1 (7.5_Full MF59)	Cohort 2 (3.75_Half MF59)	Cohort 2 (7.5_Full MF59)	Cohort 2 (15_No MF59)	Cohort 3 (3.75_Half MF59)	Cohort 3 (7.5Full MF59)	Cohort 3 (15_No MF59)	Cohort 4 (3.75_Half MF59)	Cohort 4 (7.5_Full MF59)
Number of subjects analysed	79	80	77	77	39	75	73	37	72	73
Units: Numbers
Any SAEs	6	3	3	4	2	7	3	2	8	6
At least possibly related SAEs	0	0	0	0	0	0	0	0	0	0
AEs leading to discontinuation	0	0	0	0	0	1	0	0	2	1
New onset of chronic disease	1	2	2	3	1	1	1	1	5	1

No statistical analyses for this end point

Secondary: Percentage of subjects achieving seroconversion against A/H1N1 Strain following a booster dose as measured by hemagglutination inhibition (HI) assay

Top of page

End point title

Percentage of subjects achieving seroconversion against A/H1N1 Strain following a booster dose as measured by hemagglutination inhibition (HI) assay

End point description

Immunogenicity was measured in terms of percentage of subjects achieving seroconversion or significant increase in HI titer against the A/H1N1 strain, after a booster dose with aTIV, administered 12 months after primary vaccination according to CHMP criterion. At least one CHMP criterion as assessed three weeks after the booster dose should be met within each age cohort to fulfill regulatory requirements.

End point type

Secondary

End point timeframe

Day 387 (3 weeks post booster vaccination)

End point values	Cohort 1 (3.75_Half MF59)	Cohort 1 (7.5_Full MF59)	Cohort 2 (3.75_Half MF59)	Cohort 2 (7.5_Full MF59)	Cohort 2 (15_No MF59)	Cohort 3 (3.75_Half MF59)	Cohort 3 (7.5Full MF59)	Cohort 3 (15_No MF59)	Cohort 4 (3.75_Half MF59)	Cohort 4 (7.5_Full MF59)
Number of subjects analysed	23	23	36	37	22	44	42	23	26	30
Units: Percentages of subjects
number (confidence interval 95%)	83 (61 to 95)	61 (39 to 80)	92 (78 to 98)	95 (82 to 99)	95 (77 to 100)	80 (65 to 90)	86 (71 to 95)	78 (56 to 93)	81 (61 to 93)	77 (58 to 90)

No statistical analyses for this end point

Secondary: Percentage of subjects achieving HI titers ≥1:40 agianst A/H1N1 Strain following a booster dose.

Top of page

End point title

Percentage of subjects achieving HI titers ≥1:40 agianst A/H1N1 Strain following a booster dose.

End point description

Immunogenicity was measured in terms of percentage of subjects achieving HI titers ≥1:40 against A/H1N1 strain after a booster dose with aTIV, administered 12 months after primary vaccination according to CHMP criterion. At least one CHMP criterion as assessed three weeks after the booster dose should be met within each age cohort to fulfill regulatory requirement

End point type

Secondary

End point timeframe

Day 366 and Day 387

End point values	Cohort 1 (3.75_Half MF59)	Cohort 1 (7.5_Full MF59)	Cohort 2 (3.75_Half MF59)	Cohort 2 (7.5_Full MF59)	Cohort 2 (15_No MF59)	Cohort 3 (3.75_Half MF59)	Cohort 3 (7.5Full MF59)	Cohort 3 (15_No MF59)	Cohort 4 (3.75_Half MF59)	Cohort 4 (7.5_Full MF59)
Number of subjects analysed	26	27	46	44	25	48	54	26	38	35
Units: Percentages of subjects
number (confidence interval 95%)
Day 366	96 (80 to 100)	100 (87 to 100)	85 (71 to 94)	100 (92 to 100)	64 (43 to 82)	98 (89 to 100)	98 (90 to 100)	62 (41 to 80)	95 (82 to 99)	100 (90 to 100)
Day 387 (N=23,23,36,37,22,44,42,23,26,30)	100 (85 to 100)	100 (85 to 100)	100 (90 to 100)	100 (91 to 100)	100 (85 to 100)	100 (92 to 100)	100 (92 to 100)	100 (85 to 100)	100 (87 to 100)	100 (88 to 100)

No statistical analyses for this end point

Secondary: Geometric mean Ratios against A/H1N1 strain following a booster dose as determined by HI assay.

