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Clinical Trial Results:
A Phase 3, Open label, Multi-Center, Extension Study to Evaluate the Safety, Tolerability and Immunogenicity of Novartis Meningococcal B Recombinant Vaccine When Administered as a Booster at 12 Months of Age or as a Two-dose Catch-up to Healthy Toddlers Who Participated in Study V72P13

Summary
EudraCT number	2008-006301-17
Trial protocol	IT CZ FI DE AT
Global end of trial date	19 Aug 2010

Results information
Results version number	v1(current)
This version publication date	11 May 2016
First version publication date	03 Jan 2015
Other versions

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

V72P13E1

ISRCTN number

US NCT number

NCT00847145

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Vaccines and Diagnostics, S.r.l

Sponsor organisation address

Via Fiorentina, 1, Siena, Italy, 53100

Public contact

Posting Director, Novartis Vaccines , RegistryContactVaccinesUS@novartis.com

Scientific contact

Posting Director, Novartis Vaccines , RegistryContactVaccinesUS@novartis.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-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

05 Nov 2010

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

19 Aug 2010

Was the trial ended prematurely?

Main objective of the trial

Demonstration of a sufficient immune response following a fourth (booster) dose of rMenB+OMV NZ administered at 12 months of age, either with or without concomitant MMRV vaccination, to toddlers previously primed with three doses of rMenB+OMV NZ as infants in Study V72P13.

Protection of trial subjects

This trial was performed with the ethical principles that have their origin in the Declaration of Helsinki, that are consistent with Good Clinical Practice (GCP) according to International Conference on Harmonisation (ICH) guidelines, the applicable regulatory requirements (s) for the country in which the study was conducted, and applicable standard operating procedures (SOPs). Specifically, this trial was conducted under a protocol reviewed and approved by the EC and by scientifically and medically qualified persons; the benefits of the study were in proportion to the risks; the rights and welfare of the subjects were respected; the physicians conducting the trial did not find the hazards to outweigh the potential benefits.

Background therapy

N/A

Evidence for comparator

N/A

Actual start date of recruitment

11 Feb 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?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Czech Republic: 882

Country: Number of subjects enrolled

Finland: 823

Country: Number of subjects enrolled

Germany: 38

Country: Number of subjects enrolled

Italy: 451

Country: Number of subjects enrolled

Austria: 55

Worldwide total number of subjects

2249

EEA total number of subjects

2249

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)

2249

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 at 15 sites in Finland, 12 sites in Germany, 5 sites in Austria, 27 sites in Czech Republic and 6 sites in Italy.

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

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst

Blinding implementation details

This study was partially open label (groups 1a, 1b, 2a, and 2b) and partially observer-blind (groups 3a, 3b, 4a, 4b).

Are arms mutually exclusive

Yes

12B12M (1a)

Arm description

Previously in the parent study subjects had received three doses of rMenB+OMV NZ and routine vaccine at 2, 4 and 6 months of age, respectively. These subjects received a booster (fourth) dose at 12 months of age concomitantly with one dose of MMRV vaccine in the present study.

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

1 dose of 0.5 mL

Investigational medicinal product name

MMRV

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

1 dose of 0.5 mL

12B13M (1b)

Arm description

Previously in the parent study subjects had received three doses of rMenB+OMV NZ and routine vaccine at 2, 4 and 6 months of age, respectively. These subjects received a booster (fourth) dose at 12 months and one dose of MMRV vaccine at 13 months of age in the present study.

Arm type

Experimental

Investigational medicinal product name

MMRV

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

1 dose of 0.5 mL

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

1 dose of 0.5 mL

12M13B15B (2a)

Arm description

Previously in the present study subjects had received routine vaccine at 2, 4 and 6 months of age respectively. These subjects received MMRV vaccine at 12 months of age and two catch-up doses of rMenB+OMV NZ vaccine at 13 and 15 months of age in the present study.

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

2 doses of 0.5 mL

Investigational medicinal product name

MMRV

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

1 dose of 0.5 mL

12M12B14B (2b)

Arm description

Previously in the parent study subjects had received three doses of routine vaccine at 2, 4 and 6 months of age, respectively. These subjects received two catch-up doses of rMenB+OMV NZ at 12 and 14 months of age and one dose of MMRV vaccine given concomitantly at 12 months of age in the present study.

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

2 doses of 0.5 mL

Investigational medicinal product name

MMRV

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

1 dose of 0.5 mL

12B12M (3a)

Arm description

Previously in the parent study subjects had received three doses of rMenB+OMV NZ and routine vaccinations at 2, 4 and 6 months of age respectively. These subjects had received one booster (fourth) dose of rMenB+OMV NZ at 12 months of age concomitantly with one dose of MMRV vaccine in the present study.

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

1 dose of 0.5 mL

Investigational medicinal product name

MMRV

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

1 dose of 0.5 mL

12B13M (3b)

Arm description

Previously in the present study subjects had received three doses of rMenB+OMV NZ and routine vaccinations at 12 months of age respectively. These subjects one booster (fourth) dose of rMenB+OMV NZ at 12 months of age and one dose of MMRV vaccine at 13 months of age in the present study.

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

1 dose of 0.5 mL

Investigational medicinal product name

MMRV

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

1 dose of 0.5 mL

12B12M_C (4a)

Arm description

Previously in the parent study subjects had received three doses of Meningococcal C vaccine and routine vaccine at 2, 4 and 6 months of age respectively. These subjects had received one single dose of rMenB+OMV NZ at 12 months of age concomitantly with one dose of MMRV vaccine in the present study.

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

1 dose of 0.5 mL

Investigational medicinal product name

MMRV

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for suspension for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

1 dose of 0.5 mL

12B13M_C (4b)

Arm description

Previously in the parent study subjects had received three doses of Meningococcal C vaccine and routine vaccine at 2, 4 and 6 months of age. These subjects received one single dose of rMenB+OMV NZ at 12 months of age and one dose of MMRV vaccine at 13 months of age in the present study.

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

1 dose of 0.5 mL

Investigational medicinal product name

MMRV

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

1 dose of 0.5 mL

Number of subjects in period 1	12B12M (1a)	12B13M (1b)	12M13B15B (2a)	12M12B14B (2b)	12B12M (3a)	12B13M (3b)	12B12M_C (4a)	12B13M_C (4b)
Started	629	633	285	117	137	156	152	140
Completed	623	627	274	116	131	152	143	136
Not completed	6	6	11	1	6	4	9	4
Consent withdrawn by subject	3	4	6	1	-	-	1	1
Adverse Event	-	1	1	-	-	-	-	-
Inappropriate Enrolment	-	-	-	-	1	-	-	-
Lost to follow-up	3	1	1	-	4	4	8	2
Protocol deviation	-	-	3	-	1	-	-	1

Baseline characteristics

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Reporting group title

12B12M (1a)

Reporting group description

Reporting group title

12B13M (1b)

Reporting group description

Previously in the parent study subjects had received three doses of rMenB+OMV NZ and routine vaccine at 2, 4 and 6 months of age, respectively. These subjects received a booster (fourth) dose at 12 months and one dose of MMRV vaccine at 13 months of age in the present study.

Reporting group title

12M13B15B (2a)

Reporting group description

Reporting group title

12M12B14B (2b)

Reporting group description

Reporting group title

12B12M (3a)

Reporting group description

Reporting group title

12B13M (3b)

Reporting group description

Reporting group title

12B12M_C (4a)

Reporting group description

Reporting group title

12B13M_C (4b)

Reporting group description

Reporting group values	12B12M (1a)	12B13M (1b)	12M13B15B (2a)	12M12B14B (2b)	12B12M (3a)	12B13M (3b)	12B12M_C (4a)	12B13M_C (4b)	Total
Number of subjects	629	633	285	117	137	156	152	140	2249
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)	12.3 ( 0.5 )	12.3 ( 0.5 )	12.3 ( 0.5 )	12.3 ( 0.5 )	12.2 ( 0.5 )	12.2 ( 0.4 )	12.2 ( 0.5 )	12.2 ( 0.4 )	-
Gender categorical
Units: Subjects
Female	290	330	131	55	75	81	62	73	1097
Male	339	303	154	62	62	75	90	67	1152

End points

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Reporting group title

12B12M (1a)

Reporting group description

Reporting group title

12B13M (1b)

Reporting group description

Previously in the parent study subjects had received three doses of rMenB+OMV NZ and routine vaccine at 2, 4 and 6 months of age, respectively. These subjects received a booster (fourth) dose at 12 months and one dose of MMRV vaccine at 13 months of age in the present study.

