Clinical Trial Results:
A Phase 3b, Randomized, Open-Label, Multi-Center Study to Evaluate the Safety and Immunogenicity of 2 or 3 Doses of MenACWY Conjugate Vaccine in Healthy Infants and the Effects of a Booster Dose of MenACWY Administered in the Second Year of Life.

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

Summary
EudraCT number	2014-004577-16
Trial protocol	Outside EU/EEA
Global end of trial date	10 May 2012

Results information
Results version number	v2(current)
This version publication date	01 Jun 2016
First version publication date	07 Jan 2015
Other versions	v1 (removed from public view)
Version creation reason	Correction of full data set re-QC study because of EudraCT system glitch and updates to results are required including shifting of CI values.

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

V59_36

ISRCTN number

US NCT number

NCT01214837

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Vaccines and Diagnostics

Sponsor organisation address

350 Massachusetts Avenue, Cambridge, United States, 02139

Public contact

Posting Director, Novartis Vaccines, RegistryContactVaccinesUS@novartis.com

Scientific contact

Posting Director, Novartis Vaccines, RegistryContactVaccinesUS@novartis.com

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

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

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

Yes

Analysis stage

Final

Date of interim/final analysis

01 Aug 2014

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

10 May 2012

Was the trial ended prematurely?

Main objective of the trial

To assess the immunogenicity of a 3-dose vaccination schedule of MenACWY vaccine (2 infant doses at 2 and 4 months of age followed by a toddler dose at 12 months of age) compared to a 4-dose vaccination schedule (3 infant doses at 2, 4 and 6 months of age followed by a toddler dose at 12 months of age). The study also characterized immune responses following the first, second and third infant doses, and evaluated the effect of concomitant administration of MenACWY and PCV-13 on immune responses to PCV-13 antigens.

Protection of trial subjects

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

Background therapy

Evidence for comparator

Actual start date of recruitment

11 Oct 2010

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 86

Country: Number of subjects enrolled

United States: 665

Worldwide total number of subjects

751

EEA total number of subjects

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)

751

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

A total of 751 subjects were enrolled in this study, with 127 and 129 subjects following a 4-dose vaccination schedule of MenACWY (ACWY4a and ACWY4b groups, respectively), 249 subjects following a 3-dose vaccination schedule (ACWY3 group), and 246 subjects received routine vaccinations alone

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

Laboratory staff was blinded to the study group allocation when processing serological samples.

Are arms mutually exclusive

Yes

MenACWY3

Arm description

Healthy male and female infants approximately 2 months of age received 2 infant doses at 2 and 4 months of age, with a toddler dose at 12 months of age.

Arm type

Experimental

Investigational medicinal product name

Novartis meningococcal ACWY conjugate vaccine (MenACWY- CRM197, Menveo™) and Routine Vaccines, PCV 13

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solution for solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

0.5mL of dose was administered intra muscularly

MenACWY4

Arm description

Healthy male and female infants approximately 2 months of age received a 3-dose primary series at 2, 4 and 6 months of age and a toddler dose at 12 months of age. Approximately half of the subjects had serum collected at Month 3, and the remainder had serum collected at Month 4.

Arm type

Experimental

Investigational medicinal product name

Novartis meningococcal ACWY conjugate vaccine (MenACWY- CRM197, Menveo™) and Routine Vaccines, PCV 13

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solution for solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

0.5mL of dose was administered intra muscularly

Routine vaccines

Arm description

Healthy male and female infants approximately 2 months of age received routine vaccines including PCV-13, at 2, 4, 6 and 12 months of age.

Arm type

Routine Vaccines

Investigational medicinal product name

Routine Vaccines, PCV 13

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Routine infant vaccines were to be administered to subjects according routine methods and schedules for the region.

Number of subjects in period 1	MenACWY3	MenACWY4	Routine vaccines
Started	249	256	246
Completed	195	192	184
Not completed	54	64	62
Adverse event, non-fatal	1	2	1
Death	-	-	1
Administrative Reason	2	6	4
Withdrawal by Subject	27	36	28
Inappropriate enrolment	-	1	2
Lost to follow-up	20	15	21
Unable to Classify	1	3	-
Protocol deviation	3	1	5

Baseline characteristics

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Reporting group title

MenACWY3

Reporting group description

Healthy male and female infants approximately 2 months of age received 2 infant doses at 2 and 4 months of age, with a toddler dose at 12 months of age.

Reporting group title

MenACWY4

Reporting group description

Reporting group title

Routine vaccines

Reporting group description

Healthy male and female infants approximately 2 months of age received routine vaccines including PCV-13, at 2, 4, 6 and 12 months of age.

Reporting group values	MenACWY3	MenACWY4	Routine vaccines	Total
Number of subjects	249	256	246	751
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	249	256	246	751
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	0	0	0	0
From 65-84 years	0	0	0	0
85 years and over	0	0	0	0
Age continuous
Units: days
arithmetic mean (standard deviation)	66.4 ± 7.1	66.7 ± 7.4	66.7 ± 7	-
Gender categorical
Units: Subjects
Female	126	123	106	355
Male	123	133	140	396

End points

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Reporting group title

MenACWY3

Reporting group description

Healthy male and female infants approximately 2 months of age received 2 infant doses at 2 and 4 months of age, with a toddler dose at 12 months of age.

Reporting group title

MenACWY4

Reporting group description

Reporting group title

Routine vaccines

Reporting group description

Healthy male and female infants approximately 2 months of age received routine vaccines including PCV-13, at 2, 4, 6 and 12 months of age.

Subject analysis set title

All Enrolled Set

Subject analysis set type

Intention-to-treat

Subject analysis set description

All subjects who had signed an informed consent, undergone screening procedure and were randomized.

Subject analysis set title

Toddler PCV PPS

Subject analysis set type

Per protocol

Subject analysis set description

All subjects who received doses of ACWY and PCV vaccine correctly, and provided evaluable serum samples at the relevant time points, and had no major protocol violation as defined prior to unblinding through 13 month timepoint.

Subject analysis set title

Toddler ACWY PPS

Subject analysis set type

Per protocol

Subject analysis set description

All subjects who received doses of ACWY vaccine correctly, and provided evaluable serum samples at the relevant time points, and had no major protocol violation as defined prior to unblinding through 13 month timepoint.

Subject analysis set title

Solicited Safety Set

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects in the Exposed Set with solicited adverse event data

Subject analysis set title

Unsolicited Safety Set

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects in the Exposed Set with unsolicited adverse event data.

Subject analysis set title

Infant ACWY PPS

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Infant PCV PPS

Subject analysis set type

Per protocol

Subject analysis set description

Primary: 1. Percentage of subjects with serum bactericidal activity using human complement (hSBA) ≥1:8, directed against N meningitidis serogroups A, C, W and Y.

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End point title

1. Percentage of subjects with serum bactericidal activity using human complement (hSBA) ≥1:8, directed against N meningitidis serogroups A, C, W and Y. ^[1] ^[2]

End point description

The immune response was assessed in terms of percentage of subjects with hSBA ≥ 1:8 against N. meningitidis serogroups A, C, W and Y following 4 doses of Men ACWY vaccine given to infants at 2, 4, 6 and 12 months of age. Analysis was done on the Toddler Per Protocol Population

End point type

Primary

End point timeframe

13 months of age

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There was no statistical null hypothesis associated with this immunogenicity objective.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: There was no statistical null hypothesis associated with this immunogenicity objective.

End point values	MenACWY4
Number of subjects analysed	152
Units: Percentages of Subjects
number (confidence interval 95%)
Serogroup A (N=141)	96 (91 to 98)
Serogroup C	99 (95 to 100)
Serogroup W (N=138)	99 (96 to 100)
Serogroup Y (N=146)	99 (96 to 100)

No statistical analyses for this end point

Primary: 2. Percentage of Subjects With hSBA ≥ 1:8 Against N Meningitidis Serogroups A, C, W and Y Following 4- Dose and 3-Dose Schedule of Men ACWY Vaccination.

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End point title

2. Percentage of Subjects With hSBA ≥ 1:8 Against N Meningitidis Serogroups A, C, W and Y Following 4- Dose and 3-Dose Schedule of Men ACWY Vaccination. ^[3]

End point description

The immune response was assessed in terms of percentage of subjects with hSBA ≥ 1:8 against N meningitidis serogroups A, C, W and Y following 4 doses of Men ACWY vaccine given to infants at 2, 4,6 and 12 months of age and 3 doses of Men ACWY given to infants at 2, 4 and 12 months of age. Analysis was done on Toddler ACWY PPS.

End point type

Primary

End point timeframe

13 months of age

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

End point values	MenACWY3	MenACWY4
Number of subjects analysed	160	152
Units: Percentages of Subjects
number (confidence interval 95%)
Serogroup A (N=146, 141)	88 (82 to 93)	96 (91 to 98)
Serogroup C	95 (90 to 98)	99 (95 to 100)
Serogroup W (N=153, 138)	99 (96 to 100)	99 (96 to 100)
Serogroup Y (N-154, 146)	100 (98 to 100)	99 (96 to 100)

Percentage of Subjects With hSBA ≥ 1:8

Statistical analysis description

Non-inferiority of Men ACWY 3-dose series (doses at 2, 4 and 12 months) to 4-dose series (doses at 2, 4, 6 and 12 months of age) against serogroup A at 13 months of age.

Comparison groups

MenACWY4 v MenACWY3

Number of subjects included in analysis

312

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[4]

Method

Miettinen and Nurminen method

Parameter type

Group difference

Point estimate

-7

Confidence interval

level

95%

sides

2-sided

lower limit

-14

upper limit

-1

Notes
[4] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the difference in percentage of subjects with hSBA titers ≥ 1:8 against N. meningitidis serogroups C, W and Y between the 3-dose series and (minus) the 4-dose series, is greater than -10%.

Percentage of Subjects With hSBA ≥ 1:8

Statistical analysis description

Non-inferiority of Men ACWY 3-dose series (doses at 2, 4 and 12 months) to 4-dose series (doses at 2, 4, 6 and 12 months of age) against serogroup C at 13 months of age.

Comparison groups

MenACWY3 v MenACWY4

Number of subjects included in analysis

312

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[5]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

-4

Confidence interval

level

95%

sides

2-sided

lower limit

-8

upper limit

Notes
[5] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the difference in percentage of subjects with hSBA titers ≥ 1:8 against N. meningitidis serogroups C, W and Y between the 3-dose series and (minus) the 4-dose series, is greater than -10%.

Percentage of Subjects With hSBA ≥ 1:8

Statistical analysis description

Non-inferiority of Men ACWY 3-dose series (doses at 2, 4 and 12 months) to 4-dose series (doses at 2, 4, 6 and 12 months of age) against serogroup W at 13 months of age.

Comparison groups

MenACWY3 v MenACWY4

Number of subjects included in analysis

312

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[6]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-3

upper limit

Notes
[6] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the difference in percentage of subjects with hSBA titers ≥ 1:8 against N. meningitidis serogroups C, W and Y between the 3-dose series and (minus) the 4-dose series, is greater than -10%.

Percentage of Subjects With hSBA ≥ 1:8

Statistical analysis description

Non-inferiority of Men ACWY 3-dose series (doses at 2, 4 and 12 months) to 4-dose series (doses at 2, 4, 6 and 12 months of age) against serogroup Y at 13 months of age.

Comparison groups

MenACWY3 v MenACWY4

Number of subjects included in analysis

312

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[7]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

Notes
[7] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the difference in percentage of subjects with hSBA titers ≥ 1:8 against N. meningitidis serogroups C, W and Y between the 3-dose series and (minus) the 4-dose series, is greater than -10%.

Secondary: 3. Percentage of Subjects With hSBA ≥1:8 Against N. Meningitidis Serogroups A, C, W and Y at Baseline (2 Months of Age) and at 3, 4, 5, and 7 Months of Age.

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End point title

3. Percentage of Subjects With hSBA ≥1:8 Against N. Meningitidis Serogroups A, C, W and Y at Baseline (2 Months of Age) and at 3, 4, 5, and 7 Months of Age.

End point description

Antibody levels were assessed in terms of percentage of subjects with hSBA ≥ 1:8 against N. meningitidis serogroups A, C, W and Y at baseline (2 months of age) and at 3, 4, 5 and 7 months of age.

End point type

Secondary

End point timeframe

Baseline (2 months of age), 3 months, 4 months , 5 months and 7 months of age

End point values	MenACWY3	MenACWY4	Routine vaccines
Number of subjects analysed	185	176	187
Units: Percentages of Subjects
number (confidence interval 95%)
Serogroup A (baseline; N=0,0,166)	0 (0 to 0)	0 (0 to 0)	4 (1 to 8)
Serogroup A (3 months; N=0,82,0)	0 (0 to 0)	9 (4 to 17)	0 (0 to 0)
Serogroup A (4 months; N=0,70,0)	0 (0 to 0)	4 (1 to 12)	0 (0 to 0)
Serogroup A (5 months; N=157,0,0)	43 (35 to 51)	0 (0 to 0)	0 (0 to 0)
Serogroup A (7 months; N=169,157,171)	23 (17 to 30)	84 (77 to 89)	1 (0.015 to 3)
Serogroup C (baseline; N=0,0,167)	0 (0 to 0)	0 (0 to 0)	9 (5 to 14)
Serogroup C (3 months; N=0,85,0)	0 (0 to 0)	28 (19 to 39)	0 (0 to 0)
Serogroup C (4 months; N=0,70,0)	0 (0 to 0)	41 (30 to 54)	0 (0 to 0)
Serogroup C (5 months; N=170,0,0)	86 (80 to 91)	0 (0 to 0)	0 (0 to 0)
Serogroup C (7 months)	71 (64 to 78)	95 (91 to 98)	1 (0.014 to 3)
Serogroup W (baseline; N=0,0,157)	0 (0 to 0)	0 (0 to 0)	20 (14 to 28)
Serogroup W (3 months; N=0,84,0)	0 (0 to 0)	15 (9 to 25)	0 (0 to 0)
Serogroup W (4 months; N=0,71,0)	0 (0 to 0)	35 (24 to 47)	0 (0 to 0)
Serogroup W (5 months; N=162,0,0)	86 (80 to 91)	0 (0 to 0)	0 (0 to 0)
Serogroup W (7 months; N=179,162,181)	74 (67 to 81)	99 (96 to 100)	1 (0.014 to 3)
Serogroup Y (baseline; N=0,0,150)	0 (0 to 0)	0 (0 to 0)	7 (4 to 13)
Serogroup Y (3 months; N=0,80,0)	0 (0 to 0)	8 (3 to 16)	0 (0 to 0)
Serogroup Y (4 months; N=0,69,0)	0 (0 to 0)	7 (2 to 16)	0 (0 to 0)
Serogroup Y (5 months; N=152,0,0)	67 (59 to 75)	0 (0 to 0)	0 (0 to 0)
Serogroup Y (7 months; N=170,163,173)	48 (40 to 55)	94 (90 to 97)	0 (0 to 2)

No statistical analyses for this end point

Secondary: 4. Geometric Mean hSBA Titers Against N Meningitis Serogroups A, C, W and Y at Baseline (2 Months of Age) and at 3, 4, 5, and 7 Months of Age.

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End point title

4. Geometric Mean hSBA Titers Against N Meningitis Serogroups A, C, W and Y at Baseline (2 Months of Age) and at 3, 4, 5, and 7 Months of Age.

End point description

Antibody levels were assessed in terms of geometric mean titers (GMTs) against N. meningitidis serogroups A, C, W and Y at baseline (2 Months of Age) and at 3, 4, 5, and 7 Months of Age. Analysis was done on the Infant ACWY PPS.

End point type

Secondary

End point timeframe

Baseline (2 months of age), 3 months, 4 months , 5 months and 7 months of age

End point values	MenACWY3	MenACWY4	Routine vaccines
Number of subjects analysed	185	176	187
Units: Titers
geometric mean (confidence interval 95%)
Serogroup A (baseline; N=0,0,166)	0 (0 to 0)	0 (0 to 0)	2.18 (2.05 to 2.33)
Serogroup A (3 months; N=0,82,0)	0 (0 to 0)	2.63 (2.2 to 3.15)	0 (0 to 0)
Serogroup A (4 months; N=0,70,0)	0 (0 to 0)	2.18 (2 to 2.37)	0 (0 to 0)
Serogroup A (5 months; N=157,0,0)	7.09 (5.62 to 8.94)	0 (0 to 0)	0 (0 to 0)
Serogroup A (7 months; N=169,157,171)	3.68 (3.17 to 4.29)	28 (23 to 35)	2.02 (1.98 to 2.06)
Serogroup C (baseline; N=0,0,167)	0 (0 to 0)	0 (0 to 0)	2.52 (2.28 to 2.78)
Serogroup C (3 months; N=0,85,0)	0 (0 to 0)	4.79 (3.71 to 6.19)	0 (0 to 0)
Serogroup C (4 months; N=0,70,0)	0 (0 to 0)	6.44 (4.83 to 8.59)	0 (0 to 0)
Serogroup C (5 months; N=170,0,0)	50 (39 to 64)	0 (0 to 0)	0 (0 to 0)
Serogroup C (7 months)	17 (14 to 22)	86 (70 to 104)	2.03 (1.97 to 2.08)
Serogroup W (baseline; N=0,0,157)	0 (0 to 0)	0 (0 to 0)	3.32 (2.82 to 3.9)
Serogroup W (3 months; N=0,84,0)	0 (0 to 0)	3 (2.48 to 3.61)	0 (0 to 0)
Serogroup W (4 months; N=0,71,0)	0 (0 to 0)	4.38 (3.42 to 5.61)	0 (0 to 0)
Serogroup W (5 months; N=162,0,0)	55 (42 to 71)	0 (0 to 0)	0 (0 to 0)
Serogroup W (7 months; N=179,162,181)	17 (14 to 21)	90 (77 to 104)	2.04 (1.96 to 2.11)
Serogroup Y (baseline; N=0,0,150)	0 (0 to 0)	0 (0 to 0)	2.47 (2.25 to 2.7)
Serogroup Y (3 months; N=0,80,0)	0 (0 to 0)	2.5 (2.14 to 2.93)	0 (0 to 0)
Serogroup Y (4 months; N=0,69,0)	0 (0 to 0)	2.46 (2.16 to 2.79)	0 (0 to 0)
Serogroup Y (5 months; N=152,0,0)	20 (15 to 26)	0 (0 to 0)	0 (0 to 0)
Serogroup Y (7 months; N=170,163,173)	7.56 (6.29 to 9.08)	52 (43 to 64)	2 (2 to 2)

No statistical analyses for this end point

Secondary: 5. Percentage of Subjects With hSBA ≥1:8 Following 2 and 3 Infant Doses of MenACWY.

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End point title

5. Percentage of Subjects With hSBA ≥1:8 Following 2 and 3 Infant Doses of MenACWY. ^[8]

End point description

Percentage of subjects with hSBA ≥1:8 against N meningitis serogroups A, C, W and Y was assessed following 2 and 3 infant doses of MenACWY as measured prior to the toddler dose at 12 months of age.

End point type

Secondary

End point timeframe

Percentage of Subjects With hSBA ≥1:8 Following 2 and 3 Infant Doses of MenACWY.

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

End point values	MenACWY3	MenACWY4
Number of subjects analysed	149	147
Units: Percentages of Subjects
number (confidence interval 95%)
Serogroup A (N=141,138)	6 (2 to 11)	22 (15 to 30)
Serogroup C	19 (13 to 27)	48 (39 to 56)
Serogroup W (N=149,142)	33 (25 to 41)	66 (58 to 74)
Serogroup Y (N=145,139)	25 (18 to 33)	55 (47 to 64)

No statistical analyses for this end point

Secondary: 6. Geometric Mean hSBA Titers Following 2 and 3 Infant Doses of MenACWY

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End point title

6. Geometric Mean hSBA Titers Following 2 and 3 Infant Doses of MenACWY ^[9]

End point description

The immune response was assessed in terms of GMTs against N. meningitidis serogroups A, C, W and Y following 2 and 3 infant doses of MenACWY as measured prior to the toddler dose at 12 months of age.

End point type

Secondary

End point timeframe

12 months of age.

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

End point values	MenACWY3	MenACWY4
Number of subjects analysed	149	147
Units: Titers
geometric mean (confidence interval 95%)
Serogroup A (N=141,138)	2.28 (2.09 to 2.49)	3.65 (3.08 to 4.33)
Serogroup C	3.54 (2.99 to 4.17)	8.55 (6.75 to 11)
Serogroup W (N=149,142)	5.41 (4.39 to 6.67)	13 (11 to 16)
Serogroup Y (N=145,139)	3.82 (3.24 to 4.49)	9.65 (7.79 to 12)

No statistical analyses for this end point

Secondary: 7. GMTs at 13 Months of Age After Completion of 3- and 4-Dose Series of MenACWY.

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End point title

7. GMTs at 13 Months of Age After Completion of 3- and 4-Dose Series of MenACWY. ^[10]

End point description

Immune response was assessed in terms of GMTs against N meningitis serogroups A, C, W and Y at 1 month after completion of a 3- and 4- dose series of MenACWY. Analysis was done on the Toddler ACWY PPS.

End point type

Secondary

End point timeframe

13 months of age

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

End point values	MenACWY3	MenACWY4
Number of subjects analysed	160	152
Units: Titers
geometric mean (confidence interval 95%)
Serogroup A (N=146,141)	59 (45 to 77)	94 (76 to 117)
Serogroup C	124 (99 to 156)	160 (130 to 198)
Serogroup W (N=153,138)	248 (202 to 303)	244 (195 to 305)
Serogroup Y (N=154,146)	212 (175 to 258)	254 (203 to 318)

No statistical analyses for this end point

Secondary: 8. Percentage of Subjects With 4-fold Increase in hSBA Titers Against N Meningitis Serogroups A, C, W and Y Between 12 and 13 Months of Age.

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End point title

8. Percentage of Subjects With 4-fold Increase in hSBA Titers Against N Meningitis Serogroups A, C, W and Y Between 12 and 13 Months of Age. ^[11]

End point description

The immune response was assessed in terms of percentage of subjects with 4-fold increase in hSBA titers between post and pre toddler dose against N meningitis serogroups A, C, W and Y, 1 month after completing a 3- or 4-dose series of MenACWY. Analysis was done on the Toddler PPS.

End point type

Secondary

End point timeframe

13 months of age

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

End point values	MenACWY3	MenACWY4
Number of subjects analysed	147	147
Units: Percentages of Subjects
number (confidence interval 95%)
Serogroup A (N=127,129)	88 (81 to 93)	95 (90 to 98)
Serogroup C	93 (88 to 97)	91 (85 to 95)
Serogroup W (N=140,131)	98 (94 to 100)	90 (84 to 95)
Serogroup Y (N=139,136)	100 (97 to 100)	96 (91 to 98)

No statistical analyses for this end point

Secondary: 9. Effect of Concomitant Administration of 3 or 4 Doses of MenACWY on Immune Response to PCV-13 Antigens at 13 Months of Age.

Top of page

End point title

9. Effect of Concomitant Administration of 3 or 4 Doses of MenACWY on Immune Response to PCV-13 Antigens at 13 Months of Age.

End point description

Geometric mean concentrations (GMCs) of antibodies against PCV-13 vaccine antigens at 13 months of age following concomitant administration of a 3- or 4-dose series of MenACWY with PCV-13. Analysis was done on the Toddler PCV PPS.

End point type

Secondary

End point timeframe

13 months of age.

End point values	MenACWY3	MenACWY4	Routine vaccines
Number of subjects analysed	147	117	124
Units: μg/mL
geometric mean (confidence interval 95%)
1 (N=145,116,123)	2 (1.7 to 2.36)	2.16 (1.83 to 2.56)	2.14 (1.8 to 2.54)
3 (N=139,113,118)	0.88 (0.74 to 1.05)	0.97 (0.81 to 1.15)	0.77 (0.64 to 0.93)
4 (N=146,117,123)	1.19 (0.99 to 1.42)	1.45 (1.21 to 1.75)	1.53 (1.27 to 1.86)
5 (N=140,114,117)	1.29 (1.11 to 1.49)	1.35 (1.16 to 1.57)	1.26 (1.08 to 1.48)
6A (N=146,117,124)	6.89 (5.78 to 8.21)	9.01 (7.52 to 11)	8.16 (6.77 to 9.82)
6B (N=147,117,124)	4.29 (3.6 to 5.11)	5.23 (4.36 to 6.27)	5.04 (4.18 to 6.08)
7F (N=147,116,123)	3.96 (3.42 to 4.58)	5.14 (4.41 to 5.98)	4.95 (4.23 to 5.78)
9V (N=146,117,123)	1.37 (1.17 to 1.61)	1.85 (1.56 to 2.18)	1.73 (1.46 to 2.05)
14 (N=147,117,124)	7.76 (6.51 to 9.26)	7.86 (6.55 to 9.43)	7.54 (6.25 to 9.09)
18C (N=146,116,123)	1.52 (1.28 to 1.8)	2.34 (1.96 to 2.79)	2.13 (1.78 to 2.55)
19A (N=144,114,124)	5.51 (4.61 to 6.6)	5.23 (4.34 to 6.3)	5.39 (4.45 to 6.51)
19F (N=147,117,124)	5.79 (4.9 to 6.85)	6.19 (5.21 to 7.35)	5.8 (4.86 to 6.92)
23F (N=147,117,124)	4.21 (3.49 to 5.09)	4.84 (3.98 to 5.89)	5.44 (4.45 to 6.65)

MenACWY3 vs Routine Vaccines (Serotype 1)

Statistical analysis description

To demonstrate non-inferiority of immune response to PCV-13 antigens after concomitant administration of 3 doses of Men ACWY with routine vaccines including PCV-13, versus administration of routine vaccines only, at 13 months of age for Serotype 1.

Comparison groups

MenACWY3 v Routine vaccines

Number of subjects included in analysis

271

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[12]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

0.94

Confidence interval

level

95%

sides

2-sided

lower limit

0.77

upper limit

1.13

Notes
[12] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI around the ratio of GMCs between groups (MenACWY3 to routine vaccines) is greater than 0.5.

MenACWY4 vs Routine Vaccines (Serotype 1)

Statistical analysis description

To demonstrate non-inferiority of immune response to PCV-13 antigens after concomitant administration of 4 doses of Men ACWY with routine vaccines including PCV-13, versus administration of routine vaccines only, at 13 months of age for Serotype 1.

Comparison groups

MenACWY4 v Routine vaccines

Number of subjects included in analysis

241

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[13]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.02

Confidence interval

level

95%

sides

2-sided

lower limit

0.83

upper limit

1.25

Notes
[13] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI around the ratio of GMCs between the groups (MenACWY4 to routine vaccines) is greater than 0.5.

MenACWY3 vs Routine Vaccines (Serotype 3)

Statistical analysis description

Comparison groups

MenACWY3 v Routine vaccines

Number of subjects included in analysis

271

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[14]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.14

Confidence interval

level

95%

sides

2-sided

lower limit

0.93

upper limit

1.4

Notes
[14] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI around the ratio of GMCs between groups (MenACWY3 to routine vaccines) is greater than 0.5.

MenACWY4 vs Routine Vaccines (Serotype 3)

Statistical analysis description

Comparison groups

Routine vaccines v MenACWY4

Number of subjects included in analysis

241

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[15]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.25

Confidence interval

level

95%

sides

2-sided

lower limit

1.01

upper limit

1.55

Notes
[15] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI around the ratio of GMCs between the groups (MenACWY4 to routine vaccines) is greater than 0.5.

MenACWY3 vs Routine Vaccines (Serotype 4)

Statistical analysis description

Comparison groups

MenACWY3 v Routine vaccines

Number of subjects included in analysis

271

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[16]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

0.77

Confidence interval

level

95%

sides

2-sided

lower limit

0.62

upper limit

0.96

Notes
[16] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI around the ratio of GMCs between groups (MenACWY3 to routine vaccines) is greater than 0.5.

MenACWY4 vs Routine Vaccines (serotype 4)

Statistical analysis description

Comparison groups

Routine vaccines v MenACWY4

Number of subjects included in analysis

241

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[17]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

0.94

Confidence interval

level

95%

sides

2-sided

lower limit

0.75

upper limit

1.18

Notes
[17] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI around the ratio of GMCs between the groups (MenACWY4 to routine vaccines) is greater than 0.5.

MenACWY3 vs Routine Vaccines (Serotype 5)

Statistical analysis description

Comparison groups

MenACWY3 v Routine vaccines

Number of subjects included in analysis

271

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[18]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.02

Confidence interval

level

95%

sides

2-sided

lower limit

0.86

upper limit

1.21

Notes
[18] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI around the ratio of GMCs between groups (MenACWY3 to routine vaccines) is greater than 0.5.

MenACWY4 vs Routine Vaccines (Serotype 5)

Statistical analysis description

Comparison groups

MenACWY4 v Routine vaccines

Number of subjects included in analysis

241

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[19]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.07

Confidence interval

level

95%

sides

2-sided

lower limit

0.89

upper limit

1.29

Notes
[19] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI around the ratio of GMCs between the groups (MenACWY4 to routine vaccines) is greater than 0.5

MenACWY3 vs Routine Vaccines (serotype 6A)

Statistical analysis description

Comparison groups

MenACWY3 v Routine vaccines

Number of subjects included in analysis

271

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[20]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

0.85

Confidence interval

level

95%

sides

2-sided

lower limit

0.69

upper limit

1.04

Notes
[20] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI around the ratio of GMCs between groups (MenACWY3 to routine vaccines) is greater than 0.5.

MenACWY4 vs Routine Vaccines (serotype 6A)

Comparison groups

MenACWY4 v Routine vaccines

Number of subjects included in analysis

241

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[21]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.88

upper limit

1.37

Notes
[21] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI around the ratio of GMCs between the groups (MenACWY4 to routine vaccines) is greater than 0.5.

MenACWY3 vs Routine Vaccines (serotype 6B)

Statistical analysis description

Comparison groups

MenACWY3 v Routine vaccines

Number of subjects included in analysis

271

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[22]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

0.85

Confidence interval

level

95%

sides

2-sided

lower limit

0.69

upper limit

1.05

Notes
[22] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI around the ratio of GMCs between groups (MenACWY3 to routine vaccines) is greater than 0.5.

MenACWY4 vs Routine Vaccines (serotype 6B)

Statistical analysis description

Comparison groups

MenACWY4 v Routine vaccines

Number of subjects included in analysis

241

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[23]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.83

upper limit

1.3

Notes
[23] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI around the ratio of GMCs between the groups (MenACWY4 to routine vaccines) is greater than 0.5.

MenACWY3 vs Routine Vaccines (serotype 7F)

Statistical analysis description

Comparison groups

MenACWY3 v Routine vaccines

Number of subjects included in analysis

271

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[24]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

0.8

Confidence interval

level

95%

sides

2-sided

lower limit

0.67

upper limit

0.95

Notes
[24] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI around the ratio of GMCs between groups (MenACWY3 to routine vaccines) is greater than 0.5.

MenACWY4 vs Routine Vaccines (serotype 7F)

Statistical analysis description

Comparison groups

MenACWY4 v Routine vaccines

Number of subjects included in analysis

241

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[25]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.87

upper limit

1.25

Notes
[25] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI around the ratio of GMCs between the groups (MenACWY4 to routine vaccines) is greater than 0.5.

MenACWY3 vs Routine Vaccines (serotype 9V)

Statistical analysis description

Comparison groups

MenACWY3 v Routine vaccines

Number of subjects included in analysis

271

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[26]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

0.79

Confidence interval

level

95%

sides

2-sided

lower limit

0.66

upper limit

0.96

Notes
[26] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI around the ratio of GMCs between groups (MenACWY3 to routine vaccines) is greater than 0.5.

MenACWY4 vs Routine Vaccines (serotype 9V)

Statistical analysis description

Comparison groups

MenACWY4 v Routine vaccines

Number of subjects included in analysis

241

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[27]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.07

Confidence interval

level

95%

sides

2-sided

lower limit

0.87

upper limit

1.31

Notes
[27] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI around the ratio of GMCs between the groups (MenACWY4 to routine vaccines) is greater than 0.5.

MenACWY3 vs Routine Vaccines (serotype 14)

Statistical analysis description

Comparison groups

MenACWY3 v Routine vaccines

Number of subjects included in analysis

271

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[28]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.84

upper limit

1.27

Notes
[28] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI around the ratio of GMCs between groups (MenACWY3 to routine vaccines) is greater than 0.5.

MenACWY4 vs Routine Vaccines (serotype 14)

Statistical analysis description

demonstrate non-inferiority of immune response to PCV-13 antigens after concomitant administration of 4 doses of Men ACWY with routine vaccines including PCV-13, versus administration of routine vaccines only, at 13 months of age for Serotype 14.

Comparison groups

MenACWY4 v Routine vaccines

Number of subjects included in analysis

241

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[29]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.83

upper limit

1.3

Notes
[29] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI around the ratio of GMCs between the groups (MenACWY4 to routine vaccines) is greater than 0.5.

MenACWY3 vs Routine Vaccines (serotype 18C)

Statistical analysis description

Comparison groups

MenACWY3 v Routine vaccines

Number of subjects included in analysis

271

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[30]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

0.72

Confidence interval

level

95%

sides

2-sided

lower limit

0.59

upper limit

0.87

Notes
[30] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI around the ratio of GMCs between groups (MenACWY3 to routine vaccines) is greater than 0.5.

MenACWY4 vs Routine Vaccines (serotype 18C)

Statistical analysis description

Comparison groups

MenACWY4 v Routine vaccines

Number of subjects included in analysis

241

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[31]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.89

upper limit

1.36

Notes
[31] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI around the ratio of GMCs between the groups (MenACWY4 to routine vaccines) is greater than 0.5.

MenACWY3 vs Routine Vaccines (serotype 19A)

Statistical analysis description

Comparison groups

MenACWY3 v Routine vaccines

Number of subjects included in analysis

271

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[32]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.02

Confidence interval

level

95%

sides

2-sided

lower limit

0.83

upper limit

1.27

Notes
[32] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI around the ratio of GMCs between groups (MenACWY3 to routine vaccines) is greater than 0.5.

MenACWY4 vs Routine Vaccines (serotype 19A)

Statistical analysis description

Comparison groups

MenACWY4 v Routine vaccines

Number of subjects included in analysis

241

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[33]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

0.97

Confidence interval

level

95%

sides

2-sided

lower limit

0.77

upper limit

1.21

Notes
[33] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI around the ratio of GMCs between the groups (MenACWY4 to routine vaccines) is greater than 0.5.

MenACWY3 vs Routine Vaccines (serotype 19F)

Statistical analysis description

Comparison groups

MenACWY3 v Routine vaccines

Number of subjects included in analysis

271

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[34]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.82

upper limit

1.22

Notes
[34] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI around the ratio of GMCs between groups (MenACWY3 to routine vaccines) is greater than 0.5.

MenACWY4 vs Routine Vaccines (serotype 19F)

Statistical analysis description

Comparison groups

MenACWY4 v Routine vaccines

Number of subjects included in analysis

241

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[35]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.07

Confidence interval

level

95%

sides

2-sided

lower limit

0.86

upper limit

1.32

Notes
[35] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI around the ratio of GMCs between the groups (MenACWY4 to routine vaccines) is greater than 0.5.

MenACWY3 vs Routine Vaccines (serotype 23F)

Statistical analysis description

Comparison groups

Routine vaccines v MenACWY3

Number of subjects included in analysis

271

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[36]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

0.77

Confidence interval

level

95%

sides

2-sided

lower limit

0.62

upper limit

0.97

Notes
[36] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI around the ratio of GMCs between the groups (MenACWY3 to routine vaccines) is greater than 0.5.

MenACWY4 vs Routine Vaccines (serotype 23F)

Comparison groups

MenACWY4 v Routine vaccines

Number of subjects included in analysis

241

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[37]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

0.89

Confidence interval

level

95%

sides

2-sided

lower limit

0.7

upper limit

1.13

Notes
[37] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI around the ratio of GMCs between the groups (MenACWY4 to routine vaccines) is greater than 0.5.

Secondary: 10. Effect of Concomitant Administration of 2 or 3 Doses of MenACWY on Immune Response to PCV-13 Antigens at 7 Months of Age.

Top of page

End point title

10. Effect of Concomitant Administration of 2 or 3 Doses of MenACWY on Immune Response to PCV-13 Antigens at 7 Months of Age.

End point description

Percentage of subjects with IgG concentration ≥ 0.35 μg/mL against pneumococcal conjugate vaccine (PCV-13) antigens at 7 Months of age following concomitant administration of 2 or 3 doses of MenACWY with PCV-13. Analysis was done on Infant PCV PPS

End point type

Secondary

End point timeframe

7 months of age.

End point values	MenACWY3	MenACWY4	Routine vaccines
Number of subjects analysed	160	137	158
Units: Percentages of Subjects
number (confidence interval 95%)
1 (N=159,136,156)	93.7 (88.7 to 96.9)	100 (97.3 to 100)	94.2 (89.3 to 97.3)
3 (N=150,129,147)	79.3 (72 to 85.5)	87.6 (80.6 to 92.7)	82.3 (75.2 to 88.1)
4 (N=160,137,157)	94.4 (89.6 to 97.4)	97.1 (92.7 to 99.2)	96.8 (92.7 to 99)
5 (N=156,133,154)	84 (77.3 to 89.4)	93.2 (87.5 to 96.9)	88.3 (82.2 to 92.9)
6A (N=159,136,156)	98.1 (94.6 to 99.6)	99.3 (96 to 100)	98.1 (94.5 to 99.6)
6B (N=160,137,157)	84.4 (77.8 to 89.6)	94.9 (89.8 to 97.9)	84.7 (78.1 to 90)
7F (N=158,136,156)	100 (97.7 to 100)	100 (97.3 to 100)	99.4 (96.5 to 100)
9V (N=159,136,157)	89.3 (83.4 to 93.6)	96.3 (91.6 to 98.8)	92.4 (87 to 96)
14 (N=158,136,158)	99.4 (96.5 to 100)	100 (97.3 to 100)	97.5 (93.6 to 99.3)
18C (N=158,136,157)	97.5 (93.6 to 99.3)	97.8 (93.7 to 99.5)	100 (97.7 to 100)
19A (N=158,135,156)	95.6 (91.1 to 98.2)	92.6 (86.8 to 96.4)	98.1 (94.5 to 99.6)
19F (N=159,136,158)	100 (97.7 to 100)	100 (97.3 to 100)	99.4 (96.5 to 100)
23F (N=158,136,158)	93 (87.9 to 96.5)	95.6 (90.6 to 98.4)	91.1 (85.6 to 98.4)

MenACWY3 vs Routine Vaccines (Serotype 1)

Statistical analysis description

To demonstrate non-inferiority of immune response to PCV-13 antigens after concomitant administration of 2 doses of MenACWY with routine vaccines including PCV-13, versus administration of routine vaccines only, at 7 months of age for Serotype 1.

Comparison groups

MenACWY3 v Routine vaccines

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[38]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

-0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-6.1

upper limit

Notes
[38] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the between group difference (MenACWY3 minus Routine) in percentage of subjects with IgG concentration ≥ 0.35 μg/mL against each pneumococcal anti-capsular polysaccharide is greater than -10%.

MenACWY4 vs Routine Vaccines (Serotype 1)

Statistical analysis description

Comparison groups

MenACWY4 v Routine vaccines

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[39]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

5.8

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

10.5

Notes
[39] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the between group difference (MenACWY4 minus Routine) in percentage of subjects with IgG concentration ≥ 0.35 μg/mL against each pneumococcal anti-capsular polysaccharide is greater than -10%.

MenACWY3 vs Routine Vaccines (Serotype 3)

Statistical analysis description

Comparison groups

MenACWY3 v Routine vaccines

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[40]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

-3

Confidence interval

level

95%

sides

2-sided

lower limit

-11.9

upper limit

Notes
[40] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the between group difference (MenACWY3 minus Routine) in percentage of subjects with IgG concentration ≥ 0.35 μg/mL against each pneumococcal anti-capsular polysaccharide is greater than -10%.

MenACWY4 vs Routine Vaccines (serotype 3)

Statistical analysis description

Comparison groups

MenACWY4 v Routine vaccines

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[41]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

5.3

Confidence interval

level

95%

sides

2-sided

lower limit

-3.3

upper limit

13.7

Notes
[41] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the between group difference (MenACWY4 minus Routine) in percentage of subjects with IgG concentration ≥ 0.35 μg/mL against each pneumococcal anti-capsular polysaccharide is greater than -10%.

MenACWY3 vs Routine Vaccines (serotype 4)

Statistical analysis description

Comparison groups

MenACWY3 v Routine vaccines

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[42]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

-2.4

Confidence interval

level

95%

sides

2-sided

lower limit

-7.5

upper limit

2.3

Notes
[42] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the between group difference (MenACWY3 minus Routine) in percentage of subjects with IgG concentration ≥ 0.35 μg/mL against each pneumococcal anti-capsular polysaccharide is greater than -10%.

MenACWY4 vs Routine Vaccines (serotype 4)

Statistical analysis description

Comparison groups

MenACWY4 v Routine vaccines

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[43]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-4.4

upper limit

4.7

Notes
[43] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the between group difference (MenACWY4 minus Routine) in percentage of subjects with IgG concentration ≥ 0.35 μg/mL against each pneumococcal anti-capsular polysaccharide is greater than -10%.

MenACWY3 vs Routine Vaccines (serotype 5)

Statistical analysis description

Comparison groups

MenACWY3 v Routine vaccines

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[44]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

-4.3

Confidence interval

level

95%

sides

2-sided

lower limit

-12.1

upper limit

3.4

Notes
[44] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the between group difference (MenACWY3 minus Routine) in percentage of subjects with IgG concentration ≥ 0.35 μg/mL against each pneumococcal anti-capsular polysaccharide is greater than -10%.

MenACWY4 vs Routine Vaccines (serotype 5)

Statistical analysis description

To demonstrate non-inferiority of immune response to PCV-13 antigens after concomitant administration of 3 doses of MenACWY with routine vaccines including PCV-13, versus administration of routine vaccines only, at 7 months of age for Serotype 5.

Comparison groups

MenACWY4 v Routine vaccines

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[45]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

4.9

Confidence interval

level

95%

sides

2-sided

lower limit

-1.9

upper limit

11.8

Notes
[45] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the between group difference (MenACWY3 minus Routine) in percentage of subjects with IgG concentration ≥ 0.35 μg/mL against each pneumococcal anti-capsular polysaccharide is greater than -10%.

MenACWY3 vs Routine vaccines (serogroup 6A)

Statistical analysis description

Comparison groups

MenACWY3 v Routine vaccines

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[46]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-3.7

upper limit

3.8

Notes
[46] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the between group difference (MenACWY3 minus Routine) in percentage of subjects with IgG concentration ≥ 0.35 μg/mL against each pneumococcal anti-capsular polysaccharide is greater than -10%.

MenACWY4 vs Routine vaccines (serogroup 6A)

Statistical analysis description

To demonstrate non-inferiority of immune response to PCV-13 antigens after concomitant administration of 3 doses of MenACWY with routine vaccines including PCV-13, versus administration of routine vaccines only, at 7 months of age for Serotype 6A.

Comparison groups

MenACWY4 v Routine vaccines

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[47]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-2.2

upper limit

4.8

Notes
[47] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the between group difference (MenACWY3 minus Routine) in percentage of subjects with IgG concentration ≥ 0.35 μg/mL against each pneumococcal anti-capsular polysaccharide is greater than -10%.

MenACWY3 vs Routine vaccines (serogroup 6B)

Statistical analysis description

Comparison groups

MenACWY3 v Routine vaccines

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[48]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

-0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-8.4

upper limit

7.7

Notes
[48] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the between group difference (MenACWY3 minus Routine) in percentage of subjects with IgG concentration ≥ 0.35 μg/mL against each pneumococcal anti-capsular polysaccharide is greater than -10%.

MenACWY4 vs Routine vaccines (serogroup 6B)

Statistical analysis description

Comparison groups

MenACWY4 v Routine vaccines

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[49]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

10.2

Confidence interval

level

95%

sides

2-sided

lower limit

3.4

upper limit

17.2

Notes
[49] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the between group difference (MenACWY4 minus Routine) in percentage of subjects with IgG concentration ≥ 0.35 μg/mL against each pneumococcal anti-capsular polysaccharide is greater than -10%.

MenACWY3 vs Routine vaccines (serotype 7F)

Statistical analysis description

Comparison groups

MenACWY3 v Routine vaccines

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[50]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-1.7

upper limit

3.5

Notes
[50] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the between group difference (MenACWY3 minus Routine) in percentage of subjects with IgG concentration ≥ 0.35 μg/mL against each pneumococcal anti-capsular polysaccharide is greater than -10%.

MenACWY4 vs Routine vaccines (serotype 7F)

Statistical analysis description

Comparison groups

MenACWY4 v Routine vaccines

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[51]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-2.1

upper limit

3.5

Notes
[51] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the between group difference (MenACWY4 minus Routine) in percentage of subjects with IgG concentration ≥ 0.35 μg/mL against each pneumococcal anti-capsular polysaccharide is greater than -10%.

MenACWY3 vs Routine vaccines (serotype 9V)

Statistical analysis description

Comparison groups

MenACWY3 v Routine vaccines

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[52]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

-3.1

Confidence interval

level

95%

sides

2-sided

lower limit

-9.7

upper limit

3.4

Notes
[52] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the between group difference (MenACWY3 minus Routine) in percentage of subjects with IgG concentration ≥ 0.35 μg/mL against each pneumococcal anti-capsular polysaccharide is greater than -10%.

MenACWY4 vs Routine vaccines (serotype 9V)

Statistical analysis description

Comparison groups

MenACWY4 v Routine vaccines

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[53]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1.5

upper limit

9.7

Notes
[53] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the between group difference (MenACWY4 minus Routine) in percentage of subjects with IgG concentration ≥ 0.35 μg/mL against each pneumococcal anti-capsular polysaccharide is greater than -10%.

MenACWY3 vs Routine vaccines (serotype 14)

Statistical analysis description

Comparison groups

MenACWY3 v Routine vaccines

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[54]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

1.9

Confidence interval

level

95%

sides

2-sided

lower limit

-1.2

upper limit

5.7

Notes
[54] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the between group difference (MenACWY3 minus Routine) in percentage of subjects with IgG concentration ≥ 0.35 μg/mL against each pneumococcal anti-capsular polysaccharide is greater than -10%.

MenACWY4 vs Routine vaccines (serotype 14)

Statistical analysis description

To demonstrate non-inferiority of immune response to PCV-13 antigens after concomitant administration of 3 doses of MenACWY with routine vaccines including PCV-13, versus administration of routine vaccines only, at 7 months of age for Serotype 14.

Comparison groups

MenACWY4 v Routine vaccines

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[55]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

2.5

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2

upper limit

6.3

Notes
[55] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the between group difference (MenACWY3 minus Routine) in percentage of subjects with IgG concentration ≥ 0.35 μg/mL against each pneumococcal anti-capsular polysaccharide is greater than -10%.

MenACWY3 vs Routine vaccines (serotype 18C)

Statistical analysis description

Comparison groups

MenACWY3 v Routine vaccines

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[56]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

-2.5

Confidence interval

level

95%

sides

2-sided

lower limit

-6.3

upper limit

-0.2

Notes
[56] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the between group difference (MenACWY3 minus Routine) in percentage of subjects with IgG concentration ≥ 0.35 μg/mL against each pneumococcal anti-capsular polysaccharide is greater than -10%.

MenACWY4 vs Routine vaccines (serotype 18C)

Statistical analysis description

Comparison groups

MenACWY4 v Routine vaccines

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[57]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

-2.2

Confidence interval

level

95%

sides

2-sided

lower limit

-6.2

upper limit

-0.2

Notes
[57] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the between group difference (MenACWY4 minus Routine) in percentage of subjects with IgG concentration ≥ 0.35 μg/mL against each pneumococcal anti-capsular polysaccharide is greater than -10%.

MenACWY3 vs Routine vaccines (serotype 19A)

Statistical analysis description

Comparison groups

MenACWY3 v Routine vaccines

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[58]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

-2.5

Confidence interval

level

95%

sides

2-sided

lower limit

-7.1

upper limit

1.6

Notes
[58] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the between group difference (MenACWY3 minus Routine) in percentage of subjects with IgG concentration ≥ 0.35 μg/mL against each pneumococcal anti-capsular polysaccharide is greater than -10%.

MenACWY4 vs Routine vaccines (serotype 19A)

Statistical analysis description

Comparison groups

MenACWY4 v Routine vaccines

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[59]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

-5.5

Confidence interval

level

95%

sides

2-sided

lower limit

-11.3

upper limit

-0.9

Notes
[59] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the between group difference (MenACWY4 minus Routine) in percentage of subjects with IgG concentration ≥ 0.35 μg/mL against each pneumococcal anti-capsular polysaccharide is greater than -10%.

MenACWY3 vs Routine vaccines (serotype 19F)

Statistical analysis description

Comparison groups

MenACWY3 v Routine vaccines

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[60]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-1.7

upper limit

3.4

Notes
[60] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the between group difference (MenACWY3 minus Routine) in percentage of subjects with IgG concentration ≥ 0.35 μg/mL against each pneumococcal anti-capsular polysaccharide is greater than -10%.

MenACWY4 vs Routine vaccines (serotype 19F)

Statistical analysis description

Comparison groups

MenACWY4 v Routine vaccines

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[61]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-2.1

upper limit

3.4

Notes
[61] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the between group difference (MenACWY4 minus Routine) in percentage of subjects with IgG concentration ≥ 0.35 μg/mL against each pneumococcal anti-capsular polysaccharide is greater than -10%.

MenACWY3 vs Routine vaccines (serotype 23F)

Statistical analysis description

Comparison groups

MenACWY3 v Routine vaccines

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[62]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

1.9

Confidence interval

level

95%

sides

2-sided

lower limit

-4.2

upper limit

8.2

Notes
[62] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the between group difference (MenACWY3 minus Routine) in percentage of subjects with IgG concentration ≥ 0.35 μg/mL against each pneumococcal anti-capsular polysaccharide is greater than -10%.

MenACWY4 vs Routine vaccines (serotype 23F)

Statistical analysis description

Comparison groups

MenACWY4 v Routine vaccines

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[63]

Method

Miettinen and Nurminen method

Parameter type

Risk difference (RD)

Point estimate

4.5

Confidence interval

level

95%

sides

2-sided

lower limit

-1.4

upper limit

10.5

Notes
[63] - Non-inferiority will be concluded if the lower limit of the two-sided 95% CI for the between group difference (MenACWY4 minus Routine) in percentage of subjects with IgG concentration ≥ 0.35 μg/mL against each pneumococcal anti-capsular polysaccharide is greater than -10%.

Secondary: 11. Percentage Of Subjects Reporting at Least One Severe Systemic Solicited Adverse Event

Top of page

End point title

11. Percentage Of Subjects Reporting at Least One Severe Systemic Solicited Adverse Event

End point description

Safety was assessed as the percentage of subjects who reported severe solicited systemic adverse events after administration of MenACWY with concomitant vaccines vs. concomitant vaccines alone.

End point type

Secondary

End point timeframe

Day 1 through Day 7

End point values	MenACWY3	MenACWY4	Routine vaccines
Number of subjects analysed	238	240	230
Units: Percentage of Subjects
number (not applicable)
At least one severe systemic solicited AE	18	21	18

No statistical analyses for this end point

Secondary: 12. Number Of Subjects Reporting Solicited Local or Systemic Adverse Events after any vaccination.

Top of page

End point title

12. Number Of Subjects Reporting Solicited Local or Systemic Adverse Events after any vaccination.

End point description

Safety was assessed as the number of subjects who reported solicited local or systemic adverse events after administration of MenACWY with concomitant vaccines vs. concomitant vaccines alone.

End point type

Secondary

End point timeframe

Day 1 (6 hour) to day 7

End point values	MenACWY3	MenACWY4	Routine vaccines
Number of subjects analysed	238	239	229
Units: Subjects
number (not applicable)
Injection site erythema	72	64	79
Injection site induration	60	40	74
Tenderness	117	127	126
Change in eating habits (N=238,238,229)	104	104	93
Sleepiness	153	147	149
Persistent crying	140	137	112
Irritability	173	171	152
Vomiting	68	52	54
Diarrhea	89	69	68
Fever (≥38.0°C)	55	52	41
Rash	23	19	18
Use of analgesic/antipyretic	162	173	153

No statistical analyses for this end point

Secondary: 13. Number of Subjects Reporting Unsolicited Adverse Events After Any Vaccination

Top of page

End point title

13. Number of Subjects Reporting Unsolicited Adverse Events After Any Vaccination

End point description

Safety was assessed as the number of subjects who reported unsolicited local or systemic adverse events after administration of MenACWY with concomitant vaccines vs. concomitant vaccines alone.

End point type

Secondary

End point timeframe

2 months to 13 months of age.

End point values	MenACWY3	MenACWY4	Routine vaccines
Number of subjects analysed	242	252	239
Units: Subjects
number (not applicable)
Any AE	219	220	209
At least possibly related AEs	24	32	10
SAEs	11	19	11
Deaths	0	0	1
Medically attended AEs	210	211	198
AEs resulting in premature withdrawal	1	2	2

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

2 months to 13 months of age

Adverse event reporting additional description

Solicited local and systemic and unsolicited AEs were assessed for 7 days postvaccination. Medically attended AEs and SAEs were collected throughout the study period

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

15.1

Reporting group title

MenACWY3

Reporting group description

Healthy male and female infants approximately 2 months of age received 2 infant doses at 2 and 4 months of age, with a toddler dose at 12 months of age.

Reporting group title

MenACWY4

Reporting group description

Reporting group title

Routine vaccines

Reporting group description

Healthy male and female infants approximately 2 months of age received routine vaccines including PCV-13, at 2, 4, 6 and 12 months of age.

Serious adverse events	MenACWY3	MenACWY4	Routine vaccines
Total subjects affected by serious adverse events
subjects affected / exposed	11 / 242 (4.55%)	19 / 252 (7.54%)	11 / 239 (4.60%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Injury, poisoning and procedural complications
Skull fracture
subjects affected / exposed	1 / 242 (0.41%)	0 / 252 (0.00%)	0 / 239 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Congenital megacolon
subjects affected / exposed	0 / 242 (0.00%)	0 / 252 (0.00%)	1 / 239 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Krabbe's disease
subjects affected / exposed	1 / 242 (0.41%)	0 / 252 (0.00%)	0 / 239 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Laryngomalacia
subjects affected / exposed	0 / 242 (0.00%)	0 / 252 (0.00%)	1 / 239 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardio-respiratory arrest
subjects affected / exposed	0 / 242 (0.00%)	0 / 252 (0.00%)	1 / 239 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Nervous system disorders
Convulsion
subjects affected / exposed	0 / 242 (0.00%)	2 / 252 (0.79%)	0 / 239 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoxic-ischaemic encephalopathy
subjects affected / exposed	0 / 242 (0.00%)	0 / 252 (0.00%)	1 / 239 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Nystagmus
subjects affected / exposed	0 / 242 (0.00%)	1 / 252 (0.40%)	0 / 239 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 242 (0.00%)	1 / 252 (0.40%)	0 / 239 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Anal fissure
subjects affected / exposed	0 / 242 (0.00%)	0 / 252 (0.00%)	1 / 239 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 242 (0.00%)	1 / 252 (0.40%)	0 / 239 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumomediastinum
subjects affected / exposed	1 / 242 (0.41%)	0 / 252 (0.00%)	0 / 239 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 242 (0.00%)	0 / 252 (0.00%)	1 / 239 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory acidosis
subjects affected / exposed	0 / 242 (0.00%)	0 / 252 (0.00%)	1 / 239 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sleep apnoea syndrome
subjects affected / exposed	0 / 242 (0.00%)	0 / 252 (0.00%)	1 / 239 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Breath holding
subjects affected / exposed	0 / 242 (0.00%)	1 / 252 (0.40%)	0 / 239 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Abdominal abscess
subjects affected / exposed	0 / 242 (0.00%)	1 / 252 (0.40%)	0 / 239 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abscess
subjects affected / exposed	0 / 242 (0.00%)	1 / 252 (0.40%)	0 / 239 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atypical pneumonia
subjects affected / exposed	0 / 242 (0.00%)	1 / 252 (0.40%)	0 / 239 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchiolitis
subjects affected / exposed	2 / 242 (0.83%)	2 / 252 (0.79%)	4 / 239 (1.67%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 242 (0.00%)	1 / 252 (0.40%)	0 / 239 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Croup infectious
subjects affected / exposed	0 / 242 (0.00%)	0 / 252 (0.00%)	1 / 239 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 242 (0.41%)	0 / 252 (0.00%)	1 / 239 (0.42%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 242 (0.00%)	1 / 252 (0.40%)	0 / 239 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 242 (0.41%)	0 / 252 (0.00%)	0 / 239 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Otitis media acute
subjects affected / exposed	0 / 242 (0.00%)	0 / 252 (0.00%)	1 / 239 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 242 (0.41%)	1 / 252 (0.40%)	0 / 239 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia respiratory syncytial viral
subjects affected / exposed	0 / 242 (0.00%)	0 / 252 (0.00%)	1 / 239 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal abscess
subjects affected / exposed	0 / 242 (0.00%)	1 / 252 (0.40%)	0 / 239 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory synctial virus bronchiolitis
subjects affected / exposed	2 / 242 (0.83%)	5 / 252 (1.98%)	2 / 239 (0.84%)
occurrences causally related to treatment / all	0 / 2	0 / 5	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Staphylococcal abscess
subjects affected / exposed	1 / 242 (0.41%)	0 / 252 (0.00%)	0 / 239 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 242 (0.41%)	0 / 252 (0.00%)	0 / 239 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Failure to thrive
subjects affected / exposed	1 / 242 (0.41%)	0 / 252 (0.00%)	0 / 239 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	0 / 242 (0.00%)	0 / 252 (0.00%)	1 / 239 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	MenACWY3	MenACWY4	Routine vaccines
Total subjects affected by non serious adverse events
subjects affected / exposed	238 / 242 (98.35%)	233 / 252 (92.46%)	228 / 239 (95.40%)
Nervous system disorders
Somnolence
alternative assessment type: Systematic
subjects affected / exposed	162 / 242 (66.94%)	154 / 252 (61.11%)	158 / 239 (66.11%)
occurrences all number	400	363	377
General disorders and administration site conditions
Crying
subjects affected / exposed	140 / 242 (57.85%)	138 / 252 (54.76%)	112 / 239 (46.86%)
occurrences all number	227	259	220
Injection site induration
subjects affected / exposed	65 / 242 (26.86%)	45 / 252 (17.86%)	79 / 239 (33.05%)
occurrences all number	93	72	138
Injection site erythema
alternative assessment type: Systematic
subjects affected / exposed	87 / 242 (35.95%)	80 / 252 (31.75%)	89 / 239 (37.24%)
occurrences all number	139	164	160
Injection site pain
alternative assessment type: Systematic
subjects affected / exposed	137 / 242 (56.61%)	140 / 252 (55.56%)	138 / 239 (57.74%)
occurrences all number	286	282	266
Pyrexia
alternative assessment type: Systematic
subjects affected / exposed	88 / 242 (36.36%)	88 / 252 (34.92%)	69 / 239 (28.87%)
occurrences all number	138	141	105
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	13 / 242 (5.37%)	10 / 252 (3.97%)	9 / 239 (3.77%)
occurrences all number	16	12	12
Gastrointestinal disorders
Constipation
subjects affected / exposed	10 / 242 (4.13%)	21 / 252 (8.33%)	19 / 239 (7.95%)
occurrences all number	11	23	21
Diarrhoea
alternative assessment type: Systematic
subjects affected / exposed	103 / 242 (42.56%)	78 / 252 (30.95%)	80 / 239 (33.47%)
occurrences all number	180	143	138
Gastrooesophageal reflux disease
subjects affected / exposed	11 / 242 (4.55%)	14 / 252 (5.56%)	27 / 239 (11.30%)
occurrences all number	11	14	30
Teething
subjects affected / exposed	15 / 242 (6.20%)	13 / 252 (5.16%)	19 / 239 (7.95%)
occurrences all number	16	14	24
Vomiting
subjects affected / exposed	76 / 242 (31.40%)	68 / 252 (26.98%)	67 / 239 (28.03%)
occurrences all number	127	99	110
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	32 / 242 (13.22%)	32 / 252 (12.70%)	37 / 239 (15.48%)
occurrences all number	33	34	44
Wheezing
subjects affected / exposed	12 / 242 (4.96%)	9 / 252 (3.57%)	16 / 239 (6.69%)
occurrences all number	12	9	20
Nasal congestion
subjects affected / exposed	16 / 242 (6.61%)	18 / 252 (7.14%)	14 / 239 (5.86%)
occurrences all number	18	22	18
Skin and subcutaneous tissue disorders
Dermatitis atopic
subjects affected / exposed	10 / 242 (4.13%)	11 / 252 (4.37%)	14 / 239 (5.86%)
occurrences all number	13	12	16
Eczema
subjects affected / exposed	16 / 242 (6.61%)	19 / 252 (7.54%)	20 / 239 (8.37%)
occurrences all number	18	19	22
Dermatitis diaper
subjects affected / exposed	38 / 242 (15.70%)	31 / 252 (12.30%)	22 / 239 (9.21%)
occurrences all number	41	38	33
Rash
alternative assessment type: Systematic
subjects affected / exposed	29 / 242 (11.98%)	31 / 252 (12.30%)	36 / 239 (15.06%)
occurrences all number	34	37	47
Psychiatric disorders
Irritability
alternative assessment type: Systematic
subjects affected / exposed	181 / 242 (74.79%)	179 / 252 (71.03%)	157 / 239 (65.69%)
occurrences all number	479	459	399
Eating disorder
alternative assessment type: Systematic
subjects affected / exposed	104 / 242 (42.98%)	104 / 252 (41.27%)	93 / 239 (38.91%)
occurrences all number	195	189	152
Infections and infestations
Conjunctivitis
subjects affected / exposed	42 / 242 (17.36%)	25 / 252 (9.92%)	40 / 239 (16.74%)
occurrences all number	51	31	44
Bronchiolitis
subjects affected / exposed	34 / 242 (14.05%)	36 / 252 (14.29%)	30 / 239 (12.55%)
occurrences all number	41	46	36
Candida nappy rash
subjects affected / exposed	13 / 242 (5.37%)	6 / 252 (2.38%)	7 / 239 (2.93%)
occurrences all number	14	7	7
Bronchitis
subjects affected / exposed	8 / 242 (3.31%)	19 / 252 (7.54%)	17 / 239 (7.11%)
occurrences all number	9	24	18
Candidiasis
subjects affected / exposed	14 / 242 (5.79%)	20 / 252 (7.94%)	21 / 239 (8.79%)
occurrences all number	15	23	22
Croup Infectious
subjects affected / exposed	13 / 242 (5.37%)	16 / 252 (6.35%)	16 / 239 (6.69%)
occurrences all number	13	17	19
Gastroenteritis
subjects affected / exposed	22 / 242 (9.09%)	18 / 252 (7.14%)	27 / 239 (11.30%)
occurrences all number	26	21	30
Otitis media
subjects affected / exposed	94 / 242 (38.84%)	77 / 252 (30.56%)	89 / 239 (37.24%)
occurrences all number	193	153	183
Rhinitis
subjects affected / exposed	20 / 242 (8.26%)	17 / 252 (6.75%)	15 / 239 (6.28%)
occurrences all number	25	26	20
Otitis media acute
subjects affected / exposed	23 / 242 (9.50%)	19 / 252 (7.54%)	16 / 239 (6.69%)
occurrences all number	31	24	29
Sinusitis
subjects affected / exposed	9 / 242 (3.72%)	17 / 252 (6.75%)	7 / 239 (2.93%)
occurrences all number	10	21	8
Viral infection
subjects affected / exposed	38 / 242 (15.70%)	32 / 252 (12.70%)	30 / 239 (12.55%)
occurrences all number	42	38	37
Upper respiratory tract infection
subjects affected / exposed	105 / 242 (43.39%)	107 / 252 (42.46%)	106 / 239 (44.35%)
occurrences all number	192	186	194
Viral rash
subjects affected / exposed	10 / 242 (4.13%)	10 / 252 (3.97%)	13 / 239 (5.44%)
occurrences all number	10	12	14

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Were there any global substantial amendments to the protocol? Yes

05 Jul 2011

A secondary objective was added to compare persistence of 2 vs 3-dose infant series at 12 months of age; 4-fold rise in hSBA added as an endpoint for evaluating immune response at 13 months of age (ie, following the toddler dose).

10 May 2012

Added primary objective added, to demonstrate a sufficient immune response of 4 doses of MenACWY given to infants at 2, 4, 6 and 12 months of age as measured by the percentage of subjects with serum bactericidal activity using human complement (hSBA) ≥1:8, directed against N meningitidis serogroups A, C, W and Y. Added description of tiered approach of assessing noninterference of PCV-13 concomitantly administered with MenACWY, using a hierarchical sequential testing procedure that groups the serotypes into 2 families.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
07 Jul 2011	FDA/CBER imposed a formal partial clinical hold due to insufficient information to assess the risks to subjects of translucent particles detected in the prefilled syringes (PFS) used in ongoing studies. All study sites in Canada and the USA were notified via letter to immediately stop using the PFS/vial presentation, to quarantine all doses, and to immediately switch to the vial/vial vaccine presentation.	26 Jul 2011

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 3b, Randomized, Open-Label, Multi-Center Study to Evaluate the Safety and Immunogenicity of 2 or 3 Doses of MenACWY Conjugate Vaccine in Healthy Infants and the Effects of a Booster Dose of MenACWY Administered in the Second Year of Life.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 1. Percentage of subjects with serum bactericidal activity using human complement (hSBA) ≥1:8, directed against N meningitidis serogroups A, C, W and Y.

Primary: 1. Percentage of subjects with serum bactericidal activity using human complement (hSBA) ≥1:8, directed against N meningitidis serogroups A, C, W and Y.

Primary: 2. Percentage of Subjects With hSBA ≥ 1:8 Against N Meningitidis Serogroups A, C, W and Y Following 4- Dose and 3-Dose Schedule of Men ACWY Vaccination.

Primary: 2. Percentage of Subjects With hSBA ≥ 1:8 Against N Meningitidis Serogroups A, C, W and Y Following 4- Dose and 3-Dose Schedule of Men ACWY Vaccination.

Secondary: 3. Percentage of Subjects With hSBA ≥1:8 Against N. Meningitidis Serogroups A, C, W and Y at Baseline (2 Months of Age) and at 3, 4, 5, and 7 Months of Age.

Secondary: 3. Percentage of Subjects With hSBA ≥1:8 Against N. Meningitidis Serogroups A, C, W and Y at Baseline (2 Months of Age) and at 3, 4, 5, and 7 Months of Age.

Secondary: 4. Geