Clinical Trial Results:
A Phase 2b, Open Label, Multi-Center, Extension Study to Evaluate the Safety, Tolerability and Immunogenicity of a Booster Dose of Novartis Meningococcal B Recombinant Vaccine Administered at 12, 18 or 24 Months of Age in Subjects Who Previously Received a Three-Dose Primary Series of the Novartis Meningococcal B Recombinant Vaccine as Infants in Study V72P12.

Due to a system error, the data reported in v1 is not correct and has been removed from public view.

Summary
EudraCT number	2009-011676-30
Trial protocol	GB ES DE BE IT CZ
Global end of trial date	09 Jan 2012

Results information
Results version number	v2(current)
This version publication date	03 Jun 2016
First version publication date	08 Jan 2015
Other versions	v1 (removed from public view)
Version creation reason

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

V72P12E1

ISRCTN number

US NCT number

NCT00944034

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Vaccines and Diagnostics SRL

Sponsor organisation address

Via Fiorentina 1, Siena, Italy, 53100

Public contact

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

Scientific contact

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

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

Yes

EMA paediatric investigation plan number(s)

EMEA-000139-PIP01-07

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

21 Nov 2012

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

09 Jan 2012

Was the trial ended prematurely?

Main objective of the trial

To demonstrate a sufficient immune response following a fourth (booster) dose of rMenB+OMV NZ in at least one of the time points, when given at 12, 18 or 24 months of age to toddlers previously primed with three doses of rMenB+OMV NZ as infants at 2, 4 and 6 months of age (with concomitant routine vaccines).

Protection of trial subjects

This clinical study was designated, implemented and reported in accordance with the International Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice (GCP), with applicable local regulations (including European Directive 2001/20/EC, US Code of Federal Regulations (CFR) Title 21, and Japanese Ministry of Health, Labor and Welfare), and with the ethical principles laid down in the Declaration of Helsinki. Standard immunization practices should be observed and care should be taken to administer the injection intramuscularly. As with all injectable vaccines, appropriate medical treatment and supervision should be readily available in case of anaphylactic reactions following administration of the study vaccine, in accordance with local practice/guidelines such as epinephrine 1:1000 and diphenhydramine.

Background therapy

Evidence for comparator

Actual start date of recruitment

13 Jul 2009

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

6 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Czech Republic: 252

Country: Number of subjects enrolled

Belgium: 183

Country: Number of subjects enrolled

Germany: 295

Country: Number of subjects enrolled

Italy: 290

Country: Number of subjects enrolled

Spain: 106

Country: Number of subjects enrolled

United Kingdom: 462

Worldwide total number of subjects

1588

EEA total number of subjects

1588

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)

1588

Children (2-11 years)

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

Subjects were enrolled from 6 centres in Belgium, 4 in Czech, 24 in Germany, 5 in Italy, 16 in Spain and 4 in UK who had previously participated in and completed the study V72P12.

Screening details

All enrolled subjects were included in the trial.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

B+R246_12

Arm description

Previously received rMenB+OMV NZ vaccine + routine vaccines at 2, 4 and 6 months of age followed by a booster dose of rMenB+OMV NZ vaccine at 12 months of age.

Arm type

Experimental

Investigational medicinal product name

rMenB+OMV NZ

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Each dose of 0.5 mL

B+R246_18

Arm description

Previously received rMenB+OMV NZ vaccine + routine vaccines at 2, 4 and 6 months of age followed by a booster dose of rMenB+OMV NZ vaccine at 18 months of age.

Arm type

Experimental

Investigational medicinal product name

rMenB+OMV NZ

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Each dose of 0.5 mL

B+R246_24

Arm description

Previously received rMenB+OMV NZ vaccine + routine vaccines at 2, 4 and 6 months of age followed by a booster dose of rMenB+OMV NZ vaccine at 24 months of age.

Arm type

Experimental

Investigational medicinal product name

rMenB+OMV NZ

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Each dose of 0.5 mL

B246_12

Arm description

Previously received 3 doses of rMenB+OMV NZ vaccine at 2, 4 and 6 months of age and routine vaccines at 3, 5 and 7 months of age, followed by a booster dose of rMenB+OMV NZ vaccine at 12 months of age.

Arm type

Experimental

Investigational medicinal product name

rMenB+OMV NZ

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Each dose of 0.5 mL

B246_18

Arm description

Previously received 3 doses of rMenB+OMV NZ vaccine at 2, 4 and 6 months of age and routine vaccines at 3,5 and 7 months of age, followed by a booster dose of rMenB+OMV NZ at 18 months of age.

Arm type

Experimental

Investigational medicinal product name

rMenB+OMV NZ

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Each dose of 0.5 mL

B246_24

Arm description

Previously received 3 doses of rMenB+OMV NZ vaccine at 2, 4 and 6 months of age and routine vaccines at 3, 5 and 7 months of age, followed by a booster dose of rMenB+OMV NZ at 24 months of age.

Arm type

Experimental

Investigational medicinal product name

rMenB+OMV NZ

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Each dose of 0.5 mL

B+R234_12

Arm description

Previously received rMenB+OMV NZ vaccine + routine vaccines at 2, 3 and 4 months of age followed by a booster dose of rMenB+OMV NZ at 12 months of age.

Arm type

Experimental

Investigational medicinal product name

rMenB+OMV NZ

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Each dose of 0.5 mL

B+R234_18

Arm description

Previously received rMenB+OMV NZ vaccine + routine vaccines at 2, 3 and 4 months of age followed by a booster dose of rMenB+OMV NZ vaccine at 18 months of age.

Arm type

Experimental

Investigational medicinal product name

rMenB+OMV NZ

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Each dose of 0.5 mL

B+R234_24

Arm description

Previously received rMenB+OMV NZ vaccine + routine vaccines at 2, 3 and 4 months of age followed by a booster dose of rMenB+OMV NZ vaccine at 24 months of age.

Arm type

Experimental

Investigational medicinal product name

rMenB+OMV NZ

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Each dose of 0.5 mL

B12 14

Arm description

Previously received two catch-up doses of rMenB+OMV NZ vaccine at 12 and14 months of age.

Arm type

Experimental

Investigational medicinal product name

rMenB+OMV NZ

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Each dose of 0.5 mL

B18 20

Arm description

Previously received two catch-up doses of rMenB+OMV NZ vaccine at 18 and 20 months of age.

Arm type

Experimental

Investigational medicinal product name

rMenB+OMV NZ

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Each dose of 0.5 mL

B24 26

Arm description

Previously received two catch-up doses of rMenB+OMV NZ vaccine at 24 and 26 months of age..

Arm type

Experimental

Investigational medicinal product name

rMenB+OMV NZ

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Each dose of 0.5 mL

Number of subjects in period 1	B+R246_12	B+R246_18	B+R246_24	B246_12	B246_18	B246_24	B+R234_12	B+R234_18	B+R234_24	B12 14	B18 20	B24 26
Started	188	157	152	174	164	143	106	78	73	246	51	56
Completed	183	150	143	170	150	123	102	73	63	236	50	52
Not completed	5	7	9	4	14	20	4	5	10	10	1	4
Adverse event, serious fatal	-	-	1	-	-	-	-	-	-	-	-	-
Consent withdrawn by subject	3	2	6	2	5	8	2	2	3	4	-	4
Inappropriate enrollment	-	1	-	1	2	1	-	-	1	1	-	-
Unable to classify	-	-	-	-	-	1	1	1	-	-	-	-
Lost to follow-up	-	4	2	-	5	7	-	1	5	1	1	-
Protocol deviation	2	-	-	1	2	3	-	1	1	4	-	-
Administrative reason	-	-	-	-	-	-	1	-	-	-	-	-

Baseline characteristics

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Reporting group title

B+R246_12

Reporting group description

Previously received rMenB+OMV NZ vaccine + routine vaccines at 2, 4 and 6 months of age followed by a booster dose of rMenB+OMV NZ vaccine at 12 months of age.

Reporting group title

B+R246_18

Reporting group description

Previously received rMenB+OMV NZ vaccine + routine vaccines at 2, 4 and 6 months of age followed by a booster dose of rMenB+OMV NZ vaccine at 18 months of age.

Reporting group title

B+R246_24

Reporting group description

Previously received rMenB+OMV NZ vaccine + routine vaccines at 2, 4 and 6 months of age followed by a booster dose of rMenB+OMV NZ vaccine at 24 months of age.

Reporting group title

B246_12

Reporting group description

Reporting group title

B246_18

Reporting group description

Previously received 3 doses of rMenB+OMV NZ vaccine at 2, 4 and 6 months of age and routine vaccines at 3,5 and 7 months of age, followed by a booster dose of rMenB+OMV NZ at 18 months of age.

