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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 Nonadjuvanted Cell-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	2009-013640-37
Trial protocol	DE NL BE
Global end of trial date	10 Aug 2011

Results information
Results version number	v2(current)
This version publication date	28 Jul 2016
First version publication date	01 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

V110_04

ISRCTN number

US NCT number

NCT00971100

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Vaccines and Diagnostics

Sponsor organisation address

Via Fiorentina 1, Siena, Italy, 53100

Public contact

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

Scientific contact

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

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

Yes

EMA paediatric investigation plan number(s)

EMEA-000663-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

16 Nov 2011

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

10 Aug 2011

Was the trial ended prematurely?

Main objective of the trial

To identify the preferred vaccine formulation (with or without MF59), dosage (of antigen and adjuvant) and schedule (one or two administrations) of the cell-derived H1N1 swine (sw) monovalent vaccine in healthy children and adolescents based on CHMP criteria and pairwise statistical comparisons for immunogenicity, safety and 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

19 Aug 2009

Long term follow-up planned

Yes

Long term follow-up rationale

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: 10

Country: Number of subjects enrolled

Belgium: 228

Country: Number of subjects enrolled

Germany: 239

Country: Number of subjects enrolled

Dominican Republic: 189

Worldwide total number of subjects

666

EEA total number of subjects

477

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)

240

Children (2-11 years)

316

Adolescents (12-17 years)

110

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Subjects were enrolled at seven sites in Germany, two sites in Belgium, one site in the Netherlands, two sites in Dominican Republic

Screening details

Subjects were enrolled in an age-descending manner and stratified into 4 age cohorts: 9 to 17 years (cohort 1), 3 to 8 years (cohort 2), 12 to 35 months (cohort 3), and 6 to 11 months (cohort 4).

Period 1 title

Overall Study (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 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

H1N1 Vaccine

Investigational medicinal product code

V110

Other name

FCC-H1N1sw

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Cohort 1 (7.5_Full MF59)

Arm description

Subjects aged ≥9 to ≤17 years received 2 doses of H1N1 vaccine administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Arm type

Experimental

Investigational medicinal product name

H1N1 Vaccine

Investigational medicinal product code

V110

Other name

FCC-H1N1sw

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Cohort 2 (3.75_Half MF59)

Arm description

Subjects aged ≥3 to ≤8 years received 2 doses of H1N1 vaccine administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Arm type

Experimental

Investigational medicinal product name

H1N1 Vaccine

Investigational medicinal product code

V110

Other name

FCC-H1N1sw

Pharmaceutical forms

Suspension 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 administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Arm type

Experimental

Investigational medicinal product name

H1N1 Vaccine

Investigational medicinal product code

V110

Other name

FCC-H1N1sw

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Cohort 2 (15_No MF59)

Arm description

Subjects aged ≥3 to ≤8 years received 2 doses of H1N1 vaccine administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Arm type

Experimental

Investigational medicinal product name

H1N1 Vaccine

Investigational medicinal product code

V110

Other name

FCC-H1N1sw

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Cohort 3 (3.75_Half MF59)

Arm description

Subjects aged ≥12 to ≤35 months received 2 doses of H1N1 vaccine administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Arm type

Experimental

Investigational medicinal product name

H1N1 Vaccine

Investigational medicinal product code

V110

Other name

FCC-H1N1sw

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Vaccination consisted of two 0.25 mLdoses of H1N1 vaccine (3.75mcg of H1N1 and half MF59) administered 3 weeks apart followed by one dose of 0.5mL booster vaccination with aTIV; all injections were administered IM in the deltoid muscle preferably of the non-dominant arm for subjects ≥24 months of age. For subjects aged ≤ 24 months, the injections were administered in the anterolateral aspect of thigh.

Cohort 3 (7.5_Full MF59)

Arm description

Subjects aged ≥12 to ≤35 months received 2 doses of H1N1 vaccine administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Arm type

Experimental

Investigational medicinal product name

H1N1 Vaccine

Investigational medicinal product code

V110

Other name

FCC-H1N1sw

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Vaccination consisted of two 0.5 mLdoses of H1N1 vaccine (7.5mcg of H1N1 and full MF59) administered 3 weeks apart followed by one dose of 0.5mL booster vaccination with aTIV; all injections were administered IM in the deltoid muscle preferably of the non-dominant arm for subjects ≥24 months of age. For subjects aged ≤ 24 months, the injections were administered in the anterolateral aspect of thigh.

Cohort 3 (15_No MF59)

Arm description

Subjects aged ≥12 to ≤35 months received 2 doses of H1N1 vaccine administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Arm type

Experimental

Investigational medicinal product name

H1N1 Vaccine

Investigational medicinal product code

V110

Other name

FCC-H1N1sw

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Vaccination consisted of two 0.5 mLdoses of H1N1 vaccine (15mcg of H1N1 without MF59) administered 3 weeks apart followed by one dose of 0.5mL booster vaccination with aTIV; all injections were administered IM in the deltoid muscle preferably of the non-dominant arm for subjects ≥24 months of age. For subjects aged ≤ 24 months, the injections were administered in the anterolateral aspect of thigh.

Cohort 4 (3.75_Half MF59)

Arm description

Subjects aged ≥6 to ≤11 months received 2 doses of H1N1 vaccine administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Arm type

Experimental

Investigational medicinal product name

H1N1 Vaccine

Investigational medicinal product code

V110

Other name

FCC-H1N1sw

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Vaccination consisted of two 0.25 mLdoses of H1N1 vaccine (3.75mcg of H1N1 and half MF59) administered 3 weeks apart followed by one dose of 0.5mL booster vaccination with aTIV. For subjects aged ≤ 24 months, the injections were administered in the anterolateral aspect of thigh.

Cohort 4 (7.5_Full MF59)

Arm description

Subjects aged ≥6 to ≤11 months received 2 doses of H1N1 vaccine administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Arm type

Experimental

Investigational medicinal product name

H1N1 Vaccine

Investigational medicinal product code

V110

Other name

FCC-H1N1sw

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Vaccination consisted of two 0.5 mLdoses of H1N1 vaccine (7.5mcg of H1N1 and full MF59) administered 3 weeks apart followed by one dose of 0.5mL booster vaccination with aTIV. For subjects aged ≤ 24 months, the injections were administered in the anterolateral aspect of thigh.