Top of page

End point title

Geometric mean Ratios against A/H1N1 strain following a booster dose as determined by HI assay.

End point description

Immunogenicity was measured in terms of geometric mean ratios. The ratio of postvaccination to prevaccination HI GMTs after a booster dose with aTIV, administered 12 months after primary vaccination according to CHMP criterion was assessed

End point type

Secondary

End point timeframe

Day 366 and Day 387

End point values	Cohort 1 (3.75_Half MF59)	Cohort 1 (7.5_Full MF59)	Cohort 2 (3.75_Half MF59)	Cohort 2 (7.5_Full MF59)	Cohort 2 (15_No MF59)	Cohort 3 (3.75_Half MF59)	Cohort 3 (7.5Full MF59)	Cohort 3 (15_No MF59)	Cohort 4 (3.75_Half MF59)	Cohort 4 (7.5_Full MF59)
Number of subjects analysed	23	23	36	37	22	44	42	23	26	30
Units: Ratios
geometric mean (confidence interval 95%)
Day 387/Day 366	9.52 (4.57 to 20)	5.28 (2.48 to 11)	18 (12 to 29)	13 (8.3 to 19)	17 (10 to 28)	12 (5.82 to 24)	9.14 (4.5 to 19)	31 (15 to 64)	14 (8.43 to 24)	8.11 (5.03 to 13)

No statistical analyses for this end point

Secondary: Geometric mean titers against A/H1N1 strain as determined by HI assay in pooled population

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End point title

Geometric mean titers against A/H1N1 strain as determined by HI assay in pooled population

End point description

Immunogenicity was measured in terms of geometric mean titers against A/H1N1 strain, 3 weeks after second vaccination in pooled children population

End point type

Secondary

End point timeframe

Day 1 and Day 43

End point values	Per protocol set- Day 43 All Cohorts (3.75_Half MF59)	Per protocol set- Day 43 All Cohorts (7.5_Full MF59)
Number of subjects analysed	246	237
Units: Titers
geometric mean (confidence interval 95%)
Day 1	11 (7.78 to 15)	12 (9 to 17)
Day 43	871 (711 to 1067)	1213 (987 to 1490)

Difference in HI GMTs of half and full dose MF59

Statistical analysis description

To demonstrate the non-inferiority of immune response in terms of GMTs in subjects receiving 3.75 HA and half MF59, versus subjects receiving 7.5 HA and full MF59, 3 weeks after second vaccination

Comparison groups

Per protocol set- Day 43 All Cohorts (3.75_Half MF59) v Per protocol set- Day 43 All Cohorts (7.5_Full MF59)

Number of subjects included in analysis

483

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[5]

Method

ANOVA

Parameter type

Vaccine Group ratios

Point estimate

0.72

Confidence interval

level

95%

sides

2-sided

lower limit

0.6

upper limit

0.86

Notes
[5] - Non-inferiority will be concluded if the lower limit of the two sided 95% CI for the between group difference (3.75_Half MF59-7.5_Full MF59) in terms of post-immunization GMTs (at day 43) is higher or equal to 0.5. If the hypothesis above can be rejected the same non-inferiority hypothesis were to be tested using a non-inferiority margin of 0.67

Adverse events

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Timeframe for reporting adverse events

Day 1 to Day 546

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

14.0

Reporting group title

Cohort 1 (3.75_Half MF59)

Reporting group description

Reporting group title

Cohort 1 (7.5_Full MF59)

Reporting group description

Reporting group title

Cohort 2 (3.75_Half MF59)

Reporting group description

Subjects aged 3 to 8 years received 2 doses of H1N1 vaccine (3.75mcg HA + half MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group title

Cohort 2 (7.5_Full MF59)

