Clinical Trial Results:
A Phase 2 Partially Observer-Blind Randomized Controlled Multicenter Dose- Ranging and Formulation-Finding Study of a new Novartis Meningococcal B Recombinant Vaccine evaluating the safety and immunogenicity when given concomitantly with routine vaccines in 2-month-old infants

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

Summary
EudraCT number	2009-010106-11
Trial protocol	CZ IT HU
Global end of trial date	12 Dec 2011

Results information
Results version number	v2(current)
This version publication date	01 Jun 2016
First version publication date	27 Dec 2014
Other versions	v1 (removed from public view)
Version creation reason	Correction of full data set re-QC study because of EudraCT system glitch and updates to the results are required.

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Top of page

Sponsor protocol code

V72P16

ISRCTN number

US NCT number

NCT00937521

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Vaccines and Diagnostics S.r.l.

Sponsor organisation address

Via Fiorentina, 1, Siena, Italy, 53100

Public contact

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

Scientific contact

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

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

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

06 Nov 2012

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

12 Dec 2011

Was the trial ended prematurely?

Main objective of the trial

Immunogenicity: To assess if any of seven different formulations of rMenB+OMV NZ or rMenB (no OMV) vaccine (Groups I-VI and VIII) induce sufficient immune response when given to healthy infants at 2, 3 and 4 months of age, as measured by percentage of subjects with serum bactericidal activity (SBA) titer ≥ 1:5, at 1 month after the third vaccination. Safety: To assess if any of six different formulations of rMenB+OMV NZ or rMenB (no OMV) vaccine (Group II to VI; Group VIII) will reduce the incidence of fever ≥ 38.5 C (rectal) occurring within 3 days (day 1 – 3) following first vaccination as compared to rMenB+OMV NZ (Group I).

Protection of trial subjects

This trial was conducted in accordance with the ethical principles that have their origin in the latest version of Declaration of Helsinki accepted by the local authorities, and that are consistent with Good Clinical Practices (GCPs) and the applicable regulatory requirement(s) for the country in which the trial is conducted, Good Clinical Practice (GCP) according to International Conference on Harmonisation (ICH) guidelines, and applicable Standard Operating Procedures (SOPs). Specifically, this trial was based on adequately performed laboratory and animal experimentation; the trial was conducted based on a protocol reviewed and approved by an EC; the trial was conducted by scientifically and medically qualified persons; the benefits of the study were in proportion to the risks; the rights and welfare of the subjects were respected; the physicians conducting the trial did not find the hazards to outweigh the potential benefits; each subject, or where applicable, each subject's legally acceptable representative(s) gave his or her written informed consent before any protocol-driven tests or evaluations were performed.

Background therapy

Routine infant vaccines, InfanrixHexa® and Prevenar®.

Evidence for comparator

N/A

Actual start date of recruitment

14 Jul 2009

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

6 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Hungary: 69

Country: Number of subjects enrolled

Italy: 448

Country: Number of subjects enrolled

Argentina: 5

Country: Number of subjects enrolled

Chile: 24

Country: Number of subjects enrolled

Czech Republic: 961

Worldwide total number of subjects

1507

EEA total number of subjects

1478

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)

1506

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

Subjects were enrolled from 79 sites in Czech Republic (subjects were enrolled from 71 of these sites and 8 sites had a coordinating role only); 8 sites in Hungary; 6 sites in Italy, 1 site each in Argentina and Chile.

Screening details

24 enrolled subjects were not included in the study.

Period 1 title

Overall Study - Prior to Booster Dose

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

The trial was partially observer-blinded. The inclusion of the control group receiving Menjugate (MenC group) concomitantly with routine vaccination allowed blinding of the subject’s parents/legal guardians, as well as blinding of the investigator and the study staff who evaluated the subjects (observers). However, blinding was not possible for subjects who received prophylactic administration of oral paracetamol (Par+B+OMV).

Are arms mutually exclusive

Yes

B+OMV (Group I)

Arm description

Subjects in this group received one dose of meningococcal B recombinant (rMenB+OMV NZ) adsorbed vaccine (formulation I) and routine vaccines at 2,3,4,12 months of age and MenC-CRM197 at 13 months of age.

Arm type

Experimental

Investigational medicinal product name

4CMenB

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

Prevenar

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

MenC

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

one dose of of 0.5 mL

Investigational medicinal product name

Infanrix Hexa

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

B+½ OMV (Group II)

Arm description

Subjects in this group received one dose of meningococcal B recombinant (rMenB+OMV NZ) adsorbed vaccine (formulation II) and routine vaccine at 2,3,4,12 months of age and MenC-CRM197 at 13 months of age.

Arm type

Experimental

Investigational medicinal product name

rMenB+1/2 OMV

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

Prevenar

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

MenC

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

one dose of of 0.5 mL

Investigational medicinal product name

Infanrix Hexa

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

B+1/4 OMV (Group III)

Arm description

Subjects in this group received one dose of meningococcal B recombinant (rMenB+OMV NZ) adsorbed vaccine (formulation III) and routine vaccine at 2,3,4,12 months of age and MenC-CRM197 at 13 months of age.

Arm type

Experimental

Investigational medicinal product name

rMenB+1/4 OMV

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

Prevenar

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

MenC

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

one dose of of 0.5 mL

Investigational medicinal product name

Infanrix Hexa

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

B (Group IV)

Arm description

Subjects in this group received one dose of meningococcal B recombinant (rMenB) adsorbed vaccine (formulation IV) and routine vaccine at 2,3,4,12 months of age and MenC-CRM197 at 13 months of age.

Arm type

Experimental

Investigational medicinal product name

rMenB

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

Infanrix Hexa

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

Prevenar

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

MenC

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

one dose of of 0.5 mL

½ (B+OMV) (Group V)

Arm description

Subjects in this group received one dose of meningococcal B recombinant (rMenB+OMV NZ) adsorbed vaccine (formulation V) and routine vaccine at 2,3,4,12 months of age and MenC-CRM197 at 13 months of age.

Arm type

Experimental

Investigational medicinal product name

1/2 (rMenB+OMV)

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

Prevenar

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

MenC

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

one dose of of 0.5 mL

Investigational medicinal product name

Infanrix Hexa

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

PH2 B+OMV (Group VI)

Arm description

Subjects in this group received one dose of meningococcal B recombinant (rMenB+OMV NZ) adsorbed vaccine (formulation VI) and routine vaccine at 2,3,4,12 months of age and MenC-CRM197 at 13 months of age.

Arm type

Experimental

Investigational medicinal product name

4CMenB

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

Infanrix Hexa

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

Prevenar

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

MenC

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

one dose of of 0.5 mL

MenC (Group VII)

Arm description

Subjects received one dose of meningococcal C conjugate vaccine (Menjugate®; Men C) and routine vaccine at 2,3,4 months of age, one dose of meningococcal B recombinant (rMenB+OMV NZ) adsorbed vaccine (formulation VII) and routine vaccine at 12 months of age, one dose of rMenB+OMV NZ and one dose of MenC at 13 months of age.

Arm type

Experimental

Investigational medicinal product name

4CMenB

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

two doses of 0.5 mL

Investigational medicinal product name

Infanrix Hexa

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

Prevenar

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

MenC

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

five doses of 0.5 mL each

Par+B+OMV (Group VIII)

Arm description

Subjects in this group received one dose of meningococcal B recombinant (rMenB+OMV NZ) adsorbed vaccine (formulation I) with paracetamol and routine vaccines at 2,3,4,12 months of age and MenC-CRM197 at 13 months of age.

Arm type

Experimental

Investigational medicinal product name

4CMenB

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

MenC

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

one dose of of 0.5 mL

Investigational medicinal product name

Prevenar

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

Infanrix Hexa

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

Paracetamol

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

10-15 mg/Kg

Number of subjects in period 1	B+OMV (Group I)	B+½ OMV (Group II)	B+1/4 OMV (Group III)	B (Group IV)	½ (B+OMV) (Group V)	PH2 B+OMV (Group VI)	MenC (Group VII)	Par+B+OMV (Group VIII)
Started	188	190	192	188	191	188	186	184
Completed	185	185	186	187	188	187	181	183
Not completed	3	5	6	1	3	1	5	1
Adverse Event or Death	-	-	2	-	-	-	1	-
Consent withdrawn by subject	2	1	3	-	1	-	2	1
Lost to follow-up	-	-	1	1	-	-	-	-
Inappropriate Enrollment	-	4	-	-	2	1	1	-
Protocol deviation	1	-	-	-	-	-	1	-

Period 2 title

Booster Phase

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

Are arms mutually exclusive

Yes

B+OMV (Group I)

Arm description

Arm type

Experimental

Investigational medicinal product name

4CMenB

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

Infanrix Hexa

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

Prevenar

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

MenC

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

one dose of of 0.5 mL

B+½ OMV (Group II)

Arm description

Arm type

Experimental

Investigational medicinal product name

rMenB+1/2 OMV

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

Prevenar

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

MenC

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

one dose of of 0.5 mL

Investigational medicinal product name

Infanrix Hexa

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

B+1/4 OMV (Group III)

Arm description

Arm type

Experimental

Investigational medicinal product name

rMenB+1/4 OMV

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

Prevenar

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

MenC

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

one dose of of 0.5 mL

Investigational medicinal product name

Infanrix Hexa

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

B (Group IV)

Arm description

Subjects in this group received one dose of meningococcal B recombinant (rMenB) adsorbed vaccine (formulation IV) and routine vaccine at 2,3,4,12 months of age and MenC-CRM197 at 13 months of age.

Arm type

Experimental

Investigational medicinal product name

rMenB

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

Infanrix Hexa

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

Prevenar

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

MenC

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

one dose of of 0.5 mL

½ (B+OMV) (Group V)

Arm description

Arm type

Experimental

Investigational medicinal product name

1/2 (rMenB+OMV)

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

Prevenar

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

MenC

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

one dose of of 0.5 mL

Investigational medicinal product name

Infanrix Hexa

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

PH2 B+OMV (Group VI)

Arm description

Arm type

Experimental

Investigational medicinal product name

4CMenB

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

MenC

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

one dose of of 0.5 mL

Investigational medicinal product name

Infanrix Hexa

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

Prevenar

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

MenC (Group VII)

Arm description

Subjects received one dose of meningococcal C conjugate vaccine (Menjugate®; Men C) and routine vaccine at 2,3,4 months of age, one dose of meningococcal B recombinant (rMenB+OMV NZ) adsorbed vaccine (formulation VII) and routine vaccine at 12 months of age. One dose of rMenB+OMV NZ and one dose of MenC at 13 months of age.

