Clinical Trial Results:
A Phase 3, Partially Blinded, Randomized, Multi-Center, Controlled Study to Evaluate Immunogenicity, Safety and Lot to Lot Consistency of Novartis Meningococcal B Recombinant Vaccine When Administered with Routine Infant Vaccinations to Healthy Infants

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

Summary
EudraCT number	2007-007781-38
Trial protocol	CZ FI DE IT AT
Global end of trial date	22 Jan 2010

Results information
Results version number	v2(current)
This version publication date	03 Jun 2016
First version publication date	19 Dec 2014
Other versions	v1 (removed from public view)
Version creation reason

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

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Trial information

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Sponsor protocol code

V72P13

ISRCTN number

US NCT number

NCT00657709

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)

Yes

EMA paediatric investigation plan number(s)

EMEA-000139-PIP01-07

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

17 Sep 2010

Is this the analysis of the primary completion data?

Yes

Primary completion date

22 Jan 2010

Global end of trial reached?

Yes

Global end of trial date

22 Jan 2010

Was the trial ended prematurely?

Main objective of the trial

- To assess the immunogenicity of 3 doses of rMenB+OMV NZ (3 lots combined) given to healthy infants at 2, 4 and 6 months of age concomitantly with routine infant vaccines, by evaluation of the serum bactericidal activity (SBA), at 1 month after the third vaccination. - To show the consistency of immune response from 3 lots of rMenB+OMV NZ, by serum bactericidal activity geometric mean titer response (SBA GMTs), when administered to healthy infants at 2, 4 and 6 months of age, at 1 month after the third vaccination.

Protection of trial subjects

This clinical study was designed, implemented and reported in accordance with the ICH Harmonized Tripartite Guidelines for GCP, with applicable local regulations, including the European Directive 2001/20/EC, the US CFR Title 21, and the Japanese Ministry of Health, Labor, and Welfare, Novartis codes on the protection of human rights, and with the ethical principles laid down in the Declaration of Helsinki.

Background therapy

Evidence for comparator

Actual start date of recruitment

31 Mar 2008

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Austria: 68

Country: Number of subjects enrolled

Czech Republic: 1020

Country: Number of subjects enrolled

Finland: 1717

Country: Number of subjects enrolled

Germany: 51

Country: Number of subjects enrolled

Italy: 774

Worldwide total number of subjects

3630

EEA total number of subjects

3630

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)

3630

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

16 sites in Finland, 28 sites in the Czech Republic, 13 sites in Germany,6 sites in Austria, 7 sites in Italy.

Screening details

All enrolled subjects were included in the trial.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Subject

Blinding implementation details

The trial was designed as partially open label, and partially observer-blind.

Are arms mutually exclusive

Yes

rMenB Lot1

Arm description

Subjects received one injection of rMenB+OMV NZ (Lot 1) at 2, 4, 6 months of age concomitantly with the routinely administered infant vaccines.

Arm type

Experimental

Investigational medicinal product name

Meningococcal (group B) multicomponent recombinant adsorbed vaccine

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Vaccination consisted of one 0.5 mL dose administered IM into the antero-lateral area of the thigh at 2, 4, and 6 months of age.

rMenB Lot2

Arm description

Subjects received one injection of rMenB+OMV NZ (Lot 2) at 2, 4, 6 months of age concomitantly with the routinely administered infant vaccines.

Arm type

Experimental

Investigational medicinal product name

Meningococcal (group B) multicomponent recombinant adsorbed vaccine

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Vaccination consisted of one 0.5 mL dose administered IM into the antero-lateral area of the thigh at 2, 4, and 6 months of age.

rMenB Lot3

Arm description

Subjects received one injection of rMenB+OMV NZ (Lot 3) at 2, 4, 6 months of age concomitantly with the routinely administered infant vaccines.

Arm type

Experimental

Investigational medicinal product name

Meningococcal (group B) multicomponent recombinant adsorbed vaccine

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Vaccination consisted of one 0.5 mL dose administered IM into the antero-lateral area of the thigh at 2, 4, and 6 months of age.

Routine

Arm description

Subjects received the routinely administered infant vaccines at 2, 4, 6 months of age.

Arm type

Active comparator

Investigational medicinal product name

Infanrix Hexa

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Vaccination consisted of one 0.5 mL dose administered IM into the antero-lateral area of the thigh at 2, 4, and 6 months of age.

Investigational medicinal product name

Prevenar

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Vaccination consisted of one 0.5 mL dose administered IM into the antero-lateral area of the thigh at 2, 4, and 6 months of age.

MenC + Routine

Arm description

Subjects received the routinely administered infant vaccines and Men C vaccine at 2, 4 and 6 months of age.

Arm type

Active comparator

Investigational medicinal product name

Prevenar

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Vaccination consisted of one 0.5 mL dose administered IM into the antero-lateral area of the thigh at 2, 4, and 6 months of age.

Investigational medicinal product name

Infanrix Hexa

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Vaccination consisted of one 0.5 mL dose administered IM into the antero-lateral area of the thigh at 2, 4, and 6 months of age.

Investigational medicinal product name

Meningococcal (group C) oligosaccharide diphtheria CRM-197 conjugate vaccine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Vaccination consisted of one 0.5 mL dose administered IM into the antero-lateral area of the thigh at 2, 4, and 6 months of age. The MenC vaccine was administered into right thigh, and both routine vaccines were administered into the left thigh.

Number of subjects in period 1	rMenB Lot1	rMenB Lot2	rMenB Lot3	Routine	MenC + Routine
Started	833	828	820	659	490
Completed	810	795	792	645	457
Not completed	23	33	28	14	33
Consent withdrawn by subject	7	15	15	5	9
Lost to follow-up	9	9	7	1	21
Adverse events or death	7	7	6	7	1
Protocol deviation	-	2	-	1	2

Baseline characteristics

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Reporting group title

rMenB Lot1

Reporting group description

Subjects received one injection of rMenB+OMV NZ (Lot 1) at 2, 4, 6 months of age concomitantly with the routinely administered infant vaccines.

Reporting group title

rMenB Lot2

Reporting group description

Subjects received one injection of rMenB+OMV NZ (Lot 2) at 2, 4, 6 months of age concomitantly with the routinely administered infant vaccines.

Reporting group title

rMenB Lot3

Reporting group description

Subjects received one injection of rMenB+OMV NZ (Lot 3) at 2, 4, 6 months of age concomitantly with the routinely administered infant vaccines.

Reporting group title

Routine

Reporting group description

Subjects received the routinely administered infant vaccines at 2, 4, 6 months of age.

Reporting group title

MenC + Routine

Reporting group description

Subjects received the routinely administered infant vaccines and Men C vaccine at 2, 4 and 6 months of age.

Reporting group values	rMenB Lot1	rMenB Lot2	rMenB Lot3	Routine	MenC + Routine	Total
Number of subjects	833	828	820	659	490	3630
Age categorical
Units: Subjects
Age continuous
Units: days
arithmetic mean (standard deviation)	73.8 ( 9.5 )	74.1 ( 9.6 )	73.3 ( 9.4 )	74.7 ( 9.3 )	70.6 ( 9.7 )	-
Gender categorical
Units: Subjects
Female	403	400	416	318	234	1771
Male	430	428	404	341	256	1859

End points

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Reporting group title

rMenB Lot1

Reporting group description

Subjects received one injection of rMenB+OMV NZ (Lot 1) at 2, 4, 6 months of age concomitantly with the routinely administered infant vaccines.

Reporting group title

rMenB Lot2

Reporting group description

Subjects received one injection of rMenB+OMV NZ (Lot 2) at 2, 4, 6 months of age concomitantly with the routinely administered infant vaccines.

Reporting group title

rMenB Lot3

Reporting group description

Subjects received one injection of rMenB+OMV NZ (Lot 3) at 2, 4, 6 months of age concomitantly with the routinely administered infant vaccines.

Reporting group title

Routine

Reporting group description

Subjects received the routinely administered infant vaccines at 2, 4, 6 months of age.

Reporting group title

MenC + Routine

Reporting group description

Subjects received the routinely administered infant vaccines and Men C vaccine at 2, 4 and 6 months of age.

Subject analysis set title

All enrolled population

Subject analysis set type

Full analysis

Subject analysis set description

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

Subject analysis set title

Safety population

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects enrolled who: - have received study vaccination - provided post-baseline safety data

Subject analysis set title

rMenB All - hSBA per protocol population

Subject analysis set type

Per protocol

Subject analysis set description

All subjects in the Full Analysis Set/MITT population who: - received one injection of rMenB+OMV NZ (Lot 1, 2 and 3) at 2, 4, 6 months of age concomitantly with the routinely administered infant vaccines, and - received all the relevant doses of vaccine correctly, and - provided evaluable serum samples at the relevant time points, and - had no major protocol violation as defined prior to analysis

Subject analysis set title

Immunogenicity hSBA MITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

All subjects in the enrolled population who: - actually received a study vaccination, and - provided at least one evaluable serum sample after baseline

Subject analysis set title

rMenB All Safety population

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects enrolled who received one injection of rMenB+OMV NZ (Lot 1, 2 and 3). - have received study vaccination - provided post-baseline safety data

Subject analysis set title

Immunogenicity hSBA PP

Subject analysis set type

Per protocol

Subject analysis set description

All subjects in the Full Analysis Set/MITT population who: - received all the relevant doses of vaccine correctly, and - provided evaluable serum samples at the relevant time points, and - had no major protocol violation as defined prior to analysis

Subject analysis set title

Immunogenicity Routine MITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

All subjects in the enrolled population who: - actually received a study vaccination, and - provided at least one evaluable serum sample after baseline

Subject analysis set title

Immunogenicity Polio MITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

All subjects in the enrolled population who: - actually received a study vaccination, and - provided at least one evaluable serum sample after baseline

Subject analysis set title

Immunogenicity Polio PP

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Immunogenicity Routine PP

Subject analysis set type

Per protocol

Subject analysis set description

Primary: 1. The Geometric Mean Human Serum Antibatericidal Activity Titers After Three Doses of rMenB+OMV NZ Vaccination

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End point title

1. The Geometric Mean Human Serum Antibatericidal Activity Titers After Three Doses of rMenB+OMV NZ Vaccination ^[1]

End point description

The hSBA antibody titer responses, one month after receiving the third vaccination of rMenB+OMV NZ vaccination, are reported as geometric mean titers (GMTs).