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 (7.5_Full MF59)	Cohort 3 (15_No MF59)	Cohort 4 (3.75_Half MF59)	Cohort 4 (7.5_Full MF59)
Started	80	79	72	73	39	65	73	34	75	76
Completed	23	24	30	35	14	41	49	21	66	61
Not completed	57	55	42	38	25	24	24	13	9	15
Consent withdrawn by subject	5	3	4	7	8	8	11	3	4	9
Adverse Event	2	-	-	1	1	1	-	1	1	1
Administrative Reason	48	51	32	30	13	11	10	5	3	4
Lost to follow-up	1	1	5	-	3	4	2	2	1	-
Unable to Classify	-	-	1	-	-	-	-	1	-	1
Protocol deviation	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

Subjects aged ≥9 to ≤17 years received 2 doses of H1N1 vaccine administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group title

Cohort 2 (3.75_Half MF59)

Reporting group description

Subjects aged ≥3 to ≤8 years received 2 doses of H1N1 vaccine 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 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 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 administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group title

Cohort 3 (7.5_Full MF59)

Reporting group description

Subjects aged ≥12 to ≤35 months received 2 doses of H1N1 vaccine 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 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 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 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 (7.5_Full MF59)	Cohort 3 (15_No MF59)	Cohort 4 (3.75_Half MF59)	Cohort 4 (7.5_Full MF59)	Total
Number of subjects	80	79	72	73	39	65	73	34	75	76	666
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)	13.2 ± 2.7	13.2 ± 2.7	5.5 ± 1.9	5.3 ± 1.7	5.2 ± 1.5	21.8 ± 7.3	23.1 ± 7.1	23.1 ± 7.8	8.9 ± 1.5	8.8 ± 1.7	-
Gender categorical
Units: Subjects
Female	41	37	45	31	25	34	27	14	40	42	336
Male	39	42	27	42	14	31	46	20	35	34	330

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

Subjects aged ≥9 to ≤17 years received 2 doses of H1N1 vaccine administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group title

Cohort 2 (3.75_Half MF59)

Reporting group description

Subjects aged ≥3 to ≤8 years received 2 doses of H1N1 vaccine 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 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 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 administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group title

Cohort 3 (7.5_Full MF59)

Reporting group description

Subjects aged ≥12 to ≤35 months received 2 doses of H1N1 vaccine 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 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 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 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 366

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 366) and who had no major protocol violations as pre-specified in the analysis plan

Subject analysis set title

Per protocol set- day 387

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 387) and who had no major protocol violations as pre-specified in the analysis plan

Subject analysis set title

Per protocol set- Day 43

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

Safety Set

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects in the All Exposed Set who provided post-baseline safety data.

Subject analysis set title

All Cohorts (7.5_Full MF59)

Subject analysis set type

Per protocol

Subject analysis set description

Subjects from all the cohorts receiving H1N1 vaccine (7.5 mcg+full MF59) were pooled.

Subject analysis set title

All Cohorts (3.75_Half MF59)

Subject analysis set type

Per protocol

Subject analysis set description

Subjects from all the cohorts receiving H1N1 vaccine (3.75 mcg+half MF59) were pooled.

Primary: 1. Percentages of subjects achieving seroconversion against A/H1N1 Strain as measured by hemagglutination inhibition (HI) assay.

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End point title

1. Percentages of subjects achieving seroconversion against A/H1N1 Strain 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 vaccine strain, 3 weeks after receiving 2 doses of vaccination according to CHMP criterion. Seroconversion is defined as HI ≥40 for subjects negative at baseline [<10] or at least 4-fold increase in HI titer for those positive at baseline [≥10]) on day 22 and day 43. There are no predefined CHMP criteria for the pediatric population however, the criterion is met if the percentage of subjects achieving seroconversion or at least 4-fold increase in HI antibody (at day 43) is >40%.

End point type

Primary

End point timeframe

Day 43 (3 weeks post second 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 (7.5_Full MF59)	Cohort 3 (15_No MF59)	Cohort 4 (3.75_Half MF59)	Cohort 4 (7.5_Full MF59)
Number of subjects analysed	72	71	58	60	31	51	53	25	58	54
Units: Percentages of subjects
number (confidence interval 95%)
Day 43	99 (93 to 100)	100 (95 to 100)	100 (94 to 100)	100 (94 to 100)	97 (83 to 100)	98 (90 to 100)	100 (93 to 100)	84 (64 to 95)	98 (91 to 100)	100 (93 to 100)

Cohort 1: 3.75_Half MF59 vs 7.5_Full MF59

Statistical analysis description

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

Comparison groups

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

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

other

Method

ANOVA

Parameter type

Vaccine group differences

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-4

upper limit

Cohort 2: 3.75_Half MF59 vs 7.5_Full MF59

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

118

Analysis specification

Pre-specified

Analysis type

other

Method

ANOVA

Parameter type

Vaccine group ratios

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Cohort 2: 3.75_Half MF59 vs 15_No MF59

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

Analysis specification

Pre-specified

Analysis type

other

Method

ANOVA

Parameter type

Vaccine group ratios

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-3

upper limit

Cohort 2: 7.5_Full MF59 vs 15_No MF59

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

other

Method

ANOVA

Parameter type

Vaccine group ratios

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-3

upper limit

Cohort 3: 3.75_Half MF59 vs 7.5_Full MF59

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 (7.5_Full MF59)

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

other

Method

ANOVA

Parameter type

Vaccine group ratios

Point estimate

-2

Confidence interval

level

95%

sides

2-sided

lower limit

-6

upper limit

Cohort 3: 3.75_Half MF59 vs 15_No MF59

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

other

Method

ANOVA

Parameter type

Vaccine group ratios

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Cohort 3: 7.5_Full MF59 vs 15_No MF59

Statistical analysis description

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

Comparison groups

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

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

ANOVA

Parameter type

Vaccine group ratios

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Cohort 4: 3.75_Half MF59 vs 7.5_Full MF59

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

112

Analysis specification

Pre-specified

Analysis type

other

Method

ANOVA

Parameter type

Vaccine group ratios

Point estimate

-2

Confidence interval

level

95%

sides

2-sided

lower limit

-5

upper limit

Primary: 2. Percentages of subjects achieving HI titers ≥1:40 against A/H1N1 Strain.

Top of page

End point title

2. Percentages of subjects achieving HI titers ≥1:40 against 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 43 (3 weeks post second 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 (7.5_Full MF59)	Cohort 3 (15_No MF59)	Cohort 4 (3.75_Half MF59)	Cohort 4 (7.5_Full MF59)
Number of subjects analysed	72	71	58	60	31	51	53	25	58	54
Units: Percentages of subjects
number (confidence interval 95%)
Day 1	6 (2 to 14)	3 (0 to 10)	0 (0 to 6)	2 (0.042 to 9)	0 (0 to 11)	12 (4 to 24)	13 (5 to 25)	20 (7 to 41)	17 (9 to 29)	17 (8 to 29)
Day 43	100 (95 to 100)	100 (95 to 100)	100 (94 to 100)	100 (94 to 100)	97 (83 to 100)	100 (93 to 100)	100 (93 to 100)	88 (69 to 97)	100 (94 to 100)	100 (93 to 100)

Cohort 1: 3.75_Half MF59 vs 7.5_Full MF59

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

143

Analysis specification

Pre-specified

Analysis type

other

Method

ANOVA

Parameter type

Vaccine group differences

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Cohort 2: 3.75_Half MF59 vs 7.5_Full MF59

