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Clinical Trial Results:
A Phase IIIB, Open Label, Multi-Center Extension study of V72_28 to assess antibody persistence, and the safety and tolerability of a booster dose after the completion of the vaccination course in study V72_28.

Summary
EudraCT number	2012-000657-30
Trial protocol	HU ES
Global end of trial date	17 Nov 2015

Results information
Results version number	v1(current)
This version publication date	01 Dec 2016
First version publication date	01 Dec 2016
Other versions

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

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Trial information

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Sponsor protocol code

V72_28E1

ISRCTN number

US NCT number

NCT01894919

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Vaccines and Diagnostics

Sponsor organisation address

Via Fiorentina 1, Siena, Italy, 53100

Public contact

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

Scientific contact

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

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

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

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

Yes

Analysis stage

Final

Date of interim/final analysis

05 Oct 2016

Is this the analysis of the primary completion data?

Yes

Primary completion date

16 Sep 2015

Global end of trial reached?

Yes

Global end of trial date

17 Nov 2015

Was the trial ended prematurely?

Main objective of the trial

To evaluate the antibody persistence 24 to 36 months after the completion of the vaccination course, in subjects who participated in the V72_28 (2010-021528-81) study in Groups I to IV.

Protection of trial subjects

This clinical study was designed, implemented and reported in accordance with the International conference of Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations, Novartis codes on protection of human rights, and with the ethical principles laid down in the Declaration of Helsinki (European Council 2001, US Code of Federal Regulations, ICH 1997).

Background therapy

Evidence for comparator

Actual start date of recruitment

28 Jun 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 562

Country: Number of subjects enrolled

Hungary: 289

Worldwide total number of subjects

851

EEA total number of subjects

851

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)

Children (2-11 years)

815

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Subjects were recruited from 9 study sites in Hungary and 8 study sites in Spain.

Screening details

All enrolled subjects were included in the study.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

The trial was designed as an open-label study. Subjects were assigned to one of the vaccination group/subgroup based on the group specific inclusion criteria, using a standard web-randomization procedure.

Are arms mutually exclusive

Yes

2H3H511_V

Arm description

In the parent study V72_28, subjects had received three primary doses and one booster dose of Bexsero® vaccine, at 2.5, 3.5, 5 months of age, and at 11 months of age, respectively. The subjects in this group received a fifth dose of Bexsero® vaccine in the present study.

Arm type

Experimental

Investigational medicinal product name

Bexsero®

Investigational medicinal product code

rMenB+OMV NZ

Other name

Meningococcal Recombinant serogroup B with Outer Membrane Vesicles (OMV) Vaccine

Pharmaceutical forms

Suspension for injection in pre-filled syringe

Routes of administration

Intramuscular use

Dosage and administration details

0.5 mL

2H3H511_NV

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

3H5_11_V

Arm description

In the parent study V72_28, subjects had received two primary doses and one booster dose of Bexsero® vaccine, at 3.5, 5, and 11 months of age, respectively. These subjects received a fourth dose of Bexsero® vaccine in the present study.

Arm type

Experimental

Investigational medicinal product name

Bexsero®

Investigational medicinal product code

rMenB+OMV NZ

Other name

Meningococcal Recombinant serogroup B with Outer Membrane Vesicles (OMV) Vaccine

Pharmaceutical forms

Suspension for injection in pre-filled syringe

Routes of administration

Intramuscular use

Dosage and administration details

0.5 mL

3H5_11_NV

Arm description

In the parent study V72_28, subjects had received two primary doses and one booster dose of Bexsero® vaccine, at 3.5, 5, and 11 months of age, respectively. These subjects were evaluated only for persistence.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

68_11_V

Arm description

In the parent study V72_28, subjects had received two primary doses and one booster dose of Bexsero® vaccine, at 6, 8, and 11 months of age, respectively. These subjects received a fourth dose of Bexsero® vaccine in the present study.

Arm type

Experimental

Investigational medicinal product name

Bexsero®

Investigational medicinal product code

rMenB+OMV NZ

Other name

Meningococcal Recombinant serogroup B with Outer Membrane Vesicles (OMV) Vaccine

Pharmaceutical forms

Suspension for injection in pre-filled syringe

Routes of administration

Intramuscular use

Dosage and administration details

0.5 mL

68_11_NV

Arm description

In the parent study V72_28, subjects had received two primary doses and one booster dose of Bexsero® vaccine, at 6, 8, and 11 months of age, respectively. These subjects were evaluated only for persistence.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

02_2_5_V

Arm description

In the parent study V72_28, subjects had received two catch-up doses of Bexsero® vaccine, two months apart. These subjects received a third dose of Bexsero® vaccine in the present study.

Arm type

Experimental

Investigational medicinal product name

Bexsero®

Investigational medicinal product code

rMenB+OMV NZ

Other name

Meningococcal Recombinant serogroup B with Outer Membrane Vesicles (OMV) Vaccine

Pharmaceutical forms

Suspension for injection in pre-filled syringe

Routes of administration

Intramuscular use

Dosage and administration details

0.5 mL

02_2_5_NV

Arm description

In the parent study V72_28, subjects received two catch-up doses of Bexsero® vaccine, two months apart. These subjects were evaluated only for persistence.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

02_6_10_V

Arm description

In the parent study V72_28, subjects had received two catch-up doses of Bexsero® vaccine, two months apart. These subjects received a third dose of Bexsero® vaccine in the present study.

Arm type

Experimental

Investigational medicinal product name

Bexsero®

Investigational medicinal product code

rMenB+OMV NZ

Other name

Meningococcal Recombinant serogroup B with Outer Membrane Vesicles (OMV) Vaccine

Pharmaceutical forms

Suspension for injection in pre-filled syringe

Routes of administration

Intramuscular use

Dosage and administration details

0.5 mL

02_6_10_NV

Arm description

In the parent study V72_28, subjects had received two catch-up doses of Bexsero® vaccine, two months apart. These subjects were evaluated only for persistence.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

NAIVE_123

Arm description

Newly recruited naïve subjects who received two catch-up doses of Bexsero® vaccine, one month apart, in the present study.

Arm type

Experimental

Investigational medicinal product name

Bexsero®

Investigational medicinal product code

rMenB+OMV NZ

Other name

Meningococcal Recombinant serogroup B with Outer Membrane Vesicles (OMV) Vaccine

Pharmaceutical forms

Suspension for injection in pre-filled syringe

Routes of administration

Intramuscular use

Dosage and administration details

0.5 mL

NAIVE_4A

Arm description

Newly recruited naïve subjects who received two catch-up doses of Bexsero® vaccine, one month apart, in the present study.

Arm type

Experimental

Investigational medicinal product name

Bexsero®

Investigational medicinal product code

rMenB+OMV NZ

Other name

Meningococcal Recombinant serogroup B with Outer Membrane Vesicles (OMV) Vaccine

Pharmaceutical forms

Suspension for injection in pre-filled syringe

Routes of administration

Intramuscular use

Dosage and administration details

0.5 mL

NAIVE_4B

Arm description

Newly recruited naïve subjects who received two catch-up doses of Bexsero® vaccine, one month apart, in the present study.

Arm type

Experimental

Investigational medicinal product name

Bexsero®

Investigational medicinal product code

rMenB+OMV NZ

Other name

Meningococcal Recombinant serogroup B with Outer Membrane Vesicles (OMV) Vaccine

Pharmaceutical forms

Suspension for injection in pre-filled syringe

Routes of administration

Intramuscular use

Dosage and administration details

0.5 mL

Number of subjects in period 1	2H3H511_V	2H3H511_NV	3H5_11_V	3H5_11_NV	68_11_V	68_11_NV	02_2_5_V	02_2_5_NV	02_6_10_V	02_6_10_NV	NAIVE_123	NAIVE_4A	NAIVE_4B
Started	98	47	89	43	81	39	32	36	91	90	100	55	50
Completed	96	47	89	43	78	39	32	36	91	89	98	55	50
Not completed	2	0	0	0	3	0	0	0	0	1	2	0	0
Consent withdrawn by subject	1	-	-	-	1	-	-	-	-	1	1	-	-
Adverse event, non-fatal	-	-	-	-	-	-	-	-	-	-	1	-	-
Unspecified	1	-	-	-	-	-	-	-	-	-	-	-	-
Lost to follow-up	-	-	-	-	2	-	-	-	-	-	-	-	-

Baseline characteristics

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Reporting group title

2H3H511_V

Reporting group description

Reporting group title

2H3H511_NV

Reporting group description

Reporting group title

3H5_11_V

Reporting group description

Reporting group title

3H5_11_NV

Reporting group description

Reporting group title

68_11_V

Reporting group description

Reporting group title

68_11_NV

Reporting group description

Reporting group title

02_2_5_V

Reporting group description

In the parent study V72_28, subjects had received two catch-up doses of Bexsero® vaccine, two months apart. These subjects received a third dose of Bexsero® vaccine in the present study.

Reporting group title

02_2_5_NV

Reporting group description

In the parent study V72_28, subjects received two catch-up doses of Bexsero® vaccine, two months apart. These subjects were evaluated only for persistence.

Reporting group title

02_6_10_V

Reporting group description

In the parent study V72_28, subjects had received two catch-up doses of Bexsero® vaccine, two months apart. These subjects received a third dose of Bexsero® vaccine in the present study.

Reporting group title

02_6_10_NV

Reporting group description

In the parent study V72_28, subjects had received two catch-up doses of Bexsero® vaccine, two months apart. These subjects were evaluated only for persistence.

Reporting group title

NAIVE_123

Reporting group description

Newly recruited naïve subjects who received two catch-up doses of Bexsero® vaccine, one month apart, in the present study.

Reporting group title

NAIVE_4A

Reporting group description

Newly recruited naïve subjects who received two catch-up doses of Bexsero® vaccine, one month apart, in the present study.

Reporting group title

NAIVE_4B

Reporting group description

Newly recruited naïve subjects who received two catch-up doses of Bexsero® vaccine, one month apart, in the present study.