End point type

Primary

End point timeframe

From baseline to one month after the third vaccination

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

End point values	rMenB Lot1	rMenB Lot2	rMenB Lot3
Number of subjects analysed	386	380	394
Units: Titers
geometric mean (confidence interval 95%)
44/76-SL strain (Baseline) (N=383,379,394)	1.21 (1.14 to 1.29)	1.19 (1.12 to 1.27)	1.19 (1.12 to 1.27)
44/76-SL 1 Month after 3rd vacc (N=384,377,388)	87 (80 to 95)	98 (90 to 106)	85 (78 to 93)
5/99 strain (Baseline) (N=385,379,390)	1.21 (1.14 to 1.3)	1.2 (1.12 to 1.28)	1.21 (1.13 to 1.29)
5/99 1 Month after 3rd vacc (N=384,380,388)	598 (550 to 651)	681 (626 to 741)	607 (558 to 661)
NZ98/254 strain (Baseline)	1.03 (1 to 1.06)	1.06 (1.03 to 1.1)	1.04 (1 to 1.07)
NZ98/254 1 Month after 3rd vacc (N=385,378,389)	15 (13 to 17)	14 (12 to 16)	15 (14 to 17)

1. Equivalence rMenB Lot1 and rMenB Lot2 for 44/76

Statistical analysis description

The study would be considered a success if the two-sided 95% confidence intervals (CIs) for the hSBA GMT ratios comparing rMenB Lot1 to rMenB Lot2 for 44/76-SL strain at one month after the third vaccination was contained within the equivalence interval (0.5, 2.0).

Comparison groups

rMenB Lot2 v rMenB Lot1

Number of subjects included in analysis

766

Analysis specification

Pre-specified

Analysis type

equivalence ^[2]

Method

ANOVA

Parameter type

hSBA GMT ratios

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

0.81

upper limit

0.99

Notes
[2] - The equivalence margin was (0.5, 2.0). If the two sided 95% CIs for the ratio of the hSBA GMT at one month following third vaccination was within this equivalence interval for each of the two co-primary comparisons, rMenB Lot1 and rMenB Lot2 would be equivalent for 44/76-SL strain with respect to the immune response to the vaccine lot.

2. Equivalence rMenB Lot1 and rMenB Lot3 for 44/76

Statistical analysis description

The study would be considered a success if the two-sided 95% confidence intervals (CIs) for the hSBA GMT ratios comparing rMenB Lot1 to rMenB Lot3 for 44/76-SL strain at one month after the third vaccination was contained within the equivalence interval (0.5, 2.0).

Comparison groups

rMenB Lot1 v rMenB Lot3

Number of subjects included in analysis

780

Analysis specification

Pre-specified

Analysis type

equivalence ^[3]

Method

ANOVA

Parameter type

hSBA GMT ratios

Point estimate

1.02

Confidence interval

level

95%

sides

2-sided

lower limit

0.93

upper limit

1.13

Notes
[3] - The equivalence margin was (0.5, 2.0). If the two sided 95% CIs for the ratio of the hSBA GMT at one month following third vaccination was within this equivalence interval for each of the two co-primary comparisons, rMenB Lot1 and rMenB Lot3 would be equivalent for 44/76-SL strain with respect to the immune response to the vaccine lot.

3. Equivalence rMenB Lot2 and rMenB Lot3 for 44/76

Statistical analysis description

The study would be considered a success if the two-sided 95% confidence intervals (CIs) for the hSBA GMT ratios comparing rMenB Lot2 to rMenB Lot3 for 44/76-SL strain at one month after the third vaccination was contained within the equivalence interval (0.5, 2.0).

Comparison groups

rMenB Lot2 v rMenB Lot3

Number of subjects included in analysis

774

Analysis specification

Pre-specified

Analysis type

equivalence ^[4]

Method

ANOVA

Parameter type

hSBA GMT ratios

Point estimate

1.14

Confidence interval

level

95%

sides

2-sided

lower limit

1.03

upper limit

1.27

Notes
[4] - The equivalence margin was (0.5, 2.0). If the two sided 95% CIs for the ratio of the hSBA GMT at one month following third vaccination was within this equivalence interval for each of the two co-primary comparisons, rMenB Lot2 and rMenB Lot3 would be equivalent for 44/76-SL strain with respect to the immune response to the vaccine lot.

4. Equivalence rMenB Lot1 and rMenB Lot2 for 5/99

Statistical analysis description

The study would be considered a success if the two-sided 95% confidence intervals (CIs) for the hSBA GMT ratios comparing rMenB Lot1 to rMenB Lot2 for 5/99 strain at one month after the third vaccination was contained within the equivalence interval (0.5, 2.0).

Comparison groups

rMenB Lot1 v rMenB Lot2

Number of subjects included in analysis

766

Analysis specification

Pre-specified

Analysis type

equivalence ^[5]

Method

ANOVA

Parameter type

hSBA GMT ratios

Point estimate

0.88

Confidence interval

level

95%

sides

2-sided

lower limit

0.78

upper limit

0.98

Notes
[5] - The equivalence margin was (0.5, 2.0). If the two sided 95% CIs for the ratio of the hSBA GMT at one month following third vaccination was within this equivalence interval for each of the two co-primary comparisons, rMenB Lot1 and rMenB Lot2 would be equivalent for 5/99 strain with respect to the immune response to the vaccine lot.

5. Equivalence rMenB Lot1 and rMenB Lot3 for 5/99

Statistical analysis description

The study would be considered a success if the two-sided 95% confidence intervals (CIs) for the hSBA GMT ratios comparing rMenB Lot1 to rMenB Lot3 for 5/99 strain at one month after the third vaccination was contained within the equivalence interval (0.5, 2.0).

Comparison groups

rMenB Lot1 v rMenB Lot3

Number of subjects included in analysis

780

Analysis specification

Pre-specified

Analysis type

equivalence ^[6]

Method

ANOVA

Parameter type

hSBA GMT ratios

Point estimate

0.99

Confidence interval

level

95%

sides

2-sided

lower limit

0.88

upper limit

1.1

Notes
[6] - The equivalence margin was (0.5, 2.0). If the two sided 95% CIs for the ratio of the hSBA GMT at one month following third vaccination was within this equivalence interval for each of the two co-primary comparisons, rMenB Lot1 and rMenB Lot3 would be equivalent for 5/99 strain with respect to the immune response to the vaccine lot.

6. Equivalence rMenB Lot2 and rMenB Lot3 for 5/99

Statistical analysis description

The study would be considered a success if the two-sided 95% confidence intervals (CIs) for the hSBA GMT ratios comparing rMenB Lot2 to rMenB Lot3 for 5/99 strain at one month after the third vaccination was contained within the equivalence interval (0.5, 2.0).

Comparison groups

rMenB Lot2 v rMenB Lot3

Number of subjects included in analysis

774

Analysis specification

Pre-specified

Analysis type

equivalence ^[7]

Method

ANOVA

Parameter type

hSBA GMT ratios

Point estimate

1.12

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

1.26

Notes
[7] - The equivalence margin was (0.5, 2.0). If the two sided 95% CIs for the ratio of the hSBA GMT at one month following third vaccination was within this equivalence interval for each of the two co-primary comparisons, rMenB Lot2 and rMenB Lot3 would be equivalent for 5/99 strain with respect to the immune response to the vaccine lot.

7. Equivalence rMenB Lot1 and Lot2 for NZ98/254

Statistical analysis description

The study would be considered a success if the two-sided 95% confidence intervals (CIs) for the hSBA GMT ratios comparing rMenB Lot1 to rMenB Lot2 for NZ98/254 strain at one month after the third vaccination was contained within the equivalence interval (0.5, 2.0).

Comparison groups

rMenB Lot1 v rMenB Lot2

Number of subjects included in analysis

766

Analysis specification

Pre-specified

Analysis type

equivalence ^[8]

Method

ANOVA

Parameter type

hSBA GMT ratios

Point estimate

1.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.88

upper limit

1.23

Notes
[8] - The equivalence margin was (0.5, 2.0). If the two sided 95% CIs for the ratio of the hSBA GMT at one month following third vaccination was within this equivalence interval for each of the two co-primary comparisons, rMenB Lot1 and rMenB Lot2 would be equivalent for NZ98/254 with respect to the immune response to the vaccine lot.

8. Equivalence rMenB Lot1 and Lot3 for NZ98/254

Statistical analysis description

The study would be considered a success if the two-sided 95% confidence intervals (CIs) for the hSBA GMT ratios comparing rMenB Lot1 to rMenB Lot3 for NZ98/254 strain at one month after the third vaccination was contained within the equivalence interval (0.5, 2.0).

Comparison groups

rMenB Lot1 v rMenB Lot3

Number of subjects included in analysis

780

Analysis specification

Pre-specified

Analysis type

equivalence ^[9]

Method

ANOVA

Parameter type

hSBA GMT ratios

Point estimate

0.96

Confidence interval

level

95%

sides

2-sided

lower limit

0.81

upper limit

1.13

Notes
[9] - The equivalence margin was (0.5, 2.0). If the two sided 95% CIs for the ratio of the hSBA GMT at one month following third vaccination was within this equivalence interval for each of the two co-primary comparisons, rMenB Lot1 and rMenB Lot3 would be equivalent for NZ98/254 with respect to the immune response to the vaccine lot.

9. Equivalence rMenB Lot2 and Lot3 for NZ98/254

Statistical analysis description

The study would be considered a success if the two-sided 95% confidence intervals (CIs) for the hSBA GMT ratios comparing rMenB Lot2 to rMenB Lot3 for NZ98/254 strain at one month after the third vaccination was contained within the equivalence interval (0.5, 2.0).

Comparison groups

rMenB Lot2 v rMenB Lot3

Number of subjects included in analysis

774

Analysis specification

Pre-specified

Analysis type

equivalence ^[10]

Method

ANOVA

Parameter type

hSBA GMT ratios

Point estimate

0.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.78

upper limit

1.08

Notes
[10] - The equivalence margin was (0.5, 2.0). If the two sided 95% CIs for the ratio of the hSBA GMT at one month following third vaccination was within this equivalence interval for each of the two co-primary comparisons, rMenB Lot2 and rMenB Lot3 would be equivalent for NZ98/254 with respect to the immune response to the vaccine lot.

Primary: 2. The Percentages of Subjects With hSBA Titer ≥1:5 After Receiving Three Doses of rMenB+OMV Vaccination (3 Lots Combined)

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End point title

2. The Percentages of Subjects With hSBA Titer ≥1:5 After Receiving Three Doses of rMenB+OMV Vaccination (3 Lots Combined) ^[11] ^[12]

End point description

The immunogenicity was assessed in terms of the percentages of subjects who had received the three doses of rMenB+OMV NZ (3 lots combined) given concomitantly with routine infant vaccinations and percentages of subjects who received only the routine infant vaccinations as measured by hSBA titer ≥1:5 following rMenB+OMV NZ vaccinations one month after the third vaccination is reported.

End point type

Primary

End point timeframe

From baseline to one month after the third vaccination

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: statistical analyses not applicable for this endpoint.
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: statistical analyses not applicable for this endpoint.

End point values	Routine	rMenB All - hSBA per protocol population
Number of subjects analysed	121	1160
Units: Percentages of subjects
number (confidence interval 95%)
44/76-SL strain (Baseline) (N=119, 1156)	3 (1 to 8)	3 (2 to 4)
1 Month after 3rd vacc (N=117, 1149)	3 (1 to 7)	100 (99 to 100)
5/99 strain (Baseline) (N=120, 1154)	7 (3 to 13)	4 (3 to 5)
1 Month after 3rd vacc (N=116, 1152)	2 (0 to 6)	100 (99 to 100)
NZ98/254 strain (Baseline) (N=120, 1160)	1 (0.021 to 5)	1 (1 to 2)
1 Month after 3rd vacc (N=121, 1152)	2 (0 to 6)	84 (82 to 86)

No statistical analyses for this end point

Secondary: 3. The Percentages of Subjects With hSBA Titer ≥1:5 After Receiving Three Doses of rMenB+OMV Vaccination (From 3 Lots)

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End point title

3. The Percentages of Subjects With hSBA Titer ≥1:5 After Receiving Three Doses of rMenB+OMV Vaccination (From 3 Lots) ^[13]

End point description

The immmunogenicity was evaluated to assess the consistency of the immune response from three lots of rMenB+OMV NZ in terms of percentage of subjects as measured by hSBA titer ≥1:5 when given to healthy infants at 2, 4, and 6 months of age, at 1 month after the third vaccination.