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

118

Analysis specification

Pre-specified

Analysis type

other

Method

ANOVA

Parameter type

Vaccine group ratios

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Cohort 2: 3.75_Half MF59 vs 15_No MF59

Statistical analysis description

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

Comparison groups

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

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

ANOVA

Parameter type

Vaccine group ratios

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-3

upper limit

Cohort 2: 7.5_Full MF59 vs 15_No MF59

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

other

Method

ANOVA

Parameter type

Vaccine group ratios

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-3

upper limit

Cohort 3: 3.75_Half MF59 vs 7.5_Full MF59

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 (7.5_Full MF59)

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

other

Method

ANOVA

Parameter type

Vaccine group ratios

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Cohort 3: 3.75_Half MF59 vs 15_No MF59

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

other

Method

ANOVA

Parameter type

Vaccine group ratios

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Cohort 3: 7.5_Full MF59 vs 15_No MF59

Statistical analysis description

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

Comparison groups

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

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

ANOVA

Parameter type

Vaccine group ratios

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Cohort 4: 3.75_Half MF59 vs 7.5_Full MF59

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

112

Analysis specification

Pre-specified

Analysis type

other

Method

ANOVA

Parameter type

Vaccine group ratios

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Primary: 3. Geometric mean ratios against A/H1N1 strain following 2-dose vaccination schedule as determined by HI assay

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End point title

3. 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 (3 weeks post second 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 (7.5_Full MF59)	Cohort 3 (15_No MF59)	Cohort 4 (3.75_Half MF59)	Cohort 4 (7.5_Full MF59)
Number of subjects analysed	72	71	58	60	31	51	53	25	58	54
Units: Ratios
geometric mean (confidence interval 95%)
Day 43/Day 1	47 (36 to 61)	80 (61 to 103)	86 (67 to 111)	115 (91 to 147)	28 (21 to 38)	89 (54 to 145)	108 (69 to 169)	11 (6.23 to 20)	92 (51 to 166)	129 (72 to 232)

Cohort 1: 3.75_Half MF59 vs 7.5_Full MF59

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

143

Analysis specification

Pre-specified

Analysis type

other

Method

ANOVA

Parameter type

Vaccine group ratios

Point estimate

0.59

Confidence interval

level

95%

sides

2-sided

lower limit

0.42

upper limit

0.82

Cohort 2: 3.75_Half MF59 vs 7.5_Full MF59

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

118

Analysis specification

Pre-specified

Analysis type

other

Method

ANOVA

Parameter type

Vaccine group ratios

Point estimate

0.75

Confidence interval

level

95%

sides

2-sided

lower limit

0.56

upper limit

Cohort 2: 3.75_MF59 vs 15_No MF59

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

Analysis specification

Pre-specified

Analysis type

other

Method

ANOVA

Parameter type

Vaccine group ratios

Point estimate

3.07

Confidence interval

level

95%

sides

2-sided

lower limit

2.16

upper limit

4.35

Cohort 2: 7.5_Full MF59 vs 15_no MF59

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

other

Method

ANOVA

Parameter type

Vaccine group ratios

Point estimate

4.11

Confidence interval

level

95%

sides

2-sided

lower limit

2.91

upper limit

5.81

Cohort 3: 3.75_Half MF59 vs 7.5_Full MF59

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 (7.5_Full MF59)

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

other

Method

ANOVA

Parameter type

Vaccine group ratios

Point estimate

0.82

Confidence interval

level

95%

sides

2-sided

lower limit

0.53

upper limit

1.29

Cohort 3: 3.75_Half MF59 vs 15_No MF59

Statistical analysis description

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

Comparison groups

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

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

ANOVA

Parameter type

Vaccine group ratios

Point estimate

7.9

Confidence interval

level

95%

sides

2-sided

lower limit

4.53

upper limit

Cohort 3: 7.5_Full MF 59 vs 15_No MF59

Statistical analysis description

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

Comparison groups

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

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

ANOVA

Parameter type

Vaccine group ratios

Point estimate

9.59

Confidence interval

level

95%

sides

2-sided

lower limit

5.51

upper limit

Cohort 4: 3.75_Half MF59 vs 7.5_Full MF59

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

112

Analysis specification

Pre-specified

Analysis type

other

Method

ANOVA

Parameter type

Vaccine group ratios

Point estimate

0.72

Confidence interval

level

95%

sides

2-sided

lower limit

0.48

upper limit

1.08

Primary: 4. Number of Subjects Reporting Solicited Local and Systemic Adverse Events, After Any Primary Vaccination

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End point title

4. Number of Subjects Reporting Solicited Local and Systemic Adverse Events, After Any 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 (7.5_Full MF59)	Cohort 3 (15_No MF59)	Cohort 4 (3.75_Half MF59)	Cohort 4 (7.5_Full MF59)
Number of subjects analysed	79	79	71	72	39	65	71	33	75	74
Units: Number
Ecchymosis (N=79,79,71,72,39,65,73,33,75,74)	5	7	9	9	10	4	10	5	4	0
Erythema (N=79,79,71,72,39,65,73,33,75,74)	10	16	14	23	8	13	17	8	12	7
Induration (N=79,79,71,72,39,65,73,33,75,74)	13	15	8	16	6	8	13	5	6	8
Swelling (N=79,79,71,72,39,65,73,33,75,74)	9	13	9	11	4	2	7	3	1	0
Tenderness (N=0,0,0,0,0,65,73,33,75,74)	0	0	0	0	0	9	36	13	18	26
Pain (N=79,79,70,72,39,65,73,33,75,74)	61	67	39	40	19	0	0	0	0	0
Chills (N=79,79,70,72,39,0,0,0,0,0)	3	10	3	7	2	0	0	0	0	0
Malaise (N=79,79,70,72,39,0,0,0,0,0)	10	16	12	5	7	0	0	0	0	0
Myalgia (N=79,79,70,72,39,0,0,0,0,0)	21	21	6	10	3	0	0	0	0	0
Arthralgia (N=79,79,70,72,39,0,0,0,0,0)	12	10	5	6	2	0	0	0	0	0
Headache (N=79,79,70,72,39,0,0,0,0,0)	22	25	7	8	6	0	0	0	0	0
Sweating (N=79,79,70,72,39,0,0,0,0,0)	5	3	1	1	0	0	0	0	0	0
Fatigue (N=79,79,70,72,39,0,0,0,0,0)	23	25	21	17	8	0	0	0	0	0
Nausea(N=79,79,70,72,39,0,0,0,0,0)	9	8	5	6	3	0	0	0	0	0
Diarrhea (N=0,0,0,0,0,65,73,33,75,74)	0	0	0	0	0	21	24	8	24	32
Sleepiness (N=0,0,0,0,0,65,73,33,75,74)	0	0	0	0	0	17	30	9	14	20
Vomiting (N=0,0,0,0,0,65,73,33,75,74)	0	0	0	0	0	11	18	3	17	18
Irritability (N=0,0,0,0,0,65,73,33,75,74)	0	0	0	0	0	19	18	7	14	13
Chang. eating habits (N=0,0,0,0,0,65,73,33,75,74)	0	0	0	0	0	21	26	6	18	25
Unus. Crying (N=0,0,0,0,0,65,73,33,75,74)	0	0	0	0	0	20	27	10	27	26
Shivering (N=0,0,0,0,0,65,73,33,75,74)	0	0	0	0	0	6	6	2	4	5
Fever (≥38°C) (N=79,79,70,72,39,65,73,33,75,74)	2	1	10	7	3	17	12	5	13	17
Temp (≥40°C) (N=79,79,70,72,39,65,73,33,75,74)	0	0	0	0	0	0	1	0	1	1
Stayed Home (N=79,79,70,72,39,65,73,33,75,74)	4	3	5	13	3	11	10	4	14	11
Analg.Antipy Used (N=79,79,70,72,39,65,73,33,75,74	11	12	11	16	5	28	27	14	28	31