Reporting group title

12M13B15B (2a)

Reporting group description

Reporting group title

12M12B14B (2b)

Reporting group description

Reporting group title

12B12M (3a)

Reporting group description

Reporting group title

12B13M (3b)

Reporting group description

Reporting group title

12B12M_C (4a)

Reporting group description

Reporting group title

12B13M_C (4b)

Reporting group description

Subject analysis set title

Enrolled Population

Subject analysis set type

Intention-to-treat

Subject analysis set description

all subjects who were enrolled in this study irrespective of whether they have been randomized or not

Subject analysis set title

SBA Persistence Per Protocol Population (SBA PP Persistence)

Subject analysis set type

Per protocol

Subject analysis set description

All subjects who: - received all the relevant doses of vaccine in study V72P13; - blood draw at one month after the third injection at 6 month of age (in study V72P13) and visit 1 blood draw in this study; - had no major protocol violation as defined prior to analysis.

Subject analysis set title

SBA Booster Per Protocol Population (SBA PP Booster)

Subject analysis set type

Per protocol

Subject analysis set description

All subjects who: - received all the relevant doses of vaccine in study V72P13; - received rMenB+OMV NZ booster dose; - provided evaluable serum samples at one month after the booster dose (Group 1a, 1b) and at one month after the second dose (group 2a, 2b); - blood draw at one month after the third injection at 6 month of age (in study V72P13) and visit 1 blood draw in this study; - had no major protocol violation as defined prior to analysis.

Subject analysis set title

SBA Catch-up Per Protocol Population (SBA PP Catch-up)

Subject analysis set type

Per protocol

Subject analysis set description

All subjects who: - received all the relevant doses of vaccine in study V72P13; - received two catch-up doses of rMenB+OMV NZ; - provided evaluable serum samples at one month after the second catch-up dose (group 2a, 2b); - blood draw at one month after the third injection at 6 month of age (in study V72P13) and visit 1 blood draw in this study; - had no major protocol violation as defined prior to analysis.

Subject analysis set title

Routine246

Subject analysis set type

Sub-group analysis

Subject analysis set description

combined Groups 12M13B15B and 12M12B14B

Subject analysis set title

MMRV Per Protocol Population (MMRV PP)

Subject analysis set type

Per protocol

Subject analysis set description

All subjects who: - received all the relevant doses of vaccine correctly in studies V72P13 and in the current study; - provided evaluable serum samples; - blood draw at one month after the third injection at 6 month of age (in study V72P13) and visit 1 blood draw in this study; - had no major protocol violation as defined prior to analysis.

Subject analysis set title

Men246

Subject analysis set type

Sub-group analysis

Subject analysis set description

combined Groups 12B12M (1a) and 12B13M (1b)

Subject analysis set title

12B13M

Subject analysis set type

Safety analysis

Subject analysis set description

Combination of Groups 12B13M (1b) and 12B13M (3b).

Subject analysis set title

12B12M

Subject analysis set type

Safety analysis

Subject analysis set description

Combination of Groups 12B12M (1a) and 12B12M (3a).

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-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

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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 ^[1] ^[2]

End point description

Immunogenicity was assessed in terms of the percentages of subjects with serum bactericidal antibody (SBA) titers ≥1:5 for which the lower limit of the two-sided 95% confidence interval (CI) was ≥75%, directed against N. Meningitidis serogroup B reference strains H44/76-SL, NZ98/254 and 5/99, one month after the fourth (booster) dose of meningococcal B vaccine, rMenB+OMV NZ, with or without the concomitant Measles, Mumps, Rubella, Varicella (MMRV) vaccine in toddlers who were previously vaccinated with three doses of rMenB+OMV NZ. The analysis was done on SBA PP Booster population.

End point type

Primary

End point timeframe

One month after the fourth (booster) dose.

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: There was no statistical null hypothesis associated with this immunogenicity objective.
[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: There was no statistical null hypothesis associated with this immunogenicity objective.

End point values	12B12M (1a)	12B13M (1b)
Number of subjects analysed	211	215
Units: Percentages of Subjects
number (confidence interval 95%)
Strain 44/76-SL (Baseline) (N=211, 215)	81 (75 to 86)	82 (77 to 87)
One month after booster (N=210, 212)	100 (98 to 100)	100 (98 to 100)
Strain 5/99 (Baseline) (N=210, 213)	98 (95 to 99)	100 (97 to 100)
One month after booster (N=209, 212)	100 (98 to 100)	100 (98 to 100)
Strain NZ98/254 (Baseline) (N=211, 215)	19 (14 to 25)	24 (19 to 30)
One month after booster (N=211, 213)	97 (93 to 99)	94 (90 to 97)

No statistical analyses for this end point

Secondary: Percentages of Subjects With Antibody Response After Receiving the MMRV Vaccination

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End point title

Percentages of Subjects With Antibody Response After Receiving the MMRV Vaccination ^[3]

End point description

Immunogenicity of MMRV, when given concomitantly with the fourth (booster) dose of rMenB+OMV NZ vaccine at 12 months of age, was assessed in terms of percentages of subjects with antibody responses against MMRV vaccine to demonstrate non-inferiority to that of MMRV given alone,. The specified cut-off levels for Measles, Mumps and Rubella antigens is ≥255mIU/mL, ≥10 U/mL and ≥10 IU/mL Enzyme Linked Immunosorbent Assay(ELISA) Antibody(Ab) units, respectively. For Varicella is ≥1.25 glycoprotein (gp) ELISA units/ml (seroconversion) and ≥5 gp ELISA units/ml (seroprotection). The analysis was done on MMRV PP population.

End point type

Secondary

End point timeframe

One month after the fourth (booster) dose.

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: There was no statistical null hypothesis associated with this immunogenicity objective.

End point values	12B12M (1a)	12M13B15B (2a)
Number of subjects analysed	163	156
Units: Percentages of Subjects
number (confidence interval 95%)
Measles (Schwarz, ≥255), Bas (N=152,147)	0 (0 to 2)	0 (0 to 2)
2 months after MMRV vaccine (N=151,146)	98 (94 to 100)	99 (96 to 100)
Mumps (RIT4385, ≥10), Bas (N=157,152)	0 (0 to 2)	0 (0 to 2)
2 months after MMRV vaccine (N=156, 151)	96 (92 to 99)	96 (92 to 99)
Rubella (Wistar RA 27/3, ≥10), Bas (N=163,156)	0 (0 to 2)	0 (0 to 2)
2 months after MMRV vaccine (N=162, 155)	99 (96 to 100)	100 (98 to 100)
Varicella (Oka, ≥1.25), Bas (N=147,141)	0 (0 to 2)	0 (0 to 3)
2 months after MMRV vaccine (N=146, 140)	97 (93 to 99)	99 (95 to 100)
Varicella (Oka, ≥5), Bas (N=147,141)	0 (0 to 2)	0 (0 to 3)
VarII 2 months after MMRV vaccine (N=146, 140)	79 (71 to 85)	81 (73 to 87)

non-inferiority of MMRV

Statistical analysis description

The immunogenicity in 12B12M (1a) group was considered non-inferior to that in group 12M13B15B (2a), if, for measles antigen (2 months after MMRV vaccine), the lower limit of the two-sided 95% CI for the difference in the percentages of subjects with antibody response or equal to the specified cut-off level for that antigen was greater than -10%.