End point type

Secondary

End point timeframe

From baseline to one month after the third vaccination

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

End point values	rMenB Lot1	rMenB Lot2	rMenB Lot3	Routine
Number of subjects analysed	386	380	394	121
Units: Percentages of subjects
number (confidence interval 95%)
44/76-SL (Baseline) (N=383,379,394,119)	4 (2 to 6)	2 (1 to 4)	3 (2 to 6)	3 (1 to 8)
1 Month after 3rd vacc (N=384,377,388,117)	100 (99 to 100)	100 (99 to 100)	99 (98 to 100)	3 (1 to 7)
5/99 strain (Baseline) (N=385,379,390,120)	3 (2 to 5)	4 (3 to 7)	4 (2 to 7)	7 (3 to 13)
1 Month after 3rd vacc (N=384,380,388,121)	100 (99 to 100)	100 (99 to 100)	99 (98 to 100)	2 (0 to 6)
NZ 98/254 Baseline (N =386,380,394,120)	1 (0 to 2)	2 (1 to 4)	1 (0 to 2)	1 (0.021 to 5)
1 Month after 3rd vacc (N=385,378,389,121)	84 (80 to 88)	81 (77 to 85)	85 (81 to 89)	2 (0 to 6)

1. Vaccine group difference rMenB Lot1/rMenB Lot2

Statistical analysis description

The three vaccine lots were considered equivalent if, for each of the three strains and each pair of vaccine lots, the 95% CIs of the differences in the percentages of subjects with hSBA titers ≥ 1:5 at 1 month after the third dose, was contained within the interval [-10%, 10%].

Comparison groups

rMenB Lot1 v rMenB Lot2

Number of subjects included in analysis

766

Analysis specification

Pre-specified

Analysis type

equivalence ^[14]

Method

Miettinen and Nurminen

Parameter type

Vaccine group difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Notes
[14] - The equivalence margin was (-10%, 10%). If the two sided 95% CIs of the differences in the percentages of subjects at one month following third vaccination was within this equivalence interval for each of the two comparisons, rMenB Lot1 and rMenB Lot2 would be equivalent for 44/76-SL strain.

2. Vaccine group difference rMenB Lot1/ rMenB Lot3

Statistical analysis description

Comparison groups

rMenB Lot1 v rMenB Lot3

Number of subjects included in analysis

780

Analysis specification

Pre-specified

Analysis type

equivalence ^[15]

Method

Miettinen and Nurminen

Parameter type

Vaccine group difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Notes
[15] - The equivalence margin was (-10%, 10%). If the two sided 95% CIs of the differences in the percentages of subjects at one month following third vaccination was within this equivalence interval for each of the two comparisons, rMenB Lot1 and rMenB Lot3 would be equivalent for 44/76-SL strain.

3. Vaccine group difference rMenB Lot2/ rMenB Lot3

Statistical analysis description

Comparison groups

rMenB Lot3 v rMenB Lot2

Number of subjects included in analysis

774

Analysis specification

Pre-specified

Analysis type

equivalence ^[16]

Method

Miettinen and Nurminen

Parameter type

Vaccine group difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Notes
[16] - The equivalence margin was (-10%, 10%). If the two sided 95% CIs of the differences in the percentages of subjects at one month following third vaccination was within this equivalence interval for each of the two comparisons, rMenB Lot2 and rMenB Lot3 would be equivalent for 44/76-SL strain.

4. Vaccine group difference rMenB Lot1/ rMenB Lot2

Statistical analysis description

Comparison groups

rMenB Lot1 v rMenB Lot2

Number of subjects included in analysis

766

Analysis specification

Pre-specified

Analysis type

equivalence ^[17]

Method

Miettinen and Nurminen

Parameter type

vaccine group difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Notes
[17] - The equivalence margin was (-10%, 10%). If the two sided 95% CIs of the differences in the percentages of subjects at one month following third vaccination was within this equivalence interval for each of the two comparisons, rMenB Lot1 and rMenB Lot2 would be equivalent for 5/99 strain.

5. Vaccine group difference rMenB Lot1/ rMenB Lot3

Statistical analysis description

Comparison groups

rMenB Lot1 v rMenB Lot3

Number of subjects included in analysis

780

Analysis specification

Pre-specified

Analysis type

equivalence ^[18]

Method

Miettinen and Nurminen

Parameter type

vaccine group difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Notes
[18] - The equivalence margin was (-10%, 10%). If the two sided 95% CIs of the differences in the percentages of subjects at one month following third vaccination was within this equivalence interval for each of the two comparisons, rMenB Lot1 and rMenB Lot3 would be equivalent for 5/99 strain.

6. Vaccine group difference rMenB Lot2/ rMenB Lot3

Statistical analysis description

Comparison groups

rMenB Lot2 v rMenB Lot3

Number of subjects included in analysis

774

Analysis specification

Pre-specified

Analysis type

equivalence ^[19]

Method

Miettinen and Nurminen

Parameter type

Vaccine group difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Notes
[19] - The equivalence margin was (-10%, 10%). If the two sided 95% CIs of the differences in the percentages of subjects at one month following third vaccination was within this equivalence interval for each of the two comparisons, rMenB Lot2 and rMenB Lot3 would be equivalent for 5/99 strain.

7. Vaccine group difference rMenB Lot1/ rMenB Lot2

Statistical analysis description

Comparison groups

rMenB Lot1 v rMenB Lot2

Number of subjects included in analysis

766

Analysis specification

Pre-specified

Analysis type

equivalence ^[20]

Method

Miettinen and Nurminen

Parameter type

Vaccine group difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

Notes
[20] - The equivalence margin was (-10%, 10%). If the two sided 95% CIs of the differences in the percentages of subjects at one month following third vaccination was within this equivalence interval for each of the two comparisons, rMenB Lot1 and rMenB Lot2 would be equivalent for NZ98/254 strain.

8. Vaccine group difference rMenB Lot1/ rMenB Lot3

Statistical analysis description

Comparison groups

rMenB Lot1 v rMenB Lot3

Number of subjects included in analysis

780

Analysis specification

Pre-specified

Analysis type

equivalence ^[21]

Method

Miettinen and Nurminen

Parameter type

Vaccine group difference

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-6

upper limit

Notes
[21] - The equivalence margin was (-10%, 10%). If the two sided 95% CIs of the differences in the percentages of subjects at one month following third vaccination was within this equivalence interval for each of the two comparisons, rMenB Lot1 and rMenB Lot3 would be equivalent for NZ98/254 strain.

9. Vaccine group difference rMenB Lot2/ rMenB Lot3

Statistical analysis description

Comparison groups

rMenB Lot2 v rMenB Lot3

Number of subjects included in analysis

774

Analysis specification

Pre-specified

Analysis type

equivalence ^[22]

Method

Miettinen and Nurminen

Parameter type

Vaccine group difference

Point estimate

-4

Confidence interval

level

95%

sides

2-sided

lower limit

-9

upper limit

-1

Notes
[22] - The equivalence margin was (-10%, 10%). If the two sided 95% CIs of the differences in the percentages of subjects at one month following third vaccination was within this equivalence interval for each of the two comparisons, rMenB Lot2 and rMenB Lot3 would be equivalent for NZ98/254 strain.

Secondary: 4. Geometric Mean Human Serum Bactericidal Activity Titers After the Routine Vaccination Without rMenB OMV NZ

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End point title

4. Geometric Mean Human Serum Bactericidal Activity Titers After the Routine Vaccination Without rMenB OMV NZ ^[23]

End point description

The immunogenicity was assessed in terms of prevalence of meningococcal B antibodies as measured by the hSBA, at baseline and at one month after the third vaccination, in the subjects that received routine infant vaccines without rMenB+OMV NZ.

End point type

Secondary

End point timeframe

One month after the third vaccination

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

End point values	Routine	rMenB All - hSBA per protocol population
Number of subjects analysed	121	1160
Units: Titers
geometric mean (confidence interval 95%)
44/76-SL strain (Baseline) (N=119, 1156)	1.12 (1.04 to 1.22)	1.15 (1.12 to 1.19)
1 Month after 3rd vacc (N=117, 1149)	1.2 (1.1 to 1.31)	91 (87 to 95)
5/99 strain (Baseline) (N=120, 1154)	1.21 (1.1 to 1.33)	1.18 (1.14 to 1.22)
1 Month after 3rd vacc (N=116, 1152)	1.06 (0.97 to 1.17)	635 (606 to 665)
NZ98/254 strain (Baseline) (N=120, 1160)	1.01 (0.99 to 1.04)	1.05 (1.03 to 1.07)
1 Month after 3rd vacc (N=121, 1152)	1.04 (0.98 to 1.11)	14 (13 to 15)

No statistical analyses for this end point

Secondary: 5. Geometric Mean Concentrations After Three Doses of rMenB+OMV NZ Vaccination (Against the 287-953 Antigen)

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End point title

5. Geometric Mean Concentrations After Three Doses of rMenB+OMV NZ Vaccination (Against the 287-953 Antigen) ^[24]

End point description

The immunogenicity was evaluated to characterize the immune response against vaccine antigen 287-953, as measured by ELISA at one month after third vaccination.

End point type

Secondary

End point timeframe

One month after the third vaccination

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

End point values	rMenB Lot1	rMenB Lot2	rMenB Lot3	Routine	rMenB All - hSBA per protocol population
Number of subjects analysed	615	600	611	113	1823
Units: Concentration (IU/mL)
geometric mean (confidence interval 95%)
Baseline (N=611,596,611,113)	22 (21 to 23)	22 (21 to 22)	22 (21 to 23)	21 (20 to 21)	22 (21 to 22)
1 Month after 3rd vacc (N=615,600,608,113)	3149 (2960 to 3352)	3484 (3270 to 3712)	3103 (2915 to 3304)	22 (21 to 23)	3370 (3270 to 3472)

No statistical analyses for this end point

Secondary: 6. Geometric Mean Concentrations for Antigens (Pertussis Components) for the Routine Vaccinations

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End point title

6. Geometric Mean Concentrations for Antigens (Pertussis Components) for the Routine Vaccinations ^[25]

End point description

Immunogenicity of the pertussis components (PT, FHA, pertactin) of DTPa-HBV-IPV when given concomitantly with rMenB and PCV7 would be considered non-inferior to that of the routine vaccines given alone if the lower limit of the two-sided CI for the ratio of GMCs one month after third vaccination.

