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Clinical Trial Results:
A Phase 3B, Open Label, Multi-Center Study to Evaluate the Safety, Tolerability and Immunogenicity of Novartis Meningococcal B Recombinant Vaccine When Administered Alone to Healthy Infants According to Different Immunization Schedules and to Healthy Children Aged 2 to 10 Years

Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.

Summary
EudraCT number	2010-021528-81
Trial protocol	ES HU
Global end of trial date	01 Jul 2015

Results information
Results version number	v1(current)
This version publication date	15 Apr 2016
First version publication date	15 Apr 2016
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

V72_28

ISRCTN number

US NCT number

NCT01339923

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Vaccines and Diagnostics

Sponsor organisation address

Via Fiorentina 1, Siena, Italy, 53100

Public contact

Study Start-up Associate, ICON Clinical Research Ltd, +36 28471689, zsuzsanna.tribel@iconplc.com

Scientific contact

Study Start-up Associate, ICON Clinical Research Ltd, +36 28471689, zsuzsanna.tribel@iconplc.com

Sponsor organisation name

Novartis Vaccines and Diagnostics

Sponsor organisation address

Via Fiorentina 1, Siena, Italy, 53100

Public contact

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

Scientific contact

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

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

Yes

EMA paediatric investigation plan number(s)

EMEA-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

01 Jul 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

23 Dec 2014

Global end of trial reached?

Yes

Global end of trial date

01 Jul 2015

Was the trial ended prematurely?

Main objective of the trial

To demonstrate a sufficient immune response following rMenB+OMV NZ vaccination, when given as a two dose primary series to healthy infants at 3 1/2 and 5 months of age or at 6 and 8 months of age, as measured by the percentage of subjects with serum bactericidal activity (SBA) titers of at least 4, at 1 month after the second rMenB+OMV NZ dose, directed against MenB indicator strains H44/76, 5/99 and NZ98/254.

Protection of trial subjects

This clinical study was designed, implemented and reported in accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in the Declaration of Helsinki.

Background therapy

Evidence for comparator

Actual start date of recruitment

06 Apr 2011

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Brazil: 417

Country: Number of subjects enrolled

Peru: 59

Country: Number of subjects enrolled

Spain: 653

Country: Number of subjects enrolled

Hungary: 280

Worldwide total number of subjects

1409

EEA total number of subjects

933

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)

1005

Children (2-11 years)

404

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

The study was conducted in a total of a total of 26 sites; 4 sites in Brazil, 3 sites in Peru, 10 sites in Hungary, 9 sites in Spain.

Screening details

All enrolled subjects were included in the study.

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_2h3h5_11

Arm description

Subjects approximately 2.5 months of age received 3 dose primary vaccination of rMenB+OMV NZ at 2.5, 3.5, 5 months of age, followed by a booster dose at 11 months of age.

Arm type

Experimental

Investigational medicinal product name

Meningococcal (group B) multicomponent recombinant adsorbed vaccine

Investigational medicinal product code

Other name

rMenB+OMV NZ

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

rMenB+OMV NZ Vaccine: Administration was done intramuscularly (IM), 3 doses + booster, of 0.5 mL each.

B_3h5_11

Arm description

Subjects approximately 3.5 months of age received 2 dose primary vaccination of rMenB+OMV NZ at 3.5 and 5 months of age, followed by a booster dose at 11 months of age.

Arm type

Experimental

Investigational medicinal product name

Meningococcal (group B) multicomponent recombinant adsorbed vaccine

Investigational medicinal product code

Other name

rMenB+OMV NZ

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

rMenB+OMV NZ Vaccine: Administration was done IM, 2 doses + booster, of 0.5 mL each.

B_68_11

Arm description

Subjects approximately 6 months of age received 2 dose primary vaccination of rMenB+OMV NZ at 6 and 8 months of age, followed by a booster dose at 11 months of age.

Arm type

Experimental

Investigational medicinal product name

Meningococcal (group B) multicomponent recombinant adsorbed vaccine

Investigational medicinal product code

Other name

rMenB+OMV NZ

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

rMenB+OMV NZ Vaccine: Administration was done IM, 2 doses + booster, of 0.5 mL each.

B_02_2_5

Arm description

Subjects 2-5 years of age received 2 catch-up doses of rMenB+OMV NZ, each at 0 and 2 months. Blood draw at 0 and 3 months since study start.

Arm type

Experimental

Investigational medicinal product name

Meningococcal (group B) multicomponent recombinant adsorbed vaccine

Investigational medicinal product code

Other name

rMenB+OMV NZ

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

rMenB+OMV NZ vaccine: Administration was done IM, 2 doses + booster, of 0.5 mL each.

BC_35_12

Arm description

Subjects 3 months of age received rMenB+OMV NZ + MenC-CRM and Synflorix concomitantly at 3, 5 and 12 months of age and an additional dose of Synflorix alone dose at 7 months of age.

Arm type

Experimental

Investigational medicinal product name

Meningococcal (group B) multicomponent recombinant adsorbed vaccine Meningococcal (group C) oligosaccharide diptheria CRM-197 conjugate vaccine Synflorix

Investigational medicinal product code

Other name

rMenB+OMV NZ MenC-CRM Synflorix

Pharmaceutical forms

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

Routes of administration

Intramuscular use

Dosage and administration details

rMenB+OMV NZ vaccine: Administration was done IM, 2 doses + booster, of 0.5 mL each. MenC-CRM vaccine: Administration was done IM, 2 doses booster, of 0.5 mL each. Synflorix: Administration was done IM, 3 doses + booster.

C_35_12

Arm description

Subjects 3 months of age received MenC‐CRM and Synflorix concomitantly at 3, 5 and 12 months of age and an additional dose of Synflorix alone at 7 months of age and rMenB+OMV NZ alone at 13 and 15 months of age.

Arm type

Experimental

Investigational medicinal product name

Meningococcal (group B) multicomponent recombinant adsorbed vaccine Meningococcal (group C) oligosaccharide diphtheria CRM-197 conjugate vaccine Synflorix

Investigational medicinal product code

Other name

rMenB+OMV NZ MenC-CRM Synflorix

Pharmaceutical forms

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

Routes of administration

Intramuscular use

Dosage and administration details

rMenB+OMV NZ vaccine: Administration was done IM, 2 doses + booster, of 0.5 mL each. MenC-CRM vaccine: Administration was done IM, 2 doses + booster, of 0.5 mL each. Synflorix: Administration was done IM, 3 doses + booster.

B_02_6_10

Arm description

Subjects 6-10 years of age received 2 catch-up doses of rMenB+OMV NZ, each at 0 and 2 months. Blood draw at 0 and 3 months since study start.

Arm type

Experimental

Investigational medicinal product name

Meningococcal (group B) multicomponent recombinant adsorbed vaccine

Investigational medicinal product code

Other name

rMenB+OMV NZ

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

rMenB+OMV NZ vaccine: Administration was done IM, 2 doses + booster, of 0.5 mL each.

Number of subjects in period 1	B_2h3h5_11	B_3h5_11	B_68_11	B_02_2_5	BC_35_12	C_35_12	B_02_6_10
Started	253	250	251	104	126	125	300
Completed	239	234	243	100	117	111	295
Not completed	14	16	8	4	9	14	5
Consent withdrawn by subject	7	11	6	1	3	2	4
Adverse event, non-fatal	1	1	1	-	-	1	-
Inappropriate enrollment	1	-	-	-	1	-	-
Unable to classify	1	-	1	-	1	5	-
Lost to follow-up	4	4	-	3	1	5	1
Protocol deviation	-	-	-	-	3	1	-

Baseline characteristics

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Reporting group title

B_2h3h5_11

Reporting group description

Subjects approximately 2.5 months of age received 3 dose primary vaccination of rMenB+OMV NZ at 2.5, 3.5, 5 months of age, followed by a booster dose at 11 months of age.

Reporting group title

B_3h5_11

Reporting group description

Subjects approximately 3.5 months of age received 2 dose primary vaccination of rMenB+OMV NZ at 3.5 and 5 months of age, followed by a booster dose at 11 months of age.

Reporting group title

B_68_11

Reporting group description

Subjects approximately 6 months of age received 2 dose primary vaccination of rMenB+OMV NZ at 6 and 8 months of age, followed by a booster dose at 11 months of age.

Reporting group title

B_02_2_5

Reporting group description

Subjects 2-5 years of age received 2 catch-up doses of rMenB+OMV NZ, each at 0 and 2 months. Blood draw at 0 and 3 months since study start.

Reporting group title

BC_35_12

Reporting group description

Subjects 3 months of age received rMenB+OMV NZ + MenC-CRM and Synflorix concomitantly at 3, 5 and 12 months of age and an additional dose of Synflorix alone dose at 7 months of age.

Reporting group title

C_35_12

Reporting group description

Reporting group title

B_02_6_10

Reporting group description

Subjects 6-10 years of age received 2 catch-up doses of rMenB+OMV NZ, each at 0 and 2 months. Blood draw at 0 and 3 months since study start.

Reporting group values	B_2h3h5_11	B_3h5_11	B_68_11	B_02_2_5	BC_35_12	C_35_12	B_02_6_10	Total
Number of subjects	253	250	251	104	126	125	300	1409
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)	2 ± 0.1	3 ± 0.1	6 ± 0	3.958 ± 1.117	3 ± 0.2	3 ± 0.1	8.074 ± 1.404	-
Gender categorical
Units: Subjects
Female	117	124	127	49	74	59	149	699
Male	136	126	124	55	52	66	151	710

End points

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Reporting group title

B_2h3h5_11

Reporting group description

Subjects approximately 2.5 months of age received 3 dose primary vaccination of rMenB+OMV NZ at 2.5, 3.5, 5 months of age, followed by a booster dose at 11 months of age.

Reporting group title

B_3h5_11

Reporting group description

Subjects approximately 3.5 months of age received 2 dose primary vaccination of rMenB+OMV NZ at 3.5 and 5 months of age, followed by a booster dose at 11 months of age.

Reporting group title

B_68_11

Reporting group description

Subjects approximately 6 months of age received 2 dose primary vaccination of rMenB+OMV NZ at 6 and 8 months of age, followed by a booster dose at 11 months of age.

Reporting group title

B_02_2_5

Reporting group description

Subjects 2-5 years of age received 2 catch-up doses of rMenB+OMV NZ, each at 0 and 2 months. Blood draw at 0 and 3 months since study start.

Reporting group title

BC_35_12

Reporting group description

Subjects 3 months of age received rMenB+OMV NZ + MenC-CRM and Synflorix concomitantly at 3, 5 and 12 months of age and an additional dose of Synflorix alone dose at 7 months of age.

Reporting group title

C_35_12

Reporting group description

Reporting group title

B_02_6_10

Reporting group description

Subjects 6-10 years of age received 2 catch-up doses of rMenB+OMV NZ, each at 0 and 2 months. Blood draw at 0 and 3 months since study start.

Subject analysis set title

All Enrolled Set

Subject analysis set type

Intention-to-treat

Subject analysis set description

All subjects enrolled in the study, ie., all screened subjects who provided informed consent and provided demographic and/or baseline assessments, regardless of the subjects' randomization and treatment status in the trial.

Subject analysis set title

Full Analysis set (FAS; Immunogenicity; Primary series)

Subject analysis set type

Full analysis

Subject analysis set description

All subjects in enrolled population who received at least one rMenB+OMV NZ dose or MenC-CRM (group C3512) and provided an evaluable serum sample at relevant time points (visit 4 for group B_2h3h5_11 and visit 3 for groups B_3h5_11, B_68_11, B_02, BC_35_12 and C_35_12).

Subject analysis set title

Full Analysis set (FAS; Immunogenicity; Post first dose respon

Subject analysis set type

Full analysis

Subject analysis set description

All subjects enrolled in Groups B_2h3h5_11b, B_3h5_11b and B_68_11b who received at least one rMenB+OMV NZ dose and provided an evaluable serum sample at 1, 1.5 and 2 months, respectively, after the first vaccination (visit 2).