No statistical analyses for this end point

Primary: 5. Number of Subjects Reporting Solicited Local and Systemic Adverse Events, After Booster Vaccination

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End point title

5. 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 372.

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 (7.5_Full MF59)	Cohort 3 (15_No MF59)	Cohort 4 (3.75_Half MF59)	Cohort 4 (7.5_Full MF59)
Number of subjects analysed	23	24	30	35	14	42	51	21	67	61
Units: Number
Ecchymosis	2	0	1	1	0	2	5	0	1	1
Erythema	2	3	8	5	0	6	13	4	5	9
Induration	5	3	4	5	0	4	7	3	5	4
Swelling	0	4	3	5	1	6	4	1	1	5
Inj Site Pain (N=23,24,30,35,14,0,0,0,0,0)	17	19	23	24	9	0	0	0	0	0
Tenderness (N=0,0,0,0,0,42,51,21,67,61)	0	0	0	0	0	8	18	7	11	19
Chills (N=23,24,30,35,14,0,0,0,0,0)	1	1	3	5	0	0	0	0	0	0
Malaise (N=23,24,30,35,14,0,0,0,0,0)	5	3	8	11	0	0	0	0	0	0
Myalgia (N=23,24,30,35,14,0,0,0,0,0)	7	8	4	9	4	0	0	0	0	0
Arthralgia (N=23,24,30,35,14,0,0,0,0,0)	1	2	5	5	2	0	0	0	0	0
Headache (N=23,24,30,35,14,0,0,0,0,0)	5	5	10	11	1	0	0	0	0	0
Sweating (N=23,24,30,35,14,0,0,0,0,0)	2	2	2	3	0	0	0	0	0	0
Fatigue (N=23,24,30,35,14,0,0,0,0,0)	4	2	7	10	1	0	0	0	0	0
Nausea (N=23,24,30,35,14,0,0,0,0,0)	4	2	4	6	1	0	0	0	0	0
Sleepiness (N=0,0,0,0,0,42,51,21,67,61)	0	0	0	0	0	9	6	1	5	10
Diarrhea (N=0,0,0,0,0,42,51,21,67,61)	0	0	0	0	0	6	4	1	8	6
Vomiting (N=0,0,0,0,0,42,51,21,67,61)	0	0	0	0	0	1	2	0	2	1
Irritability (N=0,0,0,0,0,42,51,21,67,61)	0	0	0	0	0	5	3	3	3	6
Chg. In eating habits (N=0,0,0,0,0,42,51,21,67,61)	0	0	0	0	0	5	4	1	2	7
Shivering (N=0,0,0,0,0,42,51,21,67,61)	0	0	0	0	0	1	3	0	3	2
Unus. Crying (N=0,0,0,0,0,42,51,21,67,61)	0	0	0	0	0	3	4	1	4	9
Fever (≥38°C)	1	0	0	8	0	6	15	2	9	13
Temp (≥40°C)	0	0	0	0	0	1	0	1	1	0
Stayed Home (N=23,24,30,35,14,41,50,21,67,61)	3	2	3	10	0	5	1	2	5	5
Analg.Antipy. Med. Used	4	3	4	8	1	8	15	5	13	19

No statistical analyses for this end point

Primary: 6. Number of Subjects Reporting Solicited Local and Systemic Adverse Events, After second seasonal flu Vaccination

Top of page

End point title

6. Number of Subjects Reporting Solicited Local and Systemic Adverse Events, After second seasonal flu Vaccination ^[3] ^[4]

End point description

Safety was assessed as the number of subjects who reported solicited local and systemic adverse events. For subjects aged <9 years of age at the time of booster received a second seasonal flu dose on day 387 for influenza vaccine naive subjects.

End point type

Primary

End point timeframe

Day 387 through day 394

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
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analyses for this end point

End point values	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 (7.5_Full MF59)	Cohort 3 (15_No MF59)	Cohort 4 (3.75_Half MF59)	Cohort 4 (7.5_Full MF59)
Number of subjects analysed	22	26	11	36	45	17	63	60
Units: Number
Injection Site Ecchymosis	0	1	0	0	1	1	1	1
Injection Site Erythema	4	6	0	10	10	2	6	6
Injection Site Induration	4	7	0	8	8	3	6	5
Injection Site Swelling	4	5	1	7	7	2	3	3
Injection Site Pain (N=22,26,11,0,0,0,0,0)	13	13	7	0	0	0	0	0
Tenderness (N=0,0,0,36,45,17,63,60)	0	0	0	8	11	4	14	13
Chills (N=22,26,11,0,0,0,0,0)	0	1	0	0	0	0	0	0
Malaise (N=22,26,11,0,0,0,0,0)	1	2	1	0	0	0	0	0
Myalgia (N=22,26,11,0,0,0,0,0)	1	2	1	0	0	0	0	0
Arthralgia (N=22,26,11,0,0,0,0,0)	1	2	1	0	0	0	0	0
Headache (N=22,26,11,0,0,0,0,0)	3	3	1	0	0	0	0	0
Sweating (N=22,26,11,0,0,0,0,0)	0	1	0	0	0	0	0	0
Fatigue (N=22,26,11,0,0,0,0,0)	3	6	2	0	0	0	0	0
Nausea (N=22,26,11,0,0,0,0,0)	1	2	1	0	0	0	0	0
Sleepiness (N=0,0,0,36,45,17,63,60)	0	0	0	1	1	1	3	5
Diarrhoea (N=0,0,0,36,45,17,63,60)	0	0	0	3	3	0	7	7
Vomiting (N=0,0,0,36,45,17,63,60)	0	0	0	1	1	0	5	2
Irritability (N=0,0,0,36,45,17,63,60)	0	0	0	2	3	3	4	2
Chg. In eating habits (N=0,0,0,36,45,17,63,60)	0	0	0	3	2	1	6	5
Shivering (N=0,0,0,36,45,17,63,60)	0	0	0	1	0	0	2	1
Unus. Crying (N=0,0,0,36,45,17,63,60)	0	0	0	1	3	1	8	3
Fever (≥38°C)	1	2	1	3	4	0	7	10
Temp (≥40°C)	0	0	0	0	0	0	0	0
Stayed Home	1	0	0	1	0	0	2	3
Analg.Antipy. Med. Used	2	6	1	3	6	1	10	11

No statistical analyses for this end point

Primary: 7. Number of Subjects Reporting Unsolicited Adverse Events after primary and booster vaccination.