End point type

Secondary

End point timeframe

One month after the third vaccination

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

End point values	Routine	rMenB All - hSBA per protocol population
Number of subjects analysed	246	241
Units: Titers
geometric mean (confidence interval 95%)
FHA (Baseline)	9.28 (8.17 to 11)	9.98 (8.78 to 11)
FHA 1 Month after 3rd vaccination (N=244, 239)	147 (136 to 158)	123 (114 to 133)
Pertactin (Baseline)	5.36 (4.71 to 6.11)	6.3 (5.52 to 7.17)
Pertactin 1Month after 3rdvaccination (N=244, 239)	139 (126 to 155)	107 (97 to 119)
PT (Baseline)	2.82 (2.68 to 2.96)	2.82 (2.68 to 2.96)
PT 1 Month after 3rd vaccination (N=244, 239)	51 (46 to 55)	41 (37 to 44)

1. Vaccine group difference -FHA

Statistical analysis description

Immunogenicity of the pertussis components (FHA) of DTPa-HBV-IPV when given concomitantly with rMenB and PCV7 would be considered non-inferior to that of routine vaccines given alone if the lower limit of the two-sided CI for the ratio of GMCs one month after the third vaccination is ≥0.67.

Comparison groups

Routine v rMenB All - hSBA per protocol population

Number of subjects included in analysis

487

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[26]

Method

ANOVA

Parameter type

Vaccine group difference

Point estimate

0.84

Confidence interval

level

95%

sides

2-sided

lower limit

0.76

upper limit

0.94

Notes
[26] - GMCs (GMCrMenB+OMV NZlot1+lot2+lot3+InfanrixHexa / GMCInfanrixHexa)

2. Vaccine group difference - Pertactin

Statistical analysis description

Immunogenicity of the pertussis components (Pertactin) of DTPa-HBV-IPV when given concomitantly with rMenB and PCV7 would be considered non-inferior to that of routine vaccines given alone if the lower limit of the two-sided CI for the ratio of GMCs one month after the third vaccination is ≥0.67.

Comparison groups

Routine v rMenB All - hSBA per protocol population

Number of subjects included in analysis

487

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[27]

Method

ANOVA

Parameter type

Vaccine group difference

Point estimate

0.77

Confidence interval

level

95%

sides

2-sided

lower limit

0.67

upper limit

0.89

Notes
[27] - GMCs (GMCrMenB+OMV NZlot1+lot2+lot3+InfanrixHexa / GMCInfanrixHexa)

3. Vaccine group difference - PT

Statistical analysis description

Immunogenicity of the pertussis components (PT) of DTPa-HBV-IPV when given concomitantly with rMenB and PCV7 would be considered non-inferior to that of routine vaccines given alone if the lower limit of the two-sided CI for the ratio of GMCs one month after the third vaccination is ≥0.67.

Comparison groups

Routine v rMenB All - hSBA per protocol population

Number of subjects included in analysis

487

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[28]

Method

ANOVA

Parameter type

vaccine group difference

Point estimate

0.8

Confidence interval

level

95%

sides

2-sided

lower limit

0.71

upper limit

0.91

Notes
[28] - GMCs (GMCrMenB+OMV NZlot1+lot2+lot3+InfanrixHexa / GMCInfanrixHexa)

Secondary: 7. Percentages of Subjects With Antibody Response Against the Routine Antigens

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End point title

7. Percentages of Subjects With Antibody Response Against the Routine Antigens ^[29]

End point description

The immunogenicity of routine infant vaccines when given concomitantly with rMenB+OMV NZ at 2, 4, and 6 months of age, was non-inferior to that of routine infant vaccines given without rMenB+OMV NZ at 1 month after third vaccination with B pertussis, diptheria and tetanus toxoid, H influenza type b, Hepatitis B antigens as measured by ELISA (Enzyme-linked immunosorbent assay) and for polio type 1, type 2 and type 3 by neutralization test (NT)(>=1:8). Diptheria and Tetanus: primary endpoint ELISA >=0.1 (international unit -IU) IU/mL and the secondary endpoint is ELISA>=1.0 IU/mL. HepB (HBV):primary endpoint ELISA >=10mU/mL. PRP-T: primary endpoint ≥ 0.15 mcg/mL and ≥ 1.00 mcg/mL.

End point type

Secondary

End point timeframe

One month after the third vaccination

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

End point values	Routine	rMenB All - hSBA per protocol population
Number of subjects analysed	246	243
Units: Percentages of Subjects
number (confidence interval 95%)
Anti-DiphtheriaToxin ≥0.1IU/mL(Baseline) N=246,241	38 (32 to 45)	38 (32 to 44)
Anti-DiphtheriaToxin ≥0.1IU/mL(post vacc)N=244,239	100 (98 to 100)	100 (98 to 100)
Anti-DiphtheriaToxin ≥1.0 IU/mL(Baseline)N=246,241	2 (1 to 5)	2 (1 to 5)
Anti-DiphtheriaToxin ≥1.0IU/mL(post vacc)N=244,239	86 (81 to 90)	80 (75 to 85)
Anti-TetanusToxin ≥0.1IU/mL(Baseline) N=246,241	95 (91 to 97)	93 (88 to 96)
Anti-TetanusToxin ≥0.1IU/mL (post vacc)N=244,239	100 (98 to 100)	100 (98 to 100)
Anti-Tetanus Toxin ≥1.0IU/mL(Baseline)N=246,241	27 (22 to 33)	24 (18 to 30)
Anti-Tetanus Toxin ≥1.0IU/mL(post vacc) N=244,239	95 (91 to 97)	91 (86 to 94)
Polio 1 ≥1:8 (Baseline) N=246,245	72 (66 to 77)	75 (69 to 80)
Polio 1 ≥1:8 (post vacc) N=248,243	97 (94 to 99)	95 (92 to 98)
Polio 2 (Baseline) N=246,245	69 (63 to 74)	68 (62 to 74)
Polio 2 (Post vacc) N=248,243	94 (90 to 97)	88 (84 to 92)
Polio 3 (Baseline) N=246,245	49 (42 to 55)	48 (41 to 54)
Polio 3 (Post vacc) N=248,243	98 (95 to 99)	97 (94 to 99)
HBV ≥10 mIU/mL (Baseline) N=248,241	15 (10 to 20)	22 (17 to 28)
HBV ≥10 mIU/mL (Post vacc) N=252,245	100 (99 to 100)	98 (95 to 99)
Anti-PRP (HIB) ≥ 0.15μg/mL(Baseline) N=246,241	55 (49 to 62)	54 (47 to 60)
Anti-PRP (HIB) ≥ 0.15μg/mL(Post vacc) N=244,239	100 (98 to 100)	99 (97 to 100)
Anti-PRP (HIB) ≥ 1.0μg/mL(Baseline) N=246,241	10 (7 to 15)	12 (9 to 17)
Anti-PRP (HIB) ≥ 1.0μg/mL(Post vacc) N=244,239	79 (73 to 84)	79 (73 to 84)
PnC4 ≥0.35μg/mL (Baseline) N=245,243	2 (1 to 5)	2 (0 to 4)
PnC4 ≥0.35μg/mL (Post vacc) N=243,242	100 (98 to 100)	98 (95 to 99)
PnC 6B ≥0.35μg/mL (Baseline) N=245,243	16 (12 to 22)	14 (10 to 19)
PnC 6B ≥0.35μg/mL (Post vacc) N=243,242	88 (83 to 92)	90 (85 to 93)
PnC 9V ≥0.35μg/mL (Baseline) N=245,243	3 (1 to 6)	4 (2 to 7)
PnC 9V ≥0.35μg/mL (Post vacc) N=243,242	100 (98 to 100)	100 (98 to 100)
PnC 14 ≥0.35μg/mL (Baseline) N=245,243	38 (31 to 44)	33 (27 to 39)
PnC 14 ≥0.35μg/mL (Post vacc) N=243,242	97 (94 to 99)	96 (93 to 98)
PnC 18C ≥0.35μg/mL(Baseline) N=245,243	17 (12 to 22)	10 (7 to 15)
PnC 18C ≥0.35μg/mL(Post vacc) N=243,242	99 (97 to 100)	98 (96 to 100)
PnC 19F ≥0.35μg/mL(Baseline) N=245,243	21 (16 to 27)	20 (15 to 26)
PnC 19F ≥0.35μg/mL(Post vacc) N=243,242	96 (93 to 98)	96 (93 to 98)
PnC 23F ≥0.35μg/mL(Baseline) N=245,243	22 (17 to 28)	16 (12 to 21)
PnC 23F ≥0.35μg/mL(Post vacc) N= 243,242	95 (92 to 97)	92 (88 to 95)

1. Group difference for diphtheria toxoids antigen

Statistical analysis description

Immunogenicity of the routine infant vaccines, when given concomitantly with rMenB+OMV NZ at 2, 4, and 6 months of age, was considered non-inferior to that of routine infant vaccines given alone, for diphtheria toxoids antigen, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response greater than or equal to the cut-offlevel ≥0.1 IU/mL for that antigen.

Comparison groups

Routine v rMenB All - hSBA per protocol population

Number of subjects included in analysis

489

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[30]

Method

Miettinen and Nurminen

Parameter type

vaccine group difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Notes
[30] - {PConcomitant Vaccine +rMenB+OMV NZlot1+lot2+lot3 minus PConcomitant Vaccine}

2. Group difference for diphtheria toxoids antigen

Statistical analysis description

Comparison groups

Routine v rMenB All - hSBA per protocol population

Number of subjects included in analysis

489

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[31]

Method

Miettinen and Nurminen

Parameter type

vaccine group difference

Point estimate

-5

Confidence interval

level

95%

sides

2-sided

lower limit

-12

upper limit

Notes
[31] - {PConcomitant Vaccine +rMenB+OMV NZlot1+lot2+lot3 minus PConcomitant Vaccine}

3. Group difference for Tetanus toxoids antigen

Statistical analysis description

Immunogenicity of the routine infant vaccines, when given concomitantly with rMenB+OMV NZ at 2, 4, and 6 months of age, was considered non-inferior to that of routine infant vaccines given alone, for Tetanus toxoids antigen, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response greater than or equal to the cut-offlevel ≥0.1 IU/mL for that antigen.

Comparison groups

Routine v rMenB All - hSBA per protocol population

Number of subjects included in analysis

489

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[32]

Method

Miettinen and Nurminen

Parameter type

Vaccine group difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

Notes
[32] - {PConcomitant Vaccine +rMenB+OMV NZlot1+lot2+lot3 minus PConcomitant Vaccine}

4. Group difference for Tetanus toxoids antigen

Statistical analysis description

Immunogenicity of the routine infant vaccines, when given concomitantly with rMenB+OMV NZ at 2, 4, and 6 months of age, was considered non-inferior to that of routine infant vaccines given alone, for Tetanus toxoids antigen, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response greater than or equal to the cut-offlevel ≥1.0 IU/mL for that antigen.