Subject analysis set title

Full Analysis set (Immunogenicity; persistence)

Subject analysis set type

Full analysis

Subject analysis set description

All subjects in enrolled population who received at least one rMenB+OMV NZ dose or MenC-CRM (group C_35_12) and provided an evaluable serum sample at relevant time points (visit 5 for groups B_2h_3h511, BC_35_12, C_35_12 and visit 4 for groups B_3h5_11, B_68_11).

Subject analysis set title

Full Analysis set (Immunogenicity; Booster)

Subject analysis set type

Full analysis

Subject analysis set description

All subjects in enrolled population who received at least one rMenB+OMV NZ dose or MenC-CRM (group C_35_12) and provided an evaluable serum sample at relevant time points (visit 6 for groups B_2h_3h5_11, BC_35_12, C_35_12 and visit 5 for groups B_3h5_11, B_68_11).

Subject analysis set title

Per protocol set (PPS; Immunogenicity; Primary series)

Subject analysis set type

Per protocol

Subject analysis set description

All subjects in FAS population, who correctly received all doses of vaccine in primary series, provided evaluable serum sample at relevant time points (visit 4 for group B_2h3h5_11 and visit 3 for groups B_3h5_11, B_68_11, B_02, BC_35_12 and C_35_12) and have no major protocol deviations.

Subject analysis set title

Per protocol set (PPS; Immunogenicity; Post first dose respons

Subject analysis set type

Per protocol

Subject analysis set description

All subjects in FAS population, who correctly received all doses of vaccine in primary series, provided evaluable serum sample at relevant time points (visit 5 for groups B_2h3h5_11, BC_35_12, C_35_12 and visit 4 for groups B_3h5_11, B_68_11) and have no major protocol deviations.

Subject analysis set title

Per protocol set (Immunogenicity; Booster)

Subject analysis set type

Per protocol

Subject analysis set description

All subjects in FAS population, who correctly received all doses of vaccine in primary series and booster dose, provided evaluable serum sample at relevant time points (visit 6 for groups B_2h3h5_11, BC_35_12, C_35_12 and visit 5 for groups B_3h5_11, B_68_11) and have no major protocol deviations.

Subject analysis set title

Overall safety set

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects in the enrolled set, who received a study vaccination and provided solicited or unsolicited adverse event data.

Subject analysis set title

Solicited safety set

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects in the enrolled set, who received a study vaccination and provided any solicited adverse event data or indicators of solicited adverse events

Subject analysis set title

Unsolicited safety set

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects in the enrolled set, who received a study vaccination and provided unsolicited adverse event data.

Subject analysis set title

B_2h3h5_11b

Subject analysis set type

Full analysis

Subject analysis set description

Subjects, approximately 2.5 months of age received 3 dose primary vaccination of rMenB+OMV NZ at 2.5, 3.5, 5 months of age, followed by a booster dose at 11 months of age. Blood draw at 3.5, 6, 11 and 12 months of age.

Subject analysis set title

B_3h5_11b

Subject analysis set type

Full analysis

Subject analysis set description

Subjects, approximately 3.5 months of age received 2 dose primary vaccination of rMenB+OMV NZ at 3.5 and 5 months of age, followed by a booster dose at 11 months of age. Blood draw at 5, 11 and 12 months of age.

Subject analysis set title

B_68_11b

Subject analysis set type

Full analysis

Subject analysis set description

Subjects, approximately 6 months of age received 2 dose primary vaccination of rMenB+OMV NZ at 3.5 and 5 months of age, followed by a booster dose at 11 months of age. Blood draw at 8, 9, 11 and 12 months of age.

Subject analysis set title

B_02_2_5

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects, 2-5 years of age received 2 catch-up doses of rMenB+OMV NZ, each at 0 and 2 months. Blood draw at 0 and 3 months since study start.

Subject analysis set title

B_02_6_10

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects, 6-10 years of age received 2 catch-up doses of rMenB+OMV NZ, each at 0 and 2 months. Blood draw at 0 and 3 months since study start.

Subject analysis set title

B_02

Subject analysis set type

Full analysis

Subject analysis set description

Subjects, 2-10 years of age received 2 catch-up doses of rMenB+OMV NZ, each at 0 and 2 months. Blood draw at 0 and 3 months since study start. rMenB + OMV NZ vaccine: 2 doses 2 months apart

Primary: Percentages of Subjects with Serum Bactericidal Activity Using Human Serum (hSBA) Titers ≥ 4 or hSBA Titers ≥ 5 (Strain M10713) Following a 2-dose Primary Series of rMenB+OMV Vaccination

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End point title

Percentages of Subjects with Serum Bactericidal Activity Using Human Serum (hSBA) Titers ≥ 4 or hSBA Titers ≥ 5 (Strain M10713) Following a 2-dose Primary Series of rMenB+OMV Vaccination ^[1] ^[2]

End point description

Immunogenicity was assessed in terms of percentages of subjects with hSBA titers ≥ 4 against N meningitidis serogroup B strains H44/76, 5/99, NZ98/254 and hSBA titers ≥ 5 against strain M10713 following 2-dose primary series of vaccination with rMenB+OMV NZ at 3.5 and 5 months of age or at 6 and 8 months of age. Analysis was done on Full analysis set (FAS)-Primary series.

End point type

Primary

End point timeframe

1 month after second vaccination

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: 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	B_3h5_11	B_68_11
Number of subjects analysed	230	238
Units: Percentages of subjects
number (confidence interval 97.5%)
H44/76 (hSBA≥ 4; N=228, 234)	100 (97 to 100)	100 (97 to 100)
5/99 (hSBA≥ 4)	100 (97 to 100)	100 (98 to 100)
NZ98/254 (hSBA≥ 4; N=230, 233)	98 (95 to 99)	99 (97 to 100)
M10713 (hSBA≥ 5; N=181, 192)	44 (35 to 52)	73 (65 to 80)

No statistical analyses for this end point

Secondary: Percentages of Subjects with hSBA Titers ≥ 4, hSBA Titers ≥ 5 (Strain M10713) and hSBA ≥ 8 Following a 3-dose Primary Series of rMenB+OMV Vaccination

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End point title

Percentages of Subjects with hSBA Titers ≥ 4, hSBA Titers ≥ 5 (Strain M10713) and hSBA ≥ 8 Following a 3-dose Primary Series of rMenB+OMV Vaccination ^[3]

End point description

Immunogenicity was assessed in terms of percentages of subjects with hSBA titers ≥ 4 against N meningitidis serogroup B strains H44/76, 5/99, NZ98/254; hSBA titers ≥ 5 against strain M10713 and hSBA titers ≥ 8 against strains H44/76, 5/99, NZ98/254, M10713, following 3-dose primary series of vaccination with rMenB+OMV NZ at 2.5, 3.5 and 5 months of age. Analysis was done on FAS-primary series.

End point type

Secondary

End point timeframe

1 month after third vaccination

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	B_2h3h5_11
Number of subjects analysed	238
Units: Percentage
number (confidence interval 95%)
H44/76 (hSBA≥ 4; 1 month after 3rd vacc; N=237)	100 (98 to 100)
5/99 (hSBA≥ 4; 1 month after 3rd vacc)	100 (98 to 100)
NZ98/254 (hSBA≥ 4; 1 month after 3rd vacc)	99 (96 to 100)
M10713 (hSBA≥ 5; 1 month after 3rd vacc; N=197)	55 (48 to 62)
H44/76 (hSBA≥ 8; 1 month after 3rd vacc; N=237)	98 (96 to 100)
5/99 (hSBA≥ 8; 1 month after 3rd vacc)	100 (98 to 100)
NZ98/254 (hSBA≥ 8; 1 month after 3rd vacc)	89 (85 to 93)
M10713 (hSBA≥ 8; 1 month after 3rd vacc; N=197)	47 (40 to 54)

No statistical analyses for this end point

Secondary: Percentages of Subjects with hSBA Titers ≥ 4 or hSBA Titers ≥ 5 (Strain M10713) and hSBA ≥ 8 Following a 2-dose Catch-up Series of rMenB+OMV Vaccination

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End point title

Percentages of Subjects with hSBA Titers ≥ 4 or hSBA Titers ≥ 5 (Strain M10713) and hSBA ≥ 8 Following a 2-dose Catch-up Series of rMenB+OMV Vaccination

End point description

Immunogenicity was assessed in terms of percentages of subjects with hSBA titers ≥ 4 against N meningitidis serogroup B strains H44/76, 5/99, NZ98/254; hSBA titers ≥ 5 against strain M10713 and hSBA titers ≥ 8 against strains H44/76, 5/99, NZ98/254, M10713; following 2-dose catch-up series of vaccination with rMenB+OMV NZ in healthy children aged 2-10 years (0, 2 month schedule). Analysis was done on FAS-primary series.

End point type

Secondary

End point timeframe

1 month after second vaccination

End point values	B_02
Number of subjects analysed	390
Units: Percentage
number (confidence interval 95%)
H44/76 (hSBA≥ 4; 1 month after 2nd vacc; N=386)	99 (97 to 100)
5/99 (hSBA≥ 4; 1 month after 2nd vacc)	99 (98 to 100)
NZ98/254 (hSBA≥ 4; 1 month after 2nd vacc; N=389)	99 (97 to 100)
M10713 (hSBA≥ 5; 1 month after 2nd vacc; N=370)	94 (91 to 96)
H44/76 (hSBA≥ 8; 1 month after 2nd vacc; N=386)	98 (96 to 99)
5/99 (hSBA≥ 8; 1 month after 2nd vacc)	99 (98 to 100)
NZ98/254 (hSBA≥ 8; 1 month after 2nd vacc; N=389)	95 (92 to 97)
M10713 (hSBA≥ 8; 1 month after 2nd vacc; N=370)	92 (89 to 94)

No statistical analyses for this end point

Secondary: Percentages of Subjects Achieving Four-fold Rise Over Baseline hSBA Titers Following a 2-dose Catch-up Series of rMenB+OMV Vaccination

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End point title

Percentages of Subjects Achieving Four-fold Rise Over Baseline hSBA Titers Following a 2-dose Catch-up Series of rMenB+OMV Vaccination

End point description

Immunogenicity was assessed in terms of percentages of subjects achieving 4-fold increase in hSBA titers as compared to baseline against N meningitidis serogroup B strains H44/76, 5/99, NZ98/254, M10713; following 2-dose catch-up series of vaccination with rMenB+OMV NZ in healthy children aged 2-10 years (0, 2 month schedule). Analysis was done on FAS- primary series.

End point type

Secondary

End point timeframe

1 month after second vaccination

End point values	B_02
Number of subjects analysed	388
Units: Percentage
number (confidence interval 95%)
H44/76 (1 month after 2nd vacc; N=385)	96 (93 to 97)
5/99 (1 month after 2nd vacc)	99 (97 to 100)
NZ98/254 (1 month after 2nd vacc; N=387)	93 (89 to 95)
M10713 (1 month after 2nd vacc; N=352)	46 (41 to 51)

No statistical analyses for this end point

Secondary: Geometric Mean hSBA Titers (GMTs) Following 2 or 3 Dose Primary Series of Vaccination with rMenB+OMV

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End point title

Geometric Mean hSBA Titers (GMTs) Following 2 or 3 Dose Primary Series of Vaccination with rMenB+OMV ^[4]

End point description

Immunogenicity was assessed in terms of Geometric mean hSBA titers (GMTs) against N meningitidis serogroup B indicator strains following 2 or 3 dose primary series of vaccination rMenB+OMV NZ (1 month after 3rd infant vaccination in B_2h3h5_11 and 1 month after 2nd infant vaccination in B_3h5_11, B_68_11 and B_02). Analysis was done on FAS-primary series.