Comparison groups

12B12M (1a) v 12M13B15B (2a)

Number of subjects included in analysis

319

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[4]

Method

95% Clopper-Pearson Confidence Intervals

Parameter type

Percentage group difference

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-5

upper limit

Notes
[4] - For the vaccine antigens Measles, the specified cut-off level was ≥255mIU/Ml to be greater than -10%.

non-inferiority of MMRV 2

Statistical analysis description

The immunogenicity in 12B12M (1a) group was considered non-inferior to that in group 12M13B15B (2a), if, for the mumps antigen (2 months after MMRV vaccine), the lower limit of the two-sided 95% CI for the difference in the percentages of subjects with antibody response or equal to the specified cut-off level for that antigen was greater than -10%.

Comparison groups

12B12M (1a) v 12M13B15B (2a)

Number of subjects included in analysis

319

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[5]

Method

95% Clopper-Pearson Confidence Intervals

Parameter type

Percentage group difference

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-5

upper limit

Notes
[5] - For the vaccine antigen mumps, the specified cut-off level was ≥10 Enzyme Linked Immunosorbent Assay(ELISA) Antibody (Ab) units to be greater than -10%.

non-inferiority of MMRV 3

Statistical analysis description

The immunogenicity in 12B12M (1a) group was considered non-inferior to that in group 12M13B15B (2a), if, for the rubella antigen (2 months after MMRV vaccine), the lower limit of the two-sided 95% CI for the difference in the percentages of subjects with antibody response or equal to the specified cut-off level for that antigen was greater than -10%.

Comparison groups

12B12M (1a) v 12M13B15B (2a)

Number of subjects included in analysis

319

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[6]

Method

95% Clopper-Pearson Confidence Intervals

Parameter type

Percentage group difference

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-4

upper limit

Notes
[6] - For the vaccine antigen rubella, the specified cut-off level was ≥10 IU/mL to be greater than -10%.

non-inferiority of MMRV 4

Statistical analysis description

The immunogenicity in 12B12M (1a) group was considered non-inferior to that in group 12M13B15B (2a), if, for the varicella antigen (2 months after MMRV vaccine), the lower limit of the two-sided 95% CI for the difference in the percentages of subjects with antibody response or equal to the specified cut-off level for that antigen was greater than -10%.

Comparison groups

12B12M (1a) v 12M13B15B (2a)

Number of subjects included in analysis

319

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[7]

Method

95% Clopper-Pearson Confidence Intervals

Parameter type

Percentage group difference

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-6

upper limit

Notes
[7] - For the vaccine antigen varicella, the specified cut-off level was ≥1.25 gp ELISA units/mL to be greater than -10%.

non-inferiority of MMRV 5

Statistical analysis description

Comparison groups

12M13B15B (2a) v 12B12M (1a)

Number of subjects included in analysis

319

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[8]

Method

95% Clopper-Pearson Confidence Intervals

Parameter type

Percentage group difference

Point estimate

-2

Confidence interval

level

95%

sides

2-sided

lower limit

-11

upper limit

Notes
[8] - For the vaccine antigen varicella, the specified cut-off level was ≥5 gp ELISA units/mL (seroprotection) to be greater than -10%.

Secondary: Geometric Mean Titers After Receiving the Booster Dose of rMenB+OMV NZ Vaccination

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End point title

Geometric Mean Titers After Receiving the Booster Dose of rMenB+OMV NZ Vaccination ^[9]

End point description

The immune response following a fourth (booster) dose of rMenB+OMV NZ administered at 12 months of age, either with (12B12M (1a)) or without (12B13M (1b)) concomitant MMRV vaccination was assessed as human serum bactericidal antibody (hSBA) titer (GMTs) one month after the fourth dose of rMenB+OMV NZ, directed against N. meningitidis serogroup B reference strains H44/76, NZ98/254 and 5/99. The analysis was done on the SBA PP Booster population.

End point type

Secondary

End point timeframe

One month after the booster (fourth) dose.

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: There was no statistical null hypothesis associated with this immunogenicity objective.

End point values	12B12M (1a)	12B13M (1b)
Number of subjects analysed	211	215
Units: Titers
geometric mean (confidence interval 95%)
Strain 44/76-SL, Baseline (N=211,215)	11 (9.27 to 12)	10 (9.11 to 12)
1 Month after Booster (N=210, 212)	139 (123 to 156)	119 (105 to 133)
Strain 5/99, Baseline (N=210, 213)	81 (71 to 93)	81 (71 to 92)
1 Month after Booster (N=209, 212)	1503 (1339 to 1686)	1429 (1274 to 1603)
Strain NZ98/254, Baseline (N=211, 215)	2.07 (1.8 to 2.38)	2.21 (1.92 to 2.55)
1 Month after Booster (N=211,213)	39 (33 to 46)	32 (27 to 37)

No statistical analyses for this end point

Secondary: Geometric Mean Titers at 12 months of age (predose 4) After Previously Receiving the Three Doses of rMenB+OMV NZ (Persistence)

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End point title

Geometric Mean Titers at 12 months of age (predose 4) After Previously Receiving the Three Doses of rMenB+OMV NZ (Persistence) ^[10]

End point description

The persistence of bactericidal antibodies at 12 months of age (pre-dose 4) in infants who previously received three doses of rMenB+OMV NZ in the parent study was assessed as hSBA GMTs directed against N. meningitidis serogroup B reference strains H44/76, NZ98/254 and 5/99. The analysis was done on the SBA PP Persistence population.

End point type

Secondary

End point timeframe

One month after third vaccination and pre dose fourth (booster) vaccination.

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: There was no statistical null hypothesis associated with this immunogenicity objective.

End point values	12B12M (1a)	12B13M (1b)	Men246	Routine246
Number of subjects analysed	139	133	272	51
Units: Titers
geometric mean (confidence interval 95%)
H44/76, 1M after 3rd vac. in parent study	91 (81 to 104)	83 (73 to 94)	87 (79 to 95)	1.19 (1.07 to 1.33)
Pre-Booster vac.in present study	11 (9 to 12)	10 (8.7 to 12)	10 (9.28 to 12)	1.08 (0.99 to 1.17)
5/99, 1M after 3rd vac. in parent study	615 (538 to 704)	620 (540 to 712)	617 (560 to 680)	1 (1 to 1)
5/99 Pre-Booster vac.in present study	85 (72 to 100)	79 (67 to 94)	82 (73 to 92)	1.03 (0.97 to 1.09)
NZ98/254 >3rd in parent study (.N=139,132,271,52)	12 (10 to 15)	14 (12 to 17)	13 (11 to 15)	1.07 (0.94 to 1.21)
Pre-booster in present study (N=139,132,271,52)	2.04 (1.72 to 2.43)	2.02 (1.69 to 2.42)	2.03 (1.79 to 2.3)	1 (1 to 1)

No statistical analyses for this end point

Secondary: Geometric Mean Titers After Receiving the Booster Dose and Single Dose of rMen+OMV NZ Vaccination (Induction of Immunological Memory)

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End point title

Geometric Mean Titers After Receiving the Booster Dose and Single Dose of rMen+OMV NZ Vaccination (Induction of Immunological Memory) ^[11]

End point description

The induction of immunological memory was assessed in toddlers who previously received three doses of rMenB+OMV NZ in Study V72P13, by comparing the SBA GMT response when administered of the fourth dose of rMenB+OMV NZ at 12 months of age (12B12M (1a)) to the response in naïve toddlers receiving a single dose of rMenB+OMV NZ at 12 months of age (12M12B14B). Immunological memory and booster response were demonstrated if the lower limit of the two-sided 95% CI for the ratio of the SBA GMTs following a fourth dose of rMenB+OMV NZ at 12 months of age compared to the SBA GMTs following a single dose of rMenB+OMV NZ at 12 months of age was ≥ 2.0. The analysis was done on the SBA PP Booster population.

End point type

Secondary

End point timeframe

One month post vaccination and pre-booster (fourth) dose vaccination.

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: There was no statistical null hypothesis associated with this immunogenicity objective.