Reporting group title

B246_24

Reporting group description

Previously received 3 doses of rMenB+OMV NZ vaccine at 2, 4 and 6 months of age and routine vaccines at 3, 5 and 7 months of age, followed by a booster dose of rMenB+OMV NZ at 24 months of age.

Reporting group title

B+R234_12

Reporting group description

Previously received rMenB+OMV NZ vaccine + routine vaccines at 2, 3 and 4 months of age followed by a booster dose of rMenB+OMV NZ at 12 months of age.

Reporting group title

B+R234_18

Reporting group description

Previously received rMenB+OMV NZ vaccine + routine vaccines at 2, 3 and 4 months of age followed by a booster dose of rMenB+OMV NZ vaccine at 18 months of age.

Reporting group title

B+R234_24

Reporting group description

Previously received rMenB+OMV NZ vaccine + routine vaccines at 2, 3 and 4 months of age followed by a booster dose of rMenB+OMV NZ vaccine at 24 months of age.

Reporting group title

B12 14

Reporting group description

Previously received two catch-up doses of rMenB+OMV NZ vaccine at 12 and14 months of age.

Reporting group title

B18 20

Reporting group description

Previously received two catch-up doses of rMenB+OMV NZ vaccine at 18 and 20 months of age.

Reporting group title

B24 26

Reporting group description

Previously received two catch-up doses of rMenB+OMV NZ vaccine at 24 and 26 months of age..

Reporting group values	B+R246_12	B+R246_18	B+R246_24	B246_12	B246_18	B246_24	B+R234_12	B+R234_18	B+R234_24	B12 14	B18 20	B24 26	Total
Number of subjects	188	157	152	174	164	143	106	78	73	246	51	56	1588
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	188	153	10	174	155	5	104	75	6	243	51	2	1166
Children (2-11 years)	0	0	135	0	0	121	0	0	60	0	0	54	370
Adolescents (12-17 years)	0	0	0	0	0	0	0	0	0	0	0	0	0
Adults (18-64 years)	0	0	0	0	0	0	0	0	0	0	0	0	0
From 65-84 years	0	0	0	0	0	0	0	0	0	0	0	0	0
85 years and over	0	0	0	0	0	0	0	0	0	0	0	0	0
Not Available	0	4	7	0	9	17	2	3	7	3	0	0	52
Age continuous
Units: months
arithmetic mean (standard deviation)	12.6 ( 1.2 )	18.1 ( 0.6 )	24 ( 0.4 )	12.7 ( 0.9 )	18.1 ( 0.5 )	24 ( 0.3 )	12.8 ( 1.4 )	18 ( 0.4 )	24 ( 0.5 )	12.6 ( 1.3 )	18 ( 0.2 )	24 ( 0.2 )	-
Gender categorical
Units: Subjects
Female	78	73	77	81	80	75	62	41	34	115	23	23	762
Male	110	84	75	93	84	68	44	37	39	131	28	33	826

Subject analysis set title

Per-protocol Population

Subject analysis set type

Per protocol

Subject analysis set description

All enrolled subjects who correctly received the vaccine, provided evaluable serum samples at the relevant time points and had no major protocol violation as defined prior to the end of the study.

Subject analysis set title

Safety Population

Subject analysis set type

Safety analysis

Subject analysis set description

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

Subject analysis sets values	Per-protocol Population	Safety Population
Number of subjects	1288	1519
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	1288	1519
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	0	0
From 65-84 years	0	0
85 years and over	0	0
Not Available	0	0
Age continuous
Units: months
arithmetic mean (standard deviation)	16.9 ( 4.7 )	17.1 ( 4.7 )
Gender categorical
Units: Subjects
Female
Male

End points

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Reporting group title

B+R246_12

Reporting group description

Previously received rMenB+OMV NZ vaccine + routine vaccines at 2, 4 and 6 months of age followed by a booster dose of rMenB+OMV NZ vaccine at 12 months of age.

Reporting group title

B+R246_18

Reporting group description

Previously received rMenB+OMV NZ vaccine + routine vaccines at 2, 4 and 6 months of age followed by a booster dose of rMenB+OMV NZ vaccine at 18 months of age.

Reporting group title

B+R246_24

Reporting group description

Previously received rMenB+OMV NZ vaccine + routine vaccines at 2, 4 and 6 months of age followed by a booster dose of rMenB+OMV NZ vaccine at 24 months of age.

Reporting group title

B246_12

Reporting group description

Reporting group title

B246_18

Reporting group description

Previously received 3 doses of rMenB+OMV NZ vaccine at 2, 4 and 6 months of age and routine vaccines at 3,5 and 7 months of age, followed by a booster dose of rMenB+OMV NZ at 18 months of age.

Reporting group title

B246_24

Reporting group description

Previously received 3 doses of rMenB+OMV NZ vaccine at 2, 4 and 6 months of age and routine vaccines at 3, 5 and 7 months of age, followed by a booster dose of rMenB+OMV NZ at 24 months of age.

Reporting group title

B+R234_12

Reporting group description

Previously received rMenB+OMV NZ vaccine + routine vaccines at 2, 3 and 4 months of age followed by a booster dose of rMenB+OMV NZ at 12 months of age.

Reporting group title

B+R234_18

Reporting group description

Previously received rMenB+OMV NZ vaccine + routine vaccines at 2, 3 and 4 months of age followed by a booster dose of rMenB+OMV NZ vaccine at 18 months of age.

Reporting group title

B+R234_24

Reporting group description

Previously received rMenB+OMV NZ vaccine + routine vaccines at 2, 3 and 4 months of age followed by a booster dose of rMenB+OMV NZ vaccine at 24 months of age.

Reporting group title

B12 14

Reporting group description

Previously received two catch-up doses of rMenB+OMV NZ vaccine at 12 and14 months of age.

Reporting group title

B18 20

Reporting group description

Previously received two catch-up doses of rMenB+OMV NZ vaccine at 18 and 20 months of age.

Reporting group title

B24 26

Reporting group description

Previously received two catch-up doses of rMenB+OMV NZ vaccine at 24 and 26 months of age..

Subject analysis set title

Per-protocol Population

Subject analysis set type

Per protocol

Subject analysis set description

All enrolled subjects who correctly received the vaccine, provided evaluable serum samples at the relevant time points and had no major protocol violation as defined prior to the end of the study.

Subject analysis set title

Safety Population

Subject analysis set type

Safety analysis

Subject analysis set description

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

Primary: Percentages of Subjects With Serum Bactericidal Antibody Titers ≥1:5 After Receiving a Fourth (Booster) Dose of rMenB+OMV NZ Vaccination in subjects who previously received 3 doses of rMenB+OMV NZ and routine vaccines at 2, 4 and 6 months of age

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End point title

Percentages of Subjects With Serum Bactericidal Antibody Titers ≥1:5 After Receiving a Fourth (Booster) Dose of rMenB+OMV NZ Vaccination in subjects who previously received 3 doses of rMenB+OMV NZ and routine vaccines at 2, 4 and 6 months of age ^[1] ^[2]

End point description

Immunogenicity was assessed in terms of percentage of subjects with serum bactericidal antibody (SBA) titers ≥1:5 against N.meningitidis serogroup reference strains H44/76, NZ98/254 and 5/99, one month after the fourth (booster) dose of meningococcal B vaccine at 12 or 18 or24 months of age who were previously vaccinated with 3 doses of rMenB+OMV NZ and routine vaccines at 2, 4 and 6 months of age.

End point type

Primary

End point timeframe

1 month after booster

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: statistical analyses not applicable for this endpoint.
[2] - 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: statistical analyses not applicable for this endpoint.

End point values	B+R246_12	B+R246_18	B+R246_24
Number of subjects analysed	159 ^[3]	118	101
Units: Percentages of subjects
number (confidence interval 98.3%)
hSBA≥ 1: 5 (H44/76 strain)	97 (93 to 99)	100 (96 to 100)	100 (95 to 100)
hSBA≥ 1: 5 (5/99 strain)	100 (97 to 100)	100 (96 to 100)	100 (95 to 100)
hSBA≥ 1: 5 (NZ 98/254 strain)	95 (89 to 98)	77 (67 to 86)	84 (74 to 92)
hSBA≥ 1: 5 (M10713 strain)	0 (0 to 0)	0 (0 to 0)	0 (0 to 0)

Notes
[3] - 44/76-SL (N= 158, 116,101) 5/99 (N= 156,118,100) NZ98/254 (N= 159,118,103) M107713 (N= 0,0,0)

No statistical analyses for this end point

Secondary: Percentages of Subjects With SBA Titers ≥1:5 After Receiving a Fourth (Booster) Dose of rMenB+OMV NZ Vaccination in subjects who previously received 3 doses of rMenB+OMV NZ at 2, 4 and 6 months of age and routine vaccines at 3, 5 and 7 months of age.