End point type

Secondary

End point timeframe

1 month after primary series vaccination

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

End point values	B_2h3h5_11	B_3h5_11	B_68_11	B_02
Number of subjects analysed	238	230	238	390
Units: Titers
geometric mean (confidence interval 95%)
H44/76 (1 m after primary vacc; N=237,228,234,386)	109 (92 to 130)	132 (110 to 158)	240 (201 to 287)	121 (109 to 135)
5/99 (1 m after primary vacc)	795 (665 to 950)	605 (502 to 729)	1157 (964 to 1390)	489 (442 to 541)
NZ98/254 1 m after primary vacc; N=238,230,233,389	34 (28 to 42)	39 (31 to 48)	65 (52 to 80)	42 (38 to 47)
M10713 (1 m after primary vacc; N=197,181,192,370)	4.86 (3.62 to 6.54)	3.39 (2.48 to 4.64)	9.96 (7.33 to 14)	35 (31 to 39)

No statistical analyses for this end point

Secondary: Geometric Mean hSBA Titers (GMTs) After First Infant Vaccination with rMenB+OMV

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End point title

Geometric Mean hSBA Titers (GMTs) After First Infant Vaccination with rMenB+OMV

End point description

Immunogenicity was assessed in terms of Geometric mean hSBA titers (GMTs) against N meningitidis serogroup B indicator strains after the first infant vaccination in groups B_2h3h5_11b, B_3h5_11b and B_68_11b (after 1 month for group B_2h3h5_11b, 1.5 months for group B_2h3h5_11b and 2 months for group B_68_11b). Analysis was done on FAS-post first dose.

End point type

Secondary

End point timeframe

1, 1.5 or 2 months after first infant vaccination

End point values	B_2h3h5_11b	B_3h5_11b	B_68_11b
Number of subjects analysed	119	115	118
Units: Titers
geometric mean (confidence interval 95%)
H44/76 1 month after 1st vacc; N=117,115,117	4.19 (3.29 to 5.35)	5.7 (4.41 to 7.37)	9.83 (7.59 to 13)
5/99 1 month after 1st vacc	20 (15 to 27)	30 (22 to 42)	37 (27 to 52)
NZ98/254 1 month after 1st vacc; N=118,114,117	2.87 (2.32 to 3.54)	2.48 (1.98 to 3.11)	2.84 (2.28 to 3.55)
M10713 1 month after 1st vacc; N=95,99,95	2.59 (1.86 to 3.6)	1.69 (1.21 to 2.36)	1.62 (1.15 to 2.28)

No statistical analyses for this end point

Secondary: Percentages of Subjects with hSBA Titers ≥ 4 or hSBA Titers ≥ 5 and hSBA ≥ 8 After First Infant Vaccination with rMenB+OMV

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End point title

Percentages of Subjects with hSBA Titers ≥ 4 or hSBA Titers ≥ 5 and hSBA ≥ 8 After First Infant Vaccination with rMenB+OMV

End point description

Immunogenicity was assessed in terms of percentages of subjects with hSBA titers ≥ 4 against N meningitidis serogroup B strains H44/76, 5/99, NZ98/254, hSBA titers ≥ 5 against strain M10713 and hSBA titers ≥ 8 against strains H44/76, 5/99, NZ98/254, M10713 after the first infant vaccination in groups B_2h3h5_11b, B_3h5_11b and B_68_11b (at 3.5, 5, and 8 months of age respectively). Analysis was done on FAS-post first dose.

End point type

Secondary

End point timeframe

Post- first dose (1 month for B_2h3h5_11b, 1.5 month for B_3h5_11b and 2 months for B_68_11b after 1st vaccination)

End point values	B_2h3h5_11b	B_3h5_11b	B_68_11b
Number of subjects analysed	119	115	118
Units: Percentage
number (confidence interval 95%)
H44/76 (hSBA≥ 4; Post 1st vacc; N=117,115,117)	62 (52 to 70)	72 (63 to 80)	82 (74 to 89)
5/99 (hSBA≥ 4; Post 1st vacc)	91 (84 to 95)	95 (89 to 98)	92 (86 to 96)
NZ98/254 (hSBA≥ 4; Post 1st vacc; N=118,114,117)	43 (34 to 53)	39 (30 to 48)	41 (32 to 50)
M10713 (hSBA≥ 5; Post1st vacc; N=95,99,95)	31 (21 to 41)	18 (11 to 27)	17 (10 to 26)
H44/76 (hSBA≥ 8; Post 1st vacc; N=117,115,117)	25 (17 to 34)	38 (29 to 48)	58 (49 to 67)
5/99 (hSBA≥ 8; Post1st vacc)	82 (73 to 88)	90 (82 to 94)	86 (79 to 92)
NZ98/254 (hSBA≥ 8; 1st vacc; N=118,114,117)	13 (7 to 20)	7 (3 to 13)	13 (7 to 20)
M10713 (hSBA≥ 8; Post1st vacc; N=95,99,95)	21 (13 to 31)	15 (9 to 24)	13 (7 to 21)

No statistical analyses for this end point

Secondary: Percentages of Subjects with hSBA Titers ≥ 4 or hSBA Titers ≥ 5 and hSBA ≥ 8 Following a Booster Dose of rMenB +OMV Vaccination

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End point title

Percentages of Subjects with hSBA Titers ≥ 4 or hSBA Titers ≥ 5 and hSBA ≥ 8 Following a Booster Dose of rMenB +OMV Vaccination ^[5]

End point description

Immunogenicity was assessed in terms of percentages of subjects with hSBA titers ≥ 4 against N meningitidis serogroup B strains H44/76, 5/99, NZ98/254; hSBA titers ≥ 5 against strain M10713; hSBA titers ≥ 8 against strains H44/76, 5/99, NZ98/254, M10713; following a booster dose of rMenB+OMV NZ given at 11 months of age (4th dose for B_2h3h5_11 and 3rd dose for B_3h5_11 and B_68_11). Analysis was done on FAS-booster.

End point type

Secondary

End point timeframe

1 month post-booster dose

Notes
[5] - 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	B_2h3h5_11	B_3h5_11	B_68_11
Number of subjects analysed	233	228	239
Units: Percentage
number (confidence interval 95%)
H44/76 (hSBA≥ 4, after booster; N=233,227,238)	100 (98 to 100)	100 (98 to 100)	100 (98 to 100)
5/99 (hSBA≥ 4, after booster)	100 (98 to 100)	100 (98 to 100)	100 (98 to 100)
NZ98/254 (hSBA≥ 4, after booster; N=231,226,236)	100 (98 to 100)	99 (96 to 100)	100 (98 to 100)
M10713 (hSBA≥ 5, after booster; N=203,181,193)	83 (77 to 88)	87 (81 to 91)	83 (77 to 88)
H44/76 (hSBA≥ 8, after booster; N=233,227,238)	100 (98 to 100)	100 (98 to 100)	100 (98 to 100)
5/99 (hSBA≥ 8, after booster)	100 (98 to 100)	100 (98 to 100)	100 (98 to 100)
NZ98/254 (hSBA≥ 8, after booster; N=231,226,236)	95 (91 to 97)	95 (91 to 98)	97 (95 to 99)
M10713 (hSBA≥ 8, after booster; N=203,181,193)	78 (72 to 84)	83 (77 to 89)	74 (67 to 80)

No statistical analyses for this end point

Secondary: Antibody Persistence in Terms of Percentages of Subjects with hSBA Titers ≥ 4 or hSBA Titers ≥ 5 (M10713) and hSBA ≥ 8 Following 2 or 3-dose Primary Series of Vaccination with rMenB+OMV NZ

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End point title

Antibody Persistence in Terms of Percentages of Subjects with hSBA Titers ≥ 4 or hSBA Titers ≥ 5 (M10713) and hSBA ≥ 8 Following 2 or 3-dose Primary Series of Vaccination with rMenB+OMV NZ ^[6]

End point description

Persistence of bactericidal antibodies at 11 months of age was assessed in terms of percentages of subjects with hSBA titers ≥ 4 against N meningitidis serogroup B strains H44/76, 5/99, NZ98/254; hSBA titers ≥ 5 against strain M10713; hSBA titers ≥ 8 against strains H44/76, 5/99, NZ98/254, M10713 in subjects who previously received a primary series of 2 or 3-doses of rMenB+OMV NZ vaccine. Analysis was done on FAS-persistence.

End point type

Secondary

End point timeframe

11 months of age (persistence)

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

End point values	B_2h3h5_11	B_3h5_11	B_68_11
Number of subjects analysed	235	233	238
Units: Percentage
number (confidence interval 95%)
H44/76 (hSBA≥ 4; 11 months of age; N=235,232,237)	87 (82 to 91)	86 (81 to 90)	100 (98 to 100)
5/99 (hSBA≥ 4; 11 months of age; N=234,230,235)	100 (98 to 100)	93 (89 to 96)	100 (98 to 100)
NZ98/254 hSBA≥ 4; 11 months of age; N=233,233,238)	54 (47 to 60)	41 (34 to 47)	90 (85 to 93)
M10713 (hSBA≥ 5; 11 months of age; N=199,177,188)	33 (26 to 40)	23 (17 to 30)	42 (35 to 49)
H44/76 (hSBA≥ 8; 11 months of age; N=235,232,237)	64 (58 to 70)	60 (53 to 66)	96 (93 to 98)
5/99 (hSBA≥ 8; 11 months of age; N=234,230,235)	94 (91 to 97)	87 (82 to 91)	99 (97 to 100)
NZ98/254 hSBA≥ 8; 11 months of age; N=233,233,238)	36 (30 to 43)	12 (8 to 17)	65 (58 to 71)
M10713 (hSBA≥ 8; 11 months of age; N=199,177,188)	24 (18 to 30)	16 (11 to 22)	36 (29 to 43)

No statistical analyses for this end point

Secondary: Antibody Persistence in Terms of Geometric Mean Titers Following 2 or 3-dose Primary Series of Vaccination with rMenB+OMV NZ

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End point title

Antibody Persistence in Terms of Geometric Mean Titers Following 2 or 3-dose Primary Series of Vaccination with rMenB+OMV NZ ^[7]

End point description

Persistence of bactericidal antibodies at 11 months of age was assessed in terms of GMTs against N meningitidis serogroup B indicator strains in subjects who previously received a primary series of 2 or 3-doses of rMenB+OMV NZ. Analysis was done on FAS-persistence.

End point type

Secondary

End point timeframe

11 months of age (persistence)

Notes
[7] - 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	B_2h3h5_11	B_3h5_11	B_68_11
Number of subjects analysed	235	233	238
Units: Titers
geometric mean (confidence interval 95%)
H44/76 (Baseline; N=111,113,120)	1.31 (1.09 to 1.57)	1.34 (1.11 to 1.62)	1.58 (1.32 to 1.9)
H44/76 (11 moa; N=235,232,237)	12 (9.64 to 14)	12 (9.36 to 14)	66 (54 to 81)
5/99 (Baseline; N=113,112,120)	1.15 (1.02 to 1.3)	1.16 (1.02 to 1.32)	0.97 (0.85 to 1.09)
5/99 (11 moa; N=234,230,235)	98 (78 to 124)	50 (39 to 63)	285 (225 to 363)
NZ98/254 (Baseline; N=113,113,122)	1.07 (0.99 to 1.15)	1.04 (0.96 to 1.12)	1 (0.93 to 1.07)
NZ98/254 (11 moa; N=233,233,238)	4.57 (3.66 to 5.71)	2.68 (2.13 to 3.38)	12 (9.79 to 15)
M10713 (Baseline; N=84,64,88)	2.36 (1.75 to 3.2)	1.52 (1.07 to 2.17)	1.29 (0.95 to 1.76)
M10713 (11 moa; N=199,177,188)	2.55 (1.89 to 3.43)	1.98 (1.45 to 2.71)	3.62 (2.66 to 4.94)

No statistical analyses for this end point

Secondary: Geometric Mean ELISA Concentrations Against Vaccine Antigen 287-953 Following 2 or 3-dose Primary Series and Booster Dose of Vaccination with rMenB+OMV NZ

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End point title

Geometric Mean ELISA Concentrations Against Vaccine Antigen 287-953 Following 2 or 3-dose Primary Series and Booster Dose of Vaccination with rMenB+OMV NZ ^[8]

End point description

Immunogenicity was assessed in terms of Geometric mean ELISA concentrations (GMCs) against N meningitidis serogroup B vaccine antigen 287-953, following 2 or 3 dose primary series and booster dose of rMenB+OMV NZ. Analysis was done on FAS-persistence and FAS-booster.