End point values	12B12M (1a)	12M12B14B (2b)
Number of subjects analysed	211	72
Units: Titers
geometric mean (confidence interval 95%)
Strain H44/76, Baseline (N=211,71)	11 (9.32 to 12)	1.18 (0.96 to 1.46)
1 M after Booster or 1st rMenB (N=210, 71)	140 (123 to 159)	15 (12 to 19)
Strain 5/99, Baseline (N=210, 71)	83 (73 to 93)	1 (0.81 to 1.24)
1 M after Booster or 1sr rMenB (N=209, 72)	1538 (1337 to 1769)	58 (46 to 74)
Strain NZ98/254, Baseline (N=211, 71)	2.05 (1.83 to 2.31)	1.03 (0.84 to 1.26)
1M after Booster or 1st rMenB (N=211, 72)	39 (34 to 46)	4.18 (3.18 to 5.5)

No statistical analyses for this end point

Secondary: Percentages of subjects with SBA titers ≥1:5 at 12 months of age (predose 4) After Previously Receiving the Three Doses of rMenB+OMV NZ (Persistence)

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End point title

Percentages of subjects with SBA titers ≥1:5 at 12 months of age (predose 4) After Previously Receiving the Three Doses of rMenB+OMV NZ (Persistence) ^[12]

End point description

The persistence of bactericidal antibodies at 12 months of age (pre-dose 4) in infants who previously received three doses of rMenB+OMV NZ in the parent study was assessed as the percentages of subjects with SBA titers ≥1:5, directed against N. meningitidis serogroup B reference strains H44/76, NZ98/254 and 5/99. The analysis was done on the SBA PP Persistence population.

End point type

Secondary

End point timeframe

One month after third vaccination and pre dose fourth (booster) 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: There was no statistical null hypothesis associated with this immunogenicity objective.

End point values	12B12M (1a)	12B13M (1b)	Men246	Routine246
Number of subjects analysed	139	133	272	51
Units: Percentages of Subjects
number (confidence interval 95%)
H44/76, 1M after 3rd vac. in P13	100 (97 to 100)	99 (96 to 100)	100 (98 to 100)	0 (0 to 7)
Pre-booster vac. in P13E1	81 (73 to 87)	82 (74 to 88)	81 (76 to 86)	2 (0.05 to 10)
5/99, 1M after 3rd vac. in P13	100 (97 to 100)	99 (96 to 100)	100 (98 to 100)	0 (0 to 7)
5/99 Pre-booster vac. in P13E1	98 (94 to 100)	100 (97 to 100)	99 (97 to 100)	0 (0 to 7)
NZ98/254, 1M after 3rd v.. P13 (.N=139,132,271,52)	81 (74 to 87)	85 (78 to 90)	83 (78 to 87)	2 (0.049 to 10)
Pre-booster vac. in P13E1 (N=139,132,271,52)	21 (14 to 29)	20 (13 to 28)	20 (16 to 26)	0 (0 to 7)

No statistical analyses for this end point

Secondary: SBA GMTs after a two-dose catch-up schedule or two-dose schedule

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End point title

SBA GMTs after a two-dose catch-up schedule or two-dose schedule ^[13]

End point description

The immunogenicity of a two-dose catch-up schedule of rMenB+OMV NZ given at 13 and 15 months (12M13B15B) or 12 and 14 months (12M12B14B) to naïve toddlers was assessed by SBA GMTs one month after the second dose. The analysis was done on the SBA PP Catch-up population.

End point type

Secondary

End point timeframe

One month after the second dose

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: There was no statistical null hypothesis associated with this immunogenicity objective.

End point values	12M13B15B (2a)	12M12B14B (2b)
Number of subjects analysed	164	68
Units: Titers
geometric mean (confidence interval 95%)
Strain H44/76, Baseline (N=161,67)	1.24 (1.15 to 1.35)	1.22 (1.07 to 1.38)
1 M after 2nd Vac. (N=163, 67)	271 (237 to 310)	248 (201 to 306)
Strain 5/99, Baseline (N=160, 67)	1.06 (1 to 1.13)	1.03 (0.94 to 1.13)
1 M after 2nd Vac. (N=164, 67)	599 (520 to 690)	627 (502 to 783)
Strain NZ98/254, Baseline (N=162, 67)	1.03 (0.98 to 1.07)	1.03 (0.97 to 1.1)
1M after 2nd Vac. (N=164, 68)	43 (38 to 49)	32 (26 to 40)

No statistical analyses for this end point

Secondary: Percentages of subjects with SBA titers ≥1:5 after a two-dose catch-up schedule or two-dose schedule

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End point title

Percentages of subjects with SBA titers ≥1:5 after a two-dose catch-up schedule or two-dose schedule ^[14]

End point description

The immunogenicity of a two-dose catch-up schedule of rMenB+OMV NZ given at 13 and 15 months (12M13B15B) or 12 and 14 months (12M12B14B) to naïve toddlers was assessed as percentages of subjects with SBA titers ≥1:5 one month after the second dose. The analysis was done on the SBA PP Catch-up population.

End point type

Secondary

End point timeframe

One month after the second dose.

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: There was no statistical null hypothesis associated with this immunogenicity objective.

End point values	12M13B15B (2a)	12M12B14B (2b)
Number of subjects analysed	164	68
Units: Percentages of Subjects
number (confidence interval 95%)
Strain H44/76, Baseline (N=161,67)	5 (2 to 10)	3 (0 to 10)
1 M after 2nd Vac. (N=163, 67)	100 (98 to 100)	100 (95 to 100)
Strain 5/99, Baseline (N=160, 67)	1 (0 to 4)	1 (0.038 to 8)
1 M after 2nd Vac. (N=164, 67)	100 (98 to 100)	100 (95 to 100)
Strain NZ98/254, Baseline (N=162, 67)	1 (0.016 to 3)	0 (0 to 5)
1M after 2nd Vac. (N=164, 68)	100 (98 to 100)	96 (88 to 99)

No statistical analyses for this end point

Secondary: ELISA Geometric Mean Concentration against vaccine antigen 287-953 one month after the fourth (booster) dose given at 12 months

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End point title

ELISA Geometric Mean Concentration against vaccine antigen 287-953 one month after the fourth (booster) dose given at 12 months ^[15]

End point description

The immune response against vaccine antigen 287-953 was measured by ELISA, one month after the fourth (booster) dose given at 12 months of age (groups 12B12M (1a), 12B13M (1b). The analysis was done on the SBA PP Booster population.

End point type

Secondary

End point timeframe

One month after the fourth (booster) dose.

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: There was no statistical null hypothesis associated with this immunogenicity objective.

End point values	12B12M (1a)	12B13M (1b)
Number of subjects analysed	213	216
Units: IU/mL
geometric mean (confidence interval 95%)
Baseline (N=212,216)	390 (351 to 433)	389 (349 to 434)
1 M after Booster (N=213, 214)	6225 (5571 to 6956)	5608 (5111 to 6154)

No statistical analyses for this end point

Secondary: ELISA Geometric Mean Concentration against vaccine antigen 287-953 after two-dose catch-up in toddlers

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End point title

ELISA Geometric Mean Concentration against vaccine antigen 287-953 after two-dose catch-up in toddlers ^[16]

End point description

The immune response against vaccine antigen 287-953was measured by ELISA one month after the first dose and one month after the second dose of a two-dose catch-up regimens (12M13B15B and 12M12B14B) in toddlers. The analysis was done on the SBA PP Catch-up population.

End point type

Secondary

End point timeframe

One month after the first dose and one month after the second dose

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: There was no statistical null hypothesis associated with this immunogenicity objective.