Arm type

Experimental

Investigational medicinal product name

4CMenB

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

two doses of 0.5 mL

Investigational medicinal product name

Prevenar

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

MenC

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

five doses of 0.5 mL each

Investigational medicinal product name

Infanrix Hexa

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Par+B+OMV (Group VIII)

Arm description

Arm type

Experimental

Investigational medicinal product name

Prevenar

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

Infanrix Hexa

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

4 doses of 0.5 mL

Investigational medicinal product name

MenC

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

one dose of of 0.5 mL

Investigational medicinal product name

Paracetamol

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

10-15 mg/Kg

Investigational medicinal product name

4CMenB

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

four doses of 0.5 mL

Number of subjects in period 2 ^[1]	B+OMV (Group I)	B+½ OMV (Group II)	B+1/4 OMV (Group III)	B (Group IV)	½ (B+OMV) (Group V)	PH2 B+OMV (Group VI)	MenC (Group VII)	Par+B+OMV (Group VIII)
Started	155	163	169	170	168	165	165	161
Completed	152	161	164	167	163	160	160	159
Not completed	3	2	5	3	5	5	5	2
Adverse Event or Death	-	-	-	-	-	-	1	-
Consent withdrawn by subject	1	-	-	1	-	-	-	2
Administrative Reason	-	-	1	-	1	1	-	-
Lost to follow-up	2	2	4	2	4	4	3	-
Protocol deviation	-	-	-	-	-	-	1	-

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: A total of 107 subjects (7% of enrolled subjects) who were enrolled before the second protocol amendment (that allowed participation in booster phase of the study) and were unwilling to participate in the booster phase were considered to have completed the study protocol after primary vaccination phase.

Baseline characteristics

Top of page

Reporting group title

B+OMV (Group I)

Reporting group description

Reporting group title

B+½ OMV (Group II)

Reporting group description

Reporting group title

B+1/4 OMV (Group III)

Reporting group description

Reporting group title

B (Group IV)

Reporting group description

Subjects in this group received one dose of meningococcal B recombinant (rMenB) adsorbed vaccine (formulation IV) and routine vaccine at 2,3,4,12 months of age and MenC-CRM197 at 13 months of age.

Reporting group title

½ (B+OMV) (Group V)

Reporting group description

Reporting group title

PH2 B+OMV (Group VI)

Reporting group description

Reporting group title

MenC (Group VII)

Reporting group description

Reporting group title

Par+B+OMV (Group VIII)

Reporting group description

Reporting group values	B+OMV (Group I)	B+½ OMV (Group II)	B+1/4 OMV (Group III)	B (Group IV)	½ (B+OMV) (Group V)	PH2 B+OMV (Group VI)	MenC (Group VII)	Par+B+OMV (Group VIII)	Total
Number of subjects	188	190	192	188	191	188	186	184	1507
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: days
arithmetic mean (standard deviation)	74 ± 10.6	74.7 ± 9.4	74.4 ± 9.7	75.3 ± 8.8	74.8 ± 9.3	74.6 ± 9	74.9 ± 9.5	74.4 ± 9	-
Gender categorical
Units: Subjects
Female	88	91	82	96	79	93	98	72	699
Male	100	99	110	92	112	95	88	112	808

End points

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Reporting group title

B+OMV (Group I)

Reporting group description

Reporting group title

B+½ OMV (Group II)

Reporting group description

Reporting group title

B+1/4 OMV (Group III)

Reporting group description

Reporting group title

B (Group IV)

Reporting group description

Subjects in this group received one dose of meningococcal B recombinant (rMenB) adsorbed vaccine (formulation IV) and routine vaccine at 2,3,4,12 months of age and MenC-CRM197 at 13 months of age.

Reporting group title

½ (B+OMV) (Group V)

Reporting group description

Reporting group title

PH2 B+OMV (Group VI)

Reporting group description

Reporting group title

MenC (Group VII)

Reporting group description

Reporting group title

Par+B+OMV (Group VIII)

Reporting group description

Reporting group title

B+OMV (Group I)

Reporting group description

Reporting group title

B+½ OMV (Group II)

Reporting group description

Reporting group title

B+1/4 OMV (Group III)

Reporting group description

Reporting group title

B (Group IV)

Reporting group description

Subjects in this group received one dose of meningococcal B recombinant (rMenB) adsorbed vaccine (formulation IV) and routine vaccine at 2,3,4,12 months of age and MenC-CRM197 at 13 months of age.

Reporting group title

½ (B+OMV) (Group V)

Reporting group description

Reporting group title

PH2 B+OMV (Group VI)

Reporting group description

Reporting group title

MenC (Group VII)

Reporting group description

Subjects received one dose of meningococcal C conjugate vaccine (Menjugate®; Men C) and routine vaccine at 2,3,4 months of age, one dose of meningococcal B recombinant (rMenB+OMV NZ) adsorbed vaccine (formulation VII) and routine vaccine at 12 months of age. One dose of rMenB+OMV NZ and one dose of MenC at 13 months of age.

Reporting group title

Par+B+OMV (Group VIII)

Reporting group description

Primary: Percentages of subjects with serum bactericidal activity (hSBA) ≥ 1:5 at 1 month after third vaccination

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End point title

Percentages of subjects with serum bactericidal activity (hSBA) ≥ 1:5 at 1 month after third vaccination ^[1]

End point description

To assess the immunogenicity of seven different formulations of 4CMenB (groups I-VI and VIII) given to healthy infants at 2,3 and 4 months of age as measured by percentages of subjects with serum bactericidal activity (SBA) titer≥1:5 against 44/76-SL, 5/99 and NZ98/254 reference strains, at 1 month after the third vaccination.. The analysis was done on the Per Protocol Primary Population at one month after third injection.

End point type

Primary

End point timeframe

At baseline (pre-vaccination) and 30 days after the third 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.

End point values	B+OMV (Group I)	B+½ OMV (Group II)	B+1/4 OMV (Group III)	B (Group IV)	½ (B+OMV) (Group V)	PH2 B+OMV (Group VI)	MenC (Group VII)	Par+B+OMV (Group VIII)
Number of subjects analysed	171	174	171	174	172	173	171	169
Units: Percentages of Subjects
number (confidence interval 95%)
44/76-SL Bas (N=166,171,168,170,169,168,168,166)	5 (2 to 9)	2 (0 to 5)	4 (1 to 8)	4 (2 to 8)	4 (2 to 8)	4 (2 to 8)	2 (1 to 6)	3 (1 to 7)
44/76-SL > 3rd (N=170,170,166,166,169,167,165,167)	100 (98 to 100)	99 (97 to 100)	99 (97 to 100)	100 (98 to 100)	99 (97 to 100)	99 (96 to 100)	6 (3 to 11)	100 (98 to 100)
5/99 Baseline (N=162,162,161,161,166,166,161,157)	5 (2 to 9)	3 (1 to 7)	6 (3 to 10)	4 (2 to 9)	8 (5 to 14)	4 (2 to 8)	6 (3 to 10)	4 (1 to 8)
5/99 > 3rd (N=165,167,161,166,165,161,159,160)	99 (97 to 100)	100 (98 to 100)	99 (97 to 100)	100 (98 to 100)	100 (98 to 100)	99 (97 to 100)	3 (1 to 7)	99 (97 to 100)
NZ98/254 Basel (N=170,174,171,174,171,173,171,169)	1 (0.015 to 3)	0 (0 to 2)	1 (0.015 to 3)	1 (0.015 to 3)	1 (0 to 4)	1 (0 to 4)	2 (0 to 5)	1 (0.015 to 3)
NZ98/254 > 3rd (171,172,169,168,172,169,168,168)	78 (71 to 84)	67 (59 to 74)	56 (48 to 64)	1 (0.015 to 3)	62 (54 to 69)	81 (74 to 87)	2 (0 to 5)	74 (67 to 81)

No statistical analyses for this end point

Primary: Number of subjects with fever ≥ 38.5 °C (rectal temperature) within 3 days (day 1-3) after first vaccination

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End point title

Number of subjects with fever ≥ 38.5 °C (rectal temperature) within 3 days (day 1-3) after first vaccination ^[2]

End point description

To assess if any of six different formulations of vaccine groups (Group II to Group VI, Group VIII) reduced the incidence of fever >=38.5C (rectal) occurring within three days (day 1-day3) following first vaccination. The analysis was done on the Safety Population.

End point type

Primary

End point timeframe

Day 1 to day 3 after first vaccination.

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

End point values	B+OMV (Group I)	B+½ OMV (Group II)	B+1/4 OMV (Group III)	B (Group IV)	½ (B+OMV) (Group V)	PH2 B+OMV (Group VI)	MenC (Group VII)	Par+B+OMV (Group VIII)
Number of subjects analysed	182	180	186	184	182	180	177	179
Units: Subjects
fever ≥ 38.5 °C (rectal temperature)	94	91	74	24	60	76	21	46

No statistical analyses for this end point

Secondary: Geometric Mean Bactericidal Titers (GMTs), One Month After Third and Booster Vaccination

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End point title

Geometric Mean Bactericidal Titers (GMTs), One Month After Third and Booster Vaccination

End point description

To assess the immune response of seven different formulations of meningococcal multi-component recombinant, adsorbed vaccine (rMenB+OMV NZ or rMenB (no OMV)) in healthy toddlers as measured by SBA geometric mean titers (GMTs) at: 1. One month after third vaccination. 2. One month after booster vaccination. The analysis was done on the Per Protocol Primary and Booster populations.

End point type

Secondary

End point timeframe

At baseline (pre-vaccination), 30 days after the third vaccination, at booster Baseline and at booster vaccination.