End point type

Secondary

End point timeframe

1 month after primary vaccination, pre-booster vaccination (persistence) and 1 month after booster vaccination

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

End point values	B_2h3h5_11	B_3h5_11	B_68_11
Number of subjects analysed	218	225	221
Units: IU/mL
geometric mean (confidence interval 95%)
1 month after primary vaccination (N=212,215,212)	4688 (3884 to 5660)	3152 (2594 to 3831)	4682 (3850 to 5694)
Pre-booster vaccination (N=213,220,215)	474 (395 to 569)	291 (241 to 351)	1270 (1052 to 1533)
1 month after booster dose	5900 (5047 to 6898)	6062 (5150 to 7135)	5898 (5016 to 6934)

No statistical analyses for this end point

Secondary: Geometric Mean ELISA Concentrations Against Vaccine Antigen 287-953 After a Two Dose Catch-up rMenB+OMV NZ Immunization Series in Children 2-10 Years of Age

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End point title

Geometric Mean ELISA Concentrations Against Vaccine Antigen 287-953 After a Two Dose Catch-up rMenB+OMV NZ Immunization Series in Children 2-10 Years of Age

End point description

Immunogenicity was assessed in terms of Geometric mean ELISA concentrations (GMCs) against N meningitidis serogroup B vaccine antigen 287-953, after a two dose catch-up immunization series with rMenB+OMV NZ in children 2-10 years of age. Analysis was done on FAS-primary series.

End point type

Secondary

End point timeframe

1 month after second vaccination

End point values	B_02
Number of subjects analysed	389
Units: IU/mL
geometric mean (confidence interval 95%)	2333 (2124 to 2562)

No statistical analyses for this end point

Secondary: Percentages of Subjects with hSBA Titers ≥ 8 Against Serogroup C Following Concomitant Administration of rMenB +OMV NZ with MenC-CRM or MenC-CRM Alone

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End point title

Percentages of Subjects with hSBA Titers ≥ 8 Against Serogroup C Following Concomitant Administration of rMenB +OMV NZ with MenC-CRM or MenC-CRM Alone ^[9]

End point description

Non-inferiority of MenC-CRM was determined following co-administration of MenC-CRM and rMenB+OMV NZ or MenC-CRM alone at 3 and 5 months and booster dose at 12 months, as measured by the percentages of subjects achieving hSBA titers ≥ 8 against serogroup C. Analysis was done on PPS-primary series and PPS-booster.

End point type

Secondary

End point timeframe

Baseline, 1 month after second vaccination and 1 month after booster vaccination

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	BC_35_12	C_35_12
Number of subjects analysed	85	72
Units: Percentage
number (confidence interval 95%)
Serogroup C (1 month after 2nd vacc)	99 (94 to 100)	100 (95 to 100)
Serogroup C (1 month after booster vacc; N=70,47)	100 (95 to 100)	100 (92 to 100)

hSBA≥ 8; 1 month after 2nd vaccination

Statistical analysis description

Non-inferiority of MenC-CRM was determined following co-administration of MenC-CRM and rMenB+OMV NZ vs MenC-CRM control group at 1 month after 2nd vaccination for serogroup C.

Comparison groups

BC_35_12 v C_35_12

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen method

Parameter type

Vaccine group difference

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-6.4

upper limit

3.9

hSBA≥ 8; 1 month after booster vaccination

Statistical analysis description

Non-inferiority of MenC-CRM was determined following co-administration of MenC-CRM and rMenB+OMV NZ vs MenC-CRM control group at 1 month after booster vaccination for serogroup C.

Comparison groups

BC_35_12 v C_35_12

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen method

Parameter type

Vaccine group difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-5.2

upper limit

7.6

Secondary: GMTs Following Concomitant Administration of rMenB+OMV NZ with MenC-CRM or MenC-CRM Alone

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End point title

GMTs Following Concomitant Administration of rMenB+OMV NZ with MenC-CRM or MenC-CRM Alone ^[10]

End point description

Immunogenicity was assessed in terms of GMTs against N meningitidis serogroup C strain following co-administration of MenC-CRM and rMenB+OMV NZ or MenC-CRM alone at 3 and 5 months and booster dose at 12 months. Analysis was done on FAS-primary series and FAS-booster.

End point type

Secondary

End point timeframe

1 month after second vaccination, 1 month after 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	BC_35_12	C_35_12
Number of subjects analysed	102	88
Units: Titers
geometric mean (confidence interval 95%)
1 month after 2nd vacc	568 (461 to 701)	905 (718 to 1141)
Pre-booster vacc (N=92,75)	36 (28 to 47)	56 (41 to 77)
1 month after booster vacc (N=99,92)	1201 (991 to 1456)	1724 (1350 to 2201)

No statistical analyses for this end point

Secondary: GMTs Following Concomitant Administration of rMenB+OMV NZ with MenC-CRM or MenC-CRM Alone - Persistence

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End point title

GMTs Following Concomitant Administration of rMenB+OMV NZ with MenC-CRM or MenC-CRM Alone - Persistence ^[11]

End point description

End point type

Secondary

End point timeframe

Pre-booster vaccination (persistence; 12 months of age)

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	BC_35_12	C_35_12
Number of subjects analysed	108	93
Units: Titers
geometric mean (confidence interval 95%)	36 (28 to 46)	56 (41 to 75)

No statistical analyses for this end point

Secondary: Percentages of Subjects with hSBA Titers ≥ 4 or hSBA Titers ≥ 5 (M10713) and hSBA ≥ 8 Following Concomitant Administration of rMenB+OMV NZ with MenC-CRM

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End point title

Percentages of Subjects with hSBA Titers ≥ 4 or hSBA Titers ≥ 5 (M10713) and hSBA ≥ 8 Following Concomitant Administration of rMenB+OMV NZ with MenC-CRM ^[12]

End point description

Immunogenicity was assessed in terms of percentages of subjects with hSBA titers ≥ 4 against N meningitidis serogroup B strains H44/76, 5/99, NZ98/254; hSBA titers ≥ 5 against strain M10713; hSBA titers ≥ 8 against strains H44/76, 5/99, NZ98/254, M10713; following co-administration of MenC-CRM and rMenB+OMV NZ at 3 and 5 months and a booster at 12 months. Analysis was done on FAS-primary series and FAS-booster.

End point type

Secondary

End point timeframe

1 month after second vaccination and 1 month after 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	BC_35_12
Number of subjects analysed	119
Units: Percentage
number (confidence interval 95%)
H44/76 (hSBA≥4; 1 month after 2nd vacc)	97 (92 to 99)
H44/76 (hSBA≥4; 1 month after booster vacc; N=114)	100 (97 to 100)
5/99 (hSBA≥4; 1 month after 2nd vacc)	96 (90 to 99)
5/99 (hSBA≥4; 1 month after booster vacc; N=113)	97 (92 to 99)
NZ98/254 (hSBA≥4; 1 month after 2nd vacc; N=118)	95 (89 to 98)
NZ98/254 (hSBA≥4; 1 mo after booster vacc; N=114)	97 (93 to 99)
M10713 (hSBA≥5; 1 month after 2nd vacc; N=98)	68 (58 to 77)
M10713 (hSBA≥5; 1 month after booster vacc; N=101)	67 (57 to 76)
H44/76 (hSBA≥8; 1 month after 2nd vacc)	97 (92 to 99)
H44/76 (hSBA≥8; 1 month after booster vacc; N=114)	99 (95 to 100)
5/99 (hSBA≥8; 1 month after 2nd vacc)	96 (90 to 99)
5/99 (hSBA≥8; 1 month after booster vacc; N=113)	97 (92 to 99)
NZ98/254 (hSBA≥8; 1 month after 2nd vacc; N=118)	87 (80 to 93)
NZ98/254 (hSBA≥8; 1 mo after booster vacc; N=114)	95 (89 to 98)
M10713 (hSBA≥8; 1 month after 2nd vacc; N=98)	60 (50 to 70)
M10713 (hSBA≥8; 1 month after booster vacc; N=101)	61 (51 to 71)

No statistical analyses for this end point

Secondary: GMTs Against N. Meningitidis Serogroup B Strains Following Concomitant Administration of rMenB+OMV NZ with MenC-CRM

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End point title

GMTs Against N. Meningitidis Serogroup B Strains Following Concomitant Administration of rMenB+OMV NZ with MenC-CRM ^[13]

End point description

Immunogenicity was assessed in terms of GMTs against N meningitidis serogroup C strain following co-administration of MenC-CRM and rMenB+OMV NZ at 3 and 5 months and booster dose at 12 months. Analysis was done on FAS-persistence and FAS-booster.

End point type

Secondary

End point timeframe

1 month after second vaccination, pre-booster vaccination and 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: There was no statistical null hypothesis associated with this immunogenicity objective.

End point values	BC_35_12
Number of subjects analysed	115
Units: Titers
geometric mean (confidence interval 95%)
H44/76 (1 month after 2nd vacc)	226 (179 to 284)
H44/76 (Pre-booster vacc)	16 (13 to 20)
H44/76 (1 month after booster vacc; N=114)	239 (198 to 288)
5/99 (1 month after 2nd vacc)	555 (409 to 753)
5/99 (Pre-booster vacc)	55 (42 to 72)
5/99 (1 month after booster vacc; N=113)	1623 (1210 to 2176)
NZ98/254 (1 month after 2nd vacc; N=114)	27 (21 to 34)
NZ98/254 (Pre-booster vacc; N=115)	2.63 (2.21 to 3.14)
NZ98/254 (1 month after booster vacc; N=114)	68 (54 to 86)
M10713 (1 month after 2nd vacc; N=89)	9.81 (7.06 to 14)
M10713 (Pre-booster vacc; N=110)	2.2 (1.72 to 2.82)
M10713 (1 month after booster vacc; N=101)	11 (7.72 to 15)

No statistical analyses for this end point

Secondary: Geometric Mean ELISA Concentrations Against Vaccine Antigen 287-953 Following Concomitant Administration of rMenB+OMV NZ with MenC-CRM

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End point title

Geometric Mean ELISA Concentrations Against Vaccine Antigen 287-953 Following Concomitant Administration of rMenB+OMV NZ with MenC-CRM ^[14]

End point description

Immunogenicity was assessed in terms of Geometric mean ELISA concentrations against N meningitidis serogroup B vaccine antigen 287-953, following co-administration of MenC-CRM and rMenB+OMV NZ at 3 and 5 months and booster dose at 12 months. Analysis was done on FAS-primary and FAS-booster.

End point type

Secondary

End point timeframe

1 month after second vaccination, pre-booster vaccination and 1 month after booster 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: There was no statistical null hypothesis associated with this immunogenicity objective.

End point values	BC_35_12
Number of subjects analysed	116
Units: IU/mL
geometric mean (confidence interval 95%)
1 month after 2nd vacc	2125 (1595 to 2830)
Pre-booster vacc (N=111)	194 (164 to 230)
1 month after booster vacc (N=113)	4281 (3411 to 5372)

No statistical analyses for this end point

Secondary: Geometric Mean ELISA Concentrations Against Vaccine Antigen 287-953 Following Concomitant Administration of rMenB+OMV NZ with MenC-CRM - Persistence

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End point title

Geometric Mean ELISA Concentrations Against Vaccine Antigen 287-953 Following Concomitant Administration of rMenB+OMV NZ with MenC-CRM - Persistence ^[15]

End point description

Immunogenicity was assessed in terms of GMTs against Geometric mean ELISA concentrations against N meningitidis serogroup B vaccine antigen 287-953, following co-administration of MenC-CRM and rMenB+OMV NZ at 3 and 5 months and booster dose at 12 months. Analysis was done on FAS-persistence.