End point values	12M13B15B (2a)	12M12B14B (2b)
Number of subjects analysed	165	68
Units: IU/mL
geometric mean (confidence interval 95%)
Baseline (N=162,66)	20 (20 to 21)	22 (19 to 24)
1 M after 1st Vac. (N=162,64)	113 (95 to 136)	120 (88 to 164)
1 M after 2nd Vac.	5698 (5030 to 6454)	7154 (5880 to 8704)

No statistical analyses for this end point

Secondary: Percentages of Subjects with Bactericidal Titers ≥ 1:5 (95% CI) Against Strain M10713 one month after the fourth (booster) dose given at 12 months

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End point title

Percentages of Subjects with Bactericidal Titers ≥ 1:5 (95% CI) Against Strain M10713 one month after the fourth (booster) dose given at 12 months ^[17]

End point description

The immune response was measured as percentages of subjects with SBA ≥ 1:5 (95% CI) against strain M10713, one month after the fourth (booster) dose given at 12 months of age (groups 12B12M (1a), 12B13M (1b). The analysis was done on the SBA PP Booster population

End point type

Secondary

End point timeframe

One month after the fourth (booster) dose.

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: There was no statistical null hypothesis associated with this immunogenicity objective.

End point values	12B12M (1a)	12B13M (1b)
Number of subjects analysed	19	27
Units: Percentages of Subjects
number (confidence interval 95%)
Pre-Booster Vac.	84 (60 to 97)	59 (39 to 78)
1 Month After Booster	100 (82 to 100)	100 (87 to 100)

No statistical analyses for this end point

Secondary: Number of subjects reporting solicited local and systemic reactions during the 7 days following rMenB+OMV NZ vaccination at 12 months of age

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End point title

Number of subjects reporting solicited local and systemic reactions during the 7 days following rMenB+OMV NZ vaccination at 12 months of age ^[18]

End point description

Safety was assessed as the number of subjects who reported solicited local and systemic reactions from day 1 through day 7 after rMenB+OMV NZ vaccination administered at 12 months. For the safety analysis purpose, Groups 12B12M (1a) and 12B12M (3a) are combined as Group 12B12M and Groups 12B13M (1b) and 12B13M (3b) are combined as Group 12B13M. Analysis performed on the Safety population.

End point type

Secondary

End point timeframe

From day 1 to day 7 after each rMenB+MV NZ vaccination.

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: All safety analyses were run in the safety population.

End point values	12B12M_C (4a)	12B13M_C (4b)	12B12M	12B13M
Number of subjects analysed	152	138	765	789
Units: Subjects
Any local	113	104	639	673
MenB Tenderness	97	80	546	563
MenB Erythema	78	81	504	539
MenB Induration	61	61	388	424
MenB Swelling	44	39	284	287
Any systemic	133	117	695	671
Change Eat. Habits	61	44	312	318
Sleepiness	64	60	362	355
Vomiting	9	10	54	36
Diarrhea	29	23	188	160
Irritability	89	75	560	540
Unusual Crying	48	48	327	294
Rash	8	7	57	56
Rash Oth.to Fever	6	0	31	0
Rash Urt.to Fever	2	0	18	0
Rash Oth.to Doc.	6	0	35	0
Rash Urt.to Doc.	2	0	23	0
Gland Swelling	4	0	12	0
Gland Par.to Doc.	0	0	0	0
Gland Sal.to Doc.	0	0	0	0
Med. Att. Fever	3	4	8	13
Fever ( ≥ 38C )	87	74	356	325
Antipyr. Med. Used	79	69	436	406

No statistical analyses for this end point

Secondary: Number of subjects reporting solicited local and systemic reactions during the 7 days following two-dose catch-up schedules of rMenB+OMV NZ vaccination

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End point title

Number of subjects reporting solicited local and systemic reactions during the 7 days following two-dose catch-up schedules of rMenB+OMV NZ vaccination ^[19]

End point description

Safety was assessed as the number of subjects who reported solicited local and systemic reactions from day 1 through day 7 after rMenB+OMV NZ vaccination administered with a two-dose catch-up schedules (groups 12M13B15B and 12M12B14B). Analysis performed on the Safety population.

End point type

Secondary

End point timeframe

From day 1 to day 7 after each rMenB+MV NZ vaccination

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: All safety analyses were run in the safety population.

End point values	12M13B15B (2a)	12M12B14B (2b)
Number of subjects analysed	284	117
Units: Subjects
Any local (1st vacc)	211	92
Any local (2nd vacc)	212	90
MenB Tenderness (1st vacc)	158	67
MenB Tenderness (2nd vacc)	181	78
MenB Erythema (1st vacc)	173	79
MenB Erythema (2nd vacc)	159	70
MenB Induration (1st vacc)	111	57
MenB Induration (2nd vacc)	115	53
MenB Swelling (1st vacc)	81	36
MenB Swelling (2nd vacc)	83	33
Any systemic (1st vacc)	216	104
Any systemic (2nd vacc)	224	99
Change Eat. Habits (1st vacc)	96	44
Change Eat. Habits (2nd vacc)	83	43
Sleepiness (1st vacc)	110	55
Sleepiness (2nd vacc)	106	48
Vomiting (1st vacc)	14	2
Vomiting (2nd vacc)	8	3
Diarrhea (1st vacc)	41	34
Diarrhea (2nd vacc)	41	25
Irritability (1st vacc)	168	82
Irritability (2nd vacc)	153	73
Unusual Crying (1st vacc)	80	41
Unusual Crying (2nd vacc)	74	42
Rash (1st vacc)	13	9
Rash (2nd vacc)	10	4
Rash Oth.to Fever (1st vacc)	0	0
Rash Oth.to Fever (2nd vacc)	0	0
Rash Urt.to Fever (1st vacc)	0	0
Rash Urt.to Fever (2nd vacc)	0	0
Rash Oth.to Doc. (1st vacc)	0	0
Rash Oth.to Doc. (2nd vacc)	0	0
Rash Urt.to Doc. (1st vacc)	0	0
Rash Urt.to Doc. (2nd vacc)	0	0
Gland Swelling (1st vacc)	0	1
Gland Swelling (2nd vacc)	0	0
Gland Par.to Doc. (1st vacc)	0	0
Gland Par.to Doc. (2nd vacc)	0	0
Gland Sal.to Doc. (1st vacc)	0	0
Gland Sal.to Doc. (2nd vacc)	0	0
Med. Att. Fever (1st vacc)	0	1
Med. Att. Fever (2nd vacc)	2	2
Fever (≥ 38C) (1st vacc)	103	54
Fever (≥ 38C) (2nd vacc)	97	50
Antipyr. Med. Used (1st vacc)	119	67
Antipyr. Med. Used (2nd vacc)	107	58

No statistical analyses for this end point

Secondary: Number of subjects reporting solicited local reactions during the 7 days following MMRV vaccination at 12 months of age

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End point title

Number of subjects reporting solicited local reactions during the 7 days following MMRV vaccination at 12 months of age ^[20]

End point description

Safety was assessed as the number of subjects who reported solicited local reactions from day 1 through day 7 after the MMRV vaccination concomitantly with rMenB+OMV NZ at 12 months of age (groups 12B12M, 12M12B14B, 12B12M_C) or after MMRV vaccination alone without rMenB+OMV NZ at 12 months (Group 12M13B15B). For the safety analysis purpose, Groups 12B12M (1a) and 12B12M (3a) are combined as Group 12B12M. Analysis performed on the Safety population.

End point type

Secondary

End point timeframe

From day 1 to day 7 after MMRV vaccination

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: All safety analyses were run in the safety population.

End point values	12M13B15B (2a)	12M12B14B (2b)	12B12M_C (4a)	12B12M
Number of subjects analysed	284	117	152	760
Units: Subjects
MMRV Tenderness	56	39	68	353
MMRV Erythema	120	52	60	345
MMRV Induration	53	18	30	161
MMRV Swelling	31	11	28	122

No statistical analyses for this end point

Secondary: Number of subjects reporting solicited systemic reactions during 8-28 days following MMRV vaccination at 12 months of age

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End point title

Number of subjects reporting solicited systemic reactions during 8-28 days following MMRV vaccination at 12 months of age ^[21]

End point description

Safety was assessed as the number of subjects who reported solicited systemic reactions from day 8 through day 28 after the MMRV vaccination concomitantly with rMenB+OMV NZ at 12 months of age (groups 12B12M, 12M12B14B, 12B12M_C) or after MMRV vaccination alone without rMenB+OMV NZ at 12 months (Group 12M13B15B). For the safety analysis purpose, Groups 12B12M (1a) and 12B12M (3a) are combined as Group 12B12M. Analysis performed on the Safety population.