Reporting group values	2H3H511_V	2H3H511_NV	3H5_11_V	3H5_11_NV	68_11_V	68_11_NV	02_2_5_V	02_2_5_NV	02_6_10_V	02_6_10_NV	NAIVE_123	NAIVE_4A	NAIVE_4B	Total
Number of subjects	98	47	89	43	81	39	32	36	91	90	100	55	50	851
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Children (2-11 years)	98	47	89	43	81	39	32	36	74	73	100	55	48	815
Adolescents (12-17 years)	0	0	0	0	0	0	0	0	17	17	0	0	2	36
Adults (18-64 years)	0	0	0	0	0	0	0	0	0	0	0	0	0	0
From 65-84 years	0	0	0	0	0	0	0	0	0	0	0	0	0	0
85 years and over	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	3.1 ( 0.2 )	3 ( 0.18 )	3.1 ( 0.23 )	3.1 ( 0.22 )	3.2 ( 0.29 )	3.2 ( 0.26 )	6.5 ( 1.15 )	6.7 ( 1.16 )	10.4 ( 1.43 )	10.4 ( 1.44 )	3.4 ( 0.29 )	5.8 ( 1.12 )	9.7 ( 1.38 )	-
Gender categorical
Units: Subjects
Female	44	27	48	22	35	23	19	15	44	46	46	26	27	422
Male	54	20	41	21	46	16	13	21	47	44	54	29	23	429

Subject analysis set title

2H3H511

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Combined 2H3H511_V group + 2H3H511_NV group - subjects who received three primary doses and one booster dose of Bexsero® vaccine, at 2.5, 3.5, 5, and 11 months of age, respectively, in the parent study V72_28.

Subject analysis set title

3H5_11

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Combined 3H5_11_V group + 3H5_11_NV group - subjects who received two primary doses and one booster dose of Bexsero® vaccine, at 3.5, 5, and 11 months of age, respectively, in the parent study V72_28.

Subject analysis set title

68_11

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Combined 68_11_V group + 68_11_NV group - subjects who received two primary doses and one booster dose of Bexsero® vaccine, at 6, 8, and 11 months of age, respectively, in the parent study V72_28.

Subject analysis set title

02_2_5

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Combined 02_2_5_V group + 02_2_5_NV group - subjects who received two catch-up doses of Bexsero® vaccine two months apart, at 2 and 5 years of age, respectively, in the parent study V72_28.

Subject analysis set title

02_6_10

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Combined 02_6_10_V group + 02_6_10_NV group - subjects who received two catch-up doses of Bexsero® vaccine two months apart, at 6 and 10 years of age, respectively, in the parent study V72_28.

Subject analysis sets values	2H3H511	3H5_11	68_11	02_2_5	02_6_10
Number of subjects	140	131	119	68	179
Age categorical
Units: Subjects
In utero	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0
Children (2-11 years)	140	131	119	68	146
Adolescents (12-17 years)	0	0	0	0	33
Adults (18-64 years)	0	0	0	0	0
From 65-84 years	0	0	0	0	0
85 years and over	0	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	3 ( 0.19 )	3.1 ( 0.23 )	3.2 ( 0.28 )	6.6 ( 1.15 )	10.4 ( 1.43 )
Gender categorical
Units: Subjects
Female	67	70	58	34	89
Male	73	61	61	34	90

End points

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Reporting group title

2H3H511_V

Reporting group description

Reporting group title

2H3H511_NV

Reporting group description

Reporting group title

3H5_11_V

Reporting group description

Reporting group title

3H5_11_NV

Reporting group description

Reporting group title

68_11_V

Reporting group description

Reporting group title

68_11_NV

Reporting group description

Reporting group title

02_2_5_V

Reporting group description

In the parent study V72_28, subjects had received two catch-up doses of Bexsero® vaccine, two months apart. These subjects received a third dose of Bexsero® vaccine in the present study.

Reporting group title

02_2_5_NV

Reporting group description

In the parent study V72_28, subjects received two catch-up doses of Bexsero® vaccine, two months apart. These subjects were evaluated only for persistence.

Reporting group title

02_6_10_V

Reporting group description

In the parent study V72_28, subjects had received two catch-up doses of Bexsero® vaccine, two months apart. These subjects received a third dose of Bexsero® vaccine in the present study.

Reporting group title

02_6_10_NV

Reporting group description

In the parent study V72_28, subjects had received two catch-up doses of Bexsero® vaccine, two months apart. These subjects were evaluated only for persistence.

Reporting group title

NAIVE_123

Reporting group description

Newly recruited naïve subjects who received two catch-up doses of Bexsero® vaccine, one month apart, in the present study.

Reporting group title

NAIVE_4A

Reporting group description

Newly recruited naïve subjects who received two catch-up doses of Bexsero® vaccine, one month apart, in the present study.

Reporting group title

NAIVE_4B

Reporting group description

Newly recruited naïve subjects who received two catch-up doses of Bexsero® vaccine, one month apart, in the present study.

Subject analysis set title

2H3H511

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

3H5_11

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

68_11

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Combined 68_11_V group + 68_11_NV group - subjects who received two primary doses and one booster dose of Bexsero® vaccine, at 6, 8, and 11 months of age, respectively, in the parent study V72_28.

Subject analysis set title

02_2_5

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Combined 02_2_5_V group + 02_2_5_NV group - subjects who received two catch-up doses of Bexsero® vaccine two months apart, at 2 and 5 years of age, respectively, in the parent study V72_28.

Subject analysis set title

02_6_10

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Combined 02_6_10_V group + 02_6_10_NV group - subjects who received two catch-up doses of Bexsero® vaccine two months apart, at 6 and 10 years of age, respectively, in the parent study V72_28.

Primary: 1. Percentage of subjects with human serum bactericidal activity titers (hSBA) ≥ 4 or ≥ 5 against Neisseria meningitidis (N. meningitidis) serogroup B strains

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End point title

1. Percentage of subjects with human serum bactericidal activity titers (hSBA) ≥ 4 or ≥ 5 against Neisseria meningitidis (N. meningitidis) serogroup B strains ^[1] ^[2]

End point description

The antibody persistence in subjects, 24 to 36 months after completion of Bexsero® vaccination course in the parent study according to different schedules, is presented in terms of the percentage of subjects in each vaccine group, with hSBA titers ≥ 4 for what concerns the H44/76, 5/99 and NZ98/254 strains, and hSBA titers ≥ 5 for M10713 strain, alongside with the corresponding antibody responses in age-matched vaccine-naïve subjects at Baseline. The functional bactericidal antibodies directed against serogroup B meningococcal were assessed by the Serum Bactericidal Assay (SBA) using human serum as the source of exogenous complement (hSBA). The analysis was performed on the Full analysis set (FAS)-persistence population, which included all subjects in the Enrolled Set who provided an evaluable serum sample at Visit 1.

End point type

Primary

End point timeframe

24 or 36 months after booster dose in the parent study; Baseline for vaccine-naïve subjects

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The scope of this primary end point was descriptive, no statistical hypothesis test was performed.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results in this study were tabulated by age group and study period. Hence for each related endpoint, they are presented for only the respective groups in the baseline period, while the results for multiple endpoints account for all baseline groups.

End point values	NAIVE_123	NAIVE_4A	NAIVE_4B	2H3H511	3H5_11	68_11	02_2_5	02_6_10
Number of subjects analysed	100	55	50	140	131	119	68	179
Units: Percentage
number (confidence interval 95%)
H44/76 (N=100;55;50;140;131;119;67;178)	38 (28.5 to 48.3)	27 (16.1 to 41)	20 (10 to 33.7)	51 (42.8 to 60)	53 (43.8 to 61.5)	61 (52 to 70.1)	52 (39.7 to 64.6)	58 (50.3 to 65.2)
5/99 (N=100;55;50;140;131;119;67;179)	3 (0.6 to 8.5)	4 (0.44 to 12.5)	8 (2.2 to 19.2)	84 (77.2 to 89.9)	88 (80.9 to 92.9)	93 (87.2 to 97.1)	79 (67.4 to 88.1)	85 (79.4 to 90.3)
NZ98/254 (N=100;55;50;140;131;119;68;179)	2 (0.24 to 7)	7 (2 to 17.6)	6 (1.3 to 16.5)	45 (36.6 to 53.6)	38 (29.8 to 47.1)	56 (46.9 to 65.4)	29 (19 to 41.7)	50 (42.2 to 57.3)
M10713 (N=93;53;49;127;111;109;65;173)	37 (26.8 to 47.2)	38 (24.8 to 52.1)	55 (40.2 to 69.3)	31 (22.8 to 39.5)	36 (27.1 to 45.7)	39 (29.4 to 48.3)	34 (22.6 to 46.6)	61 (53 to 68)

No statistical analyses for this end point

Primary: 2. Percentage of subjects with hSBA titers ≥ 8 against N.meningitidis serogroup B strains

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End point title

2. Percentage of subjects with hSBA titers ≥ 8 against N.meningitidis serogroup B strains ^[3] ^[4]

End point description

The antibody persistence in subjects, 24 to 36 months after completion of Bexsero® vaccination course in the parent study according to different schedules, is presented in terms of the percentage of subjects in each vaccine group with hSBA titers ≥ 8, alongside with the corresponding antibody responses in age-matched vaccine-naïve subjects at Baseline. The analysis was performed on the FAS-Antibody persistence population, which included all subjects in the Enrolled Set who provided an evaluable serum sample at Visit 1.

End point type

Primary

End point timeframe

24-36 months after booster dose in the parent study; Baseline for vaccine-naïve subjects

Notes
[3] - 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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results in this study were tabulated by age group and study period. Hence for each related endpoint, they are presented for only the respective groups in the baseline period, while the results for multiple endpoints account for all baseline groups.

End point values	NAIVE_123	NAIVE_4A	NAIVE_4B	2H3H511	3H5_11	68_11	02_2_5	02_6_10
Number of subjects analysed	100	55	50	140	131	119	68	179
Units: Percentage
number (confidence interval 95%)
H44/76 (N=100;55;50;140;131;119;67;178)	18 (11 to 26.9)	16 (7.8 to 28.8)	10 (3.3 to 21.8)	28 (20.6 to 36.1)	26 (18.7 to 34.3)	32 (23.7 to 41.1)	24 (14.3 to 35.9)	34 (26.8 to 41.2)
5/99 (N=100;55;50;140;131;119;67;179)	2 (0.24 to 7)	4 (0.44 to 12.5)	6 (1.3 to 16.5)	80 (72.4 to 86.3)	82 (74.8 to 88.5)	89 (82 to 94.1)	73 (60.9 to 83.2)	66 (59.1 to 73.3)
NZ98/254 (N=100;55;50;140;131;119;68;179)	0 (0 to 3.6)	2 (0.05 to 9.7)	0 (0 to 7.1)	21 (14.9 to 29.2)	18 (12.1 to 26)	29 (20.7 to 37.6)	15 (7.3 to 25.4)	28 (21.5 to 35.1)
M10713 (N=93;53;49;127;111;109;65;173)	26 (17.3 to 35.9)	36 (23.1 to 50.2)	49 (34.4 to 63.7)	24 (16.5 to 32)	22 (14.4 to 30.4)	28 (20.2 to 37.9)	31 (19.9 to 43.4)	54 (46 to 61.4)

No statistical analyses for this end point

Primary: 3. The hSBA geometric mean titers (GMTs) against N.meningitidis serogroup B strains

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End point title

3. The hSBA geometric mean titers (GMTs) against N.meningitidis serogroup B strains ^[5] ^[6]

End point description

The hSBA antibody titers in subjects, 24 to 36 months after completion of Bexsero® vaccination course according to different schedules in the parent study, are presented in terms of vaccine-group-specific GMTs, alongside with the corresponding antibody responses in age-matched vaccine-naïve subjects at Baseline. The analysis was performed on the FAS-Antibody persistence population, which included all subjects in the Enrolled Set who provided an evaluable serum sample at Visit 1.