End point type

Secondary

End point timeframe

Pre-booster vaccination (persistence; 12 months of age)

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	BC_35_12
Number of subjects analysed	115
Units: IU/mL
geometric mean (confidence interval 95%)	196 (166 to 231)

No statistical analyses for this end point

Secondary: Number of Subjects who Reported Immediate Reactions within 30 Minutes after any Vaccination with rMenB+OMV NZ

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End point title

Number of Subjects who Reported Immediate Reactions within 30 Minutes after any Vaccination with rMenB+OMV NZ

End point description

Safety was assessed in terms of number of subjects who reported immediate reactions within 30 minutes following a 4-dose regimen (2.5, 3.5, 5 and 11 months) or a 3-dose regimen (3.5, 5 and 11 months or 6, 8 and 11 months) of rMenB+OMV NZ. Analysis was done on solicited safety set.

End point type

Secondary

End point timeframe

Within 30 minutes after any vaccination

End point values	B_2h3h5_11b	B_3h5_11b	B_68_11b
Number of subjects analysed	252	249	250
Units: Subjects
Tenderness	13	9	9
Erythema	19	19	7
Induration	4	3	2
Swelling	1	2	1
Change in eating habits	0	2	1
Sleepiness	1	2	3
Unusual crying	4	3	4
Vomiting	1	0	0
Diarrhea	0	0	1
Irritability	1	2	1
Rash	0	1	1
Fever (≥38°C)	3	2	2
Medic. used for pain (N=252,248,250)	0	0	0
Medically-attended fever	0	0	0
Medic. used to treat high temp. (N=252,248,250)	1	1	0
Medic. used to prevent high temp. (N=252,248,250)	0	0	0

No statistical analyses for this end point

Secondary: Number of Subjects with Solicited Local and Systemic Adverse Events (AEs) Following a 3 or 4-dose Regimen of rMenB+OMV NZ

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End point title

Number of Subjects with Solicited Local and Systemic Adverse Events (AEs) Following a 3 or 4-dose Regimen of rMenB+OMV NZ ^[16]

End point description

Safety was assessed in terms of number of subjects with solicited local and systemic AEs after any vaccination following a 4-dose regimen (2.5, 3.5, 5 and 11 months) or as a 3-dose regimen (3.5, 5 and 11 months or 6, 8 and 11 months) of rMenB+OMV NZ. Analysis was done on solicited safety set.

End point type

Secondary

End point timeframe

Day 1 to day 7 after any 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: All safety analyses were run in the safety population.

End point values	B_2h3h5_11	B_3h5_11	B_68_11
Number of subjects analysed	247	243	246
Units: Subjects
Any local (N=245,241,244)	226	213	202
Tenderness (N=245,241,244)	200	174	166
Erythema (N=245,241,244)	164	156	157
Induration (N=245,241,244)	161	117	121
Swelling (N=245,241,244)	120	75	84
Any systemic (N=245,241,244)	238	236	233
Change in eating habits (N=245,241,244)	141	112	121
Sleepiness (N=245,241,244)	186	152	143
Irritability (N=245,241,244)	180	156	151
Vomiting (N=245,241,244)	65	39	55
Diarrhea (N=245,241,244)	91	69	74
Rash (N=245,241,244)	23	21	22
Unusual Crying (N=245,241,244)	198	186	156
Fever (≥38°C) (N=245,241,244)	197	189	184
Medic. used for pain (N=245,241,244)	129	110	109
Medic. used to prevent high temp. (N=245,241,244)	97	94	99
Medic. used to treat high temp. (N=245,242,244)	193	186	177
Medically-attended fever	16	10	15

No statistical analyses for this end point

Secondary: Number of Subjects who Reported Immediate Reactions within 30 Minutes After Any Vaccination - Groups B_02_2_5 and B_02_6_10

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End point title

Number of Subjects who Reported Immediate Reactions within 30 Minutes After Any Vaccination - Groups B_02_2_5 and B_02_6_10 ^[17]

End point description

Safety was assessed in terms of number of subjects with solicited local and systemic AEs after any vaccination in subjects aged 2 - 10 years who received 2 catch-up doses of rMenB+OMV NZ, each at 0 and 2 months. Analysis was done on solicited safety set.

End point type

Secondary

End point timeframe

Within 30 minutes after any vaccination

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

End point values	B_02_2_5	B_02_6_10
Number of subjects analysed	104	300
Units: Subjects
Pain	6	17
Erythema	6	2
Induration	1	3
Swelling	2	2
Chills (N=0,300)	0	2
Change in eating habits (N=104,0)	0	0
Sleepiness (N=104,0)	0	0
Irritability (N=104,0)	1	0
Vomiting (N=104,0)	0	0
Nausea (N=0,300)	0	2
Malaise (N=0,300)	0	4
Diarrhoea (N=104,0)	0	0
Headache	0	1
Rash	0	0
Arthralgia	0	1
Myalgia (N=0,300)	0	5
Fever (≥38°C)	0	0
Medic. used for pain	0	1
Medic. used to prevent high temp.	0	1
Medic. used to treat high temp.	0	0
Medically-attended fever	0	0

No statistical analyses for this end point

Secondary: Number of Subjects with Solicited Local and Systemic AEs in Groups B_02_2_5 and B_02_6_10

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End point title

Number of Subjects with Solicited Local and Systemic AEs in Groups B_02_2_5 and B_02_6_10

End point description

Safety was assessed in terms of number of subjects with solicited local and systemic AEs after any vaccination in subjects aged 2- 10 years who received 2 catch-up doses of rMenB+OMV NZ, each at 0 and 2 months. Analysis was done on solicited safety set.

End point type

Secondary

End point timeframe

Day 1 to day 7 after any vaccination

End point values	B_02_2_5	B_02_6_10
Number of subjects analysed	102	299
Units: Subjects
Any Local (N=100,297)	99	287
Pain (N=100,297)	98	287
Erythema (N=100,297)	58	179
Induration (N=100,297)	41	123
Swelling (N=100,297)	50	146
Any systemic (N=100,297)	78	205
Chills (N=0,296)	0	45
Change in eating habits (N=100,0)	35	0
Sleepiness (N=100,0)	39	0
Irritability (N=100,0)	49	0
Malaise (N=0,296)	0	114
Vomiting (N=100,0)	7	0
Nausea (N=0,296)	0	36
Diarrhoea (N=100,0)	12	0
Headache (N=100,296)	7	89
Rash (N=100,296)	9	20
Arthralgia (N=100,296)	35	49
Myalgia (N=0,296)	0	126
Fever (≥38°C) (N=100,296)	20	41
Medic. used for pain (N=100,296)	48	158
Medic. used to prevent high temp. (N=100,296)	7	44
Medic. used to treat high temp. (N=100,296)	20	54
Medically-attended fever	0	7

No statistical analyses for this end point

Secondary: Number of Subjects who Reported Immediate Reactions Within 30 Minutes After Any rMenB+OMV NZ or MenC-CRM Vaccination

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End point title

Number of Subjects who Reported Immediate Reactions Within 30 Minutes After Any rMenB+OMV NZ or MenC-CRM Vaccination ^[18]

End point description

Safety was assessed in terms of number of subjects with solicited local and systemic AEs after any vaccination with rMenB+OMV NZ or MenC-CRM. Analysis was done on solicited safety set.

End point type

Secondary

End point timeframe

Within 30 minutes after any 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	BC_35_12	C_35_12
Number of subjects analysed	126	124
Units: Subjects
Tenderness (rMenB+OMV NZ) (N=126,0)	7	0
Erythema (rMenB+OMV NZ) (N=126,0)	3	0
Induration (rMenB+OMV NZ) (N=126,0)	1	0
Swelling (rMenB+OMV NZ) (N=126,0)	0	0
Tenderness (MenC-CRM)	5	5
Erythema (MenC-CRM)	4	5
Induration (MenC-CRM)	0	0
Swelling (MenC-CRM)	0	0
Change in eating habits	0	0
Sleepiness	0	0
Unusual crying	0	0
Irritability	0	0
Vomiting	1	0
Diarrhea	0	0
Rash	0	0
Fever (≥38°C)	1	0
Medic. used for pain	0	0
Medic. used to prevent high temp.	0	0
Medic. used to treat high temp.	0	0
Medically-attended fever	0	0

No statistical analyses for this end point

Secondary: Number of Subjects with Solicited Local and Systemic AEs in Groups BC_35_12 and C_35_12 after any rMenB+OMV NZ or MenC-CRM Vaccination

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End point title

Number of Subjects with Solicited Local and Systemic AEs in Groups BC_35_12 and C_35_12 after any rMenB+OMV NZ or MenC-CRM Vaccination ^[19]

End point description

Safety was assessed in terms of number of subjects with solicited local and systemic AEs after any vaccination with rMenB+OMV NZ or MenC-CRM. Analysis was done on solicited safety set.

End point type

Secondary

End point timeframe

Day 1 to day 7 after any 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	BC_35_12	C_35_12
Number of subjects analysed	124	117
Units: Subjects
Any local rMenB + OMZ NV	107	0
Any local MenC-CRM	104	79
Any systemic	123	106
Tenderness (rMenB+OMV NZ) (N=123,0)	105	0
Erythema (rMenB+OMV NZ) (N=123,0)	48	0
Induration (rMenB+OMV NZ) (N=123,0)	37	0
Swelling (rMenB+OMV NZ) (N=123,0)	21	0
Tenderness (MenC-CRM) (N=123,117)	104	74
Erythema (MenC-CRM) (N=123,117)	25	24
Induration (MenC-CRM) (N=123,117)	10	26
Swelling (MenC-CRM) (N=123,117)	12	21
Change in eating habits (N=123,117)	67	47
Sleepiness (N=123,117)	93	78
Unusual crying (N=123,117)	105	87
Irritability (N=123,117)	95	66
Vomiting (N=123,117)	29	27
Diarrhea (N=123,117)	41	40
Rash (N=123,117)	8	4
Fever (≥38°C) (N=123,117)	97	45
Medic. used for pain (N=123,117)	102	69
Medic. used to prevent high temp.	49	25
Medic. used to treat high temp.	90	40
Medically-attended fever	7	12

No statistical analyses for this end point

Secondary: Number of Subjects Reporting Unsolicited AEs Following Any Vaccination with rMenB+OMV NZ in Groups B_2h3h5_11, B_3h5_11 and B_68_11

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End point title

Number of Subjects Reporting Unsolicited AEs Following Any Vaccination with rMenB+OMV NZ in Groups B_2h3h5_11, B_3h5_11 and B_68_11

End point description

Safety was assessed in terms of number of subjects reporting any unsolicited AEs (day 1-7 after any vaccination), serious adverse events (SAEs), medically attended AEs, AEs leading to premature withdrawal from the study (collected throughout the study period) following any vaccination with rMenB+OMV. Analysis was done on unsolicited safety set.