Top of page

End point title

7. Number of Subjects Reporting Unsolicited Adverse Events after primary and booster vaccination. ^[5]

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 influenza vaccine naive subjects aged <9 years of age at the time of booster received a second seasonal flu dose on day 387. All AEs were collected from day 1 to day 43 after primary vaccination, from day 366 through day 387 after booster vaccination and day 387 to day 401 for subjects who receive second seasonal flu dose

End point type

Primary

End point timeframe

Day 1 through day 43, day 366 through day 387, day 387 through day 401.

Notes
[5] - 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 (7.5_Full MF59)	Cohort 3 (15_No MF59)	Cohort 4 (3.75_Half MF59)	Cohort 4 (7.5_Full MF59)
Number of subjects analysed	79	79	71	72	39	65	71	33	75	74
Units: Number
Any AE-Primary vacc.;79,79,71,72,39,65,73,33,75,74	28	26	31	31	17	33	32	23	51	50
Possibly related AEs-79,79,71,72,39,65,73,33,75,74	15	18	15	18	11	4	9	7	20	22
Any AE-booster vacc.;74,78,80,80,37,65,74,30,75,73	3	4	6	6	1	5	10	2	20	16
Possibly related AEs-74,78,80,80,37,65,74,30,75,73	2	1	2	3	0	1	4	1	6	4
Any AE-2nd seasonal;0,0,30,35,14,41,50,21,66,60	0	0	1	5	1	1	8	2	14	17
Possibly related AEs- 0,0,30,35,14,41,50,21,66,60	0	0	0	0	0	0	2	0	3	3

No statistical analyses for this end point

Primary: 8. Number of Subjects Reporting Unsolicited Adverse Events.

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End point title

8. Number of Subjects Reporting Unsolicited Adverse Events. ^[6]

End point description

Safety was assessed as the number of subjects who reported unsolicited adverse events. 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

SAEs, NOCDs, AEs leading to withdrawal-day 1 to day 546

Notes
[6] - 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 (7.5_Full MF59)	Cohort 3 (15_No MF59)	Cohort 4 (3.75_Half MF59)	Cohort 4 (7.5_Full MF59)
Number of subjects analysed	80	79	72	73	39	65	71	34	75	76
Units: Number
Any SAEs	3	2	1	3	0	7	8	5	11	8
At least possibly related SAEs	0	1	0	0	0	0	1	0	1	0
AEs leading to discontinuation	2	0	0	1	1	1	0	1	1	1
New onset of chronic disease	0	3	0	0	0	0	0	1	1	1

No statistical analyses for this end point

Secondary: 9. Percentages of subjects achieving seroconversion against A/H1N1 Strain following a booster dose as measured by hemagglutination inhibition (HI) assay.

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End point title

9. Percentages 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 (7.5_Full MF59)	Cohort 3 (15_No MF59)	Cohort 4 (3.75_Half MF59)	Cohort 4 (7.5_Full MF59)
Number of subjects analysed	19	20	20	29	10	32	38	17	47	40
Units: Percentage of subjects
number (confidence interval 95%)
Day 387 (From Day 366)	89 (67 to 99)	80 (56 to 94)	95 (75 to 100)	100 (88 to 100)	100 (69 to 100)	94 (79 to 99)	95 (82 to 99)	100 (80 to 100)	85 (72 to 94)	90 (76 to 97)

No statistical analyses for this end point

Secondary: 10. Percentages of subjects achieving HI titers ≥1:40 agianst A/H1N1 Strain following a booster dose

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End point title

10. Percentages 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 requirements.

End point type

Secondary

End point timeframe

Day 366 and Day 387 (3 weeks post second 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 (7.5_Full MF59)	Cohort 3 (15_No MF59)	Cohort 4 (3.75_Half MF59)	Cohort 4 (7.5_Full MF59)
Number of subjects analysed	21	22	24	31	11	39	46	21	54	47
Units: Percentage of subjects
number (confidence interval 95%)
Day 366	86 (64 to 97)	95 (77 to 100)	100 (86 to 100)	100 (89 to 100)	91 (59 to 100)	100 (91 to 100)	100 (92 to 100)	71 (48 to 89)	94 (85 to 99)	100 (92 to 100)
Day 387 (N=19,20,20,29,10,32,38,17,47,40)	100 (82 to 100)	100 (83 to 100)	100 (83 to 100)	100 (88 to 100)	100 (69 to 100)	100 (89 to 100)	100 (91 to 100)	100 (80 to 100)	100 (92 to 100)	100 (91 to 100)

No statistical analyses for this end point

Secondary: 11. Geometric mean Ratios against A/H1N1 strain following a booster dose as determined by HI assay

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End point title

11. 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 (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 (7.5_Full MF59)	Cohort 3 (15_No MF59)	Cohort 4 (3.75_Half MF59)	Cohort 4 (7.5_Full MF59)
Number of subjects analysed	19	20	20	29	10	32	38	17	47	40
Units: Ratios
geometric mean (confidence interval 95%)
Day 387/Day 366	15 (6.89 to 33)	8.47 (4.34 to 17)	28 (15 to 51)	26 (16 to 43)	30 (14 to 62)	19 (9.73 to 39)	17 (8.88 to 31)	36 (16 to 81)	33 (17 to 63)	23 (11 to 46)

No statistical analyses for this end point

Secondary: 12. Geometric mean titers against A/H1N1 strain as determined by HI assay in pooled population

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End point title

12. 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 (3 weeks post second vaccination)

End point values	All Cohorts (7.5_Full MF59)	All Cohorts (3.75_Half MF59)
Number of subjects analysed	238	239
Units: Titers
geometric mean (confidence interval 95%)
Day 1	7.55 (6.03 to 9.45)	7.75 (6.16 to 9.75)
Day 43	756 (633 to 902)	539 (449 to 646)

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

All Cohorts (7.5_Full MF59) v All Cohorts (3.75_Half MF59)

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[7]

Method

ANOVA

Parameter type

Vaccine group difference

Point estimate

0.72

Confidence interval

level

95%

sides

2-sided

lower limit

0.6

upper limit

0.85

Notes
[7] - 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

Non-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

Subjects aged ≥9 to ≤17 years received 2 doses of H1N1 vaccine administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group title

Cohort 2 (3.75_Half MF59)

Reporting group description

Subjects aged ≥3 to ≤8 years received 2 doses of H1N1 vaccine 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 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 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 administered 3 weeks apart, followed by a booster dose 12 months after first vaccination with an aTIV.

Reporting group title

Cohort 3 (7.5_Full MF59)

Reporting group description

Subjects aged ≥12 to ≤35 months received 2 doses of H1N1 vaccine 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 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 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 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 (7.5_Full 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	3 / 79 (3.80%)	2 / 79 (2.53%)	1 / 71 (1.41%)	3 / 72 (4.17%)	0 / 39 (0.00%)	7 / 65 (10.77%)	8 / 73 (10.96%)	5 / 33 (15.15%)	11 / 75 (14.67%)	8 / 74 (10.81%)
number of deaths (all causes)	0	0	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0	0	0
Injury, poisoning and procedural complications
Joint Dislocation
subjects affected / exposed	1 / 79 (1.27%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 75 (0.00%)	0 / 74 (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
Toxicity to various agents
subjects affected / exposed	1 / 79 (1.27%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 75 (0.00%)	0 / 74 (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
Concussion
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	1 / 71 (1.41%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 75 (0.00%)	0 / 74 (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
Skull fracture
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	1 / 71 (1.41%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 75 (0.00%)	0 / 74 (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
Accidental exposure
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 75 (0.00%)	0 / 74 (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
Chemical poisoning
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 75 (0.00%)	1 / 74 (1.35%)
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
Nervous system disorders
Convulsion
subjects affected / exposed	0 / 79 (0.00%)	1 / 79 (1.27%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 75 (0.00%)	0 / 74 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 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
Epilepsy
subjects affected / exposed	0 / 79 (0.00%)	1 / 79 (1.27%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 75 (0.00%)	0 / 74 (0.00%)
occurrences causally related to treatment / all	0 / 0	3 / 3	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
Migraine
subjects affected / exposed	0 / 79 (0.00%)	1 / 79 (1.27%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 75 (0.00%)	0 / 74 (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
Febrile convulsion
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 75 (1.33%)	0 / 74 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 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
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 75 (0.00%)	1 / 74 (1.35%)
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
Reproductive system and breast disorders
Ovarian cyst
subjects affected / exposed	1 / 79 (1.27%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 75 (0.00%)	0 / 74 (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
Gastrointestinal disorders
Vomiting
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	2 / 73 (2.74%)	0 / 33 (0.00%)	0 / 75 (0.00%)	0 / 74 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	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
Gastritis
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 75 (1.33%)	0 / 74 (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
Respiratory, thoracic and mediastinal disorders
Adenoidal hypertrophy
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 75 (0.00%)	0 / 74 (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
Asthma
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	2 / 75 (2.67%)	0 / 74 (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 / 2	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 tract congestion
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	1 / 65 (1.54%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 75 (0.00%)	0 / 74 (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
Bronchospasm
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 75 (0.00%)	1 / 74 (1.35%)
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
Psychiatric disorders
Suicidal ideation
subjects affected / exposed	1 / 79 (1.27%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 75 (0.00%)	0 / 74 (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
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	1 / 65 (1.54%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 75 (0.00%)	0 / 74 (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
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 79 (1.27%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 75 (0.00%)	0 / 74 (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
Gastroenteritis
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	1 / 72 (1.39%)	0 / 39 (0.00%)	1 / 65 (1.54%)	0 / 73 (0.00%)	1 / 33 (3.03%)	4 / 75 (5.33%)	1 / 74 (1.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 4	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
Pneumonia
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	2 / 72 (2.78%)	0 / 39 (0.00%)	1 / 65 (1.54%)	0 / 73 (0.00%)	1 / 33 (3.03%)	0 / 75 (0.00%)	4 / 74 (5.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 4
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
Acute tonsillitis
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 75 (0.00%)	0 / 74 (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 / 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 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	3 / 65 (4.62%)	0 / 73 (0.00%)	1 / 33 (3.03%)	3 / 75 (4.00%)	0 / 74 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 1	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
Dengue fever
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	2 / 65 (3.08%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 75 (1.33%)	0 / 74 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	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
Giardiasis
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 75 (0.00%)	0 / 74 (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
Laryngitis
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	0 / 73 (0.00%)	1 / 33 (3.03%)	0 / 75 (0.00%)	0 / 74 (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
Tonsillitis
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	0 / 73 (0.00%)	1 / 33 (3.03%)	0 / 75 (0.00%)	0 / 74 (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
Upper respiratory tract infection
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	0 / 73 (0.00%)	1 / 33 (3.03%)	0 / 75 (0.00%)	0 / 74 (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
Urinary tract infection
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	0 / 73 (0.00%)	1 / 33 (3.03%)	0 / 75 (0.00%)	0 / 74 (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
Bronchiolitis
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 75 (1.33%)	0 / 74 (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
Gastroenteritis rotavirus
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 75 (1.33%)	0 / 74 (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 / 2	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 syncytial virus bronchiolitis
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 75 (1.33%)	2 / 74 (2.70%)
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 / 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
Dehydration
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	0 / 65 (0.00%)	1 / 73 (1.37%)	0 / 33 (0.00%)	0 / 75 (0.00%)	0 / 74 (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

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 (7.5_Full 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	71 / 79 (89.87%)	72 / 79 (91.14%)	63 / 71 (88.73%)	66 / 72 (91.67%)	34 / 39 (87.18%)	61 / 65 (93.85%)	65 / 73 (89.04%)	28 / 33 (84.85%)	70 / 75 (93.33%)	69 / 74 (93.24%)
Nervous system disorders
Headache
alternative assessment type: Systematic
subjects affected / exposed	28 / 79 (35.44%)	29 / 79 (36.71%)	17 / 71 (23.94%)	17 / 72 (23.61%)	9 / 39 (23.08%)	0 / 65 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 75 (0.00%)	0 / 74 (0.00%)
occurrences all number	42	47	24	24	11	0	0	0	0	0
Somnolence
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	21 / 65 (32.31%)	35 / 73 (47.95%)	9 / 33 (27.27%)	17 / 75 (22.67%)	28 / 74 (37.84%)
occurrences all number	0	0	0	0	0	41	49	13	33	48
General disorders and administration site conditions
Chills
alternative assessment type: Systematic
subjects affected / exposed	3 / 79 (3.80%)	10 / 79 (12.66%)	6 / 71 (8.45%)	11 / 72 (15.28%)	2 / 39 (5.13%)	7 / 65 (10.77%)	10 / 73 (13.70%)	2 / 33 (6.06%)	5 / 75 (6.67%)	6 / 74 (8.11%)
occurrences all number	4	12	7	13	2	10	10	2	10	9
Crying
alternative assessment type: Systematic
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 39 (0.00%)	21 / 65 (32.31%)	29 / 73 (39.73%)	10 / 33 (30.30%)	32 / 75 (42.67%)	31 / 74 (41.89%)
occurrences all number	0	0	0	0	0	34	47	13	54	52
Fatigue
alternative assessment type: Systematic
subjects affected / exposed	25 / 79 (31.65%)	28 / 79 (35.44%)	26 / 71 (36.62%)	24 / 72 (33.33%)	10 / 39 (25.64%)	0 / 65 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 75 (0.00%)	0 / 74 (0.00%)
occurrences all number	35	40	38	46	19	0	0	0	0	0
Injection site erythema
alternative assessment type: Systematic
subjects affected / exposed	12 / 79 (15.19%)	18 / 79 (22.78%)	24 / 71 (33.80%)	28 / 72 (38.89%)	8 / 39 (20.51%)	22 / 65 (33.85%)	30 / 73 (41.10%)	10 / 33 (30.30%)	16 / 75 (21.33%)	16 / 74 (21.62%)
occurrences all number	12	20	30	40	10	33	53	16	26	24
Injection site haemorrhage
alternative assessment type: Systematic
subjects affected / exposed	6 / 79 (7.59%)	7 / 79 (8.86%)	10 / 71 (14.08%)	11 / 72 (15.28%)	10 / 39 (25.64%)	6 / 65 (9.23%)	15 / 73 (20.55%)	6 / 33 (18.18%)	6 / 75 (8.00%)	1 / 74 (1.35%)
occurrences all number	10	9	13	13	13	6	20	8	9	2
Injection site induration
alternative assessment type: Systematic
subjects affected / exposed	18 / 79 (22.78%)	17 / 79 (21.52%)	15 / 71 (21.13%)	21 / 72 (29.17%)	6 / 39 (15.38%)	17 / 65 (26.15%)	23 / 73 (31.51%)	8 / 33 (24.24%)	10 / 75 (13.33%)	12 / 74 (16.22%)
occurrences all number	21	20	18	34	6	22	32	11	18	19
Injection site pain
alternative assessment type: Systematic
subjects affected / exposed	62 / 79 (78.48%)	67 / 79 (84.81%)	49 / 71 (69.01%)	49 / 72 (68.06%)	23 / 39 (58.97%)	22 / 65 (33.85%)	44 / 73 (60.27%)	17 / 33 (51.52%)	29 / 75 (38.67%)	34 / 74 (45.95%)
occurrences all number	115	131	96	103	42	32	90	32	50	69
Injection site swelling
alternative assessment type: Systematic
subjects affected / exposed	9 / 79 (11.39%)	17 / 79 (21.52%)	15 / 71 (21.13%)	19 / 72 (26.39%)	5 / 39 (12.82%)	13 / 65 (20.00%)	16 / 73 (21.92%)	5 / 33 (15.15%)	3 / 75 (4.00%)	6 / 74 (8.11%)
occurrences all number	9	21	17	22	6	16	20	6	42	8
Malaise
alternative assessment type: Systematic
subjects affected / exposed	14 / 79 (17.72%)	20 / 79 (25.32%)	20 / 71 (28.17%)	15 / 72 (20.83%)	8 / 39 (20.51%)	0 / 65 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 75 (0.00%)	0 / 74 (0.00%)
occurrences all number	17	27	23	21	16	0	0	0	0	0
Pyrexia
alternative assessment type: Systematic
subjects affected / exposed	4 / 79 (5.06%)	1 / 79 (1.27%)	19 / 71 (26.76%)	24 / 72 (33.33%)	6 / 39 (15.38%)	37 / 65 (56.92%)	38 / 73 (52.05%)	12 / 33 (36.36%)	32 / 75 (42.67%)	39 / 74 (52.70%)
occurrences all number	5	1	26	48	7	60	63	19	42	66
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	3 / 79 (3.80%)	1 / 79 (1.27%)	3 / 71 (4.23%)	2 / 72 (2.78%)	3 / 39 (7.69%)	0 / 65 (0.00%)	0 / 73 (0.00%)	1 / 33 (3.03%)	0 / 75 (0.00%)	1 / 74 (1.35%)
occurrences all number	3	2	5	2	5	0	0	1	0	1
Diarrhoea
alternative assessment type: Systematic
subjects affected / exposed	7 / 79 (8.86%)	1 / 79 (1.27%)	5 / 71 (7.04%)	6 / 72 (8.33%)	3 / 39 (7.69%)	24 / 65 (36.92%)	30 / 73 (41.10%)	10 / 33 (30.30%)	35 / 75 (46.67%)	38 / 74 (51.35%)
occurrences all number	8	1	6	8	5	41	43	15	68	84
Nausea
alternative assessment type: Systematic
subjects affected / exposed	13 / 79 (16.46%)	10 / 79 (12.66%)	10 / 71 (14.08%)	10 / 72 (13.89%)	4 / 39 (10.26%)	0 / 65 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 75 (0.00%)	0 / 74 (0.00%)
occurrences all number	14	11	10	15	8	0	0	0	0	0
Vomiting
alternative assessment type: Systematic
subjects affected / exposed	1 / 79 (1.27%)	0 / 79 (0.00%)	2 / 71 (2.82%)	5 / 72 (6.94%)	2 / 39 (5.13%)	12 / 65 (18.46%)	25 / 73 (34.25%)	4 / 33 (12.12%)	21 / 75 (28.00%)	22 / 74 (29.73%)
occurrences all number	1	0	3	27	2	19	27	6	33	31
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
subjects affected / exposed	3 / 79 (3.80%)	2 / 79 (2.53%)	4 / 71 (5.63%)	2 / 72 (2.78%)	3 / 39 (7.69%)	0 / 65 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	1 / 75 (1.33%)	0 / 74 (0.00%)
occurrences all number	3	2	4	2	3	0	0	0	1	0
Skin and subcutaneous tissue disorders
Ecchymosis
subjects affected / exposed	0 / 79 (0.00%)	1 / 79 (1.27%)	0 / 71 (0.00%)	0 / 72 (0.00%)	2 / 39 (5.13%)	0 / 65 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 75 (0.00%)	0 / 74 (0.00%)
occurrences all number	0	1	0	0	2	0	0	0	0	0
Hyperhidrosis
subjects affected / exposed	6 / 79 (7.59%)	5 / 79 (6.33%)	3 / 71 (4.23%)	4 / 72 (5.56%)	0 / 39 (0.00%)	0 / 65 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 75 (0.00%)	0 / 74 (0.00%)
occurrences all number	9	7	3	6	0	0	0	0	0	0
Psychiatric disorders
Eating disorder
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	1 / 71 (1.41%)	2 / 72 (2.78%)	0 / 39 (0.00%)	23 / 65 (35.38%)	33 / 73 (45.21%)	8 / 33 (24.24%)	24 / 75 (32.00%)	27 / 74 (36.49%)
occurrences all number	0	0	1	2	0	36	42	14	37	55
Irritability
alternative assessment type: Systematic
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	1 / 71 (1.41%)	4 / 72 (5.56%)	2 / 39 (5.13%)	21 / 65 (32.31%)	21 / 73 (28.77%)	7 / 33 (21.21%)	15 / 75 (20.00%)	17 / 74 (22.97%)
occurrences all number	0	0	1	5	2	37	35	13	26	27
Musculoskeletal and connective tissue disorders
Arthralgia
alternative assessment type: Systematic
subjects affected / exposed	13 / 79 (16.46%)	12 / 79 (15.19%)	10 / 71 (14.08%)	11 / 72 (15.28%)	4 / 39 (10.26%)	0 / 65 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 75 (0.00%)	0 / 74 (0.00%)
occurrences all number	13	15	13	14	5	0	0	0	0	0
Myalgia
alternative assessment type: Systematic
subjects affected / exposed	28 / 79 (35.44%)	28 / 79 (35.44%)	10 / 71 (14.08%)	20 / 72 (27.78%)	7 / 39 (17.95%)	0 / 65 (0.00%)	0 / 73 (0.00%)	0 / 33 (0.00%)	0 / 75 (0.00%)	0 / 74 (0.00%)
occurrences all number	32	32	12	26	10	0	0	0	0	0
Infections and infestations
Bronchitis
subjects affected / exposed	2 / 79 (2.53%)	0 / 79 (0.00%)	1 / 71 (1.41%)	1 / 72 (1.39%)	0 / 39 (0.00%)	0 / 65 (0.00%)	2 / 73 (2.74%)	3 / 33 (9.09%)	2 / 75 (2.67%)	1 / 74 (1.35%)
occurrences all number	2	0	1	1	0	0	2	4	2	1
Conjunctivitis
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 71 (0.00%)	2 / 72 (2.78%)	0 / 39 (0.00%)	1 / 65 (1.54%)	1 / 73 (1.37%)	1 / 33 (3.03%)	2 / 75 (2.67%)	6 / 74 (8.11%)
occurrences all number	0	0	0	2	0	1	1	1	3	6
Nasopharyngitis
subjects affected / exposed	1 / 79 (1.27%)	3 / 79 (3.80%)	3 / 71 (4.23%)	2 / 72 (2.78%)	1 / 39 (2.56%)	15 / 65 (23.08%)	16 / 73 (21.92%)	13 / 33 (39.39%)	40 / 75 (53.33%)	33 / 74 (44.59%)
occurrences all number	2	4	3	4	1	20	18	14	64	46
Rhinitis
subjects affected / exposed	6 / 79 (7.59%)	6 / 79 (7.59%)	5 / 71 (7.04%)	7 / 72 (9.72%)	1 / 39 (2.56%)	4 / 65 (6.15%)	2 / 73 (2.74%)	1 / 33 (3.03%)	1 / 75 (1.33%)	1 / 74 (1.35%)
occurrences all number	6	7	5	9	1	4	2	1	1	2
Tonsillitis
subjects affected / exposed	0 / 79 (0.00%)	0 / 79 (0.00%)	1 / 71 (1.41%)	1 / 72 (1.39%)	0 / 39 (0.00%)	3 / 65 (4.62%)	5 / 73 (6.85%)	0 / 33 (0.00%)	6 / 75 (8.00%)	2 / 74 (2.70%)
occurrences all number	0	0	1	2	0	3	6	0	6	2
Upper respiratory tract infection
subjects affected / exposed	4 / 79 (5.06%)	1 / 79 (1.27%)	5 / 71 (7.04%)	3 / 72 (4.17%)	3 / 39 (7.69%)	1 / 65 (1.54%)	4 / 73 (5.48%)	0 / 33 (0.00%)	1 / 75 (1.33%)	0 / 74 (0.00%)
occurrences all number	4	1	5	4	3	1	4	0	1	0

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Were there any global substantial amendments to the protocol? Yes

30 Jul 2009

To allow interim analysis of the study, if there is a request in public health interest.

07 Apr 2010

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

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: 1. Percentages of subjects achieving seroconversion against A/H1N1 Strain as measured by hemagglutination inhibition (HI) assay.

Primary: 1. Percentages of subjects achieving seroconversion against A/H1N1 Strain as measured by hemagglutination inhibition (HI) assay.

Primary: 2. Percentages of subjects achieving HI titers ≥1:40 against A/H1N1 Strain.

Primary: 2. Percentages of subjects achieving HI titers ≥1:40 against A/H1N1 Strain.

Primary: 3. Geometric mean ratios against A/H1N1 strain following 2-dose vaccination schedule as determined by HI assay

Primary: 3. Geometric mean ratios against A/H1N1 strain following 2-dose vaccination schedule as determined by HI assay

Primary: 4. Number of Subjects Reporting Solicited Local and Systemic Adverse Events, After Any Primary Vaccination

Primary: 4. Number of Subjects Reporting Solicited Local and Systemic Adverse Events, After Any Primary Vaccination

Primary: 5. Number of Subjects Reporting Solicited Local and Systemic Adverse Events, After Booster Vaccination

Primary: 5. Number of Subjects Reporting Solicited Local and Systemic Adverse Events, After Booster Vaccination

Primary: 6. Number of Subjects Reporting Solicited Local and Systemic Adverse Events, After second seasonal flu Vaccination

Primary: 6. Number of Subjects Reporting Solicited Local and Systemic Adverse Events, After second seasonal flu Vaccination

Primary: 7. Number of Subjects Reporting Unsolicited Adverse Events after primary and booster vaccination.

Primary: 7. Number of Subjects Reporting Unsolicited Adverse Events after primary and booster vaccination.

Primary: 8. Number of Subjects Reporting Unsolicited Adverse Events.

Primary: 8. Number of Subjects Reporting Unsolicited Adverse Events.

Secondary: 9. Percentages of subjects achieving seroconversion against A/H1N1 Strain following a booster dose as measured by hemagglutination inhibition (HI) assay.

Secondary: 9. Percentages of subjects achieving seroconversion against A/H1N1 Strain following a booster dose as measured by hemagglutination inhibition (HI) assay.

Secondary: 10. Percentages of subjects achieving HI titers ≥1:40 agianst A/H1N1 Strain following a booster dose

Secondary: 10. Percentages of subjects achieving HI titers ≥1:40 agianst A/H1N1 Strain following a booster dose

Secondary: 11. Geometric mean Ratios against A/H1N1 strain following a booster dose as determined by HI assay

Secondary: 11. Geometric mean Ratios against A/H1N1 strain following a booster dose as determined by HI assay

Secondary: 12. Geometric mean titers against A/H1N1 strain as determined by HI assay in pooled population

Secondary: 12. 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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