End point type

Primary

End point timeframe

24-36 months after booster dose in the parent study; Baseline for vaccine-naïve subjects

Notes
[5] - 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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results in this study were tabulated by age group and study period. Hence for each related endpoint, they are presented for only the respective groups in the baseline period, while the results for multiple endpoints account for all baseline groups.

End point values	NAIVE_123	NAIVE_4A	NAIVE_4B	2H3H511	3H5_11	68_11	02_2_5	02_6_10
Number of subjects analysed	100	55	50	140	131	119	68	179
Units: Titers
geometric mean (confidence interval 95%)
H44/76 (N=100;55;50;140;131;119;67;178)	2.79 (2.25 to 3.45)	2.33 (1.77 to 3.07)	1.93 (1.39 to 2.68)	4.17 (3.4 to 5.13)	4.48 (3.6 to 5.57)	5.62 (4.48 to 7.04)	3.97 (2.99 to 5.28)	5.75 (4.78 to 6.91)
5/99 (N=100;55;50;140;131;119;67;179)	1.15 (1.03 to 1.29)	1.2 (0.96 to 1.51)	1.38 (1.1 to 1.73)	44 (32 to 60)	52 (37 to 72)	83 (58 to 117)	21 (14 to 33)	21 (16 to 28)
NZ98/254 (N=100;55;50;140;131;119;68;179)	1.14 (1.06 to 1.22)	1.37 (1.17 to 1.61)	1.22 (1.06 to 1.41)	3.48 (2.78 to 4.36)	2.98 (2.35 to 3.78)	4.86 (3.8 to 6.22)	2.81 (2.07 to 3.82)	4.57 (3.74 to 5.59)
M10713 (N=93;53;49;127;111;109;65;173)	3.3 (2.52 to 4.32)	4.26 (2.61 to 6.97)	6.95 (4.18 to 12)	2.77 (2.06 to 3.71)	3.03 (2.2 to 4.16)	3.17 (2.3 to 4.38)	3.53 (2.38 to 5.25)	7.82 (6.04 to 10)

No statistical analyses for this end point

Primary: 4. The geometric mean ratio (GMR) of hSBA GMTs against N. meningitidis serogroup B strains

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End point title

4. The geometric mean ratio (GMR) of hSBA GMTs against N. meningitidis serogroup B strains ^[7]

End point description

The within-subjects GMR of GMTs at 24 to 36 months versus one month after completion of Bexsero® vaccination course according to different schedules vaccination in the parent study are reported. The analysis was performed on the FAS-Antibody persistence population, which included all subjects in the Enrolled Set who provided an evaluable serum sample at Visit 1.

End point type

Primary

End point timeframe

Day 1 in the present study over one month after the completion of the vaccination course in the parent study

Notes
[7] - 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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed.

End point values	2H3H511	3H5_11	68_11	02_2_5	02_6_10
Number of subjects analysed	137	130	118	68	176
Units: Ratio
geometric mean (confidence interval 95%)
H44/76 (N=137;129;118;67;173)	0.029 (0.023 to 0.036)	0.022 (0.017 to 0.028)	0.03 (0.023 to 0.038)	0.028 (0.021 to 0.038)	0.042 (0.035 to 0.052)
5/99 (N=136;130;118;66;176)	0.023 (0.017 to 0.03)	0.031 (0.023 to 0.041)	0.054 (0.04 to 0.073)	0.045 (0.031 to 0.066)	0.049 (0.038 to 0.063)
NZ98/254 (N=136;129;116;68;174)	0.059 (0.047 to 0.074)	0.038 (0.03 to 0.048)	0.07 (0.055 to 0.09)	0.061 (0.044 to 0.083)	0.095 (0.077 to 0.12)
M10713 (N=105;84;78;61;160)	0.19 (0.13 to 0.28)	0.16 (0.11 to 0.25)	0.19 (0.12 to 0.29)	0.17 (0.11 to 0.28)	0.24 (0.17 to 0.32)

No statistical analyses for this end point

Primary: 5. The GMR of hSBA GMTs against N. meningitidis serogroup B strains

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End point title

5. The GMR of hSBA GMTs against N. meningitidis serogroup B strains ^[8]

End point description

The within-subjects GMR of GMTs, at 24 to 36 months versus Visit 1 in the vaccination course according to different schedules vaccination in the parent study, are reported. The analysis was performed on the FAS-Antibody persistence population, which included all subjects in the Enrolled Set who provided an evaluable serum sample at Visit 1.

End point type

Primary

End point timeframe

Day 1 in the present study over Visit 1 in the vaccination course of the parent study

Notes
[8] - 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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed.

End point values	02_2_5	02_6_10
Number of subjects analysed	67	177
Units: Ratio
geometric mean (confidence interval 95%)
H44/76 (N=67;177)	1.88 (1.32 to 2.69)	2.94 (2.33 to 3.71)
5/99 (N=67;177)	20 (12 to 32)	14 (10 to 20)
NZ98/254 (N=67;177)	2.48 (1.76 to 3.49)	3.06 (2.44 to 3.83)
M10713 (N=56;163)	0.89 (0.49 to 1.61)	0.94 (0.64 to 1.37)

No statistical analyses for this end point

Secondary: 6. Number of subjects (35 months to 7 years of age) reporting solicited local and systemic adverse events (AEs)

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End point title

6. Number of subjects (35 months to 7 years of age) reporting solicited local and systemic adverse events (AEs) ^[9]

End point description

The number of subjects (35 months to 7 years of age) with solicited local and systemic AEs after receiving the Bexsero® booster vaccine in the present study. The analysis was performed on the Solicited safety set, which included all subjects in the Exposed Set with solicited adverse event data.

End point type

Secondary

End point timeframe

From Day 1 (6 hr) through Day 7 after vaccination

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results in this study were tabulated by age group and study period. Hence for each related endpoint, they are presented for only the respective groups in the baseline period, while the results for multiple endpoints account for all baseline groups.

End point values	2H3H511_V	3H5_11_V	68_11_V	02_2_5_V
Number of subjects analysed	97	89	80	32
Units: Subjects
Any local AEs	87	81	73	31
Erythema	60	63	42	22
Induration	48	48	33	15
Swelling	49	50	37	20
Tenderness	84	80	71	31
Any systemic AEs	66	63	54	18
Change in eating habits	31	32	30	5
Diarrhea	4	8	5	0
Irritability	54	52	46	9
Persistent Crying	31	24	25	4
Rash	13	1	3	5
Sleepiness	28	23	26	5
Vomiting	5	5	2	1
Fever (>38.0° C)	17	18	11	2
Medically-Attended Fever	1	0	2	0
Prevention of Pain and/or Fever	23	14	15	1
Treatment of Pain and/or Fever	38	39	41	13

No statistical analyses for this end point

Secondary: 7. Number of newly recruited subjects (aged 35 months to 7 years) reporting solicited local and systemic AEs

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End point title

7. Number of newly recruited subjects (aged 35 months to 7 years) reporting solicited local and systemic AEs ^[10]

End point description

The number of newly recruited subjects (aged 35 months to 7 years) reporting solicited local and systemic adverse events after receiving two catch-up doses of Bexsero® vaccine in the present study. The analysis was performed on the Solicited safety set, which included all subjects in the Exposed Set with solicited adverse event data.

End point type

Secondary

End point timeframe

From Day 1 (6 hr) through Day 7 after each vaccination

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results in this study were tabulated by age group and study period. Hence for each related endpoint, they are presented for only the respective groups in the baseline period, while the results for multiple endpoints account for all baseline groups.

End point values	NAIVE_123	NAIVE_4A
Number of subjects analysed	100	55
Units: Subjects
Any local AEs (1st vacc.) (N=100;55)	88	55
Erythema (1st vacc.) (N=100;55)	54	28
Induration (1st vacc.) (N=100;55)	38	17
Swelling (1st vacc.) (N=100;55)	40	24
Tenderness (1st vacc.) (N=100;55)	87	55
Any systemic AEs (1st vacc.) (N=100;55)	64	24
Change in Eating Habits (1st vacc.) (N=100;55)	31	5
Diarrhea (1st vacc.) (N=100;55)	4	3
Irritability (1st vacc.) (N=100;55)	40	16
Persistent Crying (1st vacc.) (N=100;55)	15	4
Rash (1st vacc.) (N=100;55)	5	3
Sleepiness (1st vacc.) (N=100;55)	18	9
Vomiting (1st vacc.) (N=100;55)	7	2
Fever (>38.0° C) (1st vacc.) (N=100;55)	15	2
Medically-Attended Fever (1st vacc.) (N=100;55)	1	0
Prevention of Pain/Fever (1st vacc.) (N=100;55)	18	3
Treatment of Pain/Fever (1st vacc.) (N=99;55)	41	22
Any local AEs (2nd vacc.) (N=99;55)	79	51
Erythema (2nd vacc.) (N=99;55)	44	32
Induration (2nd vacc.) (N=99;55)	29	22
Swelling (2nd vacc.) (N=99;55)	32	25
Tenderness (2nd vacc.) (N=99;55)	77	51
Any systemic AEs (2nd vacc.) (N=99;55)	46	18
Change in Eating Habits (2nd vacc.) (N=99;55)	15	9
Diarrhea (2nd vacc.) (N=99;55)	2	3
Irritability (2nd vacc.) (N=99;55)	25	11
Persistent Crying (2nd vacc.) (N=99;55)	13	6
Rash (2nd vacc.) (N=99;55)	2	1
Sleepiness (2nd vacc.) (N=99;55)	12	5
Vomiting (2nd vacc.) (N=99;55)	4	2
Fever (>38.0° C) (2nd vacc.) (N=99;55)	12	3
Medically-Attended Fever (2nd vacc.) (N=99;55)	0	1
Prevention of Pain/Fever (2nd vacc.) (N=99;55)	21	4
Treatment of Pain/Fever (2nd vacc.) (N=99;55)	30	13

No statistical analyses for this end point

Secondary: 8. Number of subjects (8 to 12 years of age) reporting solicited local and systemic AEs

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End point title

8. Number of subjects (8 to 12 years of age) reporting solicited local and systemic AEs ^[11]

End point description

The number of subjects (8 to 12 years of age) with solicited local and systemic adverse events after receiving a booster dose of Bexsero® vaccine in the present study. The analysis was performed on the Solicited safety set, which included all subjects in the Exposed Set with solicited adverse event data.