End point type

Secondary

End point timeframe

Until 12 months of age; Day 1 to day 7 (All AEs)

End point values	B_2h3h5_11b	B_3h5_11b	B_68_11b
Number of subjects analysed	252	249	250
Units: Subjects
All AEs (days 1-7)	200	186	196
At least possible related AEs	88	41	62
SAEs	15	18	9
At least possibly related SAEs	1	1	1
Medically attended AEs	178	179	182
AEs leading to premature withdrawal	1	1	0
Deaths	0	0	0

No statistical analyses for this end point

Secondary: Number of Subjects Reporting Unsolicited AEs Following Any Vaccination with rMenB+OMV NZ in Groups B_02_2_5 and B_02_6_10

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End point title

Number of Subjects Reporting Unsolicited AEs Following Any Vaccination with rMenB+OMV NZ in Groups B_02_2_5 and B_02_6_10 ^[20]

End point description

End point type

Secondary

End point timeframe

Day 1 to Day 7 (All AEs). Throughout the study period (SAEs, medically attended or leading to premature withdrawal AEs)

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	B_02_2_5	B_02_6_10
Number of subjects analysed	104	300
Units: Subjects
All AEs (days 1-7)	58	101
At least possible related AEs	16	24
SAEs	1	2
At least possibly related SAEs	0	0
Medically attended AEs	42	74
AEs leading to premature withdrawal	0	0
Deaths	0	0

No statistical analyses for this end point

Secondary: Number of Subjects Reporting Unsolicited AEs Following Any Vaccination with rMenB+OMV NZ in Group BC_35_12 and C_35_12

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End point title

Number of Subjects Reporting Unsolicited AEs Following Any Vaccination with rMenB+OMV NZ in Group BC_35_12 and C_35_12 ^[21]

End point description

End point type

Secondary

End point timeframe

Day 1 to Day 301 for BC_35_12 and C_35_12, Day 302 to Day 391 for C_35_12; Day 1 to day 7 (All AEs)

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	BC_35_12	C_35_12
Number of subjects analysed	126	123
Units: Subjects
All AEs (days 1-7)	103	90
At least possibly related AEs	14	12
SAEs	5	7
At least possibly related SAEs	0	0
Medically attended AEs	99	85
AEs leading to premature withdrawal	0	0
Deaths	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to 12 months of age for groups B_2h3h5_11, B_3h5_11 and B_68_11; Day 1 to Day 91 for groups B02_2_5 and B02_6_10; Day 1 to Day 301 for group BC_35_12; Day 1 to Day 391 for group C_35_12

Adverse event reporting additional description

All solicited AEs were collected by systematic assessment and unsolicited AEs were collected by non-systematic assessment.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

18.0

Reporting group title

B_68_11

Reporting group description

Subjects, approximately 6 months of age received 2 dose primary vaccination of rMenB+OMV NZ at 6 and 8 months of age, followed by a booster dose at 11 months of age.

Reporting group title

B_3h5_11

Reporting group description

Subjects, approximately 3.5 months of age received 2 dose primary vaccination of rMenB+OMV NZ at 3.5 and 5 months of age, followed by a booster dose at 11 months of age.

Reporting group title

B_2h3h5_11

Reporting group description

Subjects, approximately 2.5 months of age received 3 dose primary vaccination of rMenB+OMV NZ at 2.5, 3.5, 5 months of age, followed by a booster dose at 11 months of age

Reporting group title

C_35_12

Reporting group description

Subjects, 3 months of age received MenC‐CRM and Synflorix concomitantly at 3, 5 and 12 months of age and an additional dose of Synflorix alone at 7 months of age and rMenB+OMV NZ alone at 13 ad 15 months of age.

Reporting group title

BC_35_12

Reporting group description

Subjects, 3 months of age received rMenB+OMV NZ + MenC-CRM and Synflorix concomitantly at 3, 5 and 12 months of age and an additional dose of Synflorix alone dose at 7 months of age

Reporting group title

B_02_6_10

Reporting group description

Subjects, 6-10 years of age received 2 catch-up doses of rMenB+OMV NZ, each at 0 and 2 months. Blood draw at 0 and 3 months since study start.

Reporting group title

B_02_2_5

Reporting group description

Subjects, 2-5 years of age received 2 catch-up doses of rMenB+OMV NZ, each at 0 and 2 months. Blood draw at 0 and 3 months since study start.