End point type

Secondary

End point timeframe

From day 8 to day 28 after MMRV vaccination.

Notes
[21] - 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: All safety analyses were run in the safety population.

End point values	12M13B15B (2a)	12M12B14B (2b)	12B12M_C (4a)	12B12M
Number of subjects analysed	284	117	152	760
Units: Subjects
Rash	50	23	17	147
Rash Oth.to Fever	6	3	4	19
Rash Urt.to Fever	4	1	2	14
Rash Oth.to Doc.	3	1	3	10
Rash Urt.to Doc.	2	1	1	8
Gland Swelling	8	3	5	20
Gland Par.to Doc.	1	0	1	3
Gland Sal.to Doc.	1	0	1	5
Med. Att. Fever	19	6	15	54
Fever ( ≥ 38C )	131	46	62	338
Antipyr. Med. Used	119	55	48	324

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

All solicited and unsolicited AEs were collected from Day 1 to 7; serious adverse events (SAEs), possibly or probably related, unrelated to vaccine, medically attended and leading to premature withdrawal AEs were collected during the overall study period.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

11.1

Reporting group title

12B12M

Reporting group description

Reporting group title

12B13M

Reporting group description

Previously in the parent study subjects had received three doses of rMenB+OMV NZ and routine vaccine at 2, 4 and 6 months of age, respectively. These subjects received a booster (fourth) dose at 12 months and one dose of MMRV vaccine at 13 months of age in the present study. This group is a combination of Groups 12B13M (1b) and 12B13M (3b) for safety data analysis purposes.

Reporting group title

12M13B15B (2a)

Reporting group description

Reporting group title

12M12B14B (2b)

Reporting group description

Reporting group title

12B12M_C (4a)

Reporting group description

Reporting group title

12B13M_C (4b)

Reporting group description

Serious adverse events	12B12M	12B13M	12M13B15B (2a)	12M12B14B (2b)	12B12M_C (4a)	12B13M_C (4b)
Total subjects affected by serious adverse events
subjects affected / exposed	28 / 765 (3.66%)	40 / 789 (5.07%)	27 / 284 (9.51%)	9 / 117 (7.69%)	7 / 152 (4.61%)	2 / 139 (1.44%)
number of deaths (all causes)	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Haemangioma
subjects affected / exposed	0 / 765 (0.00%)	0 / 789 (0.00%)	1 / 284 (0.35%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemangioma of skin
subjects affected / exposed	0 / 765 (0.00%)	1 / 789 (0.13%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Kawasaki's disease
subjects affected / exposed	0 / 765 (0.00%)	0 / 789 (0.00%)	1 / 284 (0.35%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Strabismus correction
subjects affected / exposed	0 / 765 (0.00%)	1 / 789 (0.13%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Dysplasia
subjects affected / exposed	0 / 765 (0.00%)	0 / 789 (0.00%)	0 / 284 (0.00%)	0 / 117 (0.00%)	1 / 152 (0.66%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hernia
subjects affected / exposed	0 / 765 (0.00%)	0 / 789 (0.00%)	1 / 284 (0.35%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 765 (0.13%)	0 / 789 (0.00%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 765 (0.00%)	1 / 789 (0.13%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	1 / 765 (0.13%)	1 / 789 (0.13%)	1 / 284 (0.35%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental exposure to product
subjects affected / exposed	0 / 765 (0.00%)	1 / 789 (0.13%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Burns second degree
subjects affected / exposed	0 / 765 (0.00%)	1 / 789 (0.13%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Concussion
subjects affected / exposed	1 / 765 (0.13%)	2 / 789 (0.25%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	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
Contusion
subjects affected / exposed	0 / 765 (0.00%)	1 / 789 (0.13%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 765 (0.13%)	1 / 789 (0.13%)	1 / 284 (0.35%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 765 (0.00%)	1 / 789 (0.13%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Foreign body aspiration
subjects affected / exposed	0 / 765 (0.00%)	0 / 789 (0.00%)	1 / 284 (0.35%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Head injury
subjects affected / exposed	0 / 765 (0.00%)	0 / 789 (0.00%)	1 / 284 (0.35%)	1 / 117 (0.85%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mouth injury
subjects affected / exposed	1 / 765 (0.13%)	0 / 789 (0.00%)	1 / 284 (0.35%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Thermal burn
subjects affected / exposed	0 / 765 (0.00%)	1 / 789 (0.13%)	0 / 284 (0.00%)	1 / 117 (0.85%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Congenital, familial and genetic disorders
Cryptorchism
subjects affected / exposed	0 / 765 (0.00%)	0 / 789 (0.00%)	1 / 284 (0.35%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hydrocele
subjects affected / exposed	0 / 765 (0.00%)	1 / 789 (0.13%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Phimosis
subjects affected / exposed	0 / 765 (0.00%)	0 / 789 (0.00%)	0 / 284 (0.00%)	1 / 117 (0.85%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	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
Nervous system disorders
Ataxia
subjects affected / exposed	0 / 765 (0.00%)	0 / 789 (0.00%)	1 / 284 (0.35%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Convulsion
subjects affected / exposed	0 / 765 (0.00%)	1 / 789 (0.13%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile convulsion
subjects affected / exposed	4 / 765 (0.52%)	1 / 789 (0.13%)	0 / 284 (0.00%)	1 / 117 (0.85%)	1 / 152 (0.66%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	1 / 4	0 / 1	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	0 / 765 (0.00%)	0 / 789 (0.00%)	1 / 284 (0.35%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Partial seizures
subjects affected / exposed	1 / 765 (0.13%)	0 / 789 (0.00%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	1 / 765 (0.13%)	0 / 789 (0.00%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	1 / 765 (0.13%)	0 / 789 (0.00%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis ulcerative
subjects affected / exposed	0 / 765 (0.00%)	0 / 789 (0.00%)	1 / 284 (0.35%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspepsia
subjects affected / exposed	0 / 765 (0.00%)	0 / 789 (0.00%)	1 / 284 (0.35%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enteritis
subjects affected / exposed	0 / 765 (0.00%)	1 / 789 (0.13%)	0 / 284 (0.00%)	1 / 117 (0.85%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Enterocolitis
subjects affected / exposed	2 / 765 (0.26%)	0 / 789 (0.00%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 2	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
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	0 / 765 (0.00%)	1 / 789 (0.13%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rash
subjects affected / exposed	0 / 765 (0.00%)	0 / 789 (0.00%)	0 / 284 (0.00%)	1 / 117 (0.85%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	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
Urticaria
subjects affected / exposed	0 / 765 (0.00%)	1 / 789 (0.13%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Ureteric stenosis
subjects affected / exposed	0 / 765 (0.00%)	0 / 789 (0.00%)	0 / 284 (0.00%)	0 / 117 (0.00%)	1 / 152 (0.66%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vesicoureteric reflux
subjects affected / exposed	1 / 765 (0.13%)	0 / 789 (0.00%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Growth retardation
subjects affected / exposed	0 / 765 (0.00%)	0 / 789 (0.00%)	1 / 284 (0.35%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Juvenile idiopathic arthritis
subjects affected / exposed	0 / 765 (0.00%)	1 / 789 (0.13%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 765 (0.00%)	0 / 789 (0.00%)	1 / 284 (0.35%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abscess
subjects affected / exposed	1 / 765 (0.13%)	0 / 789 (0.00%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute tonsillitis
subjects affected / exposed	0 / 765 (0.00%)	1 / 789 (0.13%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bacterial infection
subjects affected / exposed	0 / 765 (0.00%)	1 / 789 (0.13%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	6 / 765 (0.78%)	3 / 789 (0.38%)	3 / 284 (1.06%)	0 / 117 (0.00%)	1 / 152 (0.66%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 8	0 / 3	0 / 3	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	0 / 765 (0.00%)	3 / 789 (0.38%)	0 / 284 (0.00%)	0 / 117 (0.00%)	1 / 152 (0.66%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	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
Campylobacter gastroenteritis
subjects affected / exposed	0 / 765 (0.00%)	0 / 789 (0.00%)	1 / 284 (0.35%)	0 / 117 (0.00%)	1 / 152 (0.66%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 765 (0.00%)	1 / 789 (0.13%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis orbital
subjects affected / exposed	1 / 765 (0.13%)	0 / 789 (0.00%)	1 / 284 (0.35%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Epstein-Barr virus infection
subjects affected / exposed	0 / 765 (0.00%)	0 / 789 (0.00%)	0 / 284 (0.00%)	0 / 117 (0.00%)	1 / 152 (0.66%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Exanthema subitum
subjects affected / exposed	0 / 765 (0.00%)	2 / 789 (0.25%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	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
Gastroenteritis
subjects affected / exposed	0 / 765 (0.00%)	1 / 789 (0.13%)	2 / 284 (0.70%)	1 / 117 (0.85%)	1 / 152 (0.66%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis rotavirus
subjects affected / exposed	0 / 765 (0.00%)	0 / 789 (0.00%)	0 / 284 (0.00%)	1 / 117 (0.85%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	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
Laryngitis
subjects affected / exposed	4 / 765 (0.52%)	4 / 789 (0.51%)	2 / 284 (0.70%)	1 / 117 (0.85%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 4	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nasopharyngitis
subjects affected / exposed	0 / 765 (0.00%)	0 / 789 (0.00%)	1 / 284 (0.35%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oral herpes
subjects affected / exposed	0 / 765 (0.00%)	1 / 789 (0.13%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Otitis media
subjects affected / exposed	0 / 765 (0.00%)	2 / 789 (0.25%)	1 / 284 (0.35%)	0 / 117 (0.00%)	1 / 152 (0.66%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Otitis media chronic
subjects affected / exposed	0 / 765 (0.00%)	1 / 789 (0.13%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumococcal sepsis
subjects affected / exposed	1 / 765 (0.13%)	1 / 789 (0.13%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Pneumonia
subjects affected / exposed	0 / 765 (0.00%)	4 / 789 (0.51%)	4 / 284 (1.41%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 4	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	1 / 765 (0.13%)	2 / 789 (0.25%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	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
Salmonellosis
subjects affected / exposed	0 / 765 (0.00%)	0 / 789 (0.00%)	1 / 284 (0.35%)	1 / 117 (0.85%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 765 (0.00%)	0 / 789 (0.00%)	2 / 284 (0.70%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 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
Tracheitis
subjects affected / exposed	0 / 765 (0.00%)	0 / 789 (0.00%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tracheobronchitis
subjects affected / exposed	1 / 765 (0.13%)	0 / 789 (0.00%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	1 / 765 (0.13%)	0 / 789 (0.00%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 765 (0.13%)	1 / 789 (0.13%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	1 / 765 (0.13%)	1 / 789 (0.13%)	0 / 284 (0.00%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Metabolism and nutrition disorders
Weight gain poor
subjects affected / exposed	0 / 765 (0.00%)	0 / 789 (0.00%)	1 / 284 (0.35%)	0 / 117 (0.00%)	0 / 152 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 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