Reporting group description

Subjects aged 3 to 8 years received 2 doses of H1N1 vaccine (7.5mcg HA + full MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group title

Cohort 2 (15_No MF59)

Reporting group description

Subjects aged 3 to 8 years received 2 doses of H1N1 vaccine (15mcg HA + no MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group title

Cohort 3 (3.75_Half MF59)

Reporting group description

Subjects aged 12 to 35 months received 2 doses of H1N1 vaccine (3.75mcg HA + half MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group title

Cohort 3 (7.5Full MF59)

Reporting group description

Subjects aged 12 to 35 months received 2 doses of H1N1 vaccine (7.5mcg HA + full MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group title

Cohort 3 (15_No MF59)

Reporting group description

Subjects aged 12 to 35 months received 2 doses of H1N1 vaccine (1.5mcg HA + no MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group title

Cohort 4 (3.75_Half MF59)

Reporting group description

Subjects aged 6 to 11 months received 2 doses of H1N1 vaccine (3.75mcg HA + half MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group title

Cohort 4 (7.5_Full MF59)

Reporting group description

Subjects aged 6 to 11 months received 2 doses of H1N1 vaccine (7.5mcg HA + full MF59) administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Serious adverse events	Cohort 1 (3.75_Half MF59)	Cohort 1 (7.5_Full MF59)	Cohort 2 (3.75_Half MF59)	Cohort 2 (7.5_Full MF59)	Cohort 2 (15_No MF59)	Cohort 3 (3.75_Half MF59)	Cohort 3 (7.5Full MF59)	Cohort 3 (15_No MF59)	Cohort 4 (3.75_Half MF59)	Cohort 4 (7.5_Full MF59)
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 94 (6.38%)	3 / 95 (3.16%)	3 / 89 (3.37%)	4 / 87 (4.60%)	2 / 44 (4.55%)	7 / 83 (8.43%)	4 / 81 (4.94%)	2 / 42 (4.76%)	8 / 81 (9.88%)	6 / 81 (7.41%)
number of deaths (all causes)	0	0	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events
Investigations
PNEUMONIA VIRAL
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	0 / 83 (0.00%)	0 / 81 (0.00%)	0 / 42 (0.00%)	0 / 81 (0.00%)	1 / 81 (1.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
LOWER LIMB FRACTURE
subjects affected / exposed	1 / 94 (1.06%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	0 / 83 (0.00%)	0 / 81 (0.00%)	0 / 42 (0.00%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
PATELLA FRACTURE
subjects affected / exposed	1 / 94 (1.06%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	0 / 83 (0.00%)	0 / 81 (0.00%)	0 / 42 (0.00%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
ACCIDENTAL EXPOSURE
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	1 / 83 (1.20%)	0 / 81 (0.00%)	0 / 42 (0.00%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
FACE INJURY
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	1 / 83 (1.20%)	0 / 81 (0.00%)	0 / 42 (0.00%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
FACIAL BONES FRACTURE
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	1 / 83 (1.20%)	0 / 81 (0.00%)	0 / 42 (0.00%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
FALL
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	1 / 83 (1.20%)	0 / 81 (0.00%)	0 / 42 (0.00%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
SKULL FRACTURE