Comparison groups

Routine v rMenB All - hSBA per protocol population

Number of subjects included in analysis

489

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[33]

Method

Miettinen and Nurminen

Parameter type

vaccine group difference

Point estimate

-4

Confidence interval

level

95%

sides

2-sided

lower limit

-9

upper limit

Notes
[33] - {PConcomitant Vaccine +rMenB+OMV NZlot1+lot2+lot3 minus PConcomitant Vaccine}

5. Group difference for polio type 1

Statistical analysis description

Immunogenicity of the polio type 1 of Diphtheria-Tetanus-Acellular Pertussis, Hepatitis B, Inactivated Poliovirus and Haemophilus influenzae type b (DTPa-HBVIPV) when given concomitantly with rMenB and Pneumococcal 7-valent conjugate vaccine (PCV7) at 2, 4, and 6 months of age was considered non-inferior to that of the confidence interval for the difference in the percentage of subjects with NT titers ≥1:8 was greater than -10%.

Comparison groups

Routine v rMenB All - hSBA per protocol population

Number of subjects included in analysis

489

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[34]

Method

Miettinen and Nurminen

Parameter type

Vaccine group difference

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-5

upper limit

Notes
[34] - {PConcomitant Vaccine +rMenB+OMV NZlot1+lot2+lot3 minus PConcomitant Vaccine}

6. Group difference for polio type 2

Statistical analysis description

Immunogenicity of the polio type 2 of Diphtheria-Tetanus-Acellular Pertussis, Hepatitis B, Inactivated Poliovirus and Haemophilus influenzae type b (DTPa-HBVIPV) when given concomitantly with rMenB and Pneumococcal 7-valent conjugate vaccine (PCV7) at 2, 4, and 6 months of age was considered non-inferior to that of the confidence interval for the difference in the percentage of subjects with NT titers ≥1:8 was greater than -10%.

Comparison groups

Routine v rMenB All - hSBA per protocol population

Number of subjects included in analysis

489

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[35]

Method

Miettinen and Nurminen

Parameter type

vaccine group difference

Point estimate

-5

Confidence interval

level

95%

sides

2-sided

lower limit

-11

upper limit

-1

Notes
[35] - {PConcomitant Vaccine +rMenB+OMV NZlot1+lot2+lot3 minus PConcomitant Vaccine}

7. Group difference for polio type 3

Statistical analysis description

Immunogenicity of the polio type 3 of Diphtheria-Tetanus-Acellular Pertussis, Hepatitis B, Inactivated Poliovirus and Haemophilus influenzae type b (DTPa-HBVIPV) when given concomitantly with rMenB and Pneumococcal 7-valent conjugate vaccine (PCV7) at 2, 4, and 6 months of age was considered non-inferior to that of the confidence interval for the difference in the percentage of subjects with NT titers ≥10.0 mIU/m was greater than -10%.

Comparison groups

Routine v rMenB All - hSBA per protocol population

Number of subjects included in analysis

489

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[36]

Method

Miettinen and Nurminen

Parameter type

vaccine group difference

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-4

upper limit

Notes
[36] - {PConcomitant Vaccine +rMenB+OMV NZlot1+lot2+lot3 minus PConcomitant Vaccine}

8. Group difference for the hepatitis B surface Ag

Statistical analysis description

Immunogenicity of the hepatitis B surface antigen component of DTPa-HBV-IPV when given concomitantly with rMenB and PCV7 vaccine at 2, 4, and 6 months of age would be considered non-inferior to that of the routine vaccinations given alone, because the lower limit of the two sided 95% confidence interval for the difference in the percentage of subjects with NT titers ≥1:8 was greater than -10%

Comparison groups

Routine v rMenB All - hSBA per protocol population

Number of subjects included in analysis

489

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[37]

Method

Miettinen and Nurminen

Parameter type

vaccine group difference

Point estimate

-2

Confidence interval

level

95%

sides

2-sided

lower limit

-5

upper limit

-1

Notes
[37] - {PConcomitant Vaccine +rMenB+OMV NZlot1+lot2+lot3 minus PConcomitant Vaccine}

9. Group difference for Anti-PRP (Hib)

Statistical analysis description

Immunogenicity of the PRP-Hib component of DTPa-HBV-IPV when given concomitantly with rMenB and PCV7 vaccine at 2, 4, and 6 months of age was considered non-inferior to that of the routine vaccinations given alone, because the lower limit of the two sided 95% confidence interval for the difference in the percentage of subjects with Hib capsular polysaccharide (PRP) antibody response greater than the protective cutoff of ≥0.15 μg/mL was greater than -10%.

Comparison groups

Routine v rMenB All - hSBA per protocol population

Number of subjects included in analysis

489

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[38]

Method

Miettinen and Nurminen

Parameter type

vaccine group difference

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-3

upper limit

Notes
[38] - {PConcomitant Vaccine +rMenB+OMV NZlot1+lot2+lot3 minus PConcomitant Vaccine}

10. Group difference for Anti-PRP (Hib)

Statistical analysis description

Comparison groups

Routine v rMenB All - hSBA per protocol population

Number of subjects included in analysis

489

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[39]

Method

Miettinen and Nurminen

Parameter type

vaccine group difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-7

upper limit

Notes
[39] - {PConcomitant Vaccine +rMenB+OMV NZlot1+lot2+lot3 minus PConcomitant Vaccine}

11. Group difference for pneumococcal antigen PnC4

Statistical analysis description

Immunogenicity of the 7 components of PCV7 when given concomitantly with rMenB and DTPa-HBV-IPV at 2, 4 and 6 months of age would be considered non-inferior to that of the routine vaccinations given alone, becaus the lower limit of the two-sided 95% confidence interval for the difference in the percentage of subjects with antibody response greater than the cutoff of ≥0.35 μg/mL was, for the pneumococcal antigen PnC4.

Comparison groups

Routine v rMenB All - hSBA per protocol population

Number of subjects included in analysis

489

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[40]

Method

Miettinen and Nurminen

Parameter type

vaccine group difference

Point estimate

-2

Confidence interval

level

95%

sides

2-sided

lower limit

-4

upper limit

Notes
[40] - {PConcomitant Vaccine +rMenB+OMV NZlot1+lot2+lot3 minus PConcomitant Vaccine}

12. Group difference for pneumococcal Ag PnC 6B

Statistical analysis description

Immunogenicity of the 7 components of PCV7 when given concomitantly with rMenB and DTPa-HBV-IPV at 2, 4, and 6 months of age was considered non-inferior to that of the routine vaccinations given alone, because the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response greater than the cutoff of ≥0.35 μg/mL, was, for PnC 6B antigen greater than -10%.

Comparison groups

Routine v rMenB All - hSBA per protocol population

Number of subjects included in analysis

489

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[41]

Method

Miettinen and Nurminen

Parameter type

vaccine group difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-4

upper limit

Notes
[41] - {PConcomitant Vaccine +rMenB+OMV NZlot1+lot2+lot3 minus PConcomitant Vaccine}

13. Group difference for pneumococcal Ag PnC 9V

Statistical analysis description

Immunogenicity of the 7 components of PCV7 when given concomitantly with rMenB and DTPa_HBV-IPV vaccine at 2, 4, and 6 months of age was considered noninferior to that of the routine vaccinations given alone, because the lower limit of the two sided 95% CI for the difference in the percentage of subjects with antibody response greater than the cutoff of ≥0.35 μg/mL, was, for PnC 9V, greater than -10%.

Comparison groups

Routine v rMenB All - hSBA per protocol population

Number of subjects included in analysis

489

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[42]

Method

Miettinen and Nurminen

Parameter type

vaccine group difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

Notes
[42] - {PConcomitant Vaccine +rMenB+OMV NZlot1+lot2+lot3 minus PConcomitant Vaccine}

14. Group difference for pneumococcal antigenPnC14

Statistical analysis description

Immunogencity of the 7 components of PCV7 vaccine when given concomitantly with rMenB and DTPa-HBV-IPV at 2, 4, and 6 months of age would be considered noninferior to that of the routine vaccinations given alone, because the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response greater than the cutoff of ≥0.35 μg/mL, was, for PnC14 antigen, greater than -10%.

Comparison groups

Routine v rMenB All - hSBA per protocol population

Number of subjects included in analysis

489

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[43]

Method

Miettinen and Nurminen

Parameter type

vaccine group difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-4

upper limit

Notes
[43] - {PConcomitant Vaccine +rMenB+OMV NZlot1+lot2+lot3 minus PConcomitant Vaccine}

15. Group difference for pneumococcal Ag PnC18C

Statistical analysis description

Comparison groups

Routine v rMenB All - hSBA per protocol population

Number of subjects included in analysis

489

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[44]

Method

Miettinen and Nurminen

Parameter type

vaccine group difference

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-3

upper limit

Notes
[44] - {PConcomitant Vaccine +rMenB+OMV NZlot1+lot2+lot3 minus PConcomitant Vaccine}

16. Group difference for pneumococcal Ag PnC19F

Statistical analysis description

Comparison groups

Routine v rMenB All - hSBA per protocol population

Number of subjects included in analysis

489

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[45]

Method

Miettinen and Nurminen

Parameter type

vaccine group difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-3

upper limit

Notes
[45] - {PConcomitant Vaccine +rMenB+OMV NZlot1+lot2+lot3 minus PConcomitant Vaccine}

17. Group difference for pneumococcal Ag PnC 23F

Statistical analysis description

Comparison groups

Routine v rMenB All - hSBA per protocol population

Number of subjects included in analysis

489

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[46]

Method

Miettinen and Nurminen

Parameter type

vaccine group difference

Point estimate

-3

Confidence interval

level

95%

sides

2-sided

lower limit

-8

upper limit

Notes
[46] - {PConcomitant Vaccine +rMenB+OMV NZlot1+lot2+lot3 minus PConcomitant Vaccine}

Secondary: 8. Percentages of Subjects With Fourfold Increase in Antibody Concentrations Against the Routine Antigens

Top of page

End point title

8. Percentages of Subjects With Fourfold Increase in Antibody Concentrations Against the Routine Antigens ^[47]

End point description

Immunogenicity was assessed in terms of the percentages of subjects with fourfold increase in antibody concentrations against the routine pertussis antigens FHA, Pertactin and PT.

End point type

Secondary

End point timeframe

One month after the third vaccination

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

End point values	Routine	rMenB All - hSBA per protocol population
Number of subjects analysed	243	238
Units: Percentages of Subjects
number (confidence interval 95%)
FHA	87 (82 to 91)	84 (79 to 88)
Pertactin	88 (84 to 92)	79 (73 to 84)
PT	95 (91 to 97)	92 (88 to 95)

1. Vaccine group difference for the FHA antigen

Statistical analysis description

Immunogenicity of the FHA antigen of DTPa-HBV-IPV when given concomitantly with rMenB and PCV7 vaccine at 2, 4 and 6 months of age was considered non-inferior to that of the routine vaccinations given alone, because the lower limit of the two-sided 95% CI for the difference in the percentage of subjects was greater than -10%.

Comparison groups

Routine v rMenB All - hSBA per protocol population

Number of subjects included in analysis

481

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[48]

Method

Miettinen and Nurminen

Parameter type

Vaccine group difference

Point estimate

-3

Confidence interval

level

95%

sides

2-sided

lower limit

-9

upper limit

Notes
[48] - {PConcomitant Vaccine +rMenB+OMV NZlot1+lot2+lot3 minus PConcomitant Vaccine}

2. Vaccine group difference for the Pertactin Ag

Statistical analysis description

Immunogenicity of the Pertactin antigen of DTPa-HBV-IPV when given concomitantly with rMenB and PCV7 vaccine at 2, 4 and 6 months of age was considered non-inferior to that of the routine vaccinations given alone, because the lower limit of the two-sided 95% CI for the difference in the percentage of subjects was greater than -10%.