End point values	B+OMV (Group I)	B+½ OMV (Group II)	B+1/4 OMV (Group III)	B (Group IV)	½ (B+OMV) (Group V)	PH2 B+OMV (Group VI)	MenC (Group VII)	Par+B+OMV (Group VIII)
Number of subjects analysed	171	174	171	174	172	173	171	169
Units: Titers
geometric mean (confidence interval 95%)
44/76-SL Base (N=166,171,168,170,169,168,168,166)	1.25 (1.14 to 1.37)	1.12 (1.03 to 1.23)	1.2 (1.1 to 1.32)	1.19 (1.08 to 1.3)	1.31 (1.19 to 1.43)	1.2 (1.09 to 1.31)	1.16 (1.09 to 1.25)	1.18 (1.08 to 1.3)
44/76-SL > 3 (N=170,170,166,166,169,167,165,167)	101 (90 to 113)	112 (101 to 126)	113 (101 to 126)	62 (56 to 70)	71 (64 to 80)	102 (92 to 114)	1.24 (1.11 to 1.39)	102 (91 to 115)
44/76-SL – Base Boost (N=69,78,74,78,71,71,74,70)	4.94 (3.76 to 6.5)	5.22 (4.03 to 6.76)	5.72 (4.41 to 7.42)	5.44 (4.19 to 7.06)	3.96 (3.02 to 5.18)	3.76 (2.87 to 4.94)	1.15 (1.03 to 1.29)	4.51 (3.43 to 5.95)
44/76-SL > Boost (N=65,73,70,75,76,71,75,63)	120 (95 to 150)	152 (122 to 189)	118 (95 to 146)	53 (43 to 66)	99 (79 to 122)	105 (84 to 131)	12 (10 to 16)	136 (107 to 172)
5/99 – Base (N=162,162,161,161,166,166,161,157)	1.18 (1.07 to 1.3)	1.09 (0.99 to 1.2)	1.12 (1.02 to 1.23)	1.13 (1.03 to 1.25)	1.3 (1.18 to 1.43)	1.16 (1.05 to 1.27)	1.21 (1.09 to 1.34)	1.07 (0.97 to 1.18)
5/99 > 3 (N=165,167,161,166,165,161,159,160)	396 (348 to 450)	503 (442 to 572)	534 (469 to 608)	389 (342 to 443)	316 (278 to 360)	371 (326 to 422)	1.15 (1.03 to 1.29)	455 (399 to 519)
5/99 Base Boost (N=71,76,80,72,77,78,70,71)	69 (53 to 88)	91 (71 to 116)	111 (87 to 141)	74 (57 to 94)	54 (42 to 68)	64 (50 to 81)	1.11 (0.95 to 1.29)	106 (82 to 136)
5/99 > Boost (N=73,77,79,72,76,74,69,76)	1950 (1573 to 2417)	1819 (1478 to 2238)	2238 (1820 to 2751)	730 (590 to 903)	983 (801 to 1205)	1321 (1074 to 1624)	41 (29 to 57)	2182 (1769 to 2691)
NZ98/254 Base (N=170,174,171,174,171,173,171,169)	1.02 (0.99 to 1.06)	1.02 (0.99 to 1.05)	1.03 (1 to 1.06)	1.04 (1 to 1.07)	1.03 (1 to 1.06)	1.04 (1.01 to 1.08)	1.06 (1 to 1.13)	1.02 (0.99 to 1.05)
NZ98/254 > 3 (N=171,172,169,168,172,169,168,168)	10 (8.59 to 12)	7.81 (6.69 to 9.12)	5.74 (4.92 to 6.71)	1.05 (0.9 to 1.23)	6.66 (5.71 to 7.77)	11 (9.16 to 13)	1.05 (1.01 to 1.1)	8.48 (7.24 to 9.93)
NZ98/254 Bas Bst N=141,155,155,150,150,153,148,143	1.6 (1.43 to 1.8)	1.28 (1.15 to 1.43)	1.23 (1.1 to 1.37)	1.11 (0.99 to 1.24)	1.35 (1.21 to 1.5)	1.41 (1.26 to 1.57)	1.03 (1 to 1.06)	1.48 (1.32 to 1.66)
NZ98/254 >Boost N=138,152,150,149,152,146,147,140	20 (16 to 24)	18 (15 to 22)	11 (9.07 to 13)	1.67 (1.38 to 2.03)	14 (12 to 17)	20 (16 to 24)	2.2 (1.89 to 2.57)	20 (17 to 25)

No statistical analyses for this end point

Secondary: Geometric Mean Bactericidal Titers, One Month After Primary and Booster Vaccination

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End point title

Geometric Mean Bactericidal Titers, One Month After Primary and Booster Vaccination ^[3]

End point description

To compare the antibody response of meningococcal multi-component recombinant, adsorbed vaccine (formulation I vs. formulation VIII) and of routine infant vaccine given with or without prophylatic administration of paracetamol medication in healthy toddlers. The analysis was done on the Per Protocol population.

End point type

Secondary

End point timeframe

At Baseline (pre-vaccination), at 30 days after the third vaccination, at booster Baseline, at 30 days after booster 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+OMV (Group I)	Par+B+OMV (Group VIII)
Number of subjects analysed	171	169
Units: Titers
geometric mean (confidence interval 95%)
44/76-SL Baseline (N=166,166)	1.25 (1.14 to 1.37)	1.18 (1.08 to 1.3)
44/76-SL > 3rd (N=170,167)	101 (90 to 113)	102 (91 to 115)
44/76-SL Baseline Booster (N=69,70)	4.94 (3.76 to 6.5)	4.51 (3.43 to 5.95)
44/76-SL > Booster (N=65,63)	120 (95 to 150)	136 (107 to 172)
5/99 Baseline (N=162,157)	1.18 (1.07 to 1.3)	1.07 (0.97 to 1.18)
5/99 > 3rd (N=165,160)	396 (348 to 450)	455 (399 to 519)
5/99 Baseline Booster (N=71,71)	69 (53 to 88)	106 (82 to 136)
5/99 > Booster (N=73,76)	1950 (1573 to 2417)	2182 (1769 to 2691)
NZ98/254 Baseline (N=170,169)	1.02 (0.99 to 1.06)	1.02 (0.99 to 1.05)
NZ98/254 > 3rd (N=171,168)	10 (8.59 to 12)	8.48 (7.24 to 9.93)
NZ98/254 Baseline Booster (N=141,143)	1.6 (1.43 to 1.8)	1.48 (1.32 to 1.66)
NZ98/254 > Booster (N=138,140)	20 (16 to 24)	20 (17 to 25)

No statistical analyses for this end point

Secondary: Geometric Mean Ratios, One Month After Primary and Booster Vaccination

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End point title

Geometric Mean Ratios, One Month After Primary and Booster Vaccination ^[4]

End point description

To compare the antibody response between meningococcal multi-component recombinant adsorbed vaccine (formulation I) and routine infant vaccine group along with meningococcal multi-component recombinant adsorbed vaccine with prophylactic administration of paracetamol medication as measured by Geometric Mean Ratios (GMRs). The analysis was done on the Per Protocol population.

End point type

Secondary

End point timeframe

After the third and the booster 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+OMV (Group I)	Par+B+OMV (Group VIII)
Number of subjects analysed	162	160
Units: Ratios
geometric mean (confidence interval 95%)
44/76-SL > 3rd (N=157,157)	80 (69 to 93)	84 (72 to 97)
44/76-SL > Booster (N=59,56)	24 (18 to 31)	28 (21 to 36)
5/99 > 3rd (N=152,142)	345 (292 to 408)	417 (350 to 497)
5/99 > Booster (N=68,68)	27 (21 to 35)	20 (16 to 25)
NZ98/254 > 3rd (N=162,160)	9.65 (8.19 to 11)	8.69 (7.36 to 10)
NZ98/254 > Booster (N=129,127)	12 (10 to 15)	14 (11 to 17)

No statistical analyses for this end point

Secondary: Percentages of Subjects With SBA titer ≥1:5, Persistence of Bactericidal Antibodies at 12 Months of Age (Pre-fourth Dose)

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End point title

Percentages of Subjects With SBA titer ≥1:5, Persistence of Bactericidal Antibodies at 12 Months of Age (Pre-fourth Dose)

End point description

To assess the persistence of bactericidal antibodies at 12 months of age after primary vaccination - three doses of one of the seven different formulations of rMenB+OMV NZ or rMenB (no OMV) (Group I-VI and VIII) and rMenB+OMV NZ with paracetamol medication. The analysis was done on the Per Protocol Booster population.

End point type

Secondary

End point timeframe

12 months (pre-fourth vaccination)

End point values	B+OMV (Group I)	B+½ OMV (Group II)	B+1/4 OMV (Group III)	B (Group IV)	½ (B+OMV) (Group V)	PH2 B+OMV (Group VI)	MenC (Group VII)	Par+B+OMV (Group VIII)
Number of subjects analysed	141	155	155	150	150	153	148	143
Units: Percentages of Subjects
number (confidence interval 95%)
44/76-SL Pre-Boost (N=69,78,74,78,71,71,74,70)	55 (43 to 67)	58 (46 to 69)	66 (54 to 77)	63 (51 to 74)	45 (33 to 57)	44 (32 to 56)	4 (1 to 11)	47 (35 to 59)
5/99 Pre-Boost (N=71,76,80,72,77,78,70,71)	97 (90 to 100)	100 (95 to 100)	100 (95 to 100)	97 (90 to 100)	97 (91 to 100)	99 (93 to 100)	1 (0.036 to 8)	100 (95 to 100)
NZ98/254 Pre-B(N=141,155,155,150,150,153,148,143)	12 (7 to 19)	6 (3 to 11)	5 (2 to 10)	3 (1 to 7)	7 (3 to 12)	8 (4 to 13)	0 (0 to 2)	11 (7 to 18)

No statistical analyses for this end point

Secondary: Percentages of Subjects With SBA titer ≥1:5, Persistence of Bactericidal Antibodies at 12 Months of Age (One Month-post Fourth Dose)

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End point title

Percentages of Subjects With SBA titer ≥1:5, Persistence of Bactericidal Antibodies at 12 Months of Age (One Month-post Fourth Dose)

End point description

To assess if any of seven different formulations of rMenB+OMV NZ or rMenB (no OMV) vaccine (groups I-VI and VIII) induced sufficient immune response when given to healthy toddlers at 12 months of age, as measured by percentage of subjects with SBA titer ≥ 1:5, at 1 month after the fourth vaccination. The analysis was done on the Per Protocol Booster population.

End point type

Secondary

End point timeframe

1 month after fourth vaccination.

End point values	B+OMV (Group I)	B+½ OMV (Group II)	B+1/4 OMV (Group III)	B (Group IV)	½ (B+OMV) (Group V)	PH2 B+OMV (Group VI)	MenC (Group VII)	Par+B+OMV (Group VIII)
Number of subjects analysed	138	152	150	149	152	146	147	140
Units: Percentages of Subjects
number (confidence interval 95%)
44/76-SL > Booster (N=65,73,70,75,76,71,75,63)	100 (94 to 100)	100 (95 to 100)	100 (95 to 100)	97 (91 to 100)	100 (95 to 100)	99 (92 to 100)	84 (74 to 91)	100 (94 to 100)
5/99 > (N=73,77,79,72,76,74,69,76)	100 (95 to 100)	100 (95 to 100)	100 (95 to 100)	100 (95 to 100)	100 (95 to 100)	100 (95 to 100)	93 (84 to 98)	100 (95 to 100)
NZ98/254 > (N=138,152,150,149,152,146,147,140)	89 (83 to 94)	89 (83 to 93)	78 (71 to 84)	18 (12 to 25)	83 (76 to 89)	88 (82 to 93)	24 (18 to 32)	90 (84 to 94)

No statistical analyses for this end point

Secondary: Geometric Mean Bactericidal Titers, After Primary and Booster Vaccinations

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End point title

Geometric Mean Bactericidal Titers, After Primary and Booster Vaccinations ^[5]

End point description

To assess the induction of immunological memory of three doses of meningococcal multi-component recombinant, adsorbed vaccine by comparing the serum bactericidal antibodies Geometric Mean Bactericidal Titers (GMTs) response in healthy toddlers administered the fourth dose at 12 months of age to the response in meningococcal B vaccine naive toddlers (Group VII) receiving the first dose of meningococcal multi-component recombinant, adsorbed vaccine at 12 months of age. The analysis was done on the Per Protocol population.

End point type

Secondary

End point timeframe

at 13 months

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+OMV (Group I)	MenC (Group VII)
Number of subjects analysed	138	147
Units: Titers
geometric mean (confidence interval 95%)
44/76-SL > Booster (N=65,75)	120 (95 to 150)	12 (10 to 16)
5/99 > Booster (N=73,69)	1950 (1573 to 2417)	41 (29 to 57)
NZ98/254 > Booster (N=138, 147)	20 (16 to 24)	2.2 (1.89 to 2.57)

No statistical analyses for this end point

Secondary: Percentages of Subjects With SBA titer ≥1:5, First Dose of Meningococcal B Vaccine (One Month After Booster)

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End point title

Percentages of Subjects With SBA titer ≥1:5, First Dose of Meningococcal B Vaccine (One Month After Booster)

End point description

To assess the immune response of first dose of meningococcal mult-component recombinant, adsorbed vaccine given at 12 months of age to toddlers who previously received three doses of MenC-CRM197 vaccine as infants (group VII). The analysis was done on the Per Protocol population.

End point type

Secondary

End point timeframe

1 month after booster.

End point values	MenC (Group VII)
Number of subjects analysed	147
Units: Percentages of Subjects
number (confidence interval 95%)
44/76-SL > Booster (N=75)	84 (74 to 91)
5/99 > Booster (N=69)	93 (84 to 98)
NZ98/254 > Booster (N=147)	24 (18 to 32)

No statistical analyses for this end point

Secondary: Safety and Reactogenicity of Study Vaccines Within 7 Days After Second and Third Vaccination

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End point title

Safety and Reactogenicity of Study Vaccines Within 7 Days After Second and Third Vaccination

End point description

To assess if any of six different formulations of rMenB+OMV NZ or rMenB (no OMV) vaccine (Group II to VI, Group VIII) reduced the incidence of fever ≥ 38.5ºC (rectal) occurring within 3 days (day 1-3) following second and third vaccination and 7 days (day 1-7) following each vaccination as compared to rMenB+OMV NZ (Group I). The analysis was performed on the safety population.

End point type

Secondary

End point timeframe

Day 1 through day 7 after second and third vaccination.

End point values	B+OMV (Group I)	B+½ OMV (Group II)	B+1/4 OMV (Group III)	B (Group IV)	½ (B+OMV) (Group V)	PH2 B+OMV (Group VI)	MenC (Group VII)	Par+B+OMV (Group VIII)
Number of subjects analysed	182	180	186	184	182	180	177	179
Units: Subjects
Second Vaccination (day 1-3)	90	82	76	35	74	89	30	33
3rd vac d 1-3 (N=181,179,185,183,181,180,177,179)	55	50	36	15	40	53	12	20
First Vaccination (day 1-7)	94	91	74	24	60	76	22	46
Second Vaccination (day 1-7)	90	82	77	36	74	90	30	35
3rd vac d 1-7 (N=181,179,185,183,181,180,177,179)	55	53	38	16	42	54	14	20
Booster d 1-7 (N=155,162,169,168,168,165,164,159)	81	86	64	43	78	68	84	58

No statistical analyses for this end point

Secondary: Number of subjects with solicited local reactions within 7 days (day 1-7) after each vaccination

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End point title

Number of subjects with solicited local reactions within 7 days (day 1-7) after each vaccination

End point description

End point type

Secondary

End point timeframe

Day 1 through day 7 after each vaccination.

End point values	B+OMV (Group I)	B+½ OMV (Group II)	B+1/4 OMV (Group III)	B (Group IV)	½ (B+OMV) (Group V)	PH2 B+OMV (Group VI)	MenC (Group VII)	Par+B+OMV (Group VIII)
Number of subjects analysed	182	180	186	184	182	180	177	179
Units: Subjects
Any Local (First Vacc)	163	155	153	123	141	157	127	137
Injection Site Tenderness (First Vacc)	114	116	111	54	97	121	48	79
Injection Site Erythema (First Vacc)	108	99	94	53	77	106	45	73
Injection Site Induration (First Vacc)	101	98	85	48	86	84	25	82
Injection Site Swelling (First Vacc)	58	49	55	24	48	60	15	41
Any Local (Second Vacc)	156	156	155	126	132	156	118	140
Injection Site Tenderness (Second Vacc)	121	116	97	48	88	116	47	85
Injection Site Erythema (Second Vacc)	104	114	114	71	90	104	44	94
Injection Site Induration (Second Vacc)	103	105	97	63	83	94	38	79
Injection Site Swelling (Second Vacc)	64	61	54	34	50	58	21	52
Any Local (3rd N=181,179,185,183,181,180,177,179)	151	147	141	122	130	152	113	128
Injection Site Tenderness (Third Vacc)	102	98	78	47	77	111	42	66
Injection Site Erythema (Third Vacc)	110	106	112	72	94	101	63	91
Injection Site Induration (Third Vacc)	97	92	92	62	79	89	55	80
Injection Site Swelling (Third Vacc)	56	56	46	35	45	58	29	47
Any Local Boost N=155,162,169,168,168,165,162,159	131	132	149	113	127	130	133	121
Injection Site Tenderness (Booster Vacc)	116	107	120	77	106	112	108	92
Injection Site Erythema (Booster Vacc)	90	101	116	67	80	85	93	81
Injection Site Induration (Booster Vacc)	73	83	95	56	66	73	62	60
Injection Site Swelling (Booster Vacc)	55	59	69	31	47	52	39	47

No statistical analyses for this end point

Secondary: Number of subjects with solicited systemic reactions within 7 days (day 1-7) after each vaccination

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End point title

Number of subjects with solicited systemic reactions within 7 days (day 1-7) after each vaccination

End point description

End point type

Secondary

End point timeframe

Day 1 through day 7 after each vaccination.

End point values	B+OMV (Group I)	B+½ OMV (Group II)	B+1/4 OMV (Group III)	B (Group IV)	½ (B+OMV) (Group V)	PH2 B+OMV (Group VI)	MenC (Group VII)	Par+B+OMV (Group VIII)
Number of subjects analysed	182	180	186	184	182	180	177	179
Units: Subjects
Any Systemic (First Vacc)	167	173	175	152	162	171	136	150
Change Eat. Habits (First Vacc)	76	87	84	52	84	90	41	66
Sleepiness (First Vacc)	120	131	119	96	117	119	92	116
Vomiting (First Vacc)	24	18	25	15	22	26	17	22
Diarrhea (First Vacc)	57	55	54	31	41	49	45	41
Irritability (First Vacc)	128	124	128	99	131	131	79	97
Unus Crying (First Vacc)	95	101	105	61	96	108	63	74
Rash (First Vacc)	6	5	5	7	10	10	4	5
Fever ( ≥ 38.5°C ) (First Vacc)	94	91	74	24	60	76	22	46
Antipyr. Med. Used (First Vacc)	102	94	92	37	74	95	32	166
Any Systemic (Second Vacc)	168	158	166	144	156	158	126	147
Change Eat. Habits (Second Vacc)	62	55	58	53	60	80	33	54
Sleepiness (Second Vacc)	105	100	102	85	92	109	75	84
Vomiting (Second Vacc)	18	18	14	15	17	20	14	20
Diarrhea (Second Vacc)	43	41	47	40	39	47	39	40
Irritability (Second Vacc)	130	121	124	94	117	126	82	99
Unus Crying (Second Vacc)	90	90	84	70	83	99	45	71
Rash (Second Vacc)	4	9	4	5	7	4	5	5
Fever ( ≥ 38.5°C ) (Second Vacc)	90	82	77	36	74	90	30	35
Antipyr. Med. Used (Second Vacc)	100	94	83	40	79	105	39	163
Any Syst (3rd N=181,179,185,182,181,180,177,179)	146	131	132	122	141	151	106	127
Change Eat. Habits (Third Vacc)	49	50	42	37	45	60	22	48
Sleepiness (Third Vacc)	75	67	82	64	77	79	52	75
Vomiting (Third Vacc)	8	18	15	12	12	13	11	20
Diarrhea (Third Vacc)	33	29	39	31	34	40	19	32
Irritability (Third Vacc)	115	97	93	74	104	115	76	84
Unus Crying (Third Vacc)	76	82	62	47	69	100	38	47
Rash (Third Vacc)	1	6	4	2	8	10	6	6
Fever ( ≥ 38.5°C ) (Third Vacc)	55	53	38	16	42	54	14	20
Antipyr. Med. Used (Third Vacc)	66	60	51	26	49	63	20	153
Any Syst(Boos N=155,162,169,169,168,165,164,159)	143	144	139	118	141	142	142	137
Change Eat. Habits (Booster Vacc)	74	77	79	52	70	80	59	66
Sleepiness (Booster Vacc)	76	90	90	63	86	88	85	80
Vomiting (Booster Vacc)	6	11	7	7	10	9	9	20
Diarrhea (Booster Vacc)	30	34	36	43	32	30	26	30
Irritability (Booster Vacc)	116	111	112	86	116	115	117	96
Unus Crying (Booster Vacc)	74	64	69	46	71	82	73	50
Rash (Booster Vacc)	5	5	8	2	8	4	6	5
Fever ( ≥ 38.5°C ) (Booster Vacc)	81	86	64	43	78	68	84	58
Antipyr. Med. Used (Booster Vacc)	84	82	83	42	75	80	92	128

No statistical analyses for this end point

Secondary: Number of subjects with unsolicited Adverse Events within 7 days (day 1-7) after each vaccination

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End point title

Number of subjects with unsolicited Adverse Events within 7 days (day 1-7) after each vaccination

End point description

To assess the safety and tolerability of each of seven different formulations of rMenB+OMV NZ or rMenB (no OMV) vaccine (group I to VI, group VIII) in terms of number of subjects reporting unsolicited Adverse Events (AEs), serious adverse events (SAEs), medically attended AEs, AEs leading to premature withdrawal (throughout the study period) within 7 days (day 1-7) after each vaccination. The analysis was performed on the safety population.

End point type

Secondary

End point timeframe

Day 1 through day 7 after each vaccination.

End point values	B+OMV (Group I)	B+½ OMV (Group II)	B+1/4 OMV (Group III)	B (Group IV)	½ (B+OMV) (Group V)	PH2 B+OMV (Group VI)	MenC (Group VII)	Par+B+OMV (Group VIII)
Number of subjects analysed	184	184	189	187	187	185	184	183
Units: Subjects
Any AE (Day 1 to 7) (First Vacc)	55	52	51	33	35	39	27	42
At least Possibly related AE (First Vacc)	48	48	43	30	27	34	22	36
Any SAE (First Vacc)	0	1	0	0	0	1	0	1
Any AE D1-7 2nd N=182,181,186,184,183,180,178,180	55	53	50	41	36	47	28	45
At least Possibly related AE (Second Vacc)	49	45	45	36	33	41	26	39
Any SAE (Second Vacc)	1	0	1	0	1	0	0	0
Any AE D1-7 3rd N=182,181,186,184,182,180,177,179	40	59	49	35	31	45	35	39
At least Possibly related AE (Third Vacc)	34	52	45	29	23	37	29	36
Any SAE (Third Vacc)	2	0	2	0	1	0	0	0
Any AE D 1-7Boos N=155,163,169,169,168,165,165,161	35	46	56	35	29	30	37	30
At least Possibly related AE (Booster Vacc)	28	41	48	23	23	26	30	25
Any SAE (Booster Vacc)	0	1	2	0	3	0	0	0

No statistical analyses for this end point

Secondary: Number of subjects with Severe Adverse Events and Adverse Events necessitating a medical office or Emergency Room (ER) visit and/or resulting in premature withdrawal of the subject from the study, throughout the study period

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End point title

Number of subjects with Severe Adverse Events and Adverse Events necessitating a medical office or Emergency Room (ER) visit and/or resulting in premature withdrawal of the subject from the study, throughout the study period

End point description

To assess the safety and tolerability of each of seven different formulations of rMenB+OMV NZ or rMenB (no OMV) vaccine (group I to VI, group VIII) in terms of number of subjects reporting Severe Adverse Events (SAEs) and Adverse Events (AEs) necessitating a medical office or Emergency Room (ER) visit and/or resulting in premature withdrawal of the subject from the study, throughout the study period. The analysis was performed on the safety population.

End point type

Secondary

End point timeframe

Overall study period.

End point values	B+OMV (Group I)	B+½ OMV (Group II)	B+1/4 OMV (Group III)	B (Group IV)	½ (B+OMV) (Group V)	PH2 B+OMV (Group VI)	MenC (Group VII)	Par+B+OMV (Group VIII)
Number of subjects analysed	184	184	189	187	187	185	184	183
Units: Subjects
AE Leading to Premature Withdrawal - Primary Vacc	0	2	2	0	0	1	2	1
Treatment Emergent SAEs - Primary Vacc	16	20	12	20	13	16	11	15
Tr E SAE Boost (N=155,163,169,169,168,165,165,161)	14	7	12	5	15	9	9	16

No statistical analyses for this end point

Secondary: Number of subjects with local and systemic reactions within 7 days (day 1-7) after second rMenB+OMV NX vaccination in MenC group

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End point title

Number of subjects with local and systemic reactions within 7 days (day 1-7) after second rMenB+OMV NX vaccination in MenC group ^[6]

End point description

To assess the safety and tolerability of two doses of rMenB+OMV NZ vaccine (Group VII) given at 12 and 13 months of age to toddlers who previously received three doses of Menjugate as infants. The analysis was performed on the safety population.

End point type

Secondary

End point timeframe

Day 1 through day 7 at 13 months age.

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: All safety analyses were run in the safety population.

End point values	MenC (Group VII)
Number of subjects analysed	156
Units: Subjects
Injection Site Tenderness	92
Injection Site Erythema	84
Injection Site Induration	59
Injection Site Swelling	35
Change Eat. Habits (N=155)	43
Sleepiness	57
Vomiting	8
Diarrhea	18
Irritability	75
Unus Crying	37
Rash	4
Fever ( ≥ 38.5°C ) (N=158)	35
Antipyr. Med. Used (N=157)	47

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

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

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

14.1

Reporting group title

B+OMV (Group I)

Reporting group description

Subjects in this group received one dose of meningococcal B recombinant (rMenB) adsorbed vaccine (formulation I) and routine vaccines at 2,3,4,12 months of age and MenC-CRM197 at 13 months of age. Group defined to be applicable Prior to Booster Phase for AEs reporting.

Reporting group title

B+½ OMV (Group II)

Reporting group description

Subjects in this group received one dose of meningococcal B recombinant (rMenB) adsorbed vaccine (formulation II) and routine vaccine at 2,3,4,12 months of age and MenC-CRM197 at 13 months of age. Group defined to be applicable Prior to Booster Phase for AEs reporting.

Reporting group title

B+1/4 OMV (Group III)

Reporting group description

Subjects in this group received one dose of meningococcal B recombinant (rMenB) adsorbed vaccine (formulation III) and routine vaccine at 2,3,4,12 months of age and MenC-CRM197 at 13 months of age. Group defined to be applicable Prior to Booster Phase for AEs reporting.

Reporting group title

B (Group IV)

Reporting group description

Subjects in this group received one dose of meningococcal B recombinant (rMenB) adsorbed vaccine (formulation IV) and routine vaccine at 2,3,4,12 months of age and MenC-CRM197 at 13 months of age. Group defined to be applicable Prior to Booster Phase for AEs reporting.

Reporting group title

½ (B+OMV) (Group V)

Reporting group description

Subjects in this group received one dose of meningococcal B recombinant (rMenB) adsorbed vaccine (formulation V) and routine vaccine at 2,3,4,12 months of age and MenC-CRM197 at 13 months of age. Group defined to be applicable Prior to Booster Phase for AEs reporting.

Reporting group title

PH2 B+OMV (Group VI)

Reporting group description

Subjects in this group received one dose of meningococcal B recombinant (rMenB) adsorbed vaccine (formulation VI) and routine vaccine at 2,3,4,12 months of age and MenC-CRM197 at 13 months of age. Group defined to be applicable Prior to Booster Phase for AEs reporting.

Reporting group title

MenC (Group VII)

Reporting group description

Subjects received one dose of meningococcal C conjugate vaccine (Menjugate®; Men C) and routine vaccine at 2,3,4 months of age and one dose of meningococcal B recombinant (rMenB) adsorbed vaccine (formulation VII) and routine vaccine at 12 months of age. One dose of MenC at 13 months of age. Group defined to be applicable Prior to Booster Phase for AEs reporting.

Reporting group title

183Par+B+OMV (Group VIII)

Reporting group description

Subjects in this group received one dose of meningococcal B recombinant (rMenB) adsorbed vaccine (formulation I) with paracetamol and routine vaccines at 2,3,4,12 months of age and MenC-CRM197 at 13 months of age. Group defined to be applicable Prior to Booster Phase for AEs reporting.

Reporting group title

B+OMV (Group I) Booster Phase

Reporting group description

Reporting group title

B+½ OMV (Group II) Booster Phase

Reporting group description

Reporting group title

B+1/4 OMV (Group III) Booster Phase

Reporting group description

Reporting group title

B (Group IV) Booster Phase

Reporting group description

Reporting group title

½ (B+OMV) (Group V) Booster Phase

Reporting group description

Reporting group title

PH2 B+OMV (Group VI) Booster Phase

Reporting group description

Reporting group title

MenC (Group VII) Booster Phase

Reporting group description

Reporting group title

Par+B+OMV (Group VIII) Booster Phase

Reporting group description

B+OMV (Group I)

B+½ OMV (Group II)

B+1/4 OMV (Group III)

B (Group IV)

½ (B+OMV) (Group V)

PH2 B+OMV (Group VI)

MenC (Group VII)

183Par+B+OMV (Group VIII)

B+OMV (Group I) Booster Phase

B+½ OMV (Group II) Booster Phase

B+1/4 OMV (Group III) Booster Phase

B (Group IV) Booster Phase

½ (B+OMV) (Group V) Booster Phase

PH2 B+OMV (Group VI) Booster Phase

MenC (Group VII) Booster Phase

Par+B+OMV (Group VIII) Booster Phase

Total subjects affected by serious adverse events

subjects affected / exposed

16 / 184 (8.70%)

20 / 184 (10.87%)

12 / 189 (6.35%)

20 / 187 (10.70%)

13 / 187 (6.95%)

16 / 185 (8.65%)

11 / 184 (5.98%)

15 / 183 (8.20%)

14 / 155 (9.03%)

7 / 163 (4.29%)

12 / 169 (7.10%)

5 / 169 (2.96%)

15 / 168 (8.93%)

9 / 165 (5.45%)

14 / 161 (8.70%)

number of deaths (all causes)

number of deaths resulting from adverse events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Fibroma

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

1 / 184 (0.54%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Neoplasm

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

1 / 161 (0.62%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Surgical and medical procedures

Cleft palate repair

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

1 / 155 (0.65%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

General disorders and administration site conditions

Pyrexia

subjects affected / exposed

1 / 184 (0.54%)

0 / 184 (0.00%)

0 / 189 (0.00%)

1 / 187 (0.53%)

0 / 187 (0.00%)

1 / 185 (0.54%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Injection site erythema

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

1 / 169 (0.59%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Immune system disorders

Milk allergy

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

1 / 155 (0.65%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory, thoracic and mediastinal disorders

Asthma

subjects affected / exposed

1 / 184 (0.54%)

0 / 184 (0.00%)

1 / 189 (0.53%)

1 / 187 (0.53%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

1 / 163 (0.61%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 2

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Dyspnoea

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

1 / 187 (0.53%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory distress

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

1 / 187 (0.53%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Adenoidal hypertrophy

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

1 / 163 (0.61%)

0 / 169 (0.00%)

1 / 168 (0.60%)

0 / 165 (0.00%)

1 / 165 (0.61%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Psychiatric disorders

Affective disorder

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

1 / 165 (0.61%)

0 / 165 (0.00%)

1 / 161 (0.62%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Investigations

Acoustic Stimulation Tests

alternative dictionary used: MedDRA 17.1

subjects affected / exposed

1 / 184 (0.54%)

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Injury, poisoning and procedural complications

Bone fissure

subjects affected / exposed

0 / 184 (0.00%)

1 / 184 (0.54%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Concussion

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

1 / 187 (0.53%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

1 / 183 (0.55%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Fall

subjects affected / exposed

0 / 184 (0.00%)

1 / 184 (0.54%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

2 / 183 (1.09%)

0 / 155 (0.00%)

0 / 163 (0.00%)

2 / 169 (1.18%)

0 / 168 (0.00%)

1 / 165 (0.61%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Foreign body aspiration

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

1 / 185 (0.54%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Foreign body

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

1 / 168 (0.60%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Head injury

subjects affected / exposed

1 / 184 (0.54%)

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

1 / 187 (0.53%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

1 / 169 (0.59%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Joint dislocation

subjects affected / exposed

0 / 184 (0.00%)

1 / 184 (0.54%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Road traffic accident

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

1 / 183 (0.55%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Thermal burn

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

1 / 155 (0.65%)

0 / 163 (0.00%)

1 / 169 (0.59%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

1 / 165 (0.61%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Toxicity to various agents

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

1 / 169 (0.59%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Accidental exposure to product

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

1 / 155 (0.65%)

0 / 163 (0.00%)

1 / 169 (0.59%)

0 / 169 (0.00%)

1 / 168 (0.60%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Congenital, familial and genetic disorders

Congenital megacolon

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

1 / 187 (0.53%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cryptorchism

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

1 / 168 (0.60%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Phimosis

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

1 / 161 (0.62%)

occurrences causally related to treatment / all

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

Cardiac disorders

Pulmonary valve stenosis

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

1 / 185 (0.54%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nervous system disorders

Febrile convulsion

subjects affected / exposed

1 / 184 (0.54%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

1 / 155 (0.65%)

1 / 163 (0.61%)

0 / 169 (0.00%)

1 / 169 (0.59%)

0 / 168 (0.00%)

1 / 165 (0.61%)

3 / 161 (1.86%)

occurrences causally related to treatment / all

0 / 1

0 / 2

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 3

deaths causally related to treatment / all

0 / 0

Guillain-Barre syndrome

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

1 / 184 (0.54%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypotonia

subjects affected / exposed

0 / 184 (0.00%)

1 / 184 (0.54%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

1 / 183 (0.55%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Myoclonic epilepsy

subjects affected / exposed

1 / 184 (0.54%)

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Partial seizures

subjects affected / exposed

0 / 184 (0.00%)

1 / 184 (0.54%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

VIth nerve paralysis

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

1 / 187 (0.53%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Somnolence

subjects affected / exposed

0 / 184 (0.00%)

1 / 184 (0.54%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Convulsion

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

1 / 168 (0.60%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood and lymphatic system disorders

Neutropenia

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

1 / 187 (0.53%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Anaemia

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

1 / 165 (0.61%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Lymphadenitis

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

1 / 168 (0.60%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

Aphthous stomatitis

subjects affected / exposed

0 / 184 (0.00%)

1 / 184 (0.54%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Enteritis

subjects affected / exposed

0 / 184 (0.00%)

1 / 189 (0.53%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Enterocolitis haemorrhagic

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

1 / 183 (0.55%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastritis

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

1 / 185 (0.54%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastrooesophageal reflux disease

subjects affected / exposed

0 / 184 (0.00%)

1 / 189 (0.53%)

0 / 187 (0.00%)

1 / 185 (0.54%)

0 / 184 (0.00%)

1 / 183 (0.55%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Inguinal hernia

subjects affected / exposed

1 / 184 (0.54%)

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

1 / 155 (0.65%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

1 / 165 (0.61%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vomiting

subjects affected / exposed

0 / 184 (0.00%)

1 / 184 (0.54%)

1 / 189 (0.53%)

0 / 187 (0.00%)

1 / 187 (0.53%)

1 / 185 (0.54%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Diarrhoea

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

1 / 168 (0.60%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Intussusception

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

1 / 168 (0.60%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Skin and subcutaneous tissue disorders

Angioedema

subjects affected / exposed

0 / 184 (0.00%)

1 / 184 (0.54%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Psoriasis

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

1 / 184 (0.54%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Rash

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

1 / 184 (0.54%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Infections and infestations

Acarodermatitis

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

1 / 185 (0.54%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Bacterial pyelonephritis

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

1 / 187 (0.53%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Bronchiolitis

subjects affected / exposed

1 / 184 (0.54%)

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

1 / 187 (0.53%)

1 / 185 (0.54%)

0 / 184 (0.00%)

0 / 183 (0.00%)

1 / 155 (0.65%)

0 / 163 (0.00%)

0 / 169 (0.00%)

1 / 168 (0.60%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 2

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Bronchitis

subjects affected / exposed

3 / 184 (1.63%)

2 / 184 (1.09%)

4 / 189 (2.12%)

4 / 187 (2.14%)

1 / 187 (0.53%)

2 / 185 (1.08%)

2 / 184 (1.09%)

1 / 183 (0.55%)

1 / 155 (0.65%)

1 / 163 (0.61%)

2 / 169 (1.18%)

0 / 169 (0.00%)

4 / 168 (2.38%)

1 / 165 (0.61%)

3 / 165 (1.82%)

2 / 161 (1.24%)

occurrences causally related to treatment / all

0 / 3

0 / 2

0 / 6

0 / 4

0 / 1

0 / 2

0 / 1

0 / 2

0 / 0

0 / 4

0 / 1

0 / 3

0 / 2

deaths causally related to treatment / all

0 / 0

Bronchopneumonia

subjects affected / exposed

1 / 184 (0.54%)

0 / 184 (0.00%)

0 / 189 (0.00%)

1 / 187 (0.53%)

0 / 187 (0.00%)

0 / 185 (0.00%)

1 / 184 (0.54%)

2 / 183 (1.09%)

1 / 155 (0.65%)

0 / 163 (0.00%)

0 / 169 (0.00%)

1 / 168 (0.60%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 2

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Corona virus infection

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

1 / 183 (0.55%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cytomegalovirus infection

subjects affected / exposed

0 / 184 (0.00%)

1 / 184 (0.54%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Exanthema subitum

subjects affected / exposed

0 / 184 (0.00%)

2 / 189 (1.06%)

0 / 187 (0.00%)

1 / 187 (0.53%)

1 / 185 (0.54%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

1 / 161 (0.62%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Gastroenteritis

subjects affected / exposed

1 / 184 (0.54%)

2 / 184 (1.09%)

1 / 189 (0.53%)

3 / 187 (1.60%)

1 / 187 (0.53%)

3 / 185 (1.62%)

1 / 184 (0.54%)

1 / 183 (0.55%)

2 / 155 (1.29%)

2 / 163 (1.23%)

1 / 169 (0.59%)

1 / 168 (0.60%)

5 / 165 (3.03%)

0 / 165 (0.00%)

3 / 161 (1.86%)

occurrences causally related to treatment / all

0 / 1

0 / 2

0 / 1

0 / 3

0 / 1

0 / 3

0 / 1

0 / 2

0 / 1

0 / 2

0 / 5

0 / 0

0 / 3

deaths causally related to treatment / all

0 / 0

Gastroenteritis rotavirus

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

1 / 187 (0.53%)

1 / 185 (0.54%)

0 / 184 (0.00%)

1 / 183 (0.55%)

0 / 155 (0.00%)

1 / 163 (0.61%)

2 / 169 (1.18%)

0 / 169 (0.00%)

1 / 168 (0.60%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 2

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastroenteritis viral

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

1 / 187 (0.53%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Infection

subjects affected / exposed

0 / 184 (0.00%)

1 / 184 (0.54%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Laryngitis

subjects affected / exposed

0 / 184 (0.00%)

1 / 189 (0.53%)

1 / 187 (0.53%)

0 / 187 (0.00%)

3 / 185 (1.62%)

0 / 184 (0.00%)

0 / 183 (0.00%)

1 / 155 (0.65%)

0 / 163 (0.00%)

1 / 169 (0.59%)

3 / 169 (1.78%)

2 / 168 (1.19%)

0 / 165 (0.00%)

2 / 165 (1.21%)

1 / 161 (0.62%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 3

0 / 0

0 / 1

0 / 0

0 / 1

0 / 3

0 / 0

0 / 2

0 / 1

deaths causally related to treatment / all

0 / 0

Nasopharyngitis

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

1 / 183 (0.55%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

1 / 165 (0.61%)

0 / 165 (0.00%)

1 / 161 (0.62%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Oral candidiasis

subjects affected / exposed

0 / 184 (0.00%)

1 / 184 (0.54%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

1 / 184 (0.54%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Oral herpes

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

1 / 184 (0.54%)

0 / 183 (0.00%)

1 / 155 (0.65%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Otitis media acute

subjects affected / exposed

0 / 184 (0.00%)

3 / 184 (1.63%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

1 / 184 (0.54%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pharyngitis

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

1 / 185 (0.54%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

1 / 161 (0.62%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Pneumonia

subjects affected / exposed

0 / 184 (0.00%)

1 / 184 (0.54%)

0 / 189 (0.00%)

0 / 187 (0.00%)

1 / 185 (0.54%)

1 / 184 (0.54%)

1 / 183 (0.55%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonia respiratory syncytial viral

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

1 / 187 (0.53%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonia viral

subjects affected / exposed

1 / 184 (0.54%)

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pyelonephritis

subjects affected / exposed

0 / 184 (0.00%)

1 / 184 (0.54%)

1 / 189 (0.53%)

1 / 187 (0.53%)

0 / 187 (0.00%)

0 / 185 (0.00%)

2 / 184 (1.09%)

1 / 183 (0.55%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 1

0 / 0

0 / 2

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pyelonephritis acute

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

2 / 187 (1.07%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory syncytial virus infection

subjects affected / exposed

0 / 184 (0.00%)

1 / 189 (0.53%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

1 / 183 (0.55%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Rhinitis

subjects affected / exposed

1 / 184 (0.54%)

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Rhinovirus infection

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

1 / 183 (0.55%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Sepsis

subjects affected / exposed

0 / 184 (0.00%)

1 / 189 (0.53%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Upper respiratory tract infection

subjects affected / exposed

0 / 184 (0.00%)

1 / 184 (0.54%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

1 / 184 (0.54%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tonsillitis

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

1 / 187 (0.53%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

1 / 161 (0.62%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Urinary tract infection

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

1 / 187 (0.53%)

1 / 185 (0.54%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Varicella

subjects affected / exposed

1 / 184 (0.54%)

0 / 184 (0.00%)

1 / 189 (0.53%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Viral infection

subjects affected / exposed

0 / 184 (0.00%)

1 / 184 (0.54%)

0 / 189 (0.00%)

2 / 187 (1.07%)

1 / 187 (0.53%)

0 / 185 (0.00%)

0 / 184 (0.00%)

1 / 183 (0.55%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

1 / 165 (0.61%)

0 / 165 (0.00%)

2 / 161 (1.24%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

Acute tonsillitis

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

1 / 168 (0.60%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Bullous impetigo

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

1 / 168 (0.60%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cystitis

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

1 / 169 (0.59%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Device related sepsis

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

1 / 169 (0.59%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Ear infection

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

1 / 168 (0.60%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pharyngotonsillitis

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

1 / 165 (0.61%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Renal abscess

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

1 / 155 (0.65%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory syncytial virus bronchitis

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

1 / 165 (0.61%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tracheitis

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

1 / 169 (0.59%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Viral myocarditis

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

1 / 165 (0.61%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Metabolism and nutrition disorders

Decreased appetite

subjects affected / exposed

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

1 / 183 (0.55%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Dehydration

subjects affected / exposed

1 / 184 (0.54%)

0 / 184 (0.00%)

0 / 189 (0.00%)

1 / 187 (0.53%)

1 / 185 (0.54%)

1 / 184 (0.54%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

1 / 168 (0.60%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

0 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

Ketosis

subjects affected / exposed

1 / 184 (0.54%)

0 / 184 (0.00%)

0 / 189 (0.00%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Weight gain poor

subjects affected / exposed

0 / 184 (0.00%)

1 / 184 (0.54%)

1 / 189 (0.53%)

0 / 187 (0.00%)

0 / 185 (0.00%)

0 / 184 (0.00%)

0 / 183 (0.00%)

0 / 155 (0.00%)

0 / 163 (0.00%)

0 / 169 (0.00%)

0 / 168 (0.00%)

0 / 165 (0.00%)

0 / 161 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

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

Non-serious adverse events	B+OMV (Group I)	B+½ OMV (Group II)	B+1/4 OMV (Group III)	B (Group IV)	½ (B+OMV) (Group V)	PH2 B+OMV (Group VI)	MenC (Group VII)	183Par+B+OMV (Group VIII)	B+OMV (Group I) Booster Phase	B+½ OMV (Group II) Booster Phase	B+1/4 OMV (Group III) Booster Phase	B (Group IV) Booster Phase	½ (B+OMV) (Group V) Booster Phase	PH2 B+OMV (Group VI) Booster Phase	MenC (Group VII) Booster Phase	Par+B+OMV (Group VIII) Booster Phase
Total subjects affected by non serious adverse events
subjects affected / exposed	181 / 184 (98.37%)	183 / 184 (99.46%)	186 / 189 (98.41%)	183 / 187 (97.86%)	180 / 187 (96.26%)	180 / 185 (97.30%)	175 / 184 (95.11%)	175 / 183 (95.63%)	151 / 155 (97.42%)	159 / 163 (97.55%)	162 / 169 (95.86%)	152 / 169 (89.94%)	154 / 168 (91.67%)	156 / 165 (94.55%)	155 / 165 (93.94%)	150 / 161 (93.17%)
Nervous system disorders
Somnolence
subjects affected / exposed	145 / 184 (78.80%)	149 / 184 (80.98%)	146 / 189 (77.25%)	131 / 187 (70.05%)	142 / 187 (75.94%)	143 / 185 (77.30%)	113 / 184 (61.41%)	134 / 183 (73.22%)	76 / 155 (49.03%)	90 / 163 (55.21%)	90 / 169 (53.25%)	63 / 169 (37.28%)	86 / 168 (51.19%)	88 / 165 (53.33%)	100 / 165 (60.61%)	80 / 161 (49.69%)
occurrences all number	310	312	320	257	298	322	244	291	77	91	97	69	92	89	149	83
General disorders and administration site conditions
Crying
subjects affected / exposed	122 / 184 (66.30%)	135 / 184 (73.37%)	137 / 189 (72.49%)	99 / 187 (52.94%)	125 / 187 (66.84%)	141 / 185 (76.22%)	87 / 184 (47.28%)	112 / 183 (61.20%)	74 / 155 (47.74%)	64 / 163 (39.26%)	69 / 169 (40.83%)	46 / 169 (27.22%)	71 / 168 (42.26%)	82 / 165 (49.70%)	85 / 165 (51.52%)	50 / 161 (31.06%)
occurrences all number	284	301	276	208	273	341	167	211	79	69	76	50	79	85	114	52
Injection site erythema
subjects affected / exposed	151 / 184 (82.07%)	150 / 184 (81.52%)	155 / 189 (82.01%)	132 / 187 (70.59%)	131 / 187 (70.05%)	150 / 185 (81.08%)	119 / 184 (64.67%)	132 / 183 (72.13%)	97 / 155 (62.58%)	107 / 163 (65.64%)	120 / 169 (71.01%)	83 / 169 (49.11%)	89 / 168 (52.98%)	96 / 165 (58.18%)	110 / 165 (66.67%)	88 / 161 (54.66%)
occurrences all number	865	853	887	661	707	811	594	661	246	281	321	204	229	241	345	234
Injection site induration
subjects affected / exposed	141 / 184 (76.63%)	139 / 184 (75.54%)	141 / 189 (74.60%)	126 / 187 (67.38%)	130 / 187 (69.52%)	130 / 185 (70.27%)	122 / 184 (66.30%)	126 / 183 (68.85%)	81 / 155 (52.26%)	90 / 163 (55.21%)	105 / 169 (62.13%)	71 / 169 (42.01%)	76 / 168 (45.24%)	81 / 165 (49.09%)	97 / 165 (58.79%)	70 / 161 (43.48%)
occurrences all number	859	837	824	676	716	756	570	665	202	244	279	185	202	204	290	186
Injection site swelling
subjects affected / exposed	97 / 184 (52.72%)	94 / 184 (51.09%)	103 / 189 (54.50%)	80 / 187 (42.78%)	88 / 187 (47.06%)	100 / 185 (54.05%)	75 / 184 (40.76%)	77 / 183 (42.08%)	57 / 155 (36.77%)	63 / 163 (38.65%)	76 / 169 (44.97%)	46 / 169 (27.22%)	53 / 168 (31.55%)	57 / 165 (34.55%)	65 / 165 (39.39%)	50 / 161 (31.06%)
occurrences all number	463	437	411	331	390	437	265	348	136	151	177	105	124	144	157	119
Injection site pain
subjects affected / exposed	150 / 184 (81.52%)	157 / 184 (85.33%)	139 / 189 (73.54%)	101 / 187 (54.01%)	131 / 187 (70.05%)	152 / 185 (82.16%)	105 / 184 (57.07%)	119 / 183 (65.03%)	121 / 155 (78.06%)	110 / 163 (67.48%)	126 / 169 (74.56%)	92 / 169 (54.44%)	111 / 168 (66.07%)	116 / 165 (70.30%)	125 / 165 (75.76%)	97 / 161 (60.25%)
occurrences all number	927	896	780	487	761	960	490	595	326	310	339	242	309	327	398	255
Pyrexia
subjects affected / exposed	136 / 184 (73.91%)	127 / 184 (69.02%)	122 / 189 (64.55%)	71 / 187 (37.97%)	114 / 187 (60.96%)	126 / 185 (68.11%)	62 / 184 (33.70%)	78 / 183 (42.62%)	86 / 155 (55.48%)	94 / 163 (57.67%)	70 / 169 (41.42%)	49 / 169 (28.99%)	85 / 168 (50.60%)	72 / 165 (43.64%)	92 / 165 (55.76%)	59 / 161 (36.65%)
occurrences all number	270	256	209	109	204	247	97	125	94	112	92	63	102	90	137	68
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	84 / 184 (45.65%)	87 / 184 (47.28%)	80 / 189 (42.33%)	67 / 187 (35.83%)	80 / 187 (42.78%)	81 / 185 (43.78%)	74 / 184 (40.22%)	73 / 183 (39.89%)	31 / 155 (20.00%)	37 / 163 (22.70%)	39 / 169 (23.08%)	47 / 169 (27.81%)	34 / 168 (20.24%)	31 / 165 (18.79%)	40 / 165 (24.24%)	34 / 161 (21.12%)
occurrences all number	169	161	178	132	143	161	129	134	33	41	45	58	40	37	53	34
Vomiting
subjects affected / exposed	38 / 184 (20.65%)	37 / 184 (20.11%)	42 / 189 (22.22%)	32 / 187 (17.11%)	36 / 187 (19.25%)	43 / 185 (23.24%)	34 / 184 (18.48%)	46 / 183 (25.14%)	6 / 155 (3.87%)	13 / 163 (7.98%)	7 / 169 (4.14%)	7 / 169 (4.14%)	10 / 168 (5.95%)	10 / 165 (6.06%)	15 / 165 (9.09%)	20 / 161 (12.42%)
occurrences all number	54	60	59	51	58	67	48	70	6	14	7	9	11	10	17	21
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	22 / 184 (11.96%)	21 / 184 (11.41%)	9 / 189 (4.76%)	19 / 187 (10.16%)	13 / 187 (6.95%)	19 / 185 (10.27%)	12 / 184 (6.52%)	10 / 183 (5.46%)	5 / 155 (3.23%)	12 / 163 (7.36%)	11 / 169 (6.51%)	9 / 169 (5.33%)	11 / 168 (6.55%)	8 / 165 (4.85%)	10 / 165 (6.06%)	7 / 161 (4.35%)
occurrences all number	32	27	11	27	19	24	15	12	6	14	14	11	15	9	11	9
Skin and subcutaneous tissue disorders
Dermatitis
subjects affected / exposed	10 / 184 (5.43%)	3 / 184 (1.63%)	7 / 189 (3.70%)	0 / 187 (0.00%)	6 / 187 (3.21%)	2 / 185 (1.08%)	13 / 184 (7.07%)	9 / 183 (4.92%)	0 / 155 (0.00%)	0 / 163 (0.00%)	0 / 169 (0.00%)	0 / 169 (0.00%)	0 / 168 (0.00%)	0 / 165 (0.00%)	0 / 165 (0.00%)	0 / 161 (0.00%)
occurrences all number	11	3	8	0	6	2	15	10	0	0	0	0	0	0	0	0
Rash
subjects affected / exposed	15 / 184 (8.15%)	18 / 184 (9.78%)	15 / 189 (7.94%)	18 / 187 (9.63%)	24 / 187 (12.83%)	26 / 185 (14.05%)	16 / 184 (8.70%)	19 / 183 (10.38%)	8 / 155 (5.16%)	6 / 163 (3.68%)	11 / 169 (6.51%)	2 / 169 (1.18%)	9 / 168 (5.36%)	6 / 165 (3.64%)	12 / 165 (7.27%)	7 / 161 (4.35%)
occurrences all number	17	28	17	21	32	32	24	27	9	7	11	2	10	7	16	8
Psychiatric disorders
Eating disorder
subjects affected / exposed	105 / 184 (57.07%)	106 / 184 (57.61%)	104 / 189 (55.03%)	84 / 187 (44.92%)	112 / 187 (59.89%)	119 / 185 (64.32%)	63 / 184 (34.24%)	93 / 183 (50.82%)	74 / 155 (47.74%)	77 / 163 (47.24%)	79 / 169 (46.75%)	52 / 169 (30.77%)	70 / 168 (41.67%)	80 / 165 (48.48%)	72 / 165 (43.64%)	66 / 161 (40.99%)
occurrences all number	193	216	196	154	200	242	102	181	77	79	89	61	79	82	112	67
Irritability
subjects affected / exposed	157 / 184 (85.33%)	159 / 184 (86.41%)	155 / 189 (82.01%)	139 / 187 (74.33%)	151 / 187 (80.75%)	153 / 185 (82.70%)	121 / 184 (65.76%)	137 / 183 (74.86%)	116 / 155 (74.84%)	111 / 163 (68.10%)	112 / 169 (66.27%)	86 / 169 (50.89%)	116 / 168 (69.05%)	115 / 165 (69.70%)	126 / 165 (76.36%)	96 / 161 (59.63%)
occurrences all number	402	381	385	296	386	400	258	311	123	118	122	99	126	123	203	102
Infections and infestations
Bronchitis
subjects affected / exposed	34 / 184 (18.48%)	34 / 184 (18.48%)	40 / 189 (21.16%)	31 / 187 (16.58%)	31 / 187 (16.58%)	43 / 185 (23.24%)	34 / 184 (18.48%)	35 / 183 (19.13%)	25 / 155 (16.13%)	18 / 163 (11.04%)	25 / 169 (14.79%)	28 / 169 (16.57%)	28 / 168 (16.67%)	19 / 165 (11.52%)	35 / 165 (21.21%)	17 / 161 (10.56%)
occurrences all number	45	54	56	49	55	55	46	52	28	24	27	38	39	26	54	19
Conjunctivitis
subjects affected / exposed	14 / 184 (7.61%)	13 / 184 (7.07%)	14 / 189 (7.41%)	13 / 187 (6.95%)	15 / 187 (8.02%)	22 / 185 (11.89%)	10 / 184 (5.43%)	17 / 183 (9.29%)	7 / 155 (4.52%)	7 / 163 (4.29%)	5 / 169 (2.96%)	13 / 169 (7.69%)	8 / 168 (4.76%)	7 / 165 (4.24%)	6 / 165 (3.64%)	10 / 161 (6.21%)
occurrences all number	15	16	17	17	19	28	13	21	7	7	5	14	11	8	6	10
Ear infection
subjects affected / exposed	10 / 184 (5.43%)	5 / 184 (2.72%)	10 / 189 (5.29%)	6 / 187 (3.21%)	7 / 187 (3.74%)	12 / 185 (6.49%)	9 / 184 (4.89%)	7 / 183 (3.83%)	8 / 155 (5.16%)	4 / 163 (2.45%)	2 / 169 (1.18%)	5 / 169 (2.96%)	9 / 168 (5.36%)	7 / 165 (4.24%)	11 / 165 (6.67%)	4 / 161 (2.48%)
occurrences all number	15	5	10	7	10	18	13	8	13	6	2	7	10	8	11	5
Exanthema subitum
subjects affected / exposed	9 / 184 (4.89%)	18 / 184 (9.78%)	17 / 189 (8.99%)	17 / 187 (9.09%)	19 / 187 (10.16%)	13 / 185 (7.03%)	20 / 184 (10.87%)	11 / 183 (6.01%)	6 / 155 (3.87%)	7 / 163 (4.29%)	8 / 169 (4.73%)	5 / 169 (2.96%)	5 / 168 (2.98%)	6 / 165 (3.64%)	7 / 165 (4.24%)	10 / 161 (6.21%)
occurrences all number	9	18	17	17	20	13	20	12	6	7	8	5	5	6	7	10
Gastroenteritis
subjects affected / exposed	10 / 184 (5.43%)	11 / 184 (5.98%)	6 / 189 (3.17%)	9 / 187 (4.81%)	6 / 187 (3.21%)	13 / 185 (7.03%)	7 / 184 (3.80%)	8 / 183 (4.37%)	5 / 155 (3.23%)	4 / 163 (2.45%)	8 / 169 (4.73%)	11 / 169 (6.51%)	12 / 168 (7.14%)	15 / 165 (9.09%)	9 / 165 (5.45%)	7 / 161 (4.35%)
occurrences all number	10	11	6	9	7	16	8	8	5	4	9	11	14	16	9	7
Nasopharyngitis
subjects affected / exposed	20 / 184 (10.87%)	22 / 184 (11.96%)	25 / 189 (13.23%)	17 / 187 (9.09%)	19 / 187 (10.16%)	24 / 185 (12.97%)	16 / 184 (8.70%)	19 / 183 (10.38%)	15 / 155 (9.68%)	10 / 163 (6.13%)	18 / 169 (10.65%)	11 / 169 (6.51%)	14 / 168 (8.33%)	15 / 165 (9.09%)	14 / 165 (8.48%)	7 / 161 (4.35%)
occurrences all number	32	24	43	22	27	31	20	29	21	12	20	11	19	18	19	10
Pharyngitis
subjects affected / exposed	21 / 184 (11.41%)	18 / 184 (9.78%)	15 / 189 (7.94%)	21 / 187 (11.23%)	25 / 187 (13.37%)	15 / 185 (8.11%)	18 / 184 (9.78%)	19 / 183 (10.38%)	11 / 155 (7.10%)	16 / 163 (9.82%)	13 / 169 (7.69%)	14 / 169 (8.28%)	22 / 168 (13.10%)	15 / 165 (9.09%)	16 / 165 (9.70%)	15 / 161 (9.32%)
occurrences all number	27	20	17	28	30	21	19	26	12	17	15	16	24	18	18	18
Rhinitis
subjects affected / exposed	21 / 184 (11.41%)	14 / 184 (7.61%)	12 / 189 (6.35%)	19 / 187 (10.16%)	21 / 187 (11.23%)	26 / 185 (14.05%)	20 / 184 (10.87%)	12 / 183 (6.56%)	7 / 155 (4.52%)	9 / 163 (5.52%)	8 / 169 (4.73%)	11 / 169 (6.51%)	10 / 168 (5.95%)	8 / 165 (4.85%)	6 / 165 (3.64%)	6 / 161 (3.73%)
occurrences all number	23	18	13	23	22	36	22	18	7	9	9	13	13	8	7	8
Tonsillitis
subjects affected / exposed	6 / 184 (3.26%)	3 / 184 (1.63%)	2 / 189 (1.06%)	12 / 187 (6.42%)	7 / 187 (3.74%)	5 / 185 (2.70%)	5 / 184 (2.72%)	4 / 183 (2.19%)	6 / 155 (3.87%)	10 / 163 (6.13%)	4 / 169 (2.37%)	8 / 169 (4.73%)	5 / 168 (2.98%)	8 / 165 (4.85%)	6 / 165 (3.64%)	9 / 161 (5.59%)
occurrences all number	6	3	2	13	7	5	5	4	7	11	4	8	5	8	6	9
Upper respiratory tract infection
subjects affected / exposed	13 / 184 (7.07%)	13 / 184 (7.07%)	10 / 189 (5.29%)	10 / 187 (5.35%)	8 / 187 (4.28%)	12 / 185 (6.49%)	9 / 184 (4.89%)	9 / 183 (4.92%)	8 / 155 (5.16%)	7 / 163 (4.29%)	8 / 169 (4.73%)	9 / 169 (5.33%)	7 / 168 (4.17%)	9 / 165 (5.45%)	8 / 165 (4.85%)	5 / 161 (3.11%)
occurrences all number	15	15	10	12	12	14	11	9	9	10	11	9	8	10	12	5
Varicella
subjects affected / exposed	5 / 184 (2.72%)	10 / 184 (5.43%)	2 / 189 (1.06%)	5 / 187 (2.67%)	7 / 187 (3.74%)	5 / 185 (2.70%)	5 / 184 (2.72%)	5 / 183 (2.73%)	0 / 155 (0.00%)	0 / 163 (0.00%)	0 / 169 (0.00%)	0 / 169 (0.00%)	0 / 168 (0.00%)	0 / 165 (0.00%)	0 / 165 (0.00%)	0 / 161 (0.00%)
occurrences all number	5	10	2	5	7	5	5	5	0	0	0	0	0	0	0	0
Viral infection
subjects affected / exposed	19 / 184 (10.33%)	27 / 184 (14.67%)	23 / 189 (12.17%)	24 / 187 (12.83%)	24 / 187 (12.83%)	17 / 185 (9.19%)	16 / 184 (8.70%)	21 / 183 (11.48%)	12 / 155 (7.74%)	14 / 163 (8.59%)	6 / 169 (3.55%)	16 / 169 (9.47%)	18 / 168 (10.71%)	9 / 165 (5.45%)	12 / 165 (7.27%)	11 / 161 (6.83%)
occurrences all number	24	30	26	31	33	21	18	25	14	14	10	19	20	11	15	13

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Were there any global substantial amendments to the protocol? Yes

21 Jan 2010

To allow subjects participating in V72P16 to participate in a Booster Phase of the study in order to receive a fourth (booster) dose of the same formulation of MenB vaccine received during primary immunization concomitantly with a booster (fourth) dose of test routine vaccines, InfanrixHexa and Prevenar. To offer a dose of Menjugate as non-test vaccine to all subjects who participated in the study in Countries where serogroup C meningococcal conjugate vaccination is recommended, with the aim of ensuring the expected level of medical care. Menjugate will be administered either during the Booster Phase of the current trial or in an ad hoc visit for those subjects not participating in the Booster Phase.

09 Dec 2010

To include the serological testing of concomitant antigens in Study Group III (and Group Vii as acontrol) in order to explore the effect of MenB vaccinations on the antibody response to concomitants vaccines. To clarify which interim analyses are performed.

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.

N/A

http://www.ncbi.nlm.nih.gov/pubmed/24763084
http://www.ncbi.nlm.nih.gov/pubmed/25153133

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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 (hSBA) ≥ 1:5 at 1 month after third vaccination

Primary: Percentages of subjects with serum bactericidal activity (hSBA) ≥ 1:5 at 1 month after third vaccination

Primary: Number of subjects with fever ≥ 38.5 °C (rectal temperature) within 3 days (day 1-3) after first vaccination

Primary: Number of subjects with fever ≥ 38.5 °C (rectal temperature) within 3 days (day 1-3) after first vaccination

Secondary: Geometric Mean Bactericidal Titers (GMTs), One Month After Third and Booster Vaccination

Secondary: Geometric Mean Bactericidal Titers (GMTs), One Month After Third and Booster Vaccination

Secondary: Geometric Mean Bactericidal Titers, One Month After Primary and Booster Vaccination

Secondary: Geometric Mean Bactericidal Titers, One Month After Primary and Booster Vaccination

Secondary: Geometric Mean Ratios, One Month After Primary and Booster Vaccination

Secondary: Geometric Mean Ratios, One Month After Primary and Booster Vaccination

Secondary: Percentages of Subjects With SBA titer ≥1:5, Persistence of Bactericidal Antibodies at 12 Months of Age (Pre-fourth Dose)

Secondary: Percentages of Subjects With SBA titer ≥1:5, Persistence of Bactericidal Antibodies at 12 Months of Age (Pre-fourth Dose)

Secondary: Percentages of Subjects With SBA titer ≥1:5, Persistence of Bactericidal Antibodies at 12 Months of Age (One Month-post Fourth Dose)

Secondary: Percentages of Subjects With SBA titer ≥1:5, Persistence of Bactericidal Antibodies at 12 Months of Age (One Month-post Fourth Dose)

Secondary: Geometric Mean Bactericidal Titers, After Primary and Booster Vaccinations

Secondary: Geometric Mean Bactericidal Titers, After Primary and Booster Vaccinations

Secondary: Percentages of Subjects With SBA titer ≥1:5, First Dose of Meningococcal B Vaccine (One Month After Booster)

Secondary: Percentages of Subjects With SBA titer ≥1:5, First Dose of Meningococcal B Vaccine (One Month After Booster)

Secondary: Safety and Reactogenicity of Study Vaccines Within 7 Days After Second and Third Vaccination

Secondary: Safety and Reactogenicity of Study Vaccines Within 7 Days After Second and Third Vaccination

Secondary: Number of subjects with solicited local reactions within 7 days (day 1-7) after each vaccination

Secondary: Number of subjects with solicited local reactions within 7 days (day 1-7) after each vaccination

Secondary: Number of subjects with solicited systemic reactions within 7 days (day 1-7) after each vaccination

Secondary: Number of subjects with solicited systemic reactions within 7 days (day 1-7) after each vaccination

Secondary: Number of subjects with unsolicited Adverse Events within 7 days (day 1-7) after each vaccination

Secondary: Number of subjects with unsolicited Adverse Events within 7 days (day 1-7) after each vaccination

Secondary: Number of subjects with Severe Adverse Events and Adverse Events necessitating a medical office or Emergency Room (ER) visit and/or resulting in premature withdrawal of the subject from the study, throughout the study period

Secondary: Number of subjects with Severe Adverse Events and Adverse Events necessitating a medical office or Emergency Room (ER) visit and/or resulting in premature withdrawal of the subject from the study, throughout the study period

Secondary: Number of subjects with local and systemic reactions within 7 days (day 1-7) after second rMenB+OMV NX vaccination in MenC group

Secondary: Number of subjects with local and systemic reactions within 7 days (day 1-7) after second rMenB+OMV NX vaccination in MenC group

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

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