End point type

Secondary

End point timeframe

From Day 1 (6 hr) through Day 7 after vaccination

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results in this study were tabulated by age group and study period. Hence for each related endpoint, they are presented for only the respective groups in the baseline period, while the results for multiple endpoints account for all baseline groups.

End point values	02_6_10_V
Number of subjects analysed	91
Units: Subjects
Any local AEs (N=91)	85
Erythema (N=91)	57
Induration (N=91)	44
Swelling (N=91)	52
Pain (N=90)	84
Any systemic AEs (N=91)	57
Arthralgia (N=90)	18
Chills (N=90)	23
Headache (N=90)	27
Malaise (N=90)	35
Myalgia (N=90)	24
Nausea (N=90)	12
Rash (N=90)	10
Fever (>38.0° C) (N=91)	10
Medically-Attended Fever (N=91)	0
Prevention of Pain and/or Fever (N=90)	12
Treatment of Pain and/or Fever (N=91)	47

No statistical analyses for this end point

Secondary: 9. Number of newly recruited naïve subjects (aged 8 to 12 years of age) reporting solicited local and systemic AEs

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End point title

9. Number of newly recruited naïve subjects (aged 8 to 12 years of age) reporting solicited local and systemic AEs ^[12]

End point description

The number of newly recruited naïve subjects (aged 8 to 12 years of age) reporting solicited local and systemic AEs after receiving two catch-up doses of Bexsero® vaccine in the present study. The analysis was performed on the Solicited safety set, which included all subjects in the Exposed Set with solicited adverse event data.

End point type

Secondary

End point timeframe

From Day 1 (6 hr) through Day 7 after each vaccination

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results in this study were tabulated by age group and study period. Hence for each related endpoint, they are presented for only the respective groups in the baseline period, while the results for multiple endpoints account for all baseline groups.

End point values	NAIVE_4B
Number of subjects analysed	50
Units: Subjects
Any local AEs (1st vacc.) (N=50)	49
Erythema (1st vacc.) (N=50)	31
Induration (1st vacc.) (N=50)	19
Swelling (1st vacc.) (N=50)	29
Pain (1st vacc.) (N=49)	47
Any systemic AEs (1st vacc.) (N=50)	24
Arthralgia (1st vacc.) (N=49)	6
Chills (1st vacc.) (N=49)	4
Headache (1st vacc.) (N=49)	15
Malaise (1st vacc.) (N=49)	7
Myalgia (1st vacc.) (N=49)	12
Nausea (1st vacc.) (N=49)	5
Rash (1st vacc.) (N=50)	1
Fever (>38.0° C) (1st vacc.) (N=50)	3
Medically-Attended Fever (1st vacc.) (N=50)	0
Prevention of Pain and/or Fever (1st vacc.) (N=50)	2
Treatment of Pain and/or Fever (1st vacc.) (N=50)	21
Any local AEs (2nd vacc.) (N=50)	43
Erythema (2nd vacc.) (N=50)	21
Induration (2nd vacc.) (N=50)	17
Swelling (2nd vacc.) (N=50)	21
Pain (2nd vacc.) (N=50)	41
Any systemic AEs (2nd vacc.) (N=50)	25
Arthralgia (2nd vacc.) (N=50)	3
Chills (2nd vacc.) (N=50)	5
Headache (2nd vacc.) (N=50)	10
Malaise (2nd vacc.) (N=50)	13
Myalgia (2nd vacc.) (N=50)	8
Nausea (2nd vacc.) (N=50)	4
Rash (2nd vacc.) (N=50)	3
Fever (>38.0° C) (2nd vacc.) (N=50)	1
Medically-Attended Fever (2nd vacc.) (N=50)	0
Prevention of Pain and/or Fever (2nd vacc.) (N=50)	3
Treatment of Pain and/or Fever (2nd vacc.) (N=50)	12

No statistical analyses for this end point

Secondary: 10. Percentage of subjects with hSBA titers ≥ 4 or ≥ 5 against N.meningitidis serogroup B strains

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End point title

10. Percentage of subjects with hSBA titers ≥ 4 or ≥ 5 against N.meningitidis serogroup B strains ^[13]

End point description

The percentage of subjects with hSBA titers ≥ 4 against H44/76, 5/99 and NZ98/254 strains, and with hSBA titers ≥ 5 against M10713 strain, after receiving the Bexsero® booster vaccination in the present study (24 to 36 months after completion of vaccination course according to different schedules in the parent study), alongside with the corresponding response after the first dose of Bexsero® vaccine in age-matched vaccine-naïve subjects. The analysis was performed on the FAS-Booster response population, which included all subjects in the Enrolled Set who received a study vaccination, provided an evaluable serum sample at Visit 2 (one month after the booster dose administration) and received all scheduled vaccinations in the parent study V72_28 (excluding naïve groups).

End point type

Secondary

End point timeframe

At 24-36 months - Visit 1 (pre-vacc.) and one month after booster vaccination - Day 31 (post-vacc.)

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: The results in this study were tabulated by age group and study period. Hence for each related endpoint, they are presented for only the respective groups in the baseline period, while the results for multiple endpoints account for all baseline groups.

End point values	2H3H511_V	3H5_11_V	68_11_V	02_2_5_V	02_6_10_V	NAIVE_123	NAIVE_4A	NAIVE_4B
Number of subjects analysed	96	86	76	32	91	96	55	50
Units: Percentage
number (confidence interval 95%)
H44/76 (pre-vacc.) (N=92;86;75;31;91;96;55;50)	48 (37.3 to 58.5)	51 (40.1 to 62.1)	64 (52.1 to 74.8)	39 (21.8 to 57.8)	59 (48.5 to 69.5)	39 (28.8 to 49)	27 (16.1 to 41)	20 (10 to 33.7)
H44/76 (post-vacc.) (N=96;86;75;32;91;96;55;50)	99 (94.3 to 99.97)	100 (95.8 to 100)	100 (95.2 to 100)	97 (83.8 to 99.92)	99 (94 to 99.97)	95 (88.3 to 98.3)	91 (80 to 97)	80 (66.3 to 90)
5/99 (pre-vacc.) (N=92;87;76;31;91;96;55;50)	84 (74.5 to 90.6)	91 (82.7 to 95.9)	95 (87.1 to 98.5)	74 (55.4 to 88.1)	86 (76.8 to 92.2)	3 (0.6 to 8.9)	4 (0.44 to 12.5)	8 (2.2 to 19.2)
5/99 (post-vacc.) (N=96;87;76;32;91;96;55;50)	99 (94.3 to 99.97)	99 (93.8 to 99.97)	97 (90.8 to 99.68)	100 (89.1 to 100)	100 (96 to 100)	88 (79.2 to 93.4)	93 (82.4 to 98)	80 (66.3 to 90)
NZ98/254 (pre-vacc.) (N=92;86;75;32;91;96;54;50)	45 (34.2 to 55.3)	42 (31.3 to 53)	52 (40.2 to 63.7)	25 (11.5 to 43.4)	47 (36.7 to 58)	2 (0.25 to 7.3)	7 (2.1 to 17.9)	6 (1.3 to 16.5)
NZ98/254 (post-vacc.) (N=96;86;75;32;91;96;54;50)	99 (94.3 to 99.97)	100 (95.8 to 100)	100 (95.2 to 100)	100 (89.1 to 100)	100 (96 to 100)	78 (68.5 to 85.9)	85 (72.9 to 93.4)	70 (55.4 to 82.1)
M10713 (pre-vacc.) (N=78;68;65;29;87;84;49;46)	36 (25.3 to 47.6)	35 (24.1 to 47.8)	45 (32.3 to 57.5)	21 (8 to 39.7)	63 (52.2 to 73.3)	39 (28.8 to 50.5)	41 (27 to 55.8)	59 (43.2 to 73)
M10713 (post-vacc.) (N=88;79;67;30;89;88;51;47)	70 (59.8 to 79.7)	81 (70.6 to 89)	97 (89.6 to 99.64)	93 (77.9 to 99.2)	96 (88.9 to 98.8)	47 (35.9 to 57.5)	59 (44.2 to 72.4)	60 (44.3 to 73.6)

No statistical analyses for this end point

Secondary: 11. Percentage of subjects with hSBA titers ≥ 8 against N.meningitidis serogroup B strains

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End point title

11. Percentage of subjects with hSBA titers ≥ 8 against N.meningitidis serogroup B strains ^[14]

End point description

The percentage of subjects with hSBA titers ≥ 8, after receiving Bexsero® booster vaccination in the present study (24 to 36 months after completion of vaccination course according to different schedules in the parent study), alongside with the corresponding response after the first dose of Bexsero® vaccine in age-matched vaccine-naïve subjects. The analysis was performed on the FAS-Booster response population, which included all subjects in the Enrolled Set who received a study vaccination, provided an evaluable serum sample at Visit 2 (one month after the booster dose administration) and received all scheduled vaccinations in the parent study V72_28 (excluding naïve groups).

End point type

Secondary

End point timeframe

At 24-36 months - Visit 1 (pre-vacc.) and one month after booster vaccination - Day 31 (post-vacc.)

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results in this study were tabulated by age group and study period. Hence for each related endpoint, they are presented for only the respective groups in the baseline period, while the results for multiple endpoints account for all baseline groups.