Serious adverse events	B_68_11	B_3h5_11	B_2h3h5_11	C_35_12	BC_35_12	B_02_6_10	B_02_2_5
Total subjects affected by serious adverse events
subjects affected / exposed	9 / 250 (3.60%)	18 / 249 (7.23%)	15 / 252 (5.95%)	8 / 123 (6.50%)	5 / 126 (3.97%)	2 / 300 (0.67%)	1 / 104 (0.96%)
number of deaths (all causes)	0	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0
Injury, poisoning and procedural complications
CONCUSSION
subjects affected / exposed	0 / 250 (0.00%)	0 / 249 (0.00%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	1 / 300 (0.33%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CONTUSION
subjects affected / exposed	0 / 250 (0.00%)	0 / 249 (0.00%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	1 / 300 (0.33%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FALL
subjects affected / exposed	0 / 250 (0.00%)	0 / 249 (0.00%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	1 / 300 (0.33%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SKULL FRACTURE
subjects affected / exposed	0 / 250 (0.00%)	0 / 249 (0.00%)	1 / 252 (0.40%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
CONGENITAL CENTRAL NERVOUS SYSTEM ANOMALY
subjects affected / exposed	0 / 250 (0.00%)	0 / 249 (0.00%)	1 / 252 (0.40%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Nervous system disorders
BENIGN INTRACRANIAL HYPERTENSION
subjects affected / exposed	0 / 250 (0.00%)	0 / 249 (0.00%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	1 / 300 (0.33%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FEBRILE CONVULSION
subjects affected / exposed	0 / 250 (0.00%)	0 / 249 (0.00%)	0 / 252 (0.00%)	1 / 123 (0.81%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GENERALISED TONIC-CLONIC SEIZURE
subjects affected / exposed	0 / 250 (0.00%)	0 / 249 (0.00%)	0 / 252 (0.00%)	1 / 123 (0.81%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	0 / 250 (0.00%)	2 / 249 (0.80%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
LYMPHADENOPATHY
subjects affected / exposed	1 / 250 (0.40%)	0 / 249 (0.00%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
PYREXIA
subjects affected / exposed	1 / 250 (0.40%)	2 / 249 (0.80%)	2 / 252 (0.79%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 2	1 / 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	0 / 0
Eye disorders
GLAUCOMA
subjects affected / exposed	0 / 250 (0.00%)	0 / 249 (0.00%)	0 / 252 (0.00%)	1 / 123 (0.81%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
ALLERGIC COLITIS
subjects affected / exposed	0 / 250 (0.00%)	1 / 249 (0.40%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
DIARRHOEA
subjects affected / exposed	0 / 250 (0.00%)	1 / 249 (0.40%)	1 / 252 (0.40%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
FOOD POISONING
subjects affected / exposed	0 / 250 (0.00%)	0 / 249 (0.00%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	1 / 300 (0.33%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INGUINAL HERNIA
subjects affected / exposed	0 / 250 (0.00%)	0 / 249 (0.00%)	1 / 252 (0.40%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
VOMITING
subjects affected / exposed	0 / 250 (0.00%)	1 / 249 (0.40%)	1 / 252 (0.40%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Respiratory, thoracic and mediastinal disorders
ADENOIDAL HYPERTROPHY
subjects affected / exposed	0 / 250 (0.00%)	0 / 249 (0.00%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	1 / 104 (0.96%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BRONCHOSPASM
subjects affected / exposed	2 / 250 (0.80%)	0 / 249 (0.00%)	0 / 252 (0.00%)	1 / 123 (0.81%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CHOKING
subjects affected / exposed	0 / 250 (0.00%)	1 / 249 (0.40%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
SLEEP APNOEA SYNDROME
subjects affected / exposed	0 / 250 (0.00%)	0 / 249 (0.00%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	1 / 104 (0.96%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
TONSILLAR HYPERTROPHY
subjects affected / exposed	0 / 250 (0.00%)	0 / 249 (0.00%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	1 / 104 (0.96%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
WHEEZING
subjects affected / exposed	0 / 250 (0.00%)	1 / 249 (0.40%)	0 / 252 (0.00%)	0 / 123 (0.00%)	1 / 126 (0.79%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
HYDRONEPHROSIS
subjects affected / exposed	0 / 250 (0.00%)	0 / 249 (0.00%)	1 / 252 (0.40%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
JUVENILE IDIOPATHIC ARTHRITIS
subjects affected / exposed	1 / 250 (0.40%)	0 / 249 (0.00%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MUSCLE SPASMS
subjects affected / exposed	0 / 250 (0.00%)	0 / 249 (0.00%)	1 / 252 (0.40%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
ATYPICAL PNEUMONIA
subjects affected / exposed	0 / 250 (0.00%)	0 / 249 (0.00%)	0 / 252 (0.00%)	0 / 123 (0.00%)	1 / 126 (0.79%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BRONCHIOLITIS
subjects affected / exposed	3 / 250 (1.20%)	2 / 249 (0.80%)	1 / 252 (0.40%)	1 / 123 (0.81%)	2 / 126 (1.59%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 1	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BRONCHITIS
subjects affected / exposed	1 / 250 (0.40%)	2 / 249 (0.80%)	2 / 252 (0.79%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	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	0 / 0
BRONCHOPNEUMONIA
subjects affected / exposed	0 / 250 (0.00%)	1 / 249 (0.40%)	1 / 252 (0.40%)	3 / 123 (2.44%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
EAR INFECTION
subjects affected / exposed	0 / 250 (0.00%)	1 / 249 (0.40%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
GASTROENTERITIS
subjects affected / exposed	2 / 250 (0.80%)	4 / 249 (1.61%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTROENTERITIS ROTAVIRUS
subjects affected / exposed	0 / 250 (0.00%)	0 / 249 (0.00%)	0 / 252 (0.00%)	1 / 123 (0.81%)	1 / 126 (0.79%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
GASTROENTERITIS SALMONELLA
subjects affected / exposed	0 / 250 (0.00%)	1 / 249 (0.40%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
LARYNGITIS
subjects affected / exposed	1 / 250 (0.40%)	0 / 249 (0.00%)	2 / 252 (0.79%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 1	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	0 / 0
LOWER RESPIRATORY TRACT INFECTION
subjects affected / exposed	0 / 250 (0.00%)	1 / 249 (0.40%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
MASTOIDITIS
subjects affected / exposed	0 / 250 (0.00%)	1 / 249 (0.40%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
NASOPHARYNGITIS
subjects affected / exposed	0 / 250 (0.00%)	0 / 249 (0.00%)	0 / 252 (0.00%)	0 / 123 (0.00%)	1 / 126 (0.79%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ORAL CANDIDIASIS
subjects affected / exposed	0 / 250 (0.00%)	1 / 249 (0.40%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
PNEUMONIA
subjects affected / exposed	1 / 250 (0.40%)	2 / 249 (0.80%)	1 / 252 (0.40%)	0 / 123 (0.00%)	2 / 126 (1.59%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PYELONEPHRITIS
subjects affected / exposed	0 / 250 (0.00%)	0 / 249 (0.00%)	1 / 252 (0.40%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RESPIRATORY SYNCYTIAL VIRUS BRONCHIOLITIS
subjects affected / exposed	0 / 250 (0.00%)	0 / 249 (0.00%)	2 / 252 (0.79%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
RESPIRATORY TRACT INFECTION VIRAL
subjects affected / exposed	1 / 250 (0.40%)	0 / 249 (0.00%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SALMONELLOSIS
subjects affected / exposed	0 / 250 (0.00%)	1 / 249 (0.40%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	1 / 250 (0.40%)	0 / 249 (0.00%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
URINARY TRACT INFECTION
subjects affected / exposed	0 / 250 (0.00%)	1 / 249 (0.40%)	1 / 252 (0.40%)	1 / 123 (0.81%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Metabolism and nutrition disorders
COW'S MILK INTOLERANCE
subjects affected / exposed	0 / 250 (0.00%)	1 / 249 (0.40%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
DEHYDRATION
subjects affected / exposed	0 / 250 (0.00%)	3 / 249 (1.20%)	1 / 252 (0.40%)	1 / 123 (0.81%)	0 / 126 (0.00%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	B_68_11	B_3h5_11	B_2h3h5_11	C_35_12	BC_35_12	B_02_6_10	B_02_2_5
Total subjects affected by non serious adverse events
subjects affected / exposed	245 / 250 (98.00%)	240 / 249 (96.39%)	246 / 252 (97.62%)	115 / 123 (93.50%)	124 / 126 (98.41%)	288 / 300 (96.00%)	100 / 104 (96.15%)
Nervous system disorders
HEADACHE
alternative assessment type: Systematic
subjects affected / exposed	0 / 250 (0.00%)	0 / 249 (0.00%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	90 / 300 (30.00%)	7 / 104 (6.73%)
occurrences all number	0	0	0	0	0	124	8
SOMNOLENCE
alternative assessment type: Systematic
subjects affected / exposed	144 / 250 (57.60%)	152 / 249 (61.04%)	186 / 252 (73.81%)	84 / 123 (68.29%)	93 / 126 (73.81%)	0 / 300 (0.00%)	39 / 104 (37.50%)
occurrences all number	256	296	450	233	214	0	51
General disorders and administration site conditions
CHILLS
alternative assessment type: Systematic
subjects affected / exposed	0 / 250 (0.00%)	0 / 249 (0.00%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	47 / 300 (15.67%)	0 / 104 (0.00%)
occurrences all number	0	0	0	0	0	51	0
CRYING
alternative assessment type: Systematic
subjects affected / exposed	157 / 250 (62.80%)	186 / 249 (74.70%)	198 / 252 (78.57%)	93 / 123 (75.61%)	105 / 126 (83.33%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences all number	333	350	554	289	271	0	0
INDURATION
alternative assessment type: Systematic
subjects affected / exposed	27 / 250 (10.80%)	23 / 249 (9.24%)	58 / 252 (23.02%)	1 / 123 (0.81%)	1 / 126 (0.79%)	6 / 300 (2.00%)	7 / 104 (6.73%)
occurrences all number	42	33	101	1	1	6	8
INJECTION SITE ERYTHEMA
alternative assessment type: Systematic
subjects affected / exposed	157 / 250 (62.80%)	160 / 249 (64.26%)	169 / 252 (67.06%)	41 / 123 (33.33%)	62 / 126 (49.21%)	180 / 300 (60.00%)	59 / 104 (56.73%)
occurrences all number	314	312	427	142	197	272	94
INJECTION SITE INDURATION
alternative assessment type: Systematic
subjects affected / exposed	122 / 250 (48.80%)	118 / 249 (47.39%)	162 / 252 (64.29%)	41 / 123 (33.33%)	42 / 126 (33.33%)	124 / 300 (41.33%)	41 / 104 (39.42%)
occurrences all number	227	209	382	107	107	173	63
INJECTION SITE PAIN
alternative assessment type: Systematic
subjects affected / exposed	168 / 250 (67.20%)	175 / 249 (70.28%)	202 / 252 (80.16%)	102 / 123 (82.93%)	114 / 126 (90.48%)	287 / 300 (95.67%)	99 / 104 (95.19%)
occurrences all number	348	340	505	469	685	537	183
INJECTION SITE SWELLING
alternative assessment type: Systematic
subjects affected / exposed	84 / 250 (33.60%)	76 / 249 (30.52%)	120 / 252 (47.62%)	35 / 123 (28.46%)	34 / 126 (26.98%)	146 / 300 (48.67%)	50 / 104 (48.08%)
occurrences all number	137	110	237	96	76	218	73
MALAISE
alternative assessment type: Systematic
subjects affected / exposed	0 / 250 (0.00%)	0 / 249 (0.00%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	117 / 300 (39.00%)	0 / 104 (0.00%)
occurrences all number	0	0	0	0	0	160	0
PYREXIA
alternative assessment type: Systematic
subjects affected / exposed	189 / 250 (75.60%)	192 / 249 (77.11%)	201 / 252 (79.76%)	77 / 123 (62.60%)	99 / 126 (78.57%)	47 / 300 (15.67%)	22 / 104 (21.15%)
occurrences all number	429	403	505	162	195	56	27
SWELLING
alternative assessment type: Systematic
subjects affected / exposed	19 / 250 (7.60%)	6 / 249 (2.41%)	26 / 252 (10.32%)	0 / 123 (0.00%)	0 / 126 (0.00%)	4 / 300 (1.33%)	6 / 104 (5.77%)
occurrences all number	20	6	36	0	0	4	6
Gastrointestinal disorders
DIARRHOEA
alternative assessment type: Systematic
subjects affected / exposed	76 / 250 (30.40%)	74 / 249 (29.72%)	96 / 252 (38.10%)	49 / 123 (39.84%)	41 / 126 (32.54%)	5 / 300 (1.67%)	12 / 104 (11.54%)
occurrences all number	134	108	172	99	61	5	15
NAUSEA
alternative assessment type: Systematic
subjects affected / exposed	0 / 250 (0.00%)	0 / 249 (0.00%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	38 / 300 (12.67%)	0 / 104 (0.00%)
occurrences all number	0	0	0	0	0	44	0
VOMITING
alternative assessment type: Systematic
subjects affected / exposed	58 / 250 (23.20%)	46 / 249 (18.47%)	69 / 252 (27.38%)	31 / 123 (25.20%)	30 / 126 (23.81%)	6 / 300 (2.00%)	8 / 104 (7.69%)
occurrences all number	93	60	110	48	44	6	12
Respiratory, thoracic and mediastinal disorders
BRONCHOSPASM
alternative assessment type: Systematic
subjects affected / exposed	3 / 250 (1.20%)	5 / 249 (2.01%)	3 / 252 (1.19%)	7 / 123 (5.69%)	8 / 126 (6.35%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences all number	5	5	4	13	9	0	0
CATARRH
alternative assessment type: Systematic
subjects affected / exposed	14 / 250 (5.60%)	14 / 249 (5.62%)	8 / 252 (3.17%)	0 / 123 (0.00%)	0 / 126 (0.00%)	2 / 300 (0.67%)	0 / 104 (0.00%)
occurrences all number	19	15	14	0	0	2	0
COUGH
alternative assessment type: Systematic
subjects affected / exposed	13 / 250 (5.20%)	6 / 249 (2.41%)	12 / 252 (4.76%)	1 / 123 (0.81%)	1 / 126 (0.79%)	5 / 300 (1.67%)	3 / 104 (2.88%)
occurrences all number	18	6	15	1	1	5	3
Skin and subcutaneous tissue disorders
ERYTHEMA
alternative assessment type: Systematic
subjects affected / exposed	12 / 250 (4.80%)	8 / 249 (3.21%)	20 / 252 (7.94%)	0 / 123 (0.00%)	2 / 126 (1.59%)	3 / 300 (1.00%)	6 / 104 (5.77%)
occurrences all number	18	11	29	0	2	4	6
RASH
alternative assessment type: Systematic
subjects affected / exposed	32 / 250 (12.80%)	28 / 249 (11.24%)	36 / 252 (14.29%)	6 / 123 (4.88%)	11 / 126 (8.73%)	21 / 300 (7.00%)	9 / 104 (8.65%)
occurrences all number	42	31	51	7	13	23	9
Psychiatric disorders
EATING DISORDER
alternative assessment type: Systematic
subjects affected / exposed	121 / 250 (48.40%)	112 / 249 (44.98%)	141 / 252 (55.95%)	64 / 123 (52.03%)	67 / 126 (53.17%)	0 / 300 (0.00%)	35 / 104 (33.65%)
occurrences all number	242	188	302	145	119	0	50
IRRITABILITY
alternative assessment type: Systematic
subjects affected / exposed	153 / 250 (61.20%)	156 / 249 (62.65%)	181 / 252 (71.83%)	79 / 123 (64.23%)	95 / 126 (75.40%)	1 / 300 (0.33%)	49 / 104 (47.12%)
occurrences all number	317	312	478	231	237	1	75
Musculoskeletal and connective tissue disorders
ARTHRALGIA
alternative assessment type: Systematic
subjects affected / exposed	0 / 250 (0.00%)	0 / 249 (0.00%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	50 / 300 (16.67%)	35 / 104 (33.65%)
occurrences all number	0	0	0	0	0	63	47
MYALGIA
alternative assessment type: Systematic
subjects affected / exposed	0 / 250 (0.00%)	0 / 249 (0.00%)	0 / 252 (0.00%)	0 / 123 (0.00%)	0 / 126 (0.00%)	127 / 300 (42.33%)	0 / 104 (0.00%)
occurrences all number	0	0	0	0	0	169	0
Infections and infestations
BRONCHIOLITIS
alternative assessment type: Systematic
subjects affected / exposed	13 / 250 (5.20%)	26 / 249 (10.44%)	18 / 252 (7.14%)	5 / 123 (4.07%)	6 / 126 (4.76%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences all number	14	29	26	5	6	0	0
BRONCHITIS
alternative assessment type: Systematic
subjects affected / exposed	33 / 250 (13.20%)	36 / 249 (14.46%)	37 / 252 (14.68%)	3 / 123 (2.44%)	0 / 126 (0.00%)	7 / 300 (2.33%)	6 / 104 (5.77%)
occurrences all number	51	53	54	3	0	7	6
BRONCHOPNEUMONIA
alternative assessment type: Systematic
subjects affected / exposed	1 / 250 (0.40%)	2 / 249 (0.80%)	0 / 252 (0.00%)	9 / 123 (7.32%)	6 / 126 (4.76%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences all number	1	2	0	11	8	0	0
CONJUNCTIVITIS
alternative assessment type: Systematic
subjects affected / exposed	17 / 250 (6.80%)	15 / 249 (6.02%)	27 / 252 (10.71%)	3 / 123 (2.44%)	2 / 126 (1.59%)	1 / 300 (0.33%)	0 / 104 (0.00%)
occurrences all number	19	16	30	3	2	1	0
EAR INFECTION
alternative assessment type: Systematic
subjects affected / exposed	16 / 250 (6.40%)	9 / 249 (3.61%)	12 / 252 (4.76%)	5 / 123 (4.07%)	1 / 126 (0.79%)	0 / 300 (0.00%)	3 / 104 (2.88%)
occurrences all number	21	9	13	5	1	0	3
GASTROENTERITIS
alternative assessment type: Systematic
subjects affected / exposed	32 / 250 (12.80%)	23 / 249 (9.24%)	25 / 252 (9.92%)	6 / 123 (4.88%)	5 / 126 (3.97%)	3 / 300 (1.00%)	1 / 104 (0.96%)
occurrences all number	37	25	31	6	6	3	1
INFLUENZA
alternative assessment type: Systematic
subjects affected / exposed	5 / 250 (2.00%)	4 / 249 (1.61%)	7 / 252 (2.78%)	2 / 123 (1.63%)	7 / 126 (5.56%)	3 / 300 (1.00%)	0 / 104 (0.00%)
occurrences all number	6	5	8	2	7	3	0
LARYNGITIS
alternative assessment type: Systematic
subjects affected / exposed	15 / 250 (6.00%)	5 / 249 (2.01%)	12 / 252 (4.76%)	0 / 123 (0.00%)	3 / 126 (2.38%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences all number	17	5	12	0	3	0	0
NASOPHARYNGITIS
alternative assessment type: Systematic
subjects affected / exposed	47 / 250 (18.80%)	31 / 249 (12.45%)	38 / 252 (15.08%)	11 / 123 (8.94%)	14 / 126 (11.11%)	5 / 300 (1.67%)	5 / 104 (4.81%)
occurrences all number	71	55	73	16	17	5	6
OTITIS MEDIA
alternative assessment type: Systematic
subjects affected / exposed	14 / 250 (5.60%)	4 / 249 (1.61%)	7 / 252 (2.78%)	0 / 123 (0.00%)	0 / 126 (0.00%)	2 / 300 (0.67%)	1 / 104 (0.96%)
occurrences all number	17	4	9	0	0	2	1
OTITIS MEDIA ACUTE
alternative assessment type: Systematic
subjects affected / exposed	14 / 250 (5.60%)	8 / 249 (3.21%)	10 / 252 (3.97%)	16 / 123 (13.01%)	12 / 126 (9.52%)	0 / 300 (0.00%)	1 / 104 (0.96%)
occurrences all number	15	10	12	20	15	0	2
PHARYNGITIS
alternative assessment type: Systematic
subjects affected / exposed	14 / 250 (5.60%)	10 / 249 (4.02%)	11 / 252 (4.37%)	10 / 123 (8.13%)	6 / 126 (4.76%)	4 / 300 (1.33%)	2 / 104 (1.92%)
occurrences all number	16	12	12	10	6	4	2
RESPIRATORY TRACT INFECTION
alternative assessment type: Systematic
subjects affected / exposed	28 / 250 (11.20%)	14 / 249 (5.62%)	18 / 252 (7.14%)	3 / 123 (2.44%)	3 / 126 (2.38%)	0 / 300 (0.00%)	0 / 104 (0.00%)
occurrences all number	37	26	30	3	3	0	0
TONSILLITIS
alternative assessment type: Systematic
subjects affected / exposed	7 / 250 (2.80%)	3 / 249 (1.20%)	6 / 252 (2.38%)	12 / 123 (9.76%)	6 / 126 (4.76%)	2 / 300 (0.67%)	1 / 104 (0.96%)
occurrences all number	10	3	7	12	6	2	1
UPPER RESPIRATORY TRACT INFECTION
alternative assessment type: Systematic
subjects affected / exposed	54 / 250 (21.60%)	56 / 249 (22.49%)	49 / 252 (19.44%)	60 / 123 (48.78%)	59 / 126 (46.83%)	6 / 300 (2.00%)	3 / 104 (2.88%)
occurrences all number	79	86	67	110	87	6	4
VIRAL INFECTION
alternative assessment type: Systematic
subjects affected / exposed	14 / 250 (5.60%)	26 / 249 (10.44%)	16 / 252 (6.35%)	10 / 123 (8.13%)	11 / 126 (8.73%)	4 / 300 (1.33%)	4 / 104 (3.85%)
occurrences all number	15	32	21	11	11	6	4