Comparison groups

Routine v rMenB All - hSBA per protocol population

Number of subjects included in analysis

481

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[49]

Method

Miettinen and Nurminen

Parameter type

Vaccine group difference

Point estimate

-9

Confidence interval

level

95%

sides

2-sided

lower limit

-16

upper limit

-3

Notes
[49] - {PConcomitant Vaccine +rMenB+OMV NZlot1+lot2+lot3 minus PConcomitant Vaccine}

3. Vaccine group difference for the PT antigen

Statistical analysis description

Immunogenicity of the PT antigen of DTPa-HBV-IPV when given concomitantly with rMenB and PCV7 vaccine at 2, 4 and 6 months of age was considered non-inferior to that of the routine vaccinations given alone, because the lower limit of the two-sided 95% CI for the difference in the percentage of subjects was greater than -10%.

Comparison groups

Routine v rMenB All - hSBA per protocol population

Number of subjects included in analysis

481

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[50]

Method

Miettinen and Nurminen

Parameter type

Vaccine group difference

Point estimate

-2

Confidence interval

level

95%

sides

2-sided

lower limit

-7

upper limit

Notes
[50] - {PConcomitant Vaccine +rMenB+OMV NZlot1+lot2+lot3 minus PConcomitant Vaccine}

Secondary: 9. Percentages of Subjects With Fourfold Rise in hSBA Titers After Three Doses of rMenB+OMV NZ Vaccination

Top of page

End point title

9. Percentages of Subjects With Fourfold Rise in hSBA Titers After Three Doses of rMenB+OMV NZ Vaccination ^[51]

End point description

Immunogenicity was assessed in terms of the percentages of subjects with fourfold rise in hSBA titers after the three doses of rMenB+OMV NZ (lot 1 or lot 2 or lot 3) vaccination at 2, 4 and 6 months of age.

End point type

Secondary

End point timeframe

One month after the third vaccination

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

End point values	rMenB Lot1	rMenB Lot2	rMenB Lot3	Routine	rMenB All - hSBA per protocol population
Number of subjects analysed	370	359	376	114	1102
Units: Percentages of Subjects
number (confidence interval 95%)
44/76-SL(N=369,356,373,111,1098)	99 (97 to 100)	100 (99 to 100)	98 (97 to 99)	1 (0.023 to 5)	99 (98 to 100)
5/99(N=370,359,369,111,1098)	100 (99 to 100)	100 (99 to 100)	99 (98 to 100)	2 (0 to 6)	100 (99 to 100)
NZ98/254(N=369,357,376,114,1102)	70 (66 to 75)	69 (64 to 74)	75 (70 to 79)	1 (0.022 to 5)	71 (69 to 74)

No statistical analyses for this end point

Secondary: 10. Percentage of Subjects With hSBA Titers ≥1:8

Top of page

End point title

10. Percentage of Subjects With hSBA Titers ≥1:8 ^[52]

End point description

Immunogenicity was assesed in terms of the percentages of subjects achieving hSBA titers ≥1:8 at one month after third vaccination with rMenB (lot 1 or lot 2 or lot 3) against the three vaccine strains.

End point type

Secondary

End point timeframe

One month after the third vaccination

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

End point values	rMenB Lot1	rMenB Lot2	rMenB Lot3	Routine	rMenB All - hSBA per protocol population
Number of subjects analysed	385	379	394	119	1156
Units: Percentages of Subjects
number (confidence interval 95%)
44/76-SL (Baseline)(N=283, 379,394,119,1156)	2 (1 to 4)	2 (1 to 3)	2 (1 to 4)	2 (0 to 6)	2 (1 to 3)
1 Month after 3rd vacc(N=384,377,388,117,1149)	100 (99 to 100)	100 (99 to 100)	99 (98 to 100)	1 (0.022 to 5)	100 (99 to 100)
5/99 (Baseline)(N=385, 379, 390, 120, 1154)	3 (1 to 5)	3 (1 to 5)	2 (1 to 4)	2 (0 to 6)	3 (2 to 4)
1 Month after 3rd vacc(N=384, 380, 388, 116, 1152)	100 (99 to 100)	100 (99 to 100)	99 (98 to 100)	2 (0 to 6)	100 (99 to 100)
NZ98/254 (Baseline)(N=386, 380, 394, 120, 1160)	1 (0.063 to 2)	1 (0 to 3)	1 (0.0064 to 1)	0 (0 to 3)	1 (0 to 1)
1 Month after 3rd vacc(N=385, 378, 389, 121, 1152)	70 (66 to 75)	70 (65 to 74)	75 (70 to 79)	1 (0.021 to 5)	72 (69 to 74)

No statistical analyses for this end point

Secondary: 11. Number of Subjects Reporting Solicited Adverse Events After Receiving Three Doses of rMenB+OMV NZ Vaccine

Top of page

End point title

11. Number of Subjects Reporting Solicited Adverse Events After Receiving Three Doses of rMenB+OMV NZ Vaccine ^[53]

End point description

The safety and tolerability of three doses of rMenB+OMV NZ when given concomitantly with routine infant vaccines at 2, 4 and 6 months of age was assessed by the number of subjects reporting solicited local and systemic adverse events.

End point type

Secondary

End point timeframe

Up to 7 days after any vaccination

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

End point values	MenC + Routine	rMenB All Safety population
Number of subjects analysed	490	2479
Units: Participants
Any Local	443	2388
Injection site tenderness	266	2147
Injection site erythema	261	2049
Injection site induration	227	1908
Injection site swelling	84	1174
Any Systemic	459	2450
Change in Eating Habits	257	1787
Sleepiness	353	2159
Vomiting	116	662
Diarrhea	164	1086
Irritability	370	2296
Unusual Crying	352	2109
Rash	43	318
Fever >= 38.5C	228	1912
Others	325	2302
Medical Attend. Fever	16	57
Analg. Antipyr. Med.Used	325	2302
Antipyr. Med.Used	314	2240

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

All serious adverse events and medically attended adverse events are collected from Day 8 after each vaccination to next vaccination or to 30 days after the last vaccination.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

12.1

Reporting group title

rMenB Lot2

Reporting group description

Subjects received one injection of rMenB+OMV NZ (Lot 2) at 2, 4, 6 months of age concomitantly with the routinely administered infant vaccines.

Reporting group title

rMenB Lot1

Reporting group description

Subjects received one injection of rMenB+OMV NZ (Lot 1) at 2, 4, 6 months of age concomitantly with the routinely administered infant vaccines.

Reporting group title

MenC + Routine

Reporting group description

Subjects received the routinely administered infant vaccines and MenC vaccine at 2, 4 and 6 months of age.

Reporting group title

rMenB Lot3

Reporting group description

Subjects received one injection of rMenB+OMV NZ (Lot 3) at 2, 4, 6 months of age concomitantly with the routinely administered infant vaccines.

Reporting group title

Routine

Reporting group description

Subjects received the routinely administered infant vaccines at 2, 4, 6 months of age