End point values	2H3H511_V	3H5_11_V	68_11_V	02_2_5_V	02_6_10_V	NAIVE_123	NAIVE_4A	NAIVE_4B
Number of subjects analysed	96	87	76	32	91	96	55	50
Units: Percentage
number (confidence interval 95%)
H44/76 (pre-vacc.) (N=92;86;75;31;91;96;55;50)	26 (17.5 to 36.3)	31 (21.8 to 42.3)	33 (22.9 to 45.2)	19 (7.5 to 37.5)	30 (20.5 to 40.2)	18 (10.7 to 26.8)	16 (7.8 to 28.8)	10 (3.3 to 21.8)
H44/76 (post-vacc.) (N=96;86;75;32;91;96;55;50)	97 (91.1 to 99.4)	98 (91.9 to 99.72)	99 (92.8 to 99.97)	97 (83.8 to 99.92)	97 (90.7 to 99.3)	68 (57.4 to 76.9)	71 (57.1 to 82.4)	60 (45.2 to 73.6)
5/99 (pre-vacc.) (N=92;87;76;31;91;96;55;50)	79 (69.6 to 87.1)	85 (75.8 to 91.8)	91 (81.9 to 96.2)	71 (52 to 85.8)	68 (57.5 to 77.5)	2 (0.25 to 7.3)	4 (0.44 to 12.5)	6 (1.3 to 16.5)
5/99 (post-vacc.) (N=96;87;76;32;91;96;55;50)	99 (94.3 to 99.97)	99 (93.8 to 99.97)	97 (90.8 to 99.68)	100 (89.1 to 100)	100 (96 to 100)	77 (67.4 to 85)	78 (65 to 88.2)	60 (45.2 to 73.6)
NZ98/254 (pre-vacc.) (N=92;86;75;32;91;96;54;50)	22 (13.8 to 31.6)	19 (11 to 28.4)	28 (18.2 to 39.6)	13 (3.5 to 29)	26 (17.7 to 36.7)	0 (0 to 3.8)	2 (0.05 to 9.9)	0 (0 to 7.1)
NZ98/54 (post-vacc.) (N=96;86;75;32;91;96;54;50)	97 (91.1 to 99.4)	98 (91.9 to 99.72)	100 (95.2 to 100)	97 (83.8 to 99.92)	97 (90.7 to 99.3)	34 (25 to 44.8)	54 (39.6 to 67.4)	40 (26.4 to 54.8)
M10713 (pre-vacc.) (N=78;68;65;29;87;84;49;46)	28 (18.6 to 39.5)	22 (12.9 to 33.8)	34 (22.6 to 46.6)	17 (5.8 to 35.8)	55 (44.1 to 65.9)	27 (18.2 to 38.2)	39 (25.2 to 53.8)	52 (36.9 to 67.1)
M10713 (post-vacc.) (N=88;79;67;30;89;88;51;47)	64 (52.7 to 73.6)	71 (59.6 to 80.6)	94 (85.4 to 98.3)	90 (73.5 to 97.9)	92 (84.5 to 96.8)	34 (24.3 to 45)	51 (36.6 to 65.2)	57 (42.2 to 71.7)

No statistical analyses for this end point

Secondary: 12. Percentage of subjects with four-fold rise in hSBA titers against N.meningitidis serogroup B strains

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End point title

12. Percentage of subjects with four-fold rise in hSBA titers against N.meningitidis serogroup B strains ^[15]

End point description

The percentage of subjects with a four-fold rise in hSBA titers after receiving Bexsero® booster vaccination in the present study to pre-vaccination (24 to 36 months after completion of vaccination course according to different schedules in the parent study), alongside with the corresponding response after the first dose of Bexsero® vaccine in age-matched vaccine-naïve subjects. The analysis was performed on the FAS-Booster response population, which included all subjects in the Enrolled Set who received a study vaccination, provided an evaluable serum sample at Visit 2 (one month after the booster dose administration) and received all scheduled vaccinations in the parent study V72_28 (excluding naïve groups).

End point type

Secondary

End point timeframe

One month after booster vaccination (Day 31) over Visit 1 of the present study (PRE)

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results in this study were tabulated by age group and study period. Hence for each related endpoint, they are presented for only the respective groups in the baseline period, while the results for multiple endpoints account for all baseline groups.

End point values	2H3H511_V	3H5_11_V	68_11_V	02_2_5_V	02_6_10_V	NAIVE_123	NAIVE_4A	NAIVE_4B
Number of subjects analysed	92	87	76	32	91	96	55	50
Units: Percentage
number (confidence interval 95%)
H44/76 (Day 31/PRE) (N=92;86;75;31;91;96;55;50)	95 (87.8 to 98.2)	95 (88.5 to 98.7)	97 (90.7 to 99.68)	94 (78.6 to 99.2)	97 (90.7 to 99.3)	43 (32.7 to 53.2)	53 (38.8 to 66.3)	46 (31.8 to 60.7)
5/99 (Day 31/PRE) (N=92;87;76;31;91;96;55;50)	98 (92.4 to 99.74)	98 (91.9 to 99.72)	95 (87.1 to 98.5)	100 (88.8 to 100)	98 (92.3 to 99.73)	77 (67.4 to 85)	76 (63 to 86.8)	60 (45.2 to 73.6)
NZ98/254 (Day 31/PRE) (N=92;86;75;32;91;96;54;50)	92 (84.9 to 96.9)	95 (88.5 to 98.7)	93 (85.1 to 97.8)	94 (79.2 to 99.2)	86 (76.8 to 92.2)	34 (25 to 44.8)	54 (39.6 to 67.4)	40 (26.4 to 54.8)
M10713 (Day 31/PRE) (N=78;68;65;29;87;84;49;46)	41 (30 to 52.7)	50 (37.6 to 62.4)	68 (54.9 to 78.8)	72 (52.8 to 87.3)	53 (41.9 to 63.7)	11 (5 to 19.4)	20 (10.2 to 34.3)	13 (4.9 to 26.3)

No statistical analyses for this end point

Secondary: 13. The hSBA antibody titers against N.meningitidis serogroup B strains

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End point title

13. The hSBA antibody titers against N.meningitidis serogroup B strains ^[16]

End point description

The hSBA antibody titers in subjects, after receiving Bexsero® booster vaccination in the present study (24 to 36 months after completion of vaccination course according to different schedules in the parent study), alongside with the corresponding response in terms of GMTs, after the first dose of Bexsero® vaccine in age-matched vaccine-naïve subjects. The analysis was performed on the FAS-Booster response population, which included all subjects in the Enrolled Set who received a study vaccination, provided an evaluable serum sample at Visit 2 (one month after the booster dose administration) and received all scheduled vaccinations in the parent study V72_28 (excluding naïve groups).

End point type

Secondary

End point timeframe

Pre-booster or pre-first dose - Visit 1 (pre-vacc.) and one month post-booster or post-first dose - Day 31 (post-vacc.)

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results in this study were tabulated by age group and study period. Hence for each related endpoint, they are presented for only the respective groups in the baseline period, while the results for multiple endpoints account for all baseline groups.

End point values	2H3H511_V	3H5_11_V	68_11_V	02_2_5_V	02_6_10_V	NAIVE_123	NAIVE_4A	NAIVE_4B
Number of subjects analysed	96	87	76	32	91	96	55	50
Units: Titers
geometric mean (confidence interval 95%)
H44/76 (pre-vacc.) (N=92;86;75;31;91;96;55;50)	3.91 (3.01 to 5.08)	4.84 (3.66 to 6.41)	6.21 (4.65 to 8.31)	3.14 (2.08 to 4.75)	6.15 (4.77 to 7.93)	2.82 (2.26 to 3.5)	2.33 (1.77 to 3.07)	1.93 (1.39 to 2.68)
H44/76 (post-vacc.) (N=96;86;75;32;91;96;55;50)	158 (116 to 215)	205 (147 to 287)	288 (204 to 408)	155 (95 to 252)	258 (190 to 349)	14 (11 to 17)	16 (12 to 23)	13 (8.67 to 20)
5/99 (pre-vacc.) (N=92;87;76;31;91;96;55;50)	39 (26 to 58)	53 (35 to 82)	89 (57 to 139)	19 (9.92 to 35)	22 (15 to 32)	1.15 (1.02 to 1.29)	1.2 (0.96 to 1.51)	1.38 (1.1 to 1.73)
5/99 (post-vacc.) (N=96;87;76;32;91;96;55;50)	2908 (2059 to 4107)	3593 (2474 to 5218)	3677 (2495 to 5419)	3205 (1860 to 5526)	2921 (2079 to 4104)	38 (28 to 54)	27 (18 to 40)	20 (12 to 33)
NZ98/254 (pre-vacc.) (N=92;86;75;32;91;96;54;50)	3.41 (2.57 to 4.54)	3.17 (2.34 to 4.31)	4.86 (3.54 to 6.67)	2.99 (1.92 to 4.65)	4.49 (3.4 to 5.92)	1.14 (1.06 to 1.23)	1.35 (1.15 to 1.59)	1.22 (1.06 to 1.41)
NZ98/254 (post-vacc.) (N=96;86;75;32;91;96;54;50)	92 (70 to 122)	91 (68 to 123)	133 (97 to 181)	71 (46 to 110)	82 (63 to 108)	6.94 (5.6 to 8.59)	13 (8.88 to 19)	8.56 (5.51 to 13)
M10713 (pre-vacc.) (N=78;68;65;29;87;84;49;46)	3.05 (2.08 to 4.46)	3.1 (2.05 to 4.68)	3.58 (2.35 to 5.45)	2.31 (1.29 to 4.13)	7.83 (5.52 to 11)	3.53 (2.64 to 4.71)	4.8 (2.86 to 8.06)	7.7 (4.55 to 13)
M10713 (post-vacc.) (N=88;79;67;30;89;88;51;47)	13 (9.15 to 18)	18 (13 to 26)	40 (27 to 59)	32 (19 to 54)	53 (38 to 73)	4.92 (3.39 to 7.13)	9.44 (5.84 to 15)	12 (6.61 to 21)

No statistical analyses for this end point

Secondary: 14. The GMR of hSBA titers against N.meningitidis serogroup B strains

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End point title

14. The GMR of hSBA titers against N.meningitidis serogroup B strains ^[17]

End point description

The within-subjects GMR of hSBA antibody titers (one month post booster vaccination versus pre-vaccination) after Bexsero® booster vaccination in the present study (24 to 36 months after completion of vaccination course according to different schedules in the parent study), alongside with the within-subject GMR for the first dose of Bexsero® vaccination of age-matched vaccine-naïve subjects. The analysis was performed on the FAS-Booster response population, which included all subjects in the Enrolled Set who received a study vaccination, provided an evaluable serum sample at Visit 2 (one month after the booster dose administration) and received all scheduled vaccinations in the parent study V72_28 (excluding naïve groups).

End point type

Secondary

End point timeframe

Day 1 (PRE) and Day 31

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results in this study were tabulated by age group and study period. Hence for each related endpoint, they are presented for only the respective groups in the baseline period, while the results for multiple endpoints account for all baseline groups.

End point values	2H3H511_V	3H5_11_V	68_11_V	02_2_5_V	02_6_10_V	NAIVE_123	NAIVE_4A	NAIVE_4B
Number of subjects analysed	92	87	76	32	91	96	55	50
Units: Ratio
geometric mean (confidence interval 95%)
H44/76 (Day 31/PRE) (N=92;86;75;31;91;96;55;50)	41 (30 to 55)	43 (31 to 59)	46 (33 to 65)	50 (31 to 80)	42 (31 to 56)	4.81 (3.81 to 6.07)	7.08 (5.07 to 9.88)	6.87 (4.62 to 10)
5/99 (Day 31/PRE) (N=92;87;76;31;91;96;55;50)	75 (54 to 104)	67 (47 to 96)	41 (29 to 60)	160 (95 to 270)	135 (98 to 186)	34 (24 to 46)	22 (15 to 34)	14 (9.11 to 23)
NZ98/254 (Day 31/PRE) (N=92;86;75;32;91;96;54;50)	28 (20 to 38)	29 (21 to 41)	27 (19 to 39)	24 (15 to 40)	18 (13 to 25)	6.07 (4.97 to 7.41)	9.58 (6.8 to 13)	7.01 (4.54 to 11)
M10713 (Day 31/PRE) (N=78;68;65;29;87;84;49;46)	4.07 (2.8 to 5.91)	5.65 (3.77 to 8.47)	11 (7.15 to 16)	13 (7.29 to 23)	6.85 (4.86 to 9.66)	1.38 (1.01 to 1.88)	2.06 (1.36 to 3.12)	1.55 (1.1 to 2.18)

No statistical analyses for this end point

Secondary: 15. Percentage of subjects with hSBA titers ≥ 4 or ≥ 5 against N.meningitidis serogroup B strains

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End point title

15. Percentage of subjects with hSBA titers ≥ 4 or ≥ 5 against N.meningitidis serogroup B strains ^[18]

End point description

The percentage of vaccine-naïve subjects with hSBA titers ≥ 4 against H44/76, 5/99 and NZ98/254 strains, and ≥ 5 against M10713 strain, one month after receiving two catch-up doses of Bexsero® booster vaccination in the present study. The analysis was performed on the FAS-Two-dose Catch-up population, which included all subjects in the Enrolled Set who received at least one study vaccination and provided evaluable serum samples whose assay results were available on at least one post-baseline visit (Visit 1 or Visit 2).

End point type

Secondary

End point timeframe

At Baseline and one month post-second vaccination (Day 61)

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results in this study were tabulated by age group and study period. Hence for each related endpoint, they are presented for only the respective groups in the baseline period, while the results for multiple endpoints account for all baseline groups.

End point values	NAIVE_123	NAIVE_4A	NAIVE_4B
Number of subjects analysed	98	54	49
Units: Percentage
number (confidence interval 95%)
H44/76 (baseline) (N=98;54;49)	38 (28.2 to 48.1)	26 (15 to 39.7)	20 (10.2 to 34.3)
H44/76 (Day 61) (N=98;54;49)	100 (96.3 to 100)	98 (90.1 to 99.95)	100 (92.7 to 100)
5/99 (baseline) (N=98;54;49)	3 (0.6 to 8.7)	4 (0.45 to 12.7)	6 (1.3 to 16.9)
5/99 (Day 61) (N=98;54;49)	100 (96.3 to 100)	100 (93.4 to 100)	100 (92.7 to 100)
NZ98/254 (baseline) (N=98;54;48)	2 (0.25 to 7.2)	7 (2.1 to 17.9)	6 (1.3 to 17.2)
NZ98/254 (Day 61) (N=98;54;48)	100 (96.3 to 100)	100 (93.4 to 100)	100 (92.6 to 100)
M10713 (baseline) (N=87;50;49)	34 (24.6 to 45.4)	40 (26.4 to 54.8)	55 (40.2 to 69.3)
M10713 (Day 61) (N=91;52;49)	75 (64.5 to 83.3)	69 (54.9 to 81.3)	76 (61.1 to 86.7)

No statistical analyses for this end point

Secondary: 16. Percentage of subjects with hSBA titers ≥ 8 against N.meningitidis serogroup B strains

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End point title

16. Percentage of subjects with hSBA titers ≥ 8 against N.meningitidis serogroup B strains ^[19]

End point description

The percentage of vaccine-naïve subjects with hSBA titers ≥ 8 against N.meningitidis serogroup B strains, one month after receiving two catch-up doses of Bexsero® booster vaccination in the present study, is reported. The analysis was performed on the FAS-Two-dose catch-up population, which included all subjects in the Enrolled Set who received at least one study vaccination and provided evaluable serum samples whose assay results were available on at least one post-baseline visit (Visit 1 or Visit 2).

End point type

Secondary

End point timeframe

At Baseline and one month post-second vaccination (Day 61)

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results in this study were tabulated by age group and study period. Hence for each related endpoint, they are presented for only the respective groups in the baseline period, while the results for multiple endpoints account for all baseline groups.

End point values	NAIVE_123	NAIVE_4A	NAIVE_4B
Number of subjects analysed	98	54	49
Units: Percentage
number (confidence interval 95%)
H44/76 (baseline) (N=98;54;49)	17 (10.4 to 26.3)	15 (6.6 to 27.1)	10 (3.4 to 22.2)
H44/76 (Day 61) (N=98;54;49)	99 (94.4 to 99.97)	96 (87.3 to 99.55)	98 (89.1 to 99.95)
5/99 (baseline) (N=98;54;49)	2 (0.25 to 7.2)	4 (0.45 to 12.7)	4 (0.5 to 14)
5/99 (Day 61) (N=98;54;49)	100 (96.3 to 100)	100 (93.4 to 100)	98 (89.1 to 99.95)
NZ98/254 (baseline) (N=98;54;48)	0 (0 to 3.7)	2 (0.05 to 9.9)	0 (0 to 7.4)
NZ98/254 (Day 61) (N=98;54;48)	96 (89.9 to 98.9)	93 (82.1 to 97.9)	94 (82.8 to 98.7)
M10713 (baseline) (N=87;50;49)	25 (16.6 to 35.7)	38 (24.7 to 52.8)	49 (34.4 to 63.7)
M10713 (Day 61) (N=91;52;49)	65 (54.1 to 74.6)	63 (49 to 76.4)	69 (54.6 to 81.7)

No statistical analyses for this end point

Secondary: 17. Percentage of subjects with four-fold rise in hSBA titers against N.meningitidis serogroup B strains

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End point title

17. Percentage of subjects with four-fold rise in hSBA titers against N.meningitidis serogroup B strains ^[20]

End point description

The percentage of naïve subjects with a four-fold rise in hSBA titers against N.meningitidis serogroup B strains from baseline, one month after receiving two catch-up doses of Bexsero® booster vaccination, in comparison to pre-vaccination in the present study, is reported. The analysis was performed on the FAS-Two-dose catch-up population, which included all subjects in the Enrolled Set who received at least one study vaccination and provided evaluable serum samples whose assay results were available on at least one post-baseline visit (Visit 1 or Visit 2).

End point type

Secondary

End point timeframe

One month post second vaccination (Day 61)

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results in this study were tabulated by age group and study period. Hence for each related endpoint, they are presented for only the respective groups in the baseline period, while the results for multiple endpoints account for all baseline groups.

End point values	NAIVE_123	NAIVE_4A	NAIVE_4B
Number of subjects analysed	98	54	49
Units: Percentage
number (confidence interval 95%)
H44/76 (N=98;54;49)	94 (87.1 to 97.7)	89 (77.4 to 95.8)	94 (83.1 to 98.7)
5/99 (N=98;54;49)	100 (96.3 to 100)	100 (93.4 to 100)	98 (89.1 to 99.95)
NZ98/254 (N=98;54;48)	94 (87.1 to 97.7)	91 (79.7 to 96.9)	94 (82.8 to 98.7)
M10713 (N=87;50;49)	37 (26.7 to 47.8)	28 (16.2 to 42.5)	22 (11.8 to 36.6)

No statistical analyses for this end point

Secondary: 18. The hSBA antibody titers in naïve subjects against N.meningitidis serogroup B strains

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End point title

18. The hSBA antibody titers in naïve subjects against N.meningitidis serogroup B strains ^[21]

End point description

The hSBA antibody titers in naïve subjects, after receiving two catch-up doses of Bexsero® vaccination in this study, are reported in terms of GMTs. The analysis was performed on the FAS-Two-dose catch-up population, which included all subjects in the Enrolled Set who received at least one study vaccination and provided evaluable serum samples whose assay results were available on at least one post-baseline visit (Visit 1 or Visit 2).

End point type

Secondary

End point timeframe

At Baseline and one month post-second vaccination (Day 61)

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results in this study were tabulated by age group and study period. Hence for each related endpoint, they are presented for only the respective groups in the baseline period, while the results for multiple endpoints account for all baseline groups.

End point values	NAIVE_123	NAIVE_4A	NAIVE_4B
Number of subjects analysed	98	54	49
Units: Titers
geometric mean (confidence interval 95%)
H44/76 (baseline) (N=98;54;49)	2.3 (1.75 to 3.01)	2.15 (1.55 to 3)	1.56 (1.11 to 2.2)
H44/76 (Day 61) (N=98;54;49)	107 (84 to 135)	74 (56 to 99)	63 (47 to 85)
5/99 (baseline) (N=98;54;49)	1.13 (0.94 to 1.36)	1.13 (0.9 to 1.41)	1.31 (1.04 to 1.65)
5/99 (Day 61) (N=98;54;49)	631 (503 to 792)	421 (319 to 555)	317 (238 to 423)
NZ98/254 (baseline) (N=98;54;48)	1.11 (0.98 to 1.26)	1.34 (1.15 to 1.56)	1.2 (1.02 to 1.4)
NZ98/254 (Day 61) (N=98;54;48)	34 (27 to 42)	37 (28 to 49)	34 (26 to 46)
M10713 (baseline) (N=87;50;49)	2.9 (1.94 to 4.34)	4.12 (2.54 to 6.69)	6.4 (3.91 to 10)
M10713 (Day 61) (N=91;52;49)	12 (7.57 to 18)	11 (6.87 to 19)	14 (8.34 to 24)

No statistical analyses for this end point

Secondary: 19. The GMRs of hSBA titers after two catch-up doses of Bexsero® vaccination versus hSBA titers at baseline

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End point title

19. The GMRs of hSBA titers after two catch-up doses of Bexsero® vaccination versus hSBA titers at baseline ^[22]

End point description

The within-subject GMRs of hSBA titers at one month after receiving the second catch-up dose to hSBA titers at baseline, for naïve subjects who received two catch-up doses of Bexsero® vaccination in this study, are reported. The analysis was performed on the FAS-Two-dose catch-up population, which included all subjects in the Enrolled Set who received at least one study vaccination and provided evaluable serum samples whose assay results were available on at least one post-baseline visit (Visit 1 or Visit 2).

End point type

Secondary

End point timeframe

Day 1 and Day 61

Notes
[22] - 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: The results in this study were tabulated by age group and study period. Hence for each related endpoint, they are presented for only the respective groups in the baseline period, while the results for multiple endpoints account for all baseline groups.

End point values	NAIVE_123	NAIVE_4A	NAIVE_4B
Number of subjects analysed	98	54	49
Units: Ratio
geometric mean (confidence interval 95%)
H44/76 (N=98;54;49)	46 (34 to 63)	34 (24 to 50)	41 (27 to 60)
5/99 (N=98;54;49)	558 (423 to 737)	373 (266 to 524)	242 (171 to 344)
NZ98/254 (N=98;54;48)	30 (24 to 39)	27 (20 to 37)	29 (21 to 39)
M10713 (N=87;50;49)	3.86 (2.62 to 5.69)	2.93 (1.84 to 4.67)	2.2 (1.37 to 3.53)

No statistical analyses for this end point

Secondary: 20. Number of subjects reporting unsolicited AEs

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End point title

20. Number of subjects reporting unsolicited AEs ^[23]

End point description

The number of subjects reporting unsolicited AEs, after receiving Bexsero® booster vaccination (24 to 36 months after completion of vaccination course according to different schedules in the parent study) or two catch-up schedule of Bexsero® vaccine, is reported. An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. 'Any' was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. 'Possibly or Probably Related' = AE assessed by the investigator as related to the vaccination. The analysis was performed on the Unsolicited safety set, which included all subjects in the Exposed Set with unsolicited AE data.

End point type

Secondary

End point timeframe

From Day 1 throughout Day 7 after any vaccination (Any AEs) and throughout the entire study period for all other AEs

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: The results in this study were tabulated by age group and study period. Hence for each related endpoint, they are presented for only the respective groups in the baseline period, while the results for multiple endpoints account for all baseline groups.

End point values	2H3H511_V	3H5_11_V	68_11_V	02_2_5_V	02_6_10_V	NAIVE_123	NAIVE_4A	NAIVE_4B
Number of subjects analysed	96	89	78	32	91	100	55	50
Units: Subjects
Any AEs	26	19	26	9	14	43	25	12
Possibly or Probably Related AEs	9	7	10	6	11	12	10	6
AEs leading to Premature Withdrawal	0	0	0	0	0	1	0	0

No statistical analyses for this end point

Secondary: 21. Number of subjects reporting Serious Adverse Events (SAEs)

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End point title

21. Number of subjects reporting Serious Adverse Events (SAEs) ^[24]

End point description

The number of subjects reporting SAEs, after receiving Bexsero® booster vaccination (24 to 36 months after completion of vaccination course according to different schedules in the parent study) or two catch-up schedule of Bexsero® vaccine, is reported. SAEs assessed include medical occurrences that result in death, are life-threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. The analysis was performed on the Unsolicited safety set, which included all subjects in the Exposed Set with unsolicited AE data.

End point type

Secondary

End point timeframe

Throughout the entire study period

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: The results in this study were tabulated by age group and study period. Hence for each related endpoint, they are presented for only the respective groups in the baseline period, while the results for multiple endpoints account for all baseline groups.

End point values	2H3H511_V	3H5_11_V	68_11_V	02_2_5_V	02_6_10_V	NAIVE_123	NAIVE_4A	NAIVE_4B
Number of subjects analysed	96	89	78	32	91	100	55	50
Units: Subjects
Any SAEs	0	0	0	0	0	0	0	0
Possibly or probably related SAEs	0	0	0	0	0	0	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Solicited and unsolicited AEs were collected from Day 1 (30 minutes ) throughout Day 7; SAEs, medically-attended AEs and AEs leading to premature withdrawal were collected throughout the entire study period.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

2H3H511_V

Reporting group description

In the parent study, subjects had received three primary doses and one booster dose of Bexsero® vaccine, at 2.5, 3.5, 5 months of age, and at 11 months of age, respectively. The subjects in this group received a fifth dose of Bexsero® vaccine in the present study.

Reporting group title

3H5_11_V

Reporting group description

In the parent study, subjects had received two primary doses and one booster dose of Bexsero® vaccine, at 3.5, 5 and 11 months of age, respectively. These subjects received a fourth dose of Bexsero® vaccine in the present study.

Reporting group title

68_11_V

Reporting group description

In the parent study, subjects had received two primary doses and one booster dose of Bexsero® vaccine, at 6, 8, and 11 months of age, respectively. These subjects received a fourth dose of Bexsero® vaccine in the present study.

Reporting group title

02_2_5_V

Reporting group description

In the parent study, subjects had received two catch-up doses of Bexsero® vaccine, two months apart. These subjects received a third dose of Bexsero® vaccine in the present study.

Reporting group title

02_6_10_V

Reporting group description

In the parent study, subjects had received two catch-up doses of Bexsero® vaccine, two months apart. These subjects received a third dose of Bexsero® vaccine in the present study.

Reporting group title

NAIVE_123

Reporting group description

Newly recruited naïve subjects who received two catch-up doses of Bexsero® vaccine, one month apart, in the present study.

Reporting group title

NAIVE_4A

Reporting group description

Newly recruited naïve subjects who received two catch-up doses of Bexsero® vaccine, one month apart, in the present study.

Reporting group title

NAIVE_4B

Reporting group description

Newly recruited naïve subjects who received two catch-up doses of Bexsero® vaccine, one month apart, in the present study.

Serious adverse events	2H3H511_V	3H5_11_V	68_11_V	02_2_5_V	02_6_10_V	NAIVE_123	NAIVE_4A	NAIVE_4B
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 97 (0.00%)	0 / 89 (0.00%)	0 / 80 (0.00%)	0 / 32 (0.00%)	0 / 91 (0.00%)	0 / 100 (0.00%)	0 / 55 (0.00%)	0 / 50 (0.00%)
number of deaths (all causes)	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0

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

Non-serious adverse events	2H3H511_V	3H5_11_V	68_11_V	02_2_5_V	02_6_10_V	NAIVE_123	NAIVE_4A	NAIVE_4B
Total subjects affected by non serious adverse events
subjects affected / exposed	91 / 97 (93.81%)	84 / 89 (94.38%)	75 / 80 (93.75%)	31 / 32 (96.88%)	86 / 91 (94.51%)	97 / 100 (97.00%)	55 / 55 (100.00%)	50 / 50 (100.00%)
Nervous system disorders
Headache
subjects affected / exposed ^[1]	0 / 96 (0.00%)	0 / 89 (0.00%)	0 / 78 (0.00%)	0 / 32 (0.00%)	27 / 91 (29.67%)	0 / 100 (0.00%)	1 / 55 (1.82%)	20 / 50 (40.00%)
occurrences all number	0	0	0	0	28	0	1	27
Somnolence
subjects affected / exposed ^[2]	28 / 96 (29.17%)	23 / 89 (25.84%)	26 / 78 (33.33%)	5 / 32 (15.63%)	0 / 91 (0.00%)	23 / 100 (23.00%)	10 / 55 (18.18%)	0 / 50 (0.00%)
occurrences all number	29	25	26	5	0	31	14	0
General disorders and administration site conditions
Chills
subjects affected / exposed ^[3]	0 / 96 (0.00%)	0 / 89 (0.00%)	0 / 78 (0.00%)	0 / 32 (0.00%)	23 / 91 (25.27%)	0 / 100 (0.00%)	0 / 55 (0.00%)	7 / 50 (14.00%)
occurrences all number	0	0	0	0	23	0	0	9
Crying
subjects affected / exposed ^[4]	31 / 96 (32.29%)	24 / 89 (26.97%)	25 / 78 (32.05%)	4 / 32 (12.50%)	0 / 91 (0.00%)	23 / 100 (23.00%)	8 / 55 (14.55%)	0 / 50 (0.00%)
occurrences all number	32	26	26	4	0	30	10	0
Injection site erythema
subjects affected / exposed ^[5]	61 / 96 (63.54%)	63 / 89 (70.79%)	42 / 78 (53.85%)	22 / 32 (68.75%)	57 / 91 (62.64%)	65 / 100 (65.00%)	38 / 55 (69.09%)	37 / 50 (74.00%)
occurrences all number	62	65	43	23	64	101	63	54
Injection site induration
subjects affected / exposed ^[6]	48 / 96 (50.00%)	48 / 89 (53.93%)	33 / 78 (42.31%)	15 / 32 (46.88%)	44 / 91 (48.35%)	48 / 100 (48.00%)	28 / 55 (50.91%)	25 / 50 (50.00%)
occurrences all number	53	52	38	17	50	76	45	42
Injection site pain
subjects affected / exposed ^[7]	84 / 96 (87.50%)	80 / 89 (89.89%)	71 / 78 (91.03%)	31 / 32 (96.88%)	84 / 91 (92.31%)	94 / 100 (94.00%)	55 / 55 (100.00%)	48 / 50 (96.00%)
occurrences all number	89	81	76	32	89	170	109	89
Injection site swelling
subjects affected / exposed ^[8]	49 / 96 (51.04%)	50 / 89 (56.18%)	37 / 78 (47.44%)	20 / 32 (62.50%)	52 / 91 (57.14%)	51 / 100 (51.00%)	36 / 55 (65.45%)	34 / 50 (68.00%)
occurrences all number	51	52	40	21	59	75	54	54
Malaise
subjects affected / exposed ^[9]	0 / 96 (0.00%)	0 / 89 (0.00%)	0 / 78 (0.00%)	0 / 32 (0.00%)	35 / 91 (38.46%)	0 / 100 (0.00%)	0 / 55 (0.00%)	16 / 50 (32.00%)
occurrences all number	0	0	0	0	36	0	0	20
Pyrexia
subjects affected / exposed ^[10]	17 / 96 (17.71%)	18 / 89 (20.22%)	12 / 78 (15.38%)	2 / 32 (6.25%)	10 / 91 (10.99%)	25 / 100 (25.00%)	5 / 55 (9.09%)	4 / 50 (8.00%)
occurrences all number	18	19	13	2	10	28	6	5
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed ^[11]	4 / 96 (4.17%)	8 / 89 (8.99%)	5 / 78 (6.41%)	0 / 32 (0.00%)	0 / 91 (0.00%)	7 / 100 (7.00%)	6 / 55 (10.91%)	0 / 50 (0.00%)
occurrences all number	5	9	5	0	0	7	7	0
Nausea
subjects affected / exposed ^[12]	0 / 96 (0.00%)	0 / 89 (0.00%)	0 / 78 (0.00%)	0 / 32 (0.00%)	12 / 91 (13.19%)	0 / 100 (0.00%)	0 / 55 (0.00%)	8 / 50 (16.00%)
occurrences all number	0	0	0	0	12	0	0	9
Vomiting
subjects affected / exposed ^[13]	5 / 96 (5.21%)	6 / 89 (6.74%)	2 / 78 (2.56%)	1 / 32 (3.13%)	0 / 91 (0.00%)	10 / 100 (10.00%)	5 / 55 (9.09%)	0 / 50 (0.00%)
occurrences all number	7	6	2	1	0	12	5	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed ^[14]	1 / 96 (1.04%)	0 / 89 (0.00%)	1 / 78 (1.28%)	2 / 32 (6.25%)	0 / 91 (0.00%)	2 / 100 (2.00%)	0 / 55 (0.00%)	0 / 50 (0.00%)
occurrences all number	1	0	1	3	0	2	0	0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed ^[15]	13 / 96 (13.54%)	1 / 89 (1.12%)	3 / 78 (3.85%)	5 / 32 (15.63%)	10 / 91 (10.99%)	8 / 100 (8.00%)	4 / 55 (7.27%)	4 / 50 (8.00%)
occurrences all number	14	1	4	5	10	8	4	5
Psychiatric disorders
Eating disorder
subjects affected / exposed ^[16]	31 / 96 (32.29%)	32 / 89 (35.96%)	30 / 78 (38.46%)	5 / 32 (15.63%)	0 / 91 (0.00%)	36 / 100 (36.00%)	13 / 55 (23.64%)	0 / 50 (0.00%)
occurrences all number	32	35	33	5	0	49	14	0
Irritability
subjects affected / exposed ^[17]	54 / 96 (56.25%)	52 / 89 (58.43%)	46 / 78 (58.97%)	9 / 32 (28.13%)	0 / 91 (0.00%)	48 / 100 (48.00%)	19 / 55 (34.55%)	1 / 50 (2.00%)
occurrences all number	54	61	49	9	0	66	27	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed ^[18]	0 / 96 (0.00%)	0 / 89 (0.00%)	0 / 78 (0.00%)	0 / 32 (0.00%)	18 / 91 (19.78%)	0 / 100 (0.00%)	0 / 55 (0.00%)	8 / 50 (16.00%)
occurrences all number	0	0	0	0	18	0	0	9
Myalgia
subjects affected / exposed ^[19]	0 / 96 (0.00%)	0 / 89 (0.00%)	0 / 78 (0.00%)	0 / 32 (0.00%)	24 / 91 (26.37%)	0 / 100 (0.00%)	0 / 55 (0.00%)	15 / 50 (30.00%)
occurrences all number	0	0	0	0	24	0	0	20
Infections and infestations
Pharyngitis
subjects affected / exposed ^[20]	3 / 96 (3.13%)	2 / 89 (2.25%)	1 / 78 (1.28%)	0 / 32 (0.00%)	0 / 91 (0.00%)	2 / 100 (2.00%)	3 / 55 (5.45%)	0 / 50 (0.00%)
occurrences all number	3	2	1	0	0	2	3	0
Tonsillitis
subjects affected / exposed ^[21]	1 / 96 (1.04%)	1 / 89 (1.12%)	2 / 78 (2.56%)	0 / 32 (0.00%)	0 / 91 (0.00%)	6 / 100 (6.00%)	4 / 55 (7.27%)	1 / 50 (2.00%)
occurrences all number	1	1	2	0	0	7	4	1

Notes
[1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Exposed set, only on subjects with their symptom sheets completed.
[2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Exposed set, only on subjects with their symptom sheets completed.
[3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Exposed set, only on subjects with their symptom sheets completed.
[4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Exposed set, only on subjects with their symptom sheets completed.
[5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Exposed set, only on subjects with their symptom sheets completed.
[6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Exposed set, only on subjects with their symptom sheets completed.
[7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Exposed set, only on subjects with their symptom sheets completed.
[8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Exposed set, only on subjects with their symptom sheets completed.
[9] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Exposed set, only on subjects with their symptom sheets completed.
[10] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Exposed set, only on subjects with their symptom sheets completed.
[11] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Exposed set, only on subjects with their symptom sheets completed.
[12] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Exposed set, only on subjects with their symptom sheets completed.
[13] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Exposed set, only on subjects with their symptom sheets completed.
[14] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Exposed set, only on subjects with their symptom sheets completed.
[15] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Exposed set, only on subjects with their symptom sheets completed.
[16] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Exposed set, only on subjects with their symptom sheets completed.
[17] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Exposed set, only on subjects with their symptom sheets completed.
[18] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Exposed set, only on subjects with their symptom sheets completed.
[19] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Exposed set, only on subjects with their symptom sheets completed.
[20] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Exposed set, only on subjects with their symptom sheets completed.
[21] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Exposed set, only on subjects with their symptom sheets completed.

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Were there any global substantial amendments to the protocol? Yes

29 Jan 2013

Changes have been implemented prior to the first protocol Submission, in order to better clarify the reminder calls intervals and next visit date after vaccination, to specify that Fever is defined as temperature ≥ 38ºC, to remove the collection of Ethnicity as a demographic data, to remove the reference to unblinding and to specify that medically attended Fever symptoms are collected during the 7 days after vaccination.

14 Oct 2013

The protocol has been amended to better clarify that the immune response following the MenB vaccination will be assessed by the percentage of subjects achieving hSBA titer of at least 4, and also to better clarify that, for the Serum Bactericidal Assays (SBA), using human serum as the source of exogenous complement (hSBA), performed at the Novartis Vaccines Clinical Serology Laboratory (Marburg, Germany), a cut-off of 5 is used to take account of the assay validation, while for hSBA not performed at the Novartis Vaccines Clinical Serology Laboratory (Marburg, Germany), a cut-off of 4 is used. This amendment also provides the opportunity to better clarify the description of response variables for the statistical plan, to better define study description and to harmonize primary and secondary endpoints with revised study objectives. The list of abbreviation has also been updated and minor editorial changes have been implemented.

28 Nov 2013

The protocol has been amended to define End of study in compliance with the Novartis Quality Manual and the Corporate Data Disclosure Policy.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: A Phase IIIB, Open Label, Multi-Center Extension study of V72_28 to assess antibody persistence, and the safety and tolerability of a booster dose after the completion of the vaccination course in study V72_28.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 1. Percentage of subjects with human serum bactericidal activity titers (hSBA) ≥ 4 or ≥ 5 against Neisseria meningitidis (N. meningitidis) serogroup B strains

Primary: 1. Percentage of subjects with human serum bactericidal activity titers (hSBA) ≥ 4 or ≥ 5 against Neisseria meningitidis (N. meningitidis) serogroup B strains

Primary: 2. Percentage of subjects with hSBA titers ≥ 8 against N.meningitidis serogroup B strains

Primary: 2. Percentage of subjects with hSBA titers ≥ 8 against N.meningitidis serogroup B strains

Primary: 3. The hSBA geometric mean titers (GMTs) against N.meningitidis serogroup B strains

Primary: 3. The hSBA geometric mean titers (GMTs) against N.meningitidis serogroup B strains

Primary: 4. The geometric mean ratio (GMR) of hSBA GMTs against N. meningitidis serogroup B strains

Primary: 4. The geometric mean ratio (GMR) of hSBA GMTs against N. meningitidis serogroup B strains

Primary: 5. The GMR of hSBA GMTs against N. meningitidis serogroup B strains

Primary: 5. The GMR of hSBA GMTs against N. meningitidis serogroup B strains

Secondary: 6. Number of subjects (35 months to 7 years of age) reporting solicited local and systemic adverse events (AEs)

Secondary: 6. Number of subjects (35 months to 7 years of age) reporting solicited local and systemic adverse events (AEs)

Secondary: 7. Number of newly recruited subjects (aged 35 months to 7 years) reporting solicited local and systemic AEs

Secondary: 7. Number of newly recruited subjects (aged 35 months to 7 years) reporting solicited local and systemic AEs

Secondary: 8. Number of subjects (8 to 12 years of age) reporting solicited local and systemic AEs

Secondary: 8. Number of subjects (8 to 12 years of age) reporting solicited local and systemic AEs

Secondary: 9. Number of newly recruited naïve subjects (aged 8 to 12 years of age) reporting solicited local and systemic AEs

Secondary: 9. Number of newly recruited naïve subjects (aged 8 to 12 years of age) reporting solicited local and systemic AEs

Secondary: 10. Percentage of subjects with hSBA titers ≥ 4 or ≥ 5 against N.meningitidis serogroup B strains

Secondary: 10. Percentage of subjects with hSBA titers ≥ 4 or ≥ 5 against N.meningitidis serogroup B strains

Secondary: 11. Percentage of subjects with hSBA titers ≥ 8 against N.meningitidis serogroup B strains

Secondary: 11. Percentage of subjects with hSBA titers ≥ 8 against N.meningitidis serogroup B strains

Secondary: 12. Percentage of subjects with four-fold rise in hSBA titers against N.meningitidis serogroup B strains

Secondary: 12. Percentage of subjects with four-fold rise in hSBA titers against N.meningitidis serogroup B strains

Secondary: 13. The hSBA antibody titers against N.meningitidis serogroup B strains

Secondary: 13. The hSBA antibody titers against N.meningitidis serogroup B strains

Secondary: 14. The GMR of hSBA titers against N.meningitidis serogroup B strains

Secondary: 14. The GMR of hSBA titers against N.meningitidis serogroup B strains

Secondary: 15. Percentage of subjects with hSBA titers ≥ 4 or ≥ 5 against N.meningitidis serogroup B strains

Secondary: 15. Percentage of subjects with hSBA titers ≥ 4 or ≥ 5 against N.meningitidis serogroup B strains

Secondary: 16. Percentage of subjects with hSBA titers ≥ 8 against N.meningitidis serogroup B strains

Secondary: 16. Percentage of subjects with hSBA titers ≥ 8 against N.meningitidis serogroup B strains

Secondary: 17. Percentage of subjects with four-fold rise in hSBA titers against N.meningitidis serogroup B strains

Secondary: 17. Percentage of subjects with four-fold rise in hSBA titers against N.meningitidis serogroup B strains

Secondary: 18. The hSBA antibody titers in naïve subjects against N.meningitidis serogroup B strains

Secondary: 18. The hSBA antibody titers in naïve subjects against N.meningitidis serogroup B strains

Secondary: 19. The GMRs of hSBA titers after two catch-up doses of Bexsero® vaccination versus hSBA titers at baseline

Secondary: 19. The GMRs of hSBA titers after two catch-up doses of Bexsero® vaccination versus hSBA titers at baseline

Secondary: 20. Number of subjects reporting unsolicited AEs

Secondary: 20. Number of subjects reporting unsolicited AEs

Secondary: 21. Number of subjects reporting Serious Adverse Events (SAEs)

Secondary: 21. Number of subjects reporting Serious Adverse Events (SAEs)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase IIIB, Open Label, Multi-Center Extension study of V72_28 to assess antibody persistence, and the safety and tolerability of a booster dose after the completion of the vaccination course in study V72_28.