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End point title

Percentages of Subjects With SBA Titers ≥1:5 After Receiving a Fourth (Booster) Dose of rMenB+OMV NZ Vaccination in subjects who previously received 3 doses of rMenB+OMV NZ at 2, 4 and 6 months of age and routine vaccines at 3, 5 and 7 months of age. ^[4]

End point description

Immunogenicity was assessed in terms of percentage of subjects with serum bactericidal antibody (SBA) titers ≥1:5 against N.meningitidis serogroup reference strains H44/76, NZ98/254 and 5/99, one month after the fourth (booster) dose of meningococcal B vaccine at 12 or 18 or 24 months of age who were previously vaccinated with 3 doses of rMenB+OMV NZ at 2, 4 and 6 months of age and routine vaccines at 3, 5 and 7 months of age.

End point type

Secondary

End point timeframe

1 month after booster

Notes
[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: statistical analyses not applicable for this endpoint.

End point values	B246_12	B246_18	B246_24
Number of subjects analysed	142 ^[5]	111	95
Units: Percentages of subjects
number (confidence interval 98.3%)
hSBA≥ 1: 5 (H44/76 strain)	100 (97 to 100)	99 (94 to 100)	100 (95 to 100)
hSBA≥ 1: 5 (5/99 strain)	100 (97 to 100)	100 (96 to 100)	100 (95 to 100)
hSBA≥ 1: 5 (NZ 98/254 strain)	96 (90 to 99)	86 (76 to 93)	89 (80 to 96)
hSBA≥ 1: 5 (M10713 strain)	0 (0 to 0)	0 (0 to 0)	0 (0 to 0)

Notes
[5] - H44/76 (N=138,111,93) 5/99 (N=142,110,92) NZ 98/254 (N=142,111,95) M10713 (N=0,0,0)

No statistical analyses for this end point

Secondary: Percentages of Subjects With Serum Bactericidal Antibody Titers ≥1:5 After Receiving a Fourth (Booster) Dose of rMenB+OMV NZ Vaccination in subjects who previously received 3 doses of rMenB+OMV NZ and routine vaccines at 2, 3 and 4 months of age.

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End point title

End point description

End point type

Secondary

End point timeframe

1 month after booster

Notes
[6] - 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: statistical analyses not applicable for this endpoint.

End point values	B+R234_12	B+R234_18	B+R234_24
Number of subjects analysed	86 ^[7]	56	48
Units: Percentages of subjects
number (confidence interval 98.3%)
hSBA≥ 1: 5 (H44/76 strain)	100 (94 to 100)	98 (88 to 100)	100 (91 to 100)
hSBA≥ 1: 5 (5/99 strain)	100 (94 to 100)	100 (92 to 100)	100 (90 to 100)
hSBA≥ 1: 5 (NZ 98/254 strain)	97 (89 to 100)	80 (65 to 91)	96 (83 to 100)
hSBA≥ 1: 5 (M10713 strain)	76 (62 to 87)	74 (57 to 87)	95 (81 to 100)

Notes
[7] - H44/76 (N=83,56,48) 5/99 (N=84,56,46) NZ 98/254 (N=86,56,48) M10713 (N=67,50,41)

No statistical analyses for this end point

Secondary: Geometric Mean Titers (GMTs) in subjects one month After Receiving a Fourth (Booster) Dose of rMenB+OMV NZ Vaccination in subjects at 12 18 or 24 months of age who previously received 3 doses of rMenB+OMV NZ at 2, 3 and 4 or 2, 4 and 6 months of age.

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End point title

Geometric Mean Titers (GMTs) in subjects one month After Receiving a Fourth (Booster) Dose of rMenB+OMV NZ Vaccination in subjects at 12 18 or 24 months of age who previously received 3 doses of rMenB+OMV NZ at 2, 3 and 4 or 2, 4 and 6 months of age. ^[8]

End point description

The serum antibody titers one month after the fourth (booster) dose of meningococcal B vaccine at 12 or 18 or24 months of age who were previously vaccinated with 3 doses of rMenB+OMV NZ at 2, 3 and 4 or 2, 4 and 6 months of age, are reported as geometric mean titers (GMTs) against N.meningitidis serogroup reference strains H44/76, NZ98/254 and 5/99.

End point type

Secondary

End point timeframe

1 month after booster

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: statistical analyses not applicable for this endpoint.

End point values	B+R246_12	B+R246_18	B+R246_24	B246_12	B246_18	B246_24	B+R234_12	B+R234_18	B+R234_24
Number of subjects analysed	159	118	103	142	111	95	86	56	48
Units: Titers
geometric mean (confidence interval 95%)
H44/76 (N=158,116,101,138,111,93,83,56,48)	125 (106 to 148)	123 (101 to 149)	108 (88 to 133)	178 (149 to 213)	164 (135 to 200)	152 (122 to 188)	135 (108 to 170)	92 (70 to 120)	128 (95 to 172)
5/99 (N=156,116,100,142,110,92,84,56,46)	1276 (1092 to 1491)	2183 (1824 to 2611)	1820 (1497 to 2212)	1713 (1454 to 2020)	2058 (1710 to 2476)	2739 (2233 to 3361)	1558 (1262 to 1923)	1486 (1148 to 1924)	2081 (1564 to 2771)
NZ 98/254 (N=159,118,103,142,111,95,86,56,48)	36 (29 to 44)	15 (12 to 19)	17 (14 to 22)	34 (27 to 42)	17 (14 to 22)	19 (15 to 25)	47 (36 to 62)	17 (12 to 24)	33 (23 to 47)
M10713 (N=0,0,0,0,0,0,67,50,41)	0 (0 to 0)	0 (0 to 0)	0 (0 to 0)	0 (0 to 0)	0 (0 to 0)	0 (0 to 0)	12 (8.52 to 17)	15 (10 to 23)	26 (17 to 41)

No statistical analyses for this end point

Secondary: GMTs in subjects one month after the fourth (booster) dose of meningococcal B vaccine at 12 months of age previously vaccinated with 3 doses of rMenB+OMV NZ at 2, 3 and 4 or 2, 4 and 6 months of age and single dose of rMenB+OMV NZ given at same age

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End point title

GMTs in subjects one month after the fourth (booster) dose of meningococcal B vaccine at 12 months of age previously vaccinated with 3 doses of rMenB+OMV NZ at 2, 3 and 4 or 2, 4 and 6 months of age and single dose of rMenB+OMV NZ given at same age ^[9]

End point description

Characterization of immunological memory by serum antibody titers one month after the fourth (booster) dose of meningococcal B vaccine at 12 months of age who were previously vaccinated with 3 doses of rMenB+OMV NZ at 2, 3 and 4 or 2, 4 and 6 months of age and single dose of rMenB+OMV NZ given at same ages, are reported as geometric mean titers (GMTs) against N.meningitidis serogroup reference strains H44/76, NZ98/254 and 5/99.

End point type

Secondary

End point timeframe

1 month after booster

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: statistical analyses not applicable for this endpoint.

End point values	B+R246_12	B246_12	B+R234_12	B12 14
Number of subjects analysed	159 ^[10]	142	86	221
Units: Titers
geometric mean (confidence interval 98.3%)
H44/76 strain	125 (102 to 154)	179 (144 to 223)	137 (104 to 181)	18 (15 to 21)
5/99 strain	1301 (1076 to 1573)	1763 (1441 to 2157)	1607 (1243 to 2077)	49 (42 to 58)
NZ 98/254 strain	37 (29 to 46)	35 (27 to 44)	48 (36 to 65)	3.71 (3.06 to 4.5)

Notes
[10] - H44/76 (N=158,138,83,217) 5/99 (N=156,142,84,216) NZ98/254 (N=159,142,86,221)

No statistical analyses for this end point

Secondary: GMTs one month after the fourth (booster) dose of meningococcal B vaccine at 18 and 24months of age who were previously vaccinated with 3 doses of rMenB+OMV NZ at 2, 3 and 4 or 2, 4 and 6 months of age and single dose of rMenB+OMV NZ given at same ages

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End point title

GMTs one month after the fourth (booster) dose of meningococcal B vaccine at 18 and 24months of age who were previously vaccinated with 3 doses of rMenB+OMV NZ at 2, 3 and 4 or 2, 4 and 6 months of age and single dose of rMenB+OMV NZ given at same ages ^[11]

End point description

Characterization of immunological memory by serum antibody titers one month after the fourth (booster) dose of meningococcal B vaccine at 18 and 24months of age who were previously vaccinated with 3 doses of rMenB+OMV NZ at 2, 3 and 4 or 2, 4 and 6 months of age and single dose of rMenB+OMV NZ given at same ages, are reported as geometric mean titers (GMTs) against N.meningitidis serogroup reference strains H44/76, NZ98/254 and 5/99.

End point type

Secondary

End point timeframe

1 month after booster

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: statistical analyses not applicable for this endpoint.

End point values	B+R246_18	B+R246_24	B246_18	B246_24	B+R234_18	B+R234_24	B18 20	B24 26
Number of subjects analysed	118	111	113	95	56	48	50	55
Units: Titers
geometric mean (confidence interval 95%)
H44/76 (N= 116,101,111,93,56,48,46,52)	126 (104 to 154)	110 (89 to 136)	162 (132 to 198)	155 (124 to 193)	93 (70 to 123)	132 (97 to 180)	18 (13 to 25)	14 (10 to 19)
5/99 (N=118,100,110,92,56,46,48,50)	2195 (1790 to 2691)	1811 (1449 to 2262)	2034 (1648 to 2511)	2735 (2166 to 3455)	1483 (1107 to 1986)	2087 (1508 to 2889)	41 (30 to 56)	30 (22 to 41)
NZ 98/254 (N=118,103,111,95,56,48,50,55)	16 (12 to 20)	18 (14 to 23)	17 (14 to 22)	20 (15 to 26)	17 (12 to 25)	34 (23 to 49)	2.76 (1.87 to 4.08)	2.1 (1.44 to 3.07)

No statistical analyses for this end point

Secondary: Two-dose catch-up regimen of rMenB+OMV NZ in unprimed toddlers aged 12, 18 or 24 months

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End point title

Two-dose catch-up regimen of rMenB+OMV NZ in unprimed toddlers aged 12, 18 or 24 months ^[12]

End point description

Immunogenicity evaluation of a two-dose catch-up regimen of rMenB+OMV NZ in unprimed toddlers aged 12, 18 or 24 months as measured by serum antibody titers one month after the second vaccination f meningococcal B vaccine at 18 and 24months of age who were previously vaccinated with 3 doses of rMenB+OMV NZ reported as geometric mean titers (GMTs) against N.meningitidis serogroup reference strains H44/76, NZ98/254 and 5/99.

End point type

Secondary

End point timeframe

1 month after second vaccination

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: statistical analyses not applicable for this endpoint.

End point values	B12 14	B18 20	B24 26
Number of subjects analysed	207	47	53
Units: Titers
geometric mean (confidence interval 95%)
H44/76 strain	188 (164 to 216)	171 (130 to 224)	177 (136 to 231)
5/99 strain	635 (548 to 735)	491 (359 to 672)	559 (417 to 749)
NZ 98/254 strain	40 (35 to 47)	23 (17 to 30)	24 (18 to 32)
M10713 strain	0 (0 to 0)	14 (8.02 to 23)	18 (11 to 29)

No statistical analyses for this end point

Secondary: Geometric Mean Concentrations against vaccine antigen 287-953 one month after fourth booster dose to previously primed toddlers at 12, 18 or 24 months of age.

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End point title

Geometric Mean Concentrations against vaccine antigen 287-953 one month after fourth booster dose to previously primed toddlers at 12, 18 or 24 months of age. ^[13]

End point description

Immunogenicity evaluation against vaccine antigen 287-953 one month after fourth booster dose to previously primed toddlers at 12, 18 or 24 months measured by ELISA.

End point type

Secondary

End point timeframe

1 month after booster vaccination

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: statistical analyses not applicable for this endpoint.

End point values	B+R246_12	B+R246_18	B+R246_24	B246_12	B246_18	B246_24	B+R234_12	B+R234_18	B+R234_24
Number of subjects analysed	162	119	108	145	114	98	86	58	48
Units: IU/mL
geometric mean (confidence interval 95%)
MENB-ELISA287-953	5334 (4670 to 6093)	6395 (5474 to 7470)	6864 (5826 to 8087)	6605 (5733 to 7609)	6418 (5477 to 7520)	8120 (6833 to 9649)	6125 (5110 to 7342)	5952 (4771 to 7426)	6774 (5305 to 8649)

No statistical analyses for this end point

Secondary: Number of children reporting solicited local and systemic adverse events after receiving a fourth booster dose of rMenB+OMV NZ vaccine at 12, 18 or 24 months of age.

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End point title

Number of children reporting solicited local and systemic adverse events after receiving a fourth booster dose of rMenB+OMV NZ vaccine at 12, 18 or 24 months of age. ^[14]

End point description

The safety and tolerability of the 4th booster dose rMenB+OMV NZ vaccine in children (12, 18 or 24 months age) is reported as number of subjects with solicited local and systemic adverse events.

End point type

Secondary

End point timeframe

From day 1 to day 7 after vaccination

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: statistical analyses not applicable for this endpoint.

End point values	B246_12	B246_18	B246_24
Number of subjects analysed	170	153	126
Units: Number
Any	156	135	116
Any Local	137	119	113
Injection site Tenderness(N=170,152,125)	104	104	105
Injection site Erythema	117	94	94
Injection site Induration	93	62	73
Injection site Swelling	57	52	50
Any Systemic	134	118	101
ChangeEat.Habits	66	59	51
Sleepiness	63	56	52
Vomiting	8	9	8
Diarrhea	37	23	27
Irritbility	104	91	83
Unusual Crying	52	51	40
Rash	7	3	7
Fever ( >= 38C )	52	55	28
Any Other	59	59	40
Body Temp. >38 C	118	98	98
Medical Attend. Fever	5	5	2
Antipypr. Med.Used	32	28	25
Antipytr. Med.Used	37	39	21

No statistical analyses for this end point

Secondary: Number of children reporting solicited local and systemic adverse events after receiving a two-dose catch-up regimen of rMenB+OMV NZ vaccine at 12, 18 or 24 months of age.

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End point title

Number of children reporting solicited local and systemic adverse events after receiving a two-dose catch-up regimen of rMenB+OMV NZ vaccine at 12, 18 or 24 months of age. ^[15]

End point description

The safety and tolerability of the two-dose catch-up regimen of rMenB+OMV NZ vaccine in children (12, 18 or 24 months age) is reported as number of subjects with solicited local and systemic adverse events.

End point type

Secondary

End point timeframe

From day 1 to day 7 after vaccination

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: statistical analyses not applicable for this endpoint.

End point values	B12 14	B18 20	B24 26
Number of subjects analysed	239	51	54
Units: Number
Injection site Tenderness (vaccination 1)	151	35	47
Injection site Tenderness (vaccination 2)	143	32	42
Injection site Erythema (vaccination 1)	151	32	39
Injection site Erythema (vaccination 2)	148	33	31
Injection site Induration (vaccination 1)	112	20	27
Injection site Induration (vaccination 2)	101	24	22
Injection site Swelling (vaccination 1)	81	15	19
Injection site Swelling (vaccination 2)	72	18	19
Change in Eating habits (vaccination 1)	95	13	25
Change in Eating habits (vaccination 2)	83	19	21
Sleepiness (vaccination 1)	106	21	18
Sleepiness (vaccination 2)	78	16	18
Vomiting (vaccination 1)	19	5	6
Vomiting (vaccination 2)	18	1	4
Diarrhea (vaccination 1)	43	13	20
Diarrhea (vaccination 2)	35	5	7
Irritbility (vaccination 1)	156	23	28
Irritbilit (vaccination 2)	126	27	23
Unusual Crying (vaccination 1)	81	13	15
Unusual Crying (vaccination 2)	67	14	15
Rash (vaccination 1)	13	5	2
Rash (vaccination 2)	10	4	0
Fever ( >= 38C ) (vaccination 1)	83	14	15
Fever ( >= 38C ) (vaccination 2)	74	15	13
Body Temp.<38 C (vaccination 1)	156	37	39
Body Temp.<38 C (vaccination 2)	163	36	39
Medical Attend. Fever (vaccination 1)	9	2	1
Medical Attend. Fever (vaccination 2)	5	1	0
Antipypr. Med.Used (vaccination 1)	49	8	8
Antipypr. Med.Used (vaccination 2)	45	9	11
Antipytr. Med.Used (vaccination 1)	66	9	11
Antipytr. Med.Used (vaccination 2)	54	11	7

No statistical analyses for this end point

Secondary: Geometric Mean Concentrations against vaccine antigen 287-953 one month after booster given after a two-dose catch-up regimen in toddlers starting at 12, 18 or 24 months of age.

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End point title

Geometric Mean Concentrations against vaccine antigen 287-953 one month after booster given after a two-dose catch-up regimen in toddlers starting at 12, 18 or 24 months of age. ^[16]

End point description

Immunogenicity evaluation against vaccine antigen 287-953 one month after booster given after a two-dose catch-up regimen in toddlers starting at 12, 18 or 24 months of age.one month after fourth booster dose to previously primed toddlers at 12, 18 or 24 months of age measured by ELISA

End point type

Secondary

End point timeframe

1 month after booster vaccination

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: statistical analyses not applicable for this endpoint.