Serious adverse events	rMenB Lot2	rMenB Lot1	MenC + Routine	rMenB Lot3	Routine
Total subjects affected by serious adverse events
subjects affected / exposed	80 / 828 (9.66%)	70 / 832 (8.41%)	28 / 490 (5.71%)	60 / 820 (7.32%)	51 / 659 (7.74%)
number of deaths (all causes)	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute lymphocytic leukaemia
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	1 / 820 (0.12%)	1 / 659 (0.15%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Kawasaki's disease
subjects affected / exposed	1 / 828 (0.12%)	1 / 832 (0.12%)	1 / 490 (0.20%)	1 / 820 (0.12%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Labial frenectomy
subjects affected / exposed	0 / 828 (0.00%)	1 / 832 (0.12%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tendon operation
subjects affected / exposed	1 / 828 (0.12%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 828 (0.12%)	3 / 832 (0.36%)	0 / 490 (0.00%)	3 / 820 (0.37%)	1 / 659 (0.15%)
occurrences causally related to treatment / all	1 / 1	3 / 3	0 / 0	1 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Decreased activity
subjects affected / exposed	0 / 828 (0.00%)	1 / 832 (0.12%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Hypersensitivity
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	1 / 820 (0.12%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Milk allergy
subjects affected / exposed	1 / 828 (0.12%)	0 / 832 (0.00%)	1 / 490 (0.20%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Balanoposthitis
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	1 / 659 (0.15%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Apnoea
subjects affected / exposed	2 / 828 (0.24%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthma
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	2 / 659 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 828 (0.00%)	1 / 832 (0.12%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Irritability
subjects affected / exposed	1 / 828 (0.12%)	1 / 832 (0.12%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Breath holding
subjects affected / exposed	1 / 828 (0.12%)	0 / 832 (0.00%)	0 / 490 (0.00%)	1 / 820 (0.12%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental exposure to product
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	1 / 820 (0.12%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bone fissure
subjects affected / exposed	0 / 828 (0.00%)	1 / 832 (0.12%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Concussion
subjects affected / exposed	1 / 828 (0.12%)	0 / 832 (0.00%)	0 / 490 (0.00%)	1 / 820 (0.12%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Contusion
subjects affected / exposed	0 / 828 (0.00%)	1 / 832 (0.12%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	3 / 828 (0.36%)	1 / 832 (0.12%)	0 / 490 (0.00%)	0 / 820 (0.00%)	2 / 659 (0.30%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Foreign body
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	1 / 820 (0.12%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Head injury
subjects affected / exposed	0 / 828 (0.00%)	2 / 832 (0.24%)	1 / 490 (0.20%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skull fracture
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	1 / 490 (0.20%)	1 / 820 (0.12%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haemorrhage
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	1 / 820 (0.12%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thermal burn
subjects affected / exposed	0 / 828 (0.00%)	1 / 832 (0.12%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vaccination complication
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	1 / 820 (0.12%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Cerebral palsy
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	1 / 659 (0.15%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Congenital coronary artery malformation
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	1 / 659 (0.15%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cryptorchism
subjects affected / exposed	1 / 828 (0.12%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Faciodigitogenital dysplasia
subjects affected / exposed	0 / 828 (0.00%)	1 / 832 (0.12%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroschisis
subjects affected / exposed	1 / 828 (0.12%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hydrocele
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	1 / 820 (0.12%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Microcephaly
subjects affected / exposed	0 / 828 (0.00%)	1 / 832 (0.12%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thalassaemia beta
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	1 / 490 (0.20%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Mitral valve incompetence
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	1 / 659 (0.15%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Convulsion
subjects affected / exposed	2 / 828 (0.24%)	1 / 832 (0.12%)	1 / 490 (0.20%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	1 / 659 (0.15%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile convulsion
subjects affected / exposed	1 / 828 (0.12%)	1 / 832 (0.12%)	0 / 490 (0.00%)	3 / 820 (0.37%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Generalised tonic-clonic seizure
subjects affected / exposed	0 / 828 (0.00%)	1 / 832 (0.12%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypotonia
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	1 / 490 (0.20%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infantile spasms
subjects affected / exposed	1 / 828 (0.12%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nystagmus
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	1 / 820 (0.12%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	1 / 490 (0.20%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	1 / 659 (0.15%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aplasia pure red cell
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	1 / 659 (0.15%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Blindness
subjects affected / exposed	0 / 828 (0.00%)	1 / 832 (0.12%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Anal fissure
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	1 / 820 (0.12%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 828 (0.12%)	1 / 832 (0.12%)	0 / 490 (0.00%)	1 / 820 (0.12%)	3 / 659 (0.46%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enteritis
subjects affected / exposed	2 / 828 (0.24%)	2 / 832 (0.24%)	0 / 490 (0.00%)	0 / 820 (0.00%)	2 / 659 (0.30%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 828 (0.12%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infantile colic
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	1 / 490 (0.20%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	1 / 828 (0.12%)	0 / 832 (0.00%)	0 / 490 (0.00%)	1 / 820 (0.12%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal haemorrhage
subjects affected / exposed	1 / 828 (0.12%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intussusception
subjects affected / exposed	0 / 828 (0.00%)	1 / 832 (0.12%)	1 / 490 (0.20%)	0 / 820 (0.00%)	1 / 659 (0.15%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	0 / 828 (0.00%)	1 / 832 (0.12%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Dermatitis allergic
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	1 / 820 (0.12%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eczema nummular
subjects affected / exposed	0 / 828 (0.00%)	1 / 832 (0.12%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rash
subjects affected / exposed	0 / 828 (0.00%)	1 / 832 (0.12%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urticaria
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	1 / 820 (0.12%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Hydronephrosis
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	1 / 490 (0.20%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vesicoureteric reflux
subjects affected / exposed	0 / 828 (0.00%)	1 / 832 (0.12%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthritis
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	1 / 490 (0.20%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fistula
subjects affected / exposed	1 / 828 (0.12%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Premature closure of cranial sutures
subjects affected / exposed	1 / 828 (0.12%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tendon disorder
subjects affected / exposed	1 / 828 (0.12%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Adenovirus infection
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	1 / 659 (0.15%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	1 / 820 (0.12%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bacterial infection
subjects affected / exposed	1 / 828 (0.12%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchiolitis
subjects affected / exposed	2 / 828 (0.24%)	4 / 832 (0.48%)	2 / 490 (0.41%)	5 / 820 (0.61%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 2	0 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	12 / 828 (1.45%)	6 / 832 (0.72%)	1 / 490 (0.20%)	7 / 820 (0.85%)	11 / 659 (1.67%)
occurrences causally related to treatment / all	0 / 12	0 / 6	0 / 1	0 / 7	0 / 12
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis viral
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	1 / 820 (0.12%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	4 / 828 (0.48%)	1 / 832 (0.12%)	0 / 490 (0.00%)	1 / 820 (0.12%)	1 / 659 (0.15%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear infection
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	1 / 820 (0.12%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Exanthema subitum
subjects affected / exposed	0 / 828 (0.00%)	2 / 832 (0.24%)	1 / 490 (0.20%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile infection
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	1 / 490 (0.20%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	7 / 828 (0.85%)	12 / 832 (1.44%)	2 / 490 (0.41%)	12 / 820 (1.46%)	7 / 659 (1.06%)
occurrences causally related to treatment / all	0 / 7	0 / 12	0 / 2	0 / 12	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis adenovirus
subjects affected / exposed	1 / 828 (0.12%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis rotavirus
subjects affected / exposed	4 / 828 (0.48%)	3 / 832 (0.36%)	2 / 490 (0.41%)	1 / 820 (0.12%)	1 / 659 (0.15%)
occurrences causally related to treatment / all	0 / 4	0 / 3	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis salmonella
subjects affected / exposed	1 / 828 (0.12%)	1 / 832 (0.12%)	1 / 490 (0.20%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
H1N1 influenza
subjects affected / exposed	1 / 828 (0.12%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	1 / 820 (0.12%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infectious mononucleosis
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	1 / 820 (0.12%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	2 / 828 (0.24%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	1 / 659 (0.15%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Laryngitis
subjects affected / exposed	4 / 828 (0.48%)	7 / 832 (0.84%)	0 / 490 (0.00%)	3 / 820 (0.37%)	3 / 659 (0.46%)
occurrences causally related to treatment / all	0 / 5	0 / 7	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 828 (0.00%)	1 / 832 (0.12%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mastitis
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	1 / 820 (0.12%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mastoiditis
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	1 / 820 (0.12%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nasopharyngitis
subjects affected / exposed	1 / 828 (0.12%)	1 / 832 (0.12%)	0 / 490 (0.00%)	1 / 820 (0.12%)	2 / 659 (0.30%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Otitis media
subjects affected / exposed	2 / 828 (0.24%)	3 / 832 (0.36%)	0 / 490 (0.00%)	6 / 820 (0.73%)	3 / 659 (0.46%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 0	0 / 6	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Otitis media acute
subjects affected / exposed	1 / 828 (0.12%)	2 / 832 (0.24%)	0 / 490 (0.00%)	0 / 820 (0.00%)	1 / 659 (0.15%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pertussis
subjects affected / exposed	1 / 828 (0.12%)	1 / 832 (0.12%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	2 / 828 (0.24%)	0 / 832 (0.00%)	1 / 490 (0.20%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	4 / 828 (0.48%)	3 / 832 (0.36%)	1 / 490 (0.20%)	3 / 820 (0.37%)	2 / 659 (0.30%)
occurrences causally related to treatment / all	0 / 4	0 / 3	0 / 1	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pseudocroup
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	1 / 490 (0.20%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	3 / 828 (0.36%)	1 / 832 (0.12%)	0 / 490 (0.00%)	6 / 820 (0.73%)	2 / 659 (0.30%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0	0 / 6	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	3 / 828 (0.36%)	2 / 832 (0.24%)	0 / 490 (0.00%)	3 / 820 (0.37%)	2 / 659 (0.30%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 0	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus bronchiolitis
subjects affected / exposed	0 / 828 (0.00%)	1 / 832 (0.12%)	1 / 490 (0.20%)	0 / 820 (0.00%)	2 / 659 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	2 / 828 (0.24%)	0 / 832 (0.00%)	0 / 490 (0.00%)	1 / 820 (0.12%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	1 / 490 (0.20%)	0 / 820 (0.00%)	1 / 659 (0.15%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	1 / 820 (0.12%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tracheitis
subjects affected / exposed	1 / 828 (0.12%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	2 / 828 (0.24%)	0 / 832 (0.00%)	1 / 490 (0.20%)	0 / 820 (0.00%)	1 / 659 (0.15%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 828 (0.00%)	2 / 832 (0.24%)	3 / 490 (0.61%)	1 / 820 (0.12%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Varicella
subjects affected / exposed	0 / 828 (0.00%)	1 / 832 (0.12%)	0 / 490 (0.00%)	1 / 820 (0.12%)	0 / 659 (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	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	1 / 828 (0.12%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral pharyngitis
subjects affected / exposed	1 / 828 (0.12%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 828 (0.12%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypercholesterolaemia
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	1 / 490 (0.20%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Obesity
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	1 / 490 (0.20%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Feeding disorder of infancy or early childhood
subjects affected / exposed	1 / 828 (0.12%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	0 / 659 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Weight gain poor
subjects affected / exposed	0 / 828 (0.00%)	0 / 832 (0.00%)	0 / 490 (0.00%)	0 / 820 (0.00%)	2 / 659 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	rMenB Lot2	rMenB Lot1	MenC + Routine	rMenB Lot3	Routine
Total subjects affected by non serious adverse events
subjects affected / exposed	825 / 828 (99.64%)	827 / 832 (99.40%)	482 / 490 (98.37%)	817 / 820 (99.63%)	652 / 659 (98.94%)
Nervous system disorders
Somnolence
subjects affected / exposed	729 / 828 (88.04%)	714 / 832 (85.82%)	353 / 490 (72.04%)	716 / 820 (87.32%)	476 / 659 (72.23%)
occurrences all number	1684	1657	711	1624	914
General disorders and administration site conditions
Crying
subjects affected / exposed	711 / 828 (85.87%)	714 / 832 (85.82%)	352 / 490 (71.84%)	685 / 820 (83.54%)	424 / 659 (64.34%)
occurrences all number	1750	1740	752	1693	822
Injection site erythema
subjects affected / exposed	733 / 828 (88.53%)	729 / 832 (87.62%)	385 / 490 (78.57%)	704 / 820 (85.85%)	497 / 659 (75.42%)
occurrences all number	4135	4171	1788	4034	1792
Injection site induration
subjects affected / exposed	680 / 828 (82.13%)	692 / 832 (83.17%)	390 / 490 (79.59%)	664 / 820 (80.98%)	452 / 659 (68.59%)
occurrences all number	3915	4024	1761	3926	1741
Injection site pain
subjects affected / exposed	736 / 828 (88.89%)	736 / 832 (88.46%)	358 / 490 (73.06%)	728 / 820 (88.78%)	415 / 659 (62.97%)
occurrences all number	4497	4472	1615	4541	1364
Injection site swelling
subjects affected / exposed	466 / 828 (56.28%)	440 / 832 (52.88%)	184 / 490 (37.55%)	436 / 820 (53.17%)	254 / 659 (38.54%)
occurrences all number	1688	1683	519	1743	653
Pyrexia
subjects affected / exposed	646 / 828 (78.02%)	656 / 832 (78.85%)	248 / 490 (50.61%)	643 / 820 (78.41%)	319 / 659 (48.41%)
occurrences all number	1338	1344	425	1332	493
Vaccination site induration
subjects affected / exposed	30 / 828 (3.62%)	42 / 832 (5.05%)	51 / 490 (10.41%)	38 / 820 (4.63%)	4 / 659 (0.61%)
occurrences all number	60	76	105	74	5
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	380 / 828 (45.89%)	370 / 832 (44.47%)	168 / 490 (34.29%)	368 / 820 (44.88%)	225 / 659 (34.14%)
occurrences all number	632	607	286	624	358
Vomiting
subjects affected / exposed	234 / 828 (28.26%)	217 / 832 (26.08%)	120 / 490 (24.49%)	216 / 820 (26.34%)	108 / 659 (16.39%)
occurrences all number	329	315	178	317	149
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	58 / 828 (7.00%)	59 / 832 (7.09%)	40 / 490 (8.16%)	60 / 820 (7.32%)	43 / 659 (6.53%)
occurrences all number	66	66	51	69	48
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	119 / 828 (14.37%)	121 / 832 (14.54%)	50 / 490 (10.20%)	110 / 820 (13.41%)	88 / 659 (13.35%)
occurrences all number	168	180	79	147	116
Psychiatric disorders
Eating disorder
subjects affected / exposed	603 / 828 (72.83%)	588 / 832 (70.67%)	257 / 490 (52.45%)	596 / 820 (72.68%)	329 / 659 (49.92%)
occurrences all number	1223	1152	492	1211	580
Irritability
subjects affected / exposed	761 / 828 (91.91%)	769 / 832 (92.43%)	370 / 490 (75.51%)	766 / 820 (93.41%)	544 / 659 (82.55%)
occurrences all number	2168	2181	877	2183	1339
Infections and infestations
Bronchitis
subjects affected / exposed	98 / 828 (11.84%)	102 / 832 (12.26%)	59 / 490 (12.04%)	94 / 820 (11.46%)	97 / 659 (14.72%)
occurrences all number	132	129	80	123	125
Conjunctivitis
subjects affected / exposed	80 / 828 (9.66%)	74 / 832 (8.89%)	16 / 490 (3.27%)	77 / 820 (9.39%)	60 / 659 (9.10%)
occurrences all number	100	91	19	91	66
Ear infection
subjects affected / exposed	70 / 828 (8.45%)	86 / 832 (10.34%)	26 / 490 (5.31%)	57 / 820 (6.95%)	59 / 659 (8.95%)
occurrences all number	106	119	38	85	91
Exanthema subitum
subjects affected / exposed	47 / 828 (5.68%)	46 / 832 (5.53%)	21 / 490 (4.29%)	46 / 820 (5.61%)	38 / 659 (5.77%)
occurrences all number	47	46	21	46	38
Gastroenteritis
subjects affected / exposed	47 / 828 (5.68%)	34 / 832 (4.09%)	14 / 490 (2.86%)	38 / 820 (4.63%)	25 / 659 (3.79%)
occurrences all number	51	34	15	41	25
Nasopharyngitis
subjects affected / exposed	79 / 828 (9.54%)	78 / 832 (9.38%)	12 / 490 (2.45%)	81 / 820 (9.88%)	73 / 659 (11.08%)
occurrences all number	108	97	12	106	107
Otitis media
subjects affected / exposed	145 / 828 (17.51%)	152 / 832 (18.27%)	28 / 490 (5.71%)	156 / 820 (19.02%)	124 / 659 (18.82%)
occurrences all number	267	256	38	284	229
Rhinitis
subjects affected / exposed	99 / 828 (11.96%)	78 / 832 (9.38%)	30 / 490 (6.12%)	58 / 820 (7.07%)	63 / 659 (9.56%)
occurrences all number	120	90	33	66	84
Upper respiratory tract infection
subjects affected / exposed	126 / 828 (15.22%)	142 / 832 (17.07%)	47 / 490 (9.59%)	133 / 820 (16.22%)	94 / 659 (14.26%)
occurrences all number	172	190	59	175	124

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Were there any global substantial amendments to the protocol? Yes

14 Aug 2008

Amendment 4: This substantial amendment was mainly issued to revise the safety assessment and assessment of concomitant vaccines as requested by the US FDA Center for Biologics Evaluation & Research (CBER): The collection of safety data was revised. This included the collection of medically attended fever events and all teething and colic events fever within 7 days after each vaccination. The immunogenicity assessment of pertussis antigens was revised. The interim analysis of the first 360 subjects was not planned any longer. The localization of routine injection sites was designated. Furthermore, the exclusion criteria were revised (i.e. family and household members of research staff were excluded from participation). The temperature measurement by axillary route was allowed, if rectal measurement was not possible, and the analysis of the data described in the protocol. The severity grading of fever was aligned with other rMenB+OMV NZ trial protocols. In order to increase the validity of the safety data it was decided to replace the final study phone call by a final study visit.

29 Oct 2008

Amendment 5: This substantial amendment addressed a request from the German competent authority (PEI): The wording of the stopping rules with respect to a fatal or life-threatening event was revised. Furthermore, this amendment addressed requests from Center for Biologics Evaluation & Research (CBER): The immunogenicity of routine vaccinations was to be assessed in the same subset of subjects evaluated for rMenB+OMV NZ hSBA responses. The analysis sequence of the co-primary immunogenicity objectives was reversed (i.e., demonstration of lot-to-lot consistency before demonstration of overall immunogenicity). Moreover, the cut-off in the analysis of hSBA results was changed and based on the new hSBA results, and sample size estimates for hSBA responses against strain 5/99 have been recalculated. This amendment also clarified how subjects from each of the immunogenicity treatment groups will be assigned to the different serological tests. A secondary immunogenicity objective (ELISA testing for antigen 287-953) was added. In addition, contraindications to further vaccinations were revised. This amendment also clarifies that subjects in the safety subset will remain blinded until the study is completed and the database is unblinded. The supply of Menjugate as a booster of the study vaccinations was clarified. The enrolment of safety subjects in Finland was allowed with this amendment. In addition, administrative changes and corrections have been implemented

Were there any global interruptions to the trial? No

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

None reported

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

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Clinical trials

Clinical Trial Results:
A Phase 3, Partially Blinded, Randomized, Multi-Center, Controlled Study to Evaluate Immunogenicity, Safety and Lot to Lot Consistency of Novartis Meningococcal B Recombinant Vaccine When Administered with Routine Infant Vaccinations to Healthy Infants

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 1. The Geometric Mean Human Serum Antibatericidal Activity Titers After Three Doses of rMenB+OMV NZ Vaccination

Primary: 1. The Geometric Mean Human Serum Antibatericidal Activity Titers After Three Doses of rMenB+OMV NZ Vaccination

Primary: 2. The Percentages of Subjects With hSBA Titer ≥1:5 After Receiving Three Doses of rMenB+OMV Vaccination (3 Lots Combined)

Primary: 2. The Percentages of Subjects With hSBA Titer ≥1:5 After Receiving Three Doses of rMenB+OMV Vaccination (3 Lots Combined)

Secondary: 3. The Percentages of Subjects With hSBA Titer ≥1:5 After Receiving Three Doses of rMenB+OMV Vaccination (From 3 Lots)

Secondary: 3. The Percentages of Subjects With hSBA Titer ≥1:5 After Receiving Three Doses of rMenB+OMV Vaccination (From 3 Lots)

Secondary: 4. Geometric Mean Human Serum Bactericidal Activity Titers After the Routine Vaccination Without rMenB OMV NZ

Secondary: 4. Geometric Mean Human Serum Bactericidal Activity Titers After the Routine Vaccination Without rMenB OMV NZ

Secondary: 5. Geometric Mean Concentrations After Three Doses of rMenB+OMV NZ Vaccination (Against the 287-953 Antigen)

Secondary: 5. Geometric Mean Concentrations After Three Doses of rMenB+OMV NZ Vaccination (Against the 287-953 Antigen)

Secondary: 6. Geometric Mean Concentrations for Antigens (Pertussis Components) for the Routine Vaccinations

Secondary: 6. Geometric Mean Concentrations for Antigens (Pertussis Components) for the Routine Vaccinations

Secondary: 7. Percentages of Subjects With Antibody Response Against the Routine Antigens

Secondary: 7. Percentages of Subjects With Antibody Response Against the Routine Antigens

Secondary: 8. Percentages of Subjects With Fourfold Increase in Antibody Concentrations Against the Routine Antigens

Secondary: 8. Percentages of Subjects With Fourfold Increase in Antibody Concentrations Against the Routine Antigens

Secondary: 9. Percentages of Subjects With Fourfold Rise in hSBA Titers After Three Doses of rMenB+OMV NZ Vaccination

Secondary: 9. Percentages of Subjects With Fourfold Rise in hSBA Titers After Three Doses of rMenB+OMV NZ Vaccination

Secondary: 10. Percentage of Subjects With hSBA Titers ≥1:8

Secondary: 10. Percentage of Subjects With hSBA Titers ≥1:8

Secondary: 11. Number of Subjects Reporting Solicited Adverse Events After Receiving Three Doses of rMenB+OMV NZ Vaccine

Secondary: 11. Number of Subjects Reporting Solicited Adverse Events After Receiving Three Doses of rMenB+OMV NZ Vaccine

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

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Clinical trials

Clinical Trial Results: A Phase 3, Partially Blinded, Randomized, Multi-Center, Controlled Study to Evaluate Immunogenicity, Safety and Lot to Lot Consistency of Novartis Meningococcal B Recombinant Vaccine When Administered with Routine Infant Vaccinations to Healthy Infants

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 1. The Geometric Mean Human Serum Antibatericidal Activity Titers After Three Doses of rMenB+OMV NZ Vaccination

Primary: 1. The Geometric Mean Human Serum Antibatericidal Activity Titers After Three Doses of rMenB+OMV NZ Vaccination

Primary: 2. The Percentages of Subjects With hSBA Titer ≥1:5 After Receiving Three Doses of rMenB+OMV Vaccination (3 Lots Combined)

Primary: 2. The Percentages of Subjects With hSBA Titer ≥1:5 After Receiving Three Doses of rMenB+OMV Vaccination (3 Lots Combined)

Secondary: 3. The Percentages of Subjects With hSBA Titer ≥1:5 After Receiving Three Doses of rMenB+OMV Vaccination (From 3 Lots)

Secondary: 3. The Percentages of Subjects With hSBA Titer ≥1:5 After Receiving Three Doses of rMenB+OMV Vaccination (From 3 Lots)

Secondary: 4. Geometric Mean Human Serum Bactericidal Activity Titers After the Routine Vaccination Without rMenB OMV NZ

Secondary: 4. Geometric Mean Human Serum Bactericidal Activity Titers After the Routine Vaccination Without rMenB OMV NZ

Secondary: 5. Geometric Mean Concentrations After Three Doses of rMenB+OMV NZ Vaccination (Against the 287-953 Antigen)

Secondary: 5. Geometric Mean Concentrations After Three Doses of rMenB+OMV NZ Vaccination (Against the 287-953 Antigen)

Secondary: 6. Geometric Mean Concentrations for Antigens (Pertussis Components) for the Routine Vaccinations

Secondary: 6. Geometric Mean Concentrations for Antigens (Pertussis Components) for the Routine Vaccinations

Secondary: 7. Percentages of Subjects With Antibody Response Against the Routine Antigens

Secondary: 7. Percentages of Subjects With Antibody Response Against the Routine Antigens

Secondary: 8. Percentages of Subjects With Fourfold Increase in Antibody Concentrations Against the Routine Antigens

Secondary: 8. Percentages of Subjects With Fourfold Increase in Antibody Concentrations Against the Routine Antigens

Secondary: 9. Percentages of Subjects With Fourfold Rise in hSBA Titers After Three Doses of rMenB+OMV NZ Vaccination

Secondary: 9. Percentages of Subjects With Fourfold Rise in hSBA Titers After Three Doses of rMenB+OMV NZ Vaccination

Secondary: 10. Percentage of Subjects With hSBA Titers ≥1:8

Secondary: 10. Percentage of Subjects With hSBA Titers ≥1:8

Secondary: 11. Number of Subjects Reporting Solicited Adverse Events After Receiving Three Doses of rMenB+OMV NZ Vaccine

Secondary: 11. Number of Subjects Reporting Solicited Adverse Events After Receiving Three Doses of rMenB+OMV NZ Vaccine

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
A Phase 3, Partially Blinded, Randomized, Multi-Center, Controlled Study to Evaluate Immunogenicity, Safety and Lot to Lot Consistency of Novartis Meningococcal B Recombinant Vaccine When Administered with Routine Infant Vaccinations to Healthy Infants