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

Non-serious adverse events	12B12M	12B13M	12M13B15B (2a)	12M12B14B (2b)	12B12M_C (4a)	12B13M_C (4b)
Total subjects affected by non serious adverse events
subjects affected / exposed	754 / 765 (98.56%)	760 / 789 (96.32%)	282 / 284 (99.30%)	116 / 117 (99.15%)	145 / 152 (95.39%)	132 / 139 (94.96%)
Nervous system disorders
Somnolence
subjects affected / exposed	362 / 765 (47.32%)	355 / 789 (44.99%)	178 / 284 (62.68%)	70 / 117 (59.83%)	64 / 152 (42.11%)	61 / 139 (43.88%)
occurrences all number	599	569	430	154	99	91
Blood and lymphatic system disorders
Lymphadenopathy
subjects affected / exposed	29 / 765 (3.79%)	4 / 789 (0.51%)	13 / 284 (4.58%)	4 / 117 (3.42%)	8 / 152 (5.26%)	1 / 139 (0.72%)
occurrences all number	48	4	24	6	14	1
General disorders and administration site conditions
Crying
subjects affected / exposed	327 / 765 (42.75%)	294 / 789 (37.26%)	132 / 284 (46.48%)	59 / 117 (50.43%)	48 / 152 (31.58%)	50 / 139 (35.97%)
occurrences all number	558	467	302	140	86	83
Injection site erythema
subjects affected / exposed	549 / 765 (71.76%)	539 / 789 (68.31%)	213 / 284 (75.00%)	94 / 117 (80.34%)	92 / 152 (60.53%)	82 / 139 (58.99%)
occurrences all number	1891	1326	1018	476	316	179
Injection site induration
subjects affected / exposed	419 / 765 (54.77%)	424 / 789 (53.74%)	165 / 284 (58.10%)	78 / 117 (66.67%)	67 / 152 (44.08%)	62 / 139 (44.60%)
occurrences all number	1392	1188	717	325	223	159
Injection site pain
subjects affected / exposed	561 / 765 (73.33%)	563 / 789 (71.36%)	224 / 284 (78.87%)	89 / 117 (76.07%)	104 / 152 (68.42%)	81 / 139 (58.27%)
occurrences all number	1648	1107	759	377	329	165
Injection site swelling
subjects affected / exposed	320 / 765 (41.83%)	287 / 789 (36.38%)	127 / 284 (44.72%)	53 / 117 (45.30%)	54 / 152 (35.53%)	40 / 139 (28.78%)
occurrences all number	874	667	418	177	166	94
Pyrexia
subjects affected / exposed	511 / 765 (66.80%)	356 / 789 (45.12%)	208 / 284 (73.24%)	85 / 117 (72.65%)	110 / 152 (72.37%)	80 / 139 (57.55%)
occurrences all number	1136	560	584	211	256	125
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	194 / 765 (25.36%)	171 / 789 (21.67%)	92 / 284 (32.39%)	48 / 117 (41.03%)	31 / 152 (20.39%)	25 / 139 (17.99%)
occurrences all number	342	268	215	101	57	38
Teething
subjects affected / exposed	13 / 765 (1.70%)	12 / 789 (1.52%)	20 / 284 (7.04%)	3 / 117 (2.56%)	2 / 152 (1.32%)	2 / 139 (1.44%)
occurrences all number	13	13	22	3	2	2
Vomiting
subjects affected / exposed	56 / 765 (7.32%)	39 / 789 (4.94%)	38 / 284 (13.38%)	5 / 117 (4.27%)	11 / 152 (7.24%)	11 / 139 (7.91%)
occurrences all number	78	53	52	7	12	21
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	33 / 765 (4.31%)	46 / 789 (5.83%)	11 / 284 (3.87%)	7 / 117 (5.98%)	9 / 152 (5.92%)	11 / 139 (7.91%)
occurrences all number	45	51	13	8	15	14
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	178 / 765 (23.27%)	65 / 789 (8.24%)	78 / 284 (27.46%)	30 / 117 (25.64%)	22 / 152 (14.47%)	9 / 139 (6.47%)
occurrences all number	310	104	141	61	46	13
Psychiatric disorders
Irritability
subjects affected / exposed	562 / 765 (73.46%)	540 / 789 (68.44%)	226 / 284 (79.58%)	95 / 117 (81.20%)	89 / 152 (58.55%)	76 / 139 (54.68%)
occurrences all number	1121	996	742	300	199	142
Eating disorder
subjects affected / exposed	313 / 765 (40.92%)	318 / 789 (40.30%)	156 / 284 (54.93%)	63 / 117 (53.85%)	61 / 152 (40.13%)	45 / 139 (32.37%)
occurrences all number	630	582	444	152	117	84
Infections and infestations
Bronchitis
subjects affected / exposed	60 / 765 (7.84%)	62 / 789 (7.86%)	38 / 284 (13.38%)	13 / 117 (11.11%)	12 / 152 (7.89%)	6 / 139 (4.32%)
occurrences all number	72	78	45	16	20	9
Conjunctivitis
subjects affected / exposed	46 / 765 (6.01%)	38 / 789 (4.82%)	22 / 284 (7.75%)	5 / 117 (4.27%)	7 / 152 (4.61%)	1 / 139 (0.72%)
occurrences all number	57	42	24	5	8	2
Ear infection
subjects affected / exposed	49 / 765 (6.41%)	59 / 789 (7.48%)	20 / 284 (7.04%)	14 / 117 (11.97%)	14 / 152 (9.21%)	6 / 139 (4.32%)
occurrences all number	60	100	37	19	18	9
Exanthema subitum
subjects affected / exposed	20 / 765 (2.61%)	27 / 789 (3.42%)	15 / 284 (5.28%)	3 / 117 (2.56%)	4 / 152 (2.63%)	2 / 139 (1.44%)
occurrences all number	21	27	15	3	4	2
Gastroenteritis
subjects affected / exposed	21 / 765 (2.75%)	25 / 789 (3.17%)	11 / 284 (3.87%)	2 / 117 (1.71%)	5 / 152 (3.29%)	7 / 139 (5.04%)
occurrences all number	22	25	11	2	6	7
Laryngitis
subjects affected / exposed	26 / 765 (3.40%)	27 / 789 (3.42%)	14 / 284 (4.93%)	7 / 117 (5.98%)	2 / 152 (1.32%)	6 / 139 (4.32%)
occurrences all number	26	29	19	7	2	6
Nasopharyngitis
subjects affected / exposed	49 / 765 (6.41%)	62 / 789 (7.86%)	37 / 284 (13.03%)	19 / 117 (16.24%)	3 / 152 (1.97%)	7 / 139 (5.04%)
occurrences all number	62	81	48	28	3	7
Otitis media
subjects affected / exposed	80 / 765 (10.46%)	79 / 789 (10.01%)	42 / 284 (14.79%)	10 / 117 (8.55%)	9 / 152 (5.92%)	7 / 139 (5.04%)
occurrences all number	121	133	56	13	10	7
Pharyngitis
subjects affected / exposed	38 / 765 (4.97%)	54 / 789 (6.84%)	19 / 284 (6.69%)	6 / 117 (5.13%)	7 / 152 (4.61%)	5 / 139 (3.60%)
occurrences all number	41	64	21	6	9	6
Rhinitis
subjects affected / exposed	30 / 765 (3.92%)	38 / 789 (4.82%)	26 / 284 (9.15%)	7 / 117 (5.98%)	3 / 152 (1.97%)	4 / 139 (2.88%)
occurrences all number	35	43	35	7	3	5
Upper respiratory tract infection
subjects affected / exposed	67 / 765 (8.76%)	59 / 789 (7.48%)	51 / 284 (17.96%)	11 / 117 (9.40%)	8 / 152 (5.26%)	9 / 139 (6.47%)
occurrences all number	83	71	66	14	12	11
Viral infection
subjects affected / exposed	33 / 765 (4.31%)	36 / 789 (4.56%)	23 / 284 (8.10%)	10 / 117 (8.55%)	1 / 152 (0.66%)	0 / 139 (0.00%)
occurrences all number	35	38	28	11	1	0