End point values	B12 14	B18 20	B24 26
Number of subjects analysed	177	44	47
Units: IU/mL
geometric mean (confidence interval 95%)	122 (101 to 147)	121 (84 to 176)	100 (69 to 144)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From day 1 to day 7 after vaccination

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

B+R246_18

Reporting group description

Previously received rMenB+OMV NZ vaccine + routine vaccines at 2, 4 and 6 months of age followed by a booster dose of rMenB+OMV NZ vaccine at 18 months of age.

Reporting group title

B+R246_12

Reporting group description

Previously received rMenB+OMV NZ vaccine + routine vaccines at 2, 4 and 6 months of age followed by a booster dose of rMenB+OMV NZ vaccine at 12 months of age.

Reporting group title

B246_18

Reporting group description

Previously received 3 doses of rMenB+OMV NZ vaccine at 2, 4 and 6 months of age and routine vaccines at 3,5 and 7 months of age, followed by a booster dose of rMenB+OMV NZ at 18 months of age.

Reporting group title

B+R246_24

Reporting group description

Previously received rMenB+OMV NZ vaccine + routine vaccines at 2, 4 and 6 months of age followed by a booster dose of rMenB+OMV NZ vaccine at 24 months of age.

Reporting group title

B246_12

Reporting group description

Reporting group title

B246_24

Reporting group description

Previously received 3 doses of rMenB+OMV NZ vaccine at 2, 4 and 6 months of age and routine vaccines at 3,5 and 7 months of age, followed by a booster dose of rMenB+OMV NZ at 24 months of age.

Reporting group title

B+R234_12

Reporting group description

Previously received rMenB+OMV NZ vaccine + routine vaccines at 2, 3 and 4 months of age followed by a booster dose of rMenB+OMV NZ at 12 months of age.

Reporting group title

B+R234_18

Reporting group description

Previously received rMenB+OMV NZ vaccine + routine vaccines at 2, 3 and 4 months of age followed by a booster dose of rMenB+OMV NZ vaccine at 18 months of age.

Reporting group title

B+R234_24

Reporting group description

Previously received rMenB+OMV NZ vaccine + routine vaccines at 2, 3 and 4 months of age followed by a booster dose of rMenB+OMV NZ vaccine at 24 months of age.

Reporting group title

B12 14

Reporting group description

Previously received two catch-up doses of rMenB+OMV NZ vaccine at 12 and14 months of age.

Reporting group title

B18 20

Reporting group description

Previously received two catch-up doses of rMenB+OMV NZ vaccine at 18 and 20 months of age.

Reporting group title

B24 26

Reporting group description

Previously received two catch-up doses of rMenB+OMV NZ vaccine at 24 and 26 months of age.

B+R246_18

B+R246_12

B246_18

B+R246_24

B246_12

B246_24

B+R234_12

B+R234_18

B+R234_24

B12 14

B18 20

B24 26

Total subjects affected by serious adverse events

subjects affected / exposed

3 / 152 (1.97%)

5 / 185 (2.70%)

7 / 153 (4.58%)

6 / 144 (4.17%)

6 / 170 (3.53%)

1 / 126 (0.79%)

5 / 104 (4.81%)

5 / 74 (6.76%)

3 / 66 (4.55%)

16 / 239 (6.69%)

0 / 51 (0.00%)

1 / 55 (1.82%)

number of deaths (all causes)

number of deaths resulting from adverse events

Injury, poisoning and procedural complications

Concussion

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

1 / 153 (0.65%)

0 / 144 (0.00%)

1 / 170 (0.59%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

1 / 239 (0.42%)

0 / 51 (0.00%)

1 / 55 (1.82%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Laceration

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

1 / 144 (0.69%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

0 / 239 (0.00%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Head injury

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

1 / 66 (1.52%)

1 / 239 (0.42%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Skull fracture

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

1 / 239 (0.42%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Accidental exposure to product

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

1 / 74 (1.35%)

0 / 66 (0.00%)

0 / 239 (0.00%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Congenital, familial and genetic disorders

Congenital aural fistula

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

1 / 239 (0.42%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nervous system disorders

Convulsion

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

1 / 144 (0.69%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

0 / 239 (0.00%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Epilepsy

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

1 / 153 (0.65%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

0 / 239 (0.00%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Febrile convulsion

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

2 / 144 (1.39%)

0 / 170 (0.00%)

0 / 126 (0.00%)

1 / 104 (0.96%)

0 / 74 (0.00%)

1 / 66 (1.52%)

3 / 239 (1.26%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

0 / 1

1 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

Autism

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

1 / 239 (0.42%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Petit mal Epilepsy

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

1 / 104 (0.96%)

0 / 74 (0.00%)

0 / 66 (0.00%)

0 / 239 (0.00%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

General disorders and administration site conditions

Pyrexia

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

1 / 104 (0.96%)

0 / 74 (0.00%)

0 / 66 (0.00%)

0 / 239 (0.00%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Social circumstances

Walking disability

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

1 / 239 (0.42%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

Coeliac Disease

subjects affected / exposed

1 / 152 (0.66%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

0 / 239 (0.00%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Acetonaemic vomiting

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

1 / 239 (0.42%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Dysphagia

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

1 / 239 (0.42%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Stomatitis

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

1 / 74 (1.35%)

0 / 66 (0.00%)

0 / 239 (0.00%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory, thoracic and mediastinal disorders

Asthma

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

1 / 153 (0.65%)

1 / 144 (0.69%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

0 / 239 (0.00%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Wheezing

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

1 / 170 (0.59%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

1 / 239 (0.42%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonia aspiration

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

1 / 239 (0.42%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Adenoidal hypertrophy

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

1 / 239 (0.42%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Skin and subcutaneous tissue disorders

Rash

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

1 / 170 (0.59%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

0 / 239 (0.00%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Urticaria

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

1 / 74 (1.35%)

0 / 66 (0.00%)

0 / 239 (0.00%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Musculoskeletal and connective tissue disorders

Arthritis reactive

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

1 / 170 (0.59%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

0 / 239 (0.00%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Infections and infestations

Abscess

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

1 / 153 (0.65%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

0 / 239 (0.00%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Bronchiolitis

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

0 / 170 (0.00%)

1 / 126 (0.79%)

0 / 104 (0.00%)

0 / 74 (0.00%)

1 / 66 (1.52%)

0 / 239 (0.00%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Bronchitis

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

1 / 170 (0.59%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

1 / 239 (0.42%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Bronchopneumonia

subjects affected / exposed

0 / 152 (0.00%)

1 / 185 (0.54%)

0 / 153 (0.00%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

1 / 239 (0.42%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Ear Infection

subjects affected / exposed

0 / 152 (0.00%)

1 / 185 (0.54%)

0 / 153 (0.00%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

0 / 239 (0.00%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Escherichia urinary tract infection

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

1 / 153 (0.65%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

0 / 239 (0.00%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastroenteritis

subjects affected / exposed

1 / 152 (0.66%)

0 / 185 (0.00%)

2 / 153 (1.31%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

2 / 74 (2.70%)

0 / 66 (0.00%)

2 / 239 (0.84%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 2

0 / 0

0 / 2

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Gastroenteritis Rotavirus

subjects affected / exposed

1 / 152 (0.66%)

1 / 185 (0.54%)

0 / 153 (0.00%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

0 / 239 (0.00%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Laryngitis

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

1 / 153 (0.65%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

0 / 239 (0.00%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pharyngitis

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

1 / 170 (0.59%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

0 / 239 (0.00%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonia

subjects affected / exposed

0 / 152 (0.00%)

2 / 185 (1.08%)

0 / 153 (0.00%)

1 / 144 (0.69%)

0 / 170 (0.00%)

0 / 126 (0.00%)

1 / 104 (0.96%)

0 / 74 (0.00%)

0 / 66 (0.00%)

0 / 239 (0.00%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory syncytial virus bronchiolitis

subjects affected / exposed

0 / 152 (0.00%)

1 / 185 (0.54%)

0 / 153 (0.00%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

0 / 239 (0.00%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tonsillitis

subjects affected / exposed

0 / 152 (0.00%)

1 / 185 (0.54%)

0 / 153 (0.00%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

1 / 66 (1.52%)

0 / 239 (0.00%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Eczema herpeticum

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

1 / 104 (0.96%)

0 / 74 (0.00%)

0 / 66 (0.00%)

0 / 239 (0.00%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Influenza

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

1 / 239 (0.42%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Periorbital cellulitis

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

1 / 239 (0.42%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonia respiratory syncytial viral

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

1 / 239 (0.42%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Superinfection bacterial

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

1 / 239 (0.42%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Upper respiratory tract infection

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

1 / 153 (0.65%)

0 / 144 (0.00%)

0 / 170 (0.00%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

0 / 239 (0.00%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Viral infection

subjects affected / exposed

0 / 152 (0.00%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

1 / 170 (0.59%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

0 / 239 (0.00%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Metabolism and nutrition disorders

Dehydration

subjects affected / exposed

1 / 152 (0.66%)