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	1 / 83 (1.20%)	0 / 81 (0.00%)	0 / 42 (0.00%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
TONSILLAR HYPERTROPHY
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	1 / 89 (1.12%)	1 / 87 (1.15%)	0 / 44 (0.00%)	0 / 83 (0.00%)	0 / 81 (0.00%)	0 / 42 (0.00%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
ADENOTONSILLECTOMY
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	1 / 87 (1.15%)	0 / 44 (0.00%)	0 / 83 (0.00%)	0 / 81 (0.00%)	0 / 42 (0.00%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
CIRCUMCISION
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	0 / 83 (0.00%)	1 / 81 (1.23%)	0 / 42 (0.00%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
FEBRILE CONVULSION
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	1 / 83 (1.20%)	0 / 81 (0.00%)	0 / 42 (0.00%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
CONSTIPATION
subjects affected / exposed	1 / 94 (1.06%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	1 / 44 (2.27%)	0 / 83 (0.00%)	0 / 81 (0.00%)	1 / 42 (2.38%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIARRHOEA
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	1 / 83 (1.20%)	0 / 81 (0.00%)	0 / 42 (0.00%)	1 / 81 (1.23%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0	0 / 0	0 / 0	0 / 0
HAEMATOCHEZIA
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	1 / 83 (1.20%)	0 / 81 (0.00%)	0 / 42 (0.00%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
ADENOIDAL HYPERTROPHY
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	1 / 89 (1.12%)	1 / 87 (1.15%)	0 / 44 (0.00%)	0 / 83 (0.00%)	0 / 81 (0.00%)	0 / 42 (0.00%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
ASTHMA
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	2 / 89 (2.25%)	0 / 87 (0.00%)	0 / 44 (0.00%)	0 / 83 (0.00%)	0 / 81 (0.00%)	0 / 42 (0.00%)	2 / 81 (2.47%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ASTHMATIC CRISIS
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	0 / 83 (0.00%)	0 / 81 (0.00%)	0 / 42 (0.00%)	1 / 81 (1.23%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
INTERSTITIAL LUNG DISEASE
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	0 / 83 (0.00%)	0 / 81 (0.00%)	0 / 42 (0.00%)	1 / 81 (1.23%)	1 / 81 (1.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
ABNORMAL BEHAVIOUR
subjects affected / exposed	1 / 94 (1.06%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	0 / 83 (0.00%)	0 / 81 (0.00%)	0 / 42 (0.00%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
APPENDICITIS
subjects affected / exposed	1 / 94 (1.06%)	1 / 95 (1.05%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	0 / 83 (0.00%)	0 / 81 (0.00%)	0 / 42 (0.00%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
CHRONIC TONSILLITIS
subjects affected / exposed	1 / 94 (1.06%)	1 / 95 (1.05%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	0 / 83 (0.00%)	0 / 81 (0.00%)	0 / 42 (0.00%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
GASTROENTERITIS
subjects affected / exposed	2 / 94 (2.13%)	0 / 95 (0.00%)	0 / 89 (0.00%)	2 / 87 (2.30%)	1 / 44 (2.27%)	0 / 83 (0.00%)	0 / 81 (0.00%)	0 / 42 (0.00%)	1 / 81 (1.23%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SALPINGITIS
subjects affected / exposed	0 / 94 (0.00%)	1 / 95 (1.05%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	0 / 83 (0.00%)	0 / 81 (0.00%)	0 / 42 (0.00%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	1 / 87 (1.15%)	0 / 44 (0.00%)	0 / 83 (0.00%)	0 / 81 (0.00%)	0 / 42 (0.00%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0	0 / 0	0 / 0	0 / 0
PYELONEPHRITIS
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	1 / 87 (1.15%)	0 / 44 (0.00%)	0 / 83 (0.00%)	0 / 81 (0.00%)	0 / 42 (0.00%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
BRONCHIOLITIS
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	0 / 83 (0.00%)	0 / 81 (0.00%)	1 / 42 (2.38%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	0 / 83 (0.00%)	0 / 81 (0.00%)	0 / 42 (0.00%)	1 / 81 (1.23%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0	0 / 0	0 / 0	0 / 0
GASTROENTERITIS ADENOVIRUS
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	1 / 83 (1.20%)	0 / 81 (0.00%)	0 / 42 (0.00%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
PHARYNGITIS
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	0 / 83 (0.00%)	1 / 81 (1.23%)	0 / 42 (0.00%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
AMOEBIC DYSENTERY
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	0 / 83 (0.00%)	0 / 81 (0.00%)	0 / 42 (0.00%)	4 / 81 (4.94%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
BRONCHOPNEUMONIA
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	0 / 83 (0.00%)	0 / 81 (0.00%)	0 / 42 (0.00%)	1 / 81 (1.23%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
OTITIS MEDIA
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	0 / 83 (0.00%)	0 / 81 (0.00%)	0 / 42 (0.00%)	1 / 81 (1.23%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA RESPIRATORY SYNCYTIAL VIRAL
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	0 / 83 (0.00%)	0 / 81 (0.00%)	0 / 42 (0.00%)	0 / 81 (0.00%)	1 / 81 (1.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
RESPIRATORY SYNCYTIAL VIRUS BRONCHIOLITIS
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	0 / 83 (0.00%)	0 / 81 (0.00%)	0 / 42 (0.00%)	0 / 81 (0.00%)	2 / 81 (2.47%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
NASOPHARYNGITIS
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	1 / 83 (1.20%)	0 / 81 (0.00%)	0 / 42 (0.00%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Cohort 1 (3.75_Half MF59)	Cohort 1 (7.5_Full MF59)	Cohort 2 (3.75_Half MF59)	Cohort 2 (7.5_Full MF59)	Cohort 2 (15_No MF59)	Cohort 3 (3.75_Half MF59)	Cohort 3 (7.5Full MF59)	Cohort 3 (15_No MF59)	Cohort 4 (3.75_Half MF59)	Cohort 4 (7.5_Full MF59)
Total subjects affected by non serious adverse events
subjects affected / exposed	66 / 94 (70.21%)	69 / 95 (72.63%)	68 / 89 (76.40%)	71 / 87 (81.61%)	31 / 44 (70.45%)	77 / 83 (92.77%)	76 / 81 (93.83%)	37 / 42 (88.10%)	76 / 81 (93.83%)	77 / 81 (95.06%)
Nervous system disorders
Headache
subjects affected / exposed	30 / 94 (31.91%)	34 / 95 (35.79%)	14 / 89 (15.73%)	25 / 87 (28.74%)	7 / 44 (15.91%)	1 / 83 (1.20%)	1 / 81 (1.23%)	1 / 42 (2.38%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences all number	45	49	22	48	8	1	1	1	0	0
Somnolence
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	39 / 83 (46.99%)	28 / 81 (34.57%)	19 / 42 (45.24%)	34 / 81 (41.98%)	48 / 81 (59.26%)
occurrences all number	0	0	0	0	0	72	43	36	68	76
General disorders and administration site conditions
Chills
subjects affected / exposed	5 / 94 (5.32%)	7 / 95 (7.37%)	10 / 89 (11.24%)	13 / 87 (14.94%)	5 / 44 (11.36%)	15 / 83 (18.07%)	12 / 81 (14.81%)	7 / 42 (16.67%)	11 / 81 (13.58%)	10 / 81 (12.35%)
occurrences all number	6	9	10	18	7	18	13	10	15	13
Crying
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	35 / 83 (42.17%)	31 / 81 (38.27%)	12 / 42 (28.57%)	38 / 81 (46.91%)	41 / 81 (50.62%)
occurrences all number	0	0	0	0	0	58	53	27	74	71
Fatigue
subjects affected / exposed	25 / 94 (26.60%)	27 / 95 (28.42%)	29 / 89 (32.58%)	28 / 87 (32.18%)	12 / 44 (27.27%)	0 / 83 (0.00%)	0 / 81 (0.00%)	0 / 42 (0.00%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences all number	36	37	43	47	17	0	0	0	0	0
Injection Site Erythema
subjects affected / exposed	21 / 94 (22.34%)	22 / 95 (23.16%)	37 / 89 (41.57%)	40 / 87 (45.98%)	12 / 44 (27.27%)	39 / 83 (46.99%)	39 / 81 (48.15%)	15 / 42 (35.71%)	36 / 81 (44.44%)	34 / 81 (41.98%)
occurrences all number	27	28	65	61	18	72	66	23	62	64
Injection Site Haemorrhage
subjects affected / exposed	10 / 94 (10.64%)	9 / 95 (9.47%)	12 / 89 (13.48%)	14 / 87 (16.09%)	8 / 44 (18.18%)	15 / 83 (18.07%)	18 / 81 (22.22%)	5 / 42 (11.90%)	11 / 81 (13.58%)	9 / 81 (11.11%)
occurrences all number	12	12	14	19	10	20	24	7	14	10
Injection Site Induration
subjects affected / exposed	18 / 94 (19.15%)	21 / 95 (22.11%)	18 / 89 (20.22%)	22 / 87 (25.29%)	8 / 44 (18.18%)	29 / 83 (34.94%)	27 / 81 (33.33%)	5 / 42 (11.90%)	18 / 81 (22.22%)	21 / 81 (25.93%)
occurrences all number	26	24	23	32	8	42	36	6	29	29
Injection Site Pain
subjects affected / exposed	54 / 94 (57.45%)	60 / 95 (63.16%)	55 / 89 (61.80%)	57 / 87 (65.52%)	23 / 44 (52.27%)	46 / 83 (55.42%)	46 / 81 (56.79%)	21 / 42 (50.00%)	37 / 81 (45.68%)	41 / 81 (50.62%)
occurrences all number	101	114	98	129	44	86	85	36	64	69
Injection Site Swelling
subjects affected / exposed	13 / 94 (13.83%)	14 / 95 (14.74%)	11 / 89 (12.36%)	19 / 87 (21.84%)	7 / 44 (15.91%)	22 / 83 (26.51%)	14 / 81 (17.28%)	5 / 42 (11.90%)	18 / 81 (22.22%)	15 / 81 (18.52%)
occurrences all number	16	16	17	29	8	32	15	7	23	19
Pyrexia
subjects affected / exposed	7 / 94 (7.45%)	6 / 95 (6.32%)	17 / 89 (19.10%)	12 / 87 (13.79%)	7 / 44 (15.91%)	31 / 83 (37.35%)	36 / 81 (44.44%)	11 / 42 (26.19%)	30 / 81 (37.04%)	38 / 81 (46.91%)
occurrences all number	7	6	27	20	11	41	53	18	46	65
Malaise
subjects affected / exposed	19 / 94 (20.21%)	15 / 95 (15.79%)	22 / 89 (24.72%)	19 / 87 (21.84%)	8 / 44 (18.18%)	1 / 83 (1.20%)	0 / 81 (0.00%)	0 / 42 (0.00%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences all number	23	21	26	31	8	1	0	0	0	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	0 / 94 (0.00%)	2 / 95 (2.11%)	2 / 89 (2.25%)	3 / 87 (3.45%)	0 / 44 (0.00%)	26 / 83 (31.33%)	26 / 81 (32.10%)	12 / 42 (28.57%)	32 / 81 (39.51%)	38 / 81 (46.91%)
occurrences all number	0	2	2	3	0	48	42	19	68	69
Nausea
subjects affected / exposed	13 / 94 (13.83%)	14 / 95 (14.74%)	18 / 89 (20.22%)	12 / 87 (13.79%)	5 / 44 (11.36%)	1 / 83 (1.20%)	1 / 81 (1.23%)	0 / 42 (0.00%)	0 / 81 (0.00%)	1 / 81 (1.23%)
occurrences all number	13	19	21	20	6	1	1	0	0	1
Vomiting
subjects affected / exposed	1 / 94 (1.06%)	1 / 95 (1.05%)	1 / 89 (1.12%)	2 / 87 (2.30%)	1 / 44 (2.27%)	16 / 83 (19.28%)	16 / 81 (19.75%)	8 / 42 (19.05%)	20 / 81 (24.69%)	23 / 81 (28.40%)
occurrences all number	1	1	1	2	1	20	17	10	33	33
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	3 / 94 (3.19%)	3 / 95 (3.16%)	7 / 89 (7.87%)	10 / 87 (11.49%)	4 / 44 (9.09%)	6 / 83 (7.23%)	2 / 81 (2.47%)	4 / 42 (9.52%)	4 / 81 (4.94%)	4 / 81 (4.94%)
occurrences all number	3	3	8	12	4	6	2	4	4	6
Skin and subcutaneous tissue disorders
Hyperhidrosis
subjects affected / exposed	4 / 94 (4.26%)	8 / 95 (8.42%)	4 / 89 (4.49%)	8 / 87 (9.20%)	4 / 44 (9.09%)	0 / 83 (0.00%)	0 / 81 (0.00%)	0 / 42 (0.00%)	1 / 81 (1.23%)	1 / 81 (1.23%)
occurrences all number	5	9	8	11	5	0	0	0	1	0
Psychiatric disorders
Irritability
subjects affected / exposed	1 / 94 (1.06%)	1 / 95 (1.05%)	0 / 89 (0.00%)	1 / 87 (1.15%)	0 / 44 (0.00%)	38 / 83 (45.78%)	30 / 81 (37.04%)	14 / 42 (33.33%)	32 / 81 (39.51%)	38 / 81 (46.91%)
occurrences all number	1	1	0	1	0	60	54	30	58	69
Eating Disorder
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	33 / 83 (39.76%)	23 / 81 (28.40%)	14 / 42 (33.33%)	31 / 81 (38.27%)	35 / 81 (43.21%)
occurrences all number	0	0	0	0	0	52	36	20	45	55
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	12 / 94 (12.77%)	13 / 95 (13.68%)	8 / 89 (8.99%)	18 / 87 (20.69%)	6 / 44 (13.64%)	0 / 83 (0.00%)	0 / 81 (0.00%)	0 / 42 (0.00%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences all number	14	16	10	26	6	0	0	0	0	0
Myalgia
subjects affected / exposed	24 / 94 (25.53%)	26 / 95 (27.37%)	15 / 89 (16.85%)	25 / 87 (28.74%)	4 / 44 (9.09%)	0 / 83 (0.00%)	0 / 81 (0.00%)	0 / 42 (0.00%)	0 / 81 (0.00%)	0 / 81 (0.00%)
occurrences all number	31	39	20	40	5	0	0	0	0	0
Infections and infestations
Bronchitis
subjects affected / exposed	2 / 94 (2.13%)	0 / 95 (0.00%)	8 / 89 (8.99%)	3 / 87 (3.45%)	3 / 44 (6.82%)	10 / 83 (12.05%)	9 / 81 (11.11%)	6 / 42 (14.29%)	13 / 81 (16.05%)	9 / 81 (11.11%)
occurrences all number	2	0	9	3	4	12	10	6	21	10
Conjunctivitis
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	5 / 83 (6.02%)	1 / 81 (1.23%)	1 / 42 (2.38%)	4 / 81 (4.94%)	3 / 81 (3.70%)
occurrences all number	0	0	0	0	0	5	1	1	5	3
Ear Infection
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	1 / 89 (1.12%)	0 / 87 (0.00%)	0 / 44 (0.00%)	5 / 83 (6.02%)	1 / 81 (1.23%)	0 / 42 (0.00%)	0 / 81 (0.00%)	1 / 81 (1.23%)
occurrences all number	0	0	1	0	0	5	1	0	0	2
Gastroenteritis
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	4 / 89 (4.49%)	0 / 87 (0.00%)	1 / 44 (2.27%)	6 / 83 (7.23%)	2 / 81 (2.47%)	1 / 42 (2.38%)	4 / 81 (4.94%)	3 / 81 (3.70%)
occurrences all number	0	0	4	0	1	6	2	2	4	4
Nasopharyngitis
subjects affected / exposed	6 / 94 (6.38%)	5 / 95 (5.26%)	12 / 89 (13.48%)	8 / 87 (9.20%)	3 / 44 (6.82%)	27 / 83 (32.53%)	19 / 81 (23.46%)	14 / 42 (33.33%)	34 / 81 (41.98%)	28 / 81 (34.57%)
occurrences all number	6	5	12	11	3	36	28	19	51	38
Pharyngitis
subjects affected / exposed	3 / 94 (3.19%)	0 / 95 (0.00%)	2 / 89 (2.25%)	4 / 87 (4.60%)	0 / 44 (0.00%)	7 / 83 (8.43%)	4 / 81 (4.94%)	0 / 42 (0.00%)	8 / 81 (9.88%)	7 / 81 (8.64%)
occurrences all number	3	0	2	4	0	7	4	0	8	8
Rhinitis
subjects affected / exposed	5 / 94 (5.32%)	2 / 95 (2.11%)	0 / 89 (0.00%)	3 / 87 (3.45%)	3 / 44 (6.82%)	2 / 83 (2.41%)	1 / 81 (1.23%)	0 / 42 (0.00%)	6 / 81 (7.41%)	3 / 81 (3.70%)
occurrences all number	5	2	2	4	3	2	1	0	6	4
Varicella
subjects affected / exposed	0 / 94 (0.00%)	0 / 95 (0.00%)	0 / 89 (0.00%)	0 / 87 (0.00%)	0 / 44 (0.00%)	0 / 83 (0.00%)	1 / 81 (1.23%)	2 / 42 (4.76%)	3 / 81 (3.70%)	0 / 81 (0.00%)
occurrences all number	0	0	0	0	0	1	2	3	1	0

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Were there any global substantial amendments to the protocol? Yes

26 Oct 2009

•Subgroup analysis based on previous seasonal influenza vaccination was performed •Differences addressing within-group comparisons were not calculated for binary data due to the lack of appropriate validated standard software. •Center as qualitative factor was not included in the models for binary data as in a lot of instances algorithms do not converge or results highly depended on the choice of the “addcell” options in SAS proc catmod. •Center was included as qualitative factor only in models for normal distributed data to obtain adjusted estimates

23 Nov 2009

Four minor changes for further clarity (i.e.stopping rules, public disclosure of study results and clarification of exclusion criteria).

30 Nov 2009

To allow interim analyses if there is a request in public health interest

06 Feb 2010

To address the EMEA request, multivariate analysis of immunogenicity data was performed at day 22 and day 43. The description of multivariate analysis is in section 16.1.9.

07 Nov 2010

To address the change that the booster will be administered using the egg-derived, seasonal, trivalent MF59 adjuvanted vaccine Fluad.

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

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of subjects achieving seroconversion against A/H1N1 Strain as measured by hemagglutination inhibition assay

Primary: Percentage of subjects achieving seroconversion against A/H1N1 Strain as measured by hemagglutination inhibition assay

Primary: Percentage of subjects achieving HI titers ≥1:40 agianst A/H1N1 Strain.

Primary: Percentage of subjects achieving HI titers ≥1:40 agianst A/H1N1 Strain.

Primary: Geometric mean Ratios against A/H1N1 strain following 2-dose vaccination schedule as determined by HI assay

Primary: Geometric mean Ratios against A/H1N1 strain following 2-dose vaccination schedule as determined by HI assay

Primary: Number of Subjects Reporting Solicited Local and Systemic Adverse Events, After Primary Vaccination

Primary: Number of Subjects Reporting Solicited Local and Systemic Adverse Events, After Primary Vaccination

Primary: Number of Subjects Reporting Solicited Local and Systemic Adverse Events, After booster Vaccination

Primary: Number of Subjects Reporting Solicited Local and Systemic Adverse Events, After booster Vaccination

Primary: Number of Subjects Reporting Unsolicited Adverse Events after primary and booster vaccination.

Primary: Number of Subjects Reporting Unsolicited Adverse Events after primary and booster vaccination.

Primary: Number of Subjects Reporting Unsolicited Adverse Events

Primary: Number of Subjects Reporting Unsolicited Adverse Events

Secondary: Percentage of subjects achieving seroconversion against A/H1N1 Strain following a booster dose as measured by hemagglutination inhibition (HI) assay

Secondary: Percentage of subjects achieving seroconversion against A/H1N1 Strain following a booster dose as measured by hemagglutination inhibition (HI) assay

Secondary: Percentage of subjects achieving HI titers ≥1:40 agianst A/H1N1 Strain following a booster dose.

Secondary: Percentage of subjects achieving HI titers ≥1:40 agianst A/H1N1 Strain following a booster dose.

Secondary: Geometric mean Ratios against A/H1N1 strain following a booster dose as determined by HI assay.

Secondary: Geometric mean Ratios against A/H1N1 strain following a booster dose as determined by HI assay.

Secondary: Geometric mean titers against A/H1N1 strain as determined by HI assay in pooled population

Secondary: Geometric mean titers against A/H1N1 strain as determined by HI assay in pooled population

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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