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Were there any global substantial amendments to the protocol? Yes

10 Feb 2009

Change of planned subjects. Change of Groups with respect to the parent study V72P13. Modification to serology and blood samples schedule.

28 Apr 2009

To clarify about non-investigational vaccines offered based on the preferences/recommendations of each participating country. To modify age related inclusion criteria.

04 Feb 2010

To clarify main analysis of the study and definition of the MITT (Modified Intention-To-Treat) Population.

Were there any global interruptions to the trial? No

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

None reported

http://www.ncbi.nlm.nih.gov/pubmed/23324563

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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

Primary: Percentages of Subjects With Serum Bactericidal Antibody Titers ≥1:5 After Receiving a Fourth (Booster) Dose of rMenB+OMV NZ Vaccination

Secondary: Percentages of Subjects With Antibody Response After Receiving the MMRV Vaccination

Secondary: Percentages of Subjects With Antibody Response After Receiving the MMRV Vaccination

Secondary: Geometric Mean Titers After Receiving the Booster Dose of rMenB+OMV NZ Vaccination

Secondary: Geometric Mean Titers After Receiving the Booster Dose of rMenB+OMV NZ Vaccination

Secondary: Geometric Mean Titers at 12 months of age (predose 4) After Previously Receiving the Three Doses of rMenB+OMV NZ (Persistence)

Secondary: Geometric Mean Titers at 12 months of age (predose 4) After Previously Receiving the Three Doses of rMenB+OMV NZ (Persistence)

Secondary: Geometric Mean Titers After Receiving the Booster Dose and Single Dose of rMen+OMV NZ Vaccination (Induction of Immunological Memory)

Secondary: Geometric Mean Titers After Receiving the Booster Dose and Single Dose of rMen+OMV NZ Vaccination (Induction of Immunological Memory)

Secondary: Percentages of subjects with SBA titers ≥1:5 at 12 months of age (predose 4) After Previously Receiving the Three Doses of rMenB+OMV NZ (Persistence)

Secondary: Percentages of subjects with SBA titers ≥1:5 at 12 months of age (predose 4) After Previously Receiving the Three Doses of rMenB+OMV NZ (Persistence)

Secondary: SBA GMTs after a two-dose catch-up schedule or two-dose schedule

Secondary: SBA GMTs after a two-dose catch-up schedule or two-dose schedule

Secondary: Percentages of subjects with SBA titers ≥1:5 after a two-dose catch-up schedule or two-dose schedule

Secondary: Percentages of subjects with SBA titers ≥1:5 after a two-dose catch-up schedule or two-dose schedule

Secondary: ELISA Geometric Mean Concentration against vaccine antigen 287-953 one month after the fourth (booster) dose given at 12 months

Secondary: ELISA Geometric Mean Concentration against vaccine antigen 287-953 one month after the fourth (booster) dose given at 12 months

Secondary: ELISA Geometric Mean Concentration against vaccine antigen 287-953 after two-dose catch-up in toddlers

Secondary: ELISA Geometric Mean Concentration against vaccine antigen 287-953 after two-dose catch-up in toddlers

Secondary: Percentages of Subjects with Bactericidal Titers ≥ 1:5 (95% CI) Against Strain M10713 one month after the fourth (booster) dose given at 12 months

Secondary: Percentages of Subjects with Bactericidal Titers ≥ 1:5 (95% CI) Against Strain M10713 one month after the fourth (booster) dose given at 12 months

Secondary: Number of subjects reporting solicited local and systemic reactions during the 7 days following rMenB+OMV NZ vaccination at 12 months of age

Secondary: Number of subjects reporting solicited local and systemic reactions during the 7 days following rMenB+OMV NZ vaccination at 12 months of age

Secondary: Number of subjects reporting solicited local and systemic reactions during the 7 days following two-dose catch-up schedules of rMenB+OMV NZ vaccination

Secondary: Number of subjects reporting solicited local and systemic reactions during the 7 days following two-dose catch-up schedules of rMenB+OMV NZ vaccination

Secondary: Number of subjects reporting solicited local reactions during the 7 days following MMRV vaccination at 12 months of age

Secondary: Number of subjects reporting solicited local reactions during the 7 days following MMRV vaccination at 12 months of age

Secondary: Number of subjects reporting solicited systemic reactions during 8-28 days following MMRV vaccination at 12 months of age

Secondary: Number of subjects reporting solicited systemic reactions during 8-28 days following MMRV vaccination at 12 months of age

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

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