0 / 185 (0.00%)

0 / 153 (0.00%)

0 / 144 (0.00%)

1 / 170 (0.59%)

0 / 126 (0.00%)

0 / 104 (0.00%)

0 / 74 (0.00%)

0 / 66 (0.00%)

0 / 239 (0.00%)

0 / 51 (0.00%)

0 / 55 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

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

Non-serious adverse events	B+R246_18	B+R246_12	B246_18	B+R246_24	B246_12	B246_24	B+R234_12	B+R234_18	B+R234_24	B12 14	B18 20	B24 26
Total subjects affected by non serious adverse events
subjects affected / exposed	147 / 152 (96.71%)	180 / 185 (97.30%)	139 / 153 (90.85%)	140 / 144 (97.22%)	163 / 170 (95.88%)	116 / 126 (92.06%)	102 / 104 (98.08%)	73 / 74 (98.65%)	62 / 66 (93.94%)	230 / 239 (96.23%)	50 / 51 (98.04%)	54 / 55 (98.18%)
Nervous system disorders
Somnolence
subjects affected / exposed	61 / 152 (40.13%)	72 / 185 (38.92%)	56 / 153 (36.60%)	72 / 144 (50.00%)	63 / 170 (37.06%)	52 / 126 (41.27%)	50 / 104 (48.08%)	33 / 74 (44.59%)	27 / 66 (40.91%)	129 / 239 (53.97%)	25 / 51 (49.02%)	28 / 55 (50.91%)
occurrences all number	67	77	66	77	74	55	55	33	29	206	39	44
General disorders and administration site conditions
Crying
subjects affected / exposed	43 / 152 (28.29%)	56 / 185 (30.27%)	51 / 153 (33.33%)	46 / 144 (31.94%)	52 / 170 (30.59%)	40 / 126 (31.75%)	41 / 104 (39.42%)	18 / 74 (24.32%)	22 / 66 (33.33%)	105 / 239 (43.93%)	17 / 51 (33.33%)	25 / 55 (45.45%)
occurrences all number	48	61	56	49	60	45	41	19	24	164	28	32
Induration
subjects affected / exposed	0 / 152 (0.00%)	2 / 185 (1.08%)	3 / 153 (1.96%)	2 / 144 (1.39%)	3 / 170 (1.76%)	4 / 126 (3.17%)	2 / 104 (1.92%)	0 / 74 (0.00%)	0 / 66 (0.00%)	2 / 239 (0.84%)	1 / 51 (1.96%)	4 / 55 (7.27%)
occurrences all number	0	2	3	2	3	4	2	0	0	2	2	6
Injection site erythema
subjects affected / exposed	100 / 152 (65.79%)	127 / 185 (68.65%)	94 / 153 (61.44%)	109 / 144 (75.69%)	117 / 170 (68.82%)	94 / 126 (74.60%)	76 / 104 (73.08%)	52 / 74 (70.27%)	49 / 66 (74.24%)	179 / 239 (74.90%)	38 / 51 (74.51%)	41 / 55 (74.55%)
occurrences all number	104	134	103	112	128	97	81	53	52	325	72	76
Injection site induration
subjects affected / exposed	74 / 152 (48.68%)	101 / 185 (54.59%)	62 / 153 (40.52%)	76 / 144 (52.78%)	93 / 170 (54.71%)	73 / 126 (57.94%)	52 / 104 (50.00%)	41 / 74 (55.41%)	35 / 66 (53.03%)	148 / 239 (61.92%)	27 / 51 (52.94%)	33 / 55 (60.00%)
occurrences all number	86	122	77	84	114	84	66	46	39	251	54	55
Injection site pain
subjects affected / exposed	114 / 152 (75.00%)	107 / 185 (57.84%)	104 / 153 (67.97%)	118 / 144 (81.94%)	104 / 170 (61.18%)	105 / 126 (83.33%)	70 / 104 (67.31%)	56 / 74 (75.68%)	51 / 66 (77.27%)	187 / 239 (78.24%)	41 / 51 (80.39%)	51 / 55 (92.73%)
occurrences all number	119	110	110	120	106	108	74	58	53	306	74	90
Injection site swelling
subjects affected / exposed	53 / 152 (34.87%)	73 / 185 (39.46%)	52 / 153 (33.99%)	63 / 144 (43.75%)	57 / 170 (33.53%)	50 / 126 (39.68%)	32 / 104 (30.77%)	36 / 74 (48.65%)	25 / 66 (37.88%)	107 / 239 (44.77%)	21 / 51 (41.18%)	24 / 55 (43.64%)
occurrences all number	56	79	58	65	61	51	36	36	27	169	34	42
Pyrexia
subjects affected / exposed	57 / 152 (37.50%)	78 / 185 (42.16%)	59 / 153 (38.56%)	50 / 144 (34.72%)	60 / 170 (35.29%)	32 / 126 (25.40%)	53 / 104 (50.96%)	28 / 74 (37.84%)	27 / 66 (40.91%)	133 / 239 (55.65%)	24 / 51 (47.06%)	22 / 55 (40.00%)
occurrences all number	63	99	78	58	78	39	66	34	28	226	41	32
Swelling
subjects affected / exposed	1 / 152 (0.66%)	1 / 185 (0.54%)	2 / 153 (1.31%)	2 / 144 (1.39%)	1 / 170 (0.59%)	2 / 126 (1.59%)	0 / 104 (0.00%)	0 / 74 (0.00%)	0 / 66 (0.00%)	1 / 239 (0.42%)	1 / 51 (1.96%)	3 / 55 (5.45%)
occurrences all number	1	1	2	2	1	2	0	0	0	1	1	3
Gastrointestinal disorders
Constipation
subjects affected / exposed	2 / 152 (1.32%)	2 / 185 (1.08%)	1 / 153 (0.65%)	1 / 144 (0.69%)	2 / 170 (1.18%)	1 / 126 (0.79%)	1 / 104 (0.96%)	0 / 74 (0.00%)	0 / 66 (0.00%)	2 / 239 (0.84%)	3 / 51 (5.88%)	2 / 55 (3.64%)
occurrences all number	2	2	1	1	2	1	2	0	0	2	3	2
Diarrhoea
subjects affected / exposed	26 / 152 (17.11%)	39 / 185 (21.08%)	27 / 153 (17.65%)	32 / 144 (22.22%)	40 / 170 (23.53%)	27 / 126 (21.43%)	21 / 104 (20.19%)	18 / 74 (24.32%)	13 / 66 (19.70%)	72 / 239 (30.13%)	16 / 51 (31.37%)	21 / 55 (38.18%)
occurrences all number	30	51	30	38	47	36	29	20	14	109	24	30
Enteritis
subjects affected / exposed	0 / 152 (0.00%)	5 / 185 (2.70%)	3 / 153 (1.96%)	1 / 144 (0.69%)	2 / 170 (1.18%)	3 / 126 (2.38%)	2 / 104 (1.92%)	1 / 74 (1.35%)	2 / 66 (3.03%)	4 / 239 (1.67%)	3 / 51 (5.88%)	1 / 55 (1.82%)
occurrences all number	0	5	3	1	2	4	2	1	2	6	3	1
Teething
subjects affected / exposed	3 / 152 (1.97%)	8 / 185 (4.32%)	0 / 153 (0.00%)	1 / 144 (0.69%)	2 / 170 (1.18%)	0 / 126 (0.00%)	3 / 104 (2.88%)	2 / 74 (2.70%)	0 / 66 (0.00%)	15 / 239 (6.28%)	1 / 51 (1.96%)	0 / 55 (0.00%)
occurrences all number	3	8	0	1	2	0	3	2	0	22	1	0
Vomiting
subjects affected / exposed	16 / 152 (10.53%)	15 / 185 (8.11%)	12 / 153 (7.84%)	11 / 144 (7.64%)	13 / 170 (7.65%)	10 / 126 (7.94%)	15 / 104 (14.42%)	8 / 74 (10.81%)	2 / 66 (3.03%)	41 / 239 (17.15%)	7 / 51 (13.73%)	8 / 55 (14.55%)
occurrences all number	19	19	13	12	16	11	17	10	2	54	7	10
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	12 / 152 (7.89%)	14 / 185 (7.57%)	8 / 153 (5.23%)	5 / 144 (3.47%)	13 / 170 (7.65%)	7 / 126 (5.56%)	3 / 104 (2.88%)	4 / 74 (5.41%)	2 / 66 (3.03%)	24 / 239 (10.04%)	6 / 51 (11.76%)	8 / 55 (14.55%)
occurrences all number	16	16	10	5	17	7	3	7	2	27	6	11
Skin and subcutaneous tissue disorders
Dermatitis diaper
subjects affected / exposed	2 / 152 (1.32%)	9 / 185 (4.86%)	5 / 153 (3.27%)	2 / 144 (1.39%)	6 / 170 (3.53%)	0 / 126 (0.00%)	2 / 104 (1.92%)	4 / 74 (5.41%)	0 / 66 (0.00%)	13 / 239 (5.44%)	1 / 51 (1.96%)	2 / 55 (3.64%)
occurrences all number	2	10	6	2	6	0	2	5	0	16	1	2
Erythema
subjects affected / exposed	2 / 152 (1.32%)	0 / 185 (0.00%)	2 / 153 (1.31%)	1 / 144 (0.69%)	1 / 170 (0.59%)	2 / 126 (1.59%)	1 / 104 (0.96%)	0 / 74 (0.00%)	1 / 66 (1.52%)	3 / 239 (1.26%)	1 / 51 (1.96%)	3 / 55 (5.45%)
occurrences all number	2	0	2	1	1	2	1	0	1	3	2	3
Rash
subjects affected / exposed	9 / 152 (5.92%)	9 / 185 (4.86%)	5 / 153 (3.27%)	20 / 144 (13.89%)	8 / 170 (4.71%)	9 / 126 (7.14%)	10 / 104 (9.62%)	7 / 74 (9.46%)	5 / 66 (7.58%)	26 / 239 (10.88%)	8 / 51 (15.69%)	4 / 55 (7.27%)
occurrences all number	12	10	5	23	10	10	12	9	5	32	9	4
Dermatitis
subjects affected / exposed	1 / 152 (0.66%)	4 / 185 (2.16%)	0 / 153 (0.00%)	1 / 144 (0.69%)	4 / 170 (2.35%)	1 / 126 (0.79%)	1 / 104 (0.96%)	1 / 74 (1.35%)	1 / 66 (1.52%)	3 / 239 (1.26%)	2 / 51 (3.92%)	3 / 55 (5.45%)
occurrences all number	1	4	0	1	4	1	1	1	1	4	3	3
Psychiatric disorders
Eating disorder
subjects affected / exposed	70 / 152 (46.05%)	64 / 185 (34.59%)	59 / 153 (38.56%)	68 / 144 (47.22%)	66 / 170 (38.82%)	51 / 126 (40.48%)	41 / 104 (39.42%)	29 / 74 (39.19%)	28 / 66 (42.42%)	126 / 239 (52.72%)	21 / 51 (41.18%)	34 / 55 (61.82%)
occurrences all number	82	68	66	73	80	57	48	31	29	205	39	51
Irritability
subjects affected / exposed	100 / 152 (65.79%)	110 / 185 (59.46%)	91 / 153 (59.48%)	92 / 144 (63.89%)	104 / 170 (61.18%)	83 / 126 (65.87%)	72 / 104 (69.23%)	53 / 74 (71.62%)	44 / 66 (66.67%)	177 / 239 (74.06%)	32 / 51 (62.75%)	35 / 55 (63.64%)
occurrences all number	118	119	105	102	116	95	78	56	49	333	55	59
Infections and infestations
Bronchitis
subjects affected / exposed	11 / 152 (7.24%)	7 / 185 (3.78%)	7 / 153 (4.58%)	5 / 144 (3.47%)	19 / 170 (11.18%)	5 / 126 (3.97%)	9 / 104 (8.65%)	6 / 74 (8.11%)	4 / 66 (6.06%)	19 / 239 (7.95%)	3 / 51 (5.88%)	9 / 55 (16.36%)
occurrences all number	15	8	12	6	22	5	10	10	4	25	3	15
Candida nappy rash
subjects affected / exposed	0 / 152 (0.00%)	0 / 185 (0.00%)	0 / 153 (0.00%)	0 / 144 (0.00%)	0 / 170 (0.00%)	1 / 126 (0.79%)	1 / 104 (0.96%)	1 / 74 (1.35%)	0 / 66 (0.00%)	2 / 239 (0.84%)	3 / 51 (5.88%)	1 / 55 (1.82%)
occurrences all number	0	0	0	0	0	1	1	1	0	2	5	1
Conjunctivitis
subjects affected / exposed	11 / 152 (7.24%)	11 / 185 (5.95%)	10 / 153 (6.54%)	3 / 144 (2.08%)	10 / 170 (5.88%)	7 / 126 (5.56%)	5 / 104 (4.81%)	1 / 74 (1.35%)	3 / 66 (4.55%)	15 / 239 (6.28%)	4 / 51 (7.84%)	4 / 55 (7.27%)
occurrences all number	12	12	12	3	12	7	6	1	3	19	6	4
Ear infection
subjects affected / exposed	8 / 152 (5.26%)	12 / 185 (6.49%)	5 / 153 (3.27%)	6 / 144 (4.17%)	13 / 170 (7.65%)	6 / 126 (4.76%)	14 / 104 (13.46%)	5 / 74 (6.76%)	3 / 66 (4.55%)	29 / 239 (12.13%)	6 / 51 (11.76%)	4 / 55 (7.27%)
occurrences all number	9	20	5	6	14	7	17	7	4	45	7	5
Fungal infection
subjects affected / exposed	0 / 152 (0.00%)	2 / 185 (1.08%)	0 / 153 (0.00%)	0 / 144 (0.00%)	1 / 170 (0.59%)	0 / 126 (0.00%)	1 / 104 (0.96%)	0 / 74 (0.00%)	0 / 66 (0.00%)	1 / 239 (0.42%)	1 / 51 (1.96%)	3 / 55 (5.45%)
occurrences all number	0	2	0	0	2	0	1	0	0	1	1	3
Gastroenteritis
subjects affected / exposed	6 / 152 (3.95%)	17 / 185 (9.19%)	5 / 153 (3.27%)	4 / 144 (2.78%)	9 / 170 (5.29%)	7 / 126 (5.56%)	4 / 104 (3.85%)	2 / 74 (2.70%)	0 / 66 (0.00%)	10 / 239 (4.18%)	4 / 51 (7.84%)	2 / 55 (3.64%)
occurrences all number	7	19	6	4	10	7	4	2	0	10	6	2
Infection
subjects affected / exposed	0 / 152 (0.00%)	1 / 185 (0.54%)	3 / 153 (1.96%)	2 / 144 (1.39%)	0 / 170 (0.00%)	2 / 126 (1.59%)	2 / 104 (1.92%)	1 / 74 (1.35%)	1 / 66 (1.52%)	2 / 239 (0.84%)	3 / 51 (5.88%)	3 / 55 (5.45%)
occurrences all number	0	1	4	2	0	7	2	1	1	6	12	6
Influenza
subjects affected / exposed	4 / 152 (2.63%)	3 / 185 (1.62%)	2 / 153 (1.31%)	1 / 144 (0.69%)	3 / 170 (1.76%)	1 / 126 (0.79%)	0 / 104 (0.00%)	2 / 74 (2.70%)	0 / 66 (0.00%)	1 / 239 (0.42%)	1 / 51 (1.96%)	5 / 55 (9.09%)
occurrences all number	4	3	2	1	4	1	0	2	0	1	2	7
Lice infestation
subjects affected / exposed	0 / 152 (0.00%)	0 / 185 (0.00%)	0 / 153 (0.00%)	0 / 144 (0.00%)	1 / 170 (0.59%)	0 / 126 (0.00%)	0 / 104 (0.00%)	0 / 74 (0.00%)	0 / 66 (0.00%)	0 / 239 (0.00%)	0 / 51 (0.00%)	4 / 55 (7.27%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	4
Nasopharyngitis
subjects affected / exposed	6 / 152 (3.95%)	14 / 185 (7.57%)	12 / 153 (7.84%)	10 / 144 (6.94%)	13 / 170 (7.65%)	4 / 126 (3.17%)	7 / 104 (6.73%)	5 / 74 (6.76%)	2 / 66 (3.03%)	21 / 239 (8.79%)	8 / 51 (15.69%)	7 / 55 (12.73%)
occurrences all number	6	20	15	12	16	4	7	6	2	30	9	9
Otitis media
subjects affected / exposed	4 / 152 (2.63%)	3 / 185 (1.62%)	4 / 153 (2.61%)	2 / 144 (1.39%)	6 / 170 (3.53%)	2 / 126 (1.59%)	3 / 104 (2.88%)	2 / 74 (2.70%)	4 / 66 (6.06%)	11 / 239 (4.60%)	2 / 51 (3.92%)	4 / 55 (7.27%)
occurrences all number	6	3	4	2	6	3	3	2	4	14	2	5
Pharyngitis
subjects affected / exposed	8 / 152 (5.26%)	7 / 185 (3.78%)	14 / 153 (9.15%)	3 / 144 (2.08%)	5 / 170 (2.94%)	6 / 126 (4.76%)	5 / 104 (4.81%)	3 / 74 (4.05%)	3 / 66 (4.55%)	16 / 239 (6.69%)	3 / 51 (5.88%)	1 / 55 (1.82%)
occurrences all number	10	8	18	5	8	7	5	3	3	21	5	1
Respiratory tract infection
subjects affected / exposed	3 / 152 (1.97%)	9 / 185 (4.86%)	3 / 153 (1.96%)	2 / 144 (1.39%)	6 / 170 (3.53%)	3 / 126 (2.38%)	5 / 104 (4.81%)	2 / 74 (2.70%)	2 / 66 (3.03%)	8 / 239 (3.35%)	5 / 51 (9.80%)	6 / 55 (10.91%)
occurrences all number	3	15	4	7	6	3	9	2	2	13	7	9
Rhinitis
subjects affected / exposed	5 / 152 (3.29%)	10 / 185 (5.41%)	4 / 153 (2.61%)	4 / 144 (2.78%)	12 / 170 (7.06%)	7 / 126 (5.56%)	4 / 104 (3.85%)	3 / 74 (4.05%)	1 / 66 (1.52%)	17 / 239 (7.11%)	2 / 51 (3.92%)	5 / 55 (9.09%)
occurrences all number	5	11	5	4	15	7	4	4	1	22	3	5
Scarlet fever
subjects affected / exposed	1 / 152 (0.66%)	0 / 185 (0.00%)	2 / 153 (1.31%)	2 / 144 (1.39%)	0 / 170 (0.00%)	1 / 126 (0.79%)	0 / 104 (0.00%)	0 / 74 (0.00%)	0 / 66 (0.00%)	1 / 239 (0.42%)	3 / 51 (5.88%)	0 / 55 (0.00%)
occurrences all number	1	0	2	2	0	1	0	0	0	1	4	0
Tonsillitis
subjects affected / exposed	9 / 152 (5.92%)	6 / 185 (3.24%)	6 / 153 (3.92%)	7 / 144 (4.86%)	9 / 170 (5.29%)	3 / 126 (2.38%)	5 / 104 (4.81%)	3 / 74 (4.05%)	3 / 66 (4.55%)	14 / 239 (5.86%)	2 / 51 (3.92%)	3 / 55 (5.45%)
occurrences all number	9	6	7	10	9	3	6	4	4	14	2	5
Upper respiratory tract infection
subjects affected / exposed	8 / 152 (5.26%)	10 / 185 (5.41%)	15 / 153 (9.80%)	0 / 144 (0.00%)	6 / 170 (3.53%)	5 / 126 (3.97%)	10 / 104 (9.62%)	2 / 74 (2.70%)	0 / 66 (0.00%)	18 / 239 (7.53%)	2 / 51 (3.92%)	5 / 55 (9.09%)
occurrences all number	10	12	19	0	6	6	15	2	0	24	2	5
Varicella
subjects affected / exposed	1 / 152 (0.66%)	4 / 185 (2.16%)	2 / 153 (1.31%)	2 / 144 (1.39%)	2 / 170 (1.18%)	7 / 126 (5.56%)	2 / 104 (1.92%)	0 / 74 (0.00%)	5 / 66 (7.58%)	9 / 239 (3.77%)	5 / 51 (9.80%)	1 / 55 (1.82%)
occurrences all number	1	4	2	2	2	7	2	0	5	9	5	1
Viral infection
subjects affected / exposed	6 / 152 (3.95%)	12 / 185 (6.49%)	10 / 153 (6.54%)	6 / 144 (4.17%)	7 / 170 (4.12%)	5 / 126 (3.97%)	5 / 104 (4.81%)	5 / 74 (6.76%)	6 / 66 (9.09%)	21 / 239 (8.79%)	8 / 51 (15.69%)	3 / 55 (5.45%)
occurrences all number	7	12	11	6	9	5	6	6	6	27	10	3

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentages of Subjects With Serum Bactericidal Antibody Titers ≥1:5 After Receiving a Fourth (Booster) Dose of rMenB+OMV NZ Vaccination in subjects who previously received 3 doses of rMenB+OMV NZ and routine vaccines at 2, 4 and 6 months of age

Primary: Percentages of Subjects With Serum Bactericidal Antibody Titers ≥1:5 After Receiving a Fourth (Booster) Dose of rMenB+OMV NZ Vaccination in subjects who previously received 3 doses of rMenB+OMV NZ and routine vaccines at 2, 4 and 6 months of age

Secondary: Percentages of Subjects With SBA Titers ≥1:5 After Receiving a Fourth (Booster) Dose of rMenB+OMV NZ Vaccination in subjects who previously received 3 doses of rMenB+OMV NZ at 2, 4 and 6 months of age and routine vaccines at 3, 5 and 7 months of age.

Secondary: Percentages of Subjects With SBA Titers ≥1:5 After Receiving a Fourth (Booster) Dose of rMenB+OMV NZ Vaccination in subjects who previously received 3 doses of rMenB+OMV NZ at 2, 4 and 6 months of age and routine vaccines at 3, 5 and 7 months of age.

Secondary: Percentages of Subjects With Serum Bactericidal Antibody Titers ≥1:5 After Receiving a Fourth (Booster) Dose of rMenB+OMV NZ Vaccination in subjects who previously received 3 doses of rMenB+OMV NZ and routine vaccines at 2, 3 and 4 months of age.

Secondary: Percentages of Subjects With Serum Bactericidal Antibody Titers ≥1:5 After Receiving a Fourth (Booster) Dose of rMenB+OMV NZ Vaccination in subjects who previously received 3 doses of rMenB+OMV NZ and routine vaccines at 2, 3 and 4 months of age.

Secondary: Geometric Mean Titers (GMTs) in subjects one month After Receiving a Fourth (Booster) Dose of rMenB+OMV NZ Vaccination in subjects at 12 18 or 24 months of age who previously received 3 doses of rMenB+OMV NZ at 2, 3 and 4 or 2, 4 and 6 months of age.

Secondary: Geometric Mean Titers (GMTs) in subjects one month After Receiving a Fourth (Booster) Dose of rMenB+OMV NZ Vaccination in subjects at 12 18 or 24 months of age who previously received 3 doses of rMenB+OMV NZ at 2, 3 and 4 or 2, 4 and 6 months of age.

Secondary: GMTs in subjects one month after the fourth (booster) dose of meningococcal B vaccine at 12 months of age previously vaccinated with 3 doses of rMenB+OMV NZ at 2, 3 and 4 or 2, 4 and 6 months of age and single dose of rMenB+OMV NZ given at same age

Secondary: GMTs in subjects one month after the fourth (booster) dose of meningococcal B vaccine at 12 months of age previously vaccinated with 3 doses of rMenB+OMV NZ at 2, 3 and 4 or 2, 4 and 6 months of age and single dose of rMenB+OMV NZ given at same age

Secondary: GMTs one month after the fourth (booster) dose of meningococcal B vaccine at 18 and 24months of age who were previously vaccinated with 3 doses of rMenB+OMV NZ at 2, 3 and 4 or 2, 4 and 6 months of age and single dose of rMenB+OMV NZ given at same ages

Secondary: GMTs one month after the fourth (booster) dose of meningococcal B vaccine at 18 and 24months of age who were previously vaccinated with 3 doses of rMenB+OMV NZ at 2, 3 and 4 or 2, 4 and 6 months of age and single dose of rMenB+OMV NZ given at same ages

Secondary: Two-dose catch-up regimen of rMenB+OMV NZ in unprimed toddlers aged 12, 18 or 24 months

Secondary: Two-dose catch-up regimen of rMenB+OMV NZ in unprimed toddlers aged 12, 18 or 24 months

Secondary: Geometric Mean Concentrations against vaccine antigen 287-953 one month after fourth booster dose to previously primed toddlers at 12, 18 or 24 months of age.

Secondary: Geometric Mean Concentrations against vaccine antigen 287-953 one month after fourth booster dose to previously primed toddlers at 12, 18 or 24 months of age.

Secondary: Number of children reporting solicited local and systemic adverse events after receiving a fourth booster dose of rMenB+OMV NZ vaccine at 12, 18 or 24 months of age.

Secondary: Number of children reporting solicited local and systemic adverse events after receiving a fourth booster dose of rMenB+OMV NZ vaccine at 12, 18 or 24 months of age.

Secondary: Number of children reporting solicited local and systemic adverse events after receiving a two-dose catch-up regimen of rMenB+OMV NZ vaccine at 12, 18 or 24 months of age.

Secondary: Number of children reporting solicited local and systemic adverse events after receiving a two-dose catch-up regimen of rMenB+OMV NZ vaccine at 12, 18 or 24 months of age.

Secondary: Geometric Mean Concentrations against vaccine antigen 287-953 one month after booster given after a two-dose catch-up regimen in toddlers starting at 12, 18 or 24 months of age.

Secondary: Geometric Mean Concentrations against vaccine antigen 287-953 one month after booster given after a two-dose catch-up regimen in toddlers starting at 12, 18 or 24 months of age.

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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