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Were there any global substantial amendments to the protocol? Yes

02 May 2011

Alignment of the protocol with the actual SAE notification and reporting process

20 Feb 2012

New arms to test concomitant MenB + MenC administration

29 Aug 2013

hSBA cut-off adjustement following serological test outsource

26 Nov 2013

Inclusion of an interim analysis on a subset of subjects in Group II - End of trial definition

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 Activity Using Human Serum (hSBA) Titers ≥ 4 or hSBA Titers ≥ 5 (Strain M10713) Following a 2-dose Primary Series of rMenB+OMV Vaccination

Primary: Percentages of Subjects with Serum Bactericidal Activity Using Human Serum (hSBA) Titers ≥ 4 or hSBA Titers ≥ 5 (Strain M10713) Following a 2-dose Primary Series of rMenB+OMV Vaccination

Secondary: Percentages of Subjects with hSBA Titers ≥ 4, hSBA Titers ≥ 5 (Strain M10713) and hSBA ≥ 8 Following a 3-dose Primary Series of rMenB+OMV Vaccination

Secondary: Percentages of Subjects with hSBA Titers ≥ 4, hSBA Titers ≥ 5 (Strain M10713) and hSBA ≥ 8 Following a 3-dose Primary Series of rMenB+OMV Vaccination

Secondary: Percentages of Subjects with hSBA Titers ≥ 4 or hSBA Titers ≥ 5 (Strain M10713) and hSBA ≥ 8 Following a 2-dose Catch-up Series of rMenB+OMV Vaccination

Secondary: Percentages of Subjects with hSBA Titers ≥ 4 or hSBA Titers ≥ 5 (Strain M10713) and hSBA ≥ 8 Following a 2-dose Catch-up Series of rMenB+OMV Vaccination

Secondary: Percentages of Subjects Achieving Four-fold Rise Over Baseline hSBA Titers Following a 2-dose Catch-up Series of rMenB+OMV Vaccination

Secondary: Percentages of Subjects Achieving Four-fold Rise Over Baseline hSBA Titers Following a 2-dose Catch-up Series of rMenB+OMV Vaccination

Secondary: Geometric Mean hSBA Titers (GMTs) Following 2 or 3 Dose Primary Series of Vaccination with rMenB+OMV

Secondary: Geometric Mean hSBA Titers (GMTs) Following 2 or 3 Dose Primary Series of Vaccination with rMenB+OMV

Secondary: Geometric Mean hSBA Titers (GMTs) After First Infant Vaccination with rMenB+OMV

Secondary: Geometric Mean hSBA Titers (GMTs) After First Infant Vaccination with rMenB+OMV

Secondary: Percentages of Subjects with hSBA Titers ≥ 4 or hSBA Titers ≥ 5 and hSBA ≥ 8 After First Infant Vaccination with rMenB+OMV

Secondary: Percentages of Subjects with hSBA Titers ≥ 4 or hSBA Titers ≥ 5 and hSBA ≥ 8 After First Infant Vaccination with rMenB+OMV

Secondary: Percentages of Subjects with hSBA Titers ≥ 4 or hSBA Titers ≥ 5 and hSBA ≥ 8 Following a Booster Dose of rMenB +OMV Vaccination

Secondary: Percentages of Subjects with hSBA Titers ≥ 4 or hSBA Titers ≥ 5 and hSBA ≥ 8 Following a Booster Dose of rMenB +OMV Vaccination

Secondary: Antibody Persistence in Terms of Percentages of Subjects with hSBA Titers ≥ 4 or hSBA Titers ≥ 5 (M10713) and hSBA ≥ 8 Following 2 or 3-dose Primary Series of Vaccination with rMenB+OMV NZ

Secondary: Antibody Persistence in Terms of Percentages of Subjects with hSBA Titers ≥ 4 or hSBA Titers ≥ 5 (M10713) and hSBA ≥ 8 Following 2 or 3-dose Primary Series of Vaccination with rMenB+OMV NZ

Secondary: Antibody Persistence in Terms of Geometric Mean Titers Following 2 or 3-dose Primary Series of Vaccination with rMenB+OMV NZ

Secondary: Antibody Persistence in Terms of Geometric Mean Titers Following 2 or 3-dose Primary Series of Vaccination with rMenB+OMV NZ

Secondary: Geometric Mean ELISA Concentrations Against Vaccine Antigen 287-953 Following 2 or 3-dose Primary Series and Booster Dose of Vaccination with rMenB+OMV NZ

Secondary: Geometric Mean ELISA Concentrations Against Vaccine Antigen 287-953 Following 2 or 3-dose Primary Series and Booster Dose of Vaccination with rMenB+OMV NZ

Secondary: Geometric Mean ELISA Concentrations Against Vaccine Antigen 287-953 After a Two Dose Catch-up rMenB+OMV NZ Immunization Series in Children 2-10 Years of Age

Secondary: Geometric Mean ELISA Concentrations Against Vaccine Antigen 287-953 After a Two Dose Catch-up rMenB+OMV NZ Immunization Series in Children 2-10 Years of Age

Secondary: Percentages of Subjects with hSBA Titers ≥ 8 Against Serogroup C Following Concomitant Administration of rMenB +OMV NZ with MenC-CRM or MenC-CRM Alone

Secondary: Percentages of Subjects with hSBA Titers ≥ 8 Against Serogroup C Following Concomitant Administration of rMenB +OMV NZ with MenC-CRM or MenC-CRM Alone

Secondary: GMTs Following Concomitant Administration of rMenB+OMV NZ with MenC-CRM or MenC-CRM Alone

Secondary: GMTs Following Concomitant Administration of rMenB+OMV NZ with MenC-CRM or MenC-CRM Alone

Secondary: GMTs Following Concomitant Administration of rMenB+OMV NZ with MenC-CRM or MenC-CRM Alone - Persistence

Secondary: GMTs Following Concomitant Administration of rMenB+OMV NZ with MenC-CRM or MenC-CRM Alone - Persistence

Secondary: Percentages of Subjects with hSBA Titers ≥ 4 or hSBA Titers ≥ 5 (M10713) and hSBA ≥ 8 Following Concomitant Administration of rMenB+OMV NZ with MenC-CRM

Secondary: Percentages of Subjects with hSBA Titers ≥ 4 or hSBA Titers ≥ 5 (M10713) and hSBA ≥ 8 Following Concomitant Administration of rMenB+OMV NZ with MenC-CRM

Secondary: GMTs Against N. Meningitidis Serogroup B Strains Following Concomitant Administration of rMenB+OMV NZ with MenC-CRM

Secondary: GMTs Against N. Meningitidis Serogroup B Strains Following Concomitant Administration of rMenB+OMV NZ with MenC-CRM

Secondary: Geometric Mean ELISA Concentrations Against Vaccine Antigen 287-953 Following Concomitant Administration of rMenB+OMV NZ with MenC-CRM

Secondary: Geometric Mean ELISA Concentrations Against Vaccine Antigen 287-953 Following Concomitant Administration of rMenB+OMV NZ with MenC-CRM

Secondary: Geometric Mean ELISA Concentrations Against Vaccine Antigen 287-953 Following Concomitant Administration of rMenB+OMV NZ with MenC-CRM - Persistence

Secondary: Geometric Mean ELISA Concentrations Against Vaccine Antigen 287-953 Following Concomitant Administration of rMenB+OMV NZ with MenC-CRM - Persistence

Secondary: Number of Subjects who Reported Immediate Reactions within 30 Minutes after any Vaccination with rMenB+OMV NZ

Secondary: Number of Subjects who Reported Immediate Reactions within 30 Minutes after any Vaccination with rMenB+OMV NZ

Secondary: Number of Subjects with Solicited Local and Systemic Adverse Events (AEs) Following a 3 or 4-dose Regimen of rMenB+OMV NZ

Secondary: Number of Subjects with Solicited Local and Systemic Adverse Events (AEs) Following a 3 or 4-dose Regimen of rMenB+OMV NZ

Secondary: Number of Subjects who Reported Immediate Reactions within 30 Minutes After Any Vaccination - Groups B_02_2_5 and B_02_6_10

Secondary: Number of Subjects who Reported Immediate Reactions within 30 Minutes After Any Vaccination - Groups B_02_2_5 and B_02_6_10

Secondary: Number of Subjects with Solicited Local and Systemic AEs in Groups B_02_2_5 and B_02_6_10

Secondary: Number of Subjects with Solicited Local and Systemic AEs in Groups B_02_2_5 and B_02_6_10

Secondary: Number of Subjects who Reported Immediate Reactions Within 30 Minutes After Any rMenB+OMV NZ or MenC-CRM Vaccination

Secondary: Number of Subjects who Reported Immediate Reactions Within 30 Minutes After Any rMenB+OMV NZ or MenC-CRM Vaccination

Secondary: Number of Subjects with Solicited Local and Systemic AEs in Groups BC_35_12 and C_35_12 after any rMenB+OMV NZ or MenC-CRM Vaccination

Secondary: Number of Subjects with Solicited Local and Systemic AEs in Groups BC_35_12 and C_35_12 after any rMenB+OMV NZ or MenC-CRM Vaccination

Secondary: Number of Subjects Reporting Unsolicited AEs Following Any Vaccination with rMenB+OMV NZ in Groups B_2h3h5_11, B_3h5_11 and B_68_11

Secondary: Number of Subjects Reporting Unsolicited AEs Following Any Vaccination with rMenB+OMV NZ in Groups B_2h3h5_11, B_3h5_11 and B_68_11

Secondary: Number of Subjects Reporting Unsolicited AEs Following Any Vaccination with rMenB+OMV NZ in Groups B_02_2_5 and B_02_6_10

Secondary: Number of Subjects Reporting Unsolicited AEs Following Any Vaccination with rMenB+OMV NZ in Groups B_02_2_5 and B_02_6_10

Secondary: Number of Subjects Reporting Unsolicited AEs Following Any Vaccination with rMenB+OMV NZ in Group BC_35_12 and C_35_12

Secondary: Number of Subjects Reporting Unsolicited AEs Following Any Vaccination with rMenB+OMV NZ in Group BC_35_12 and C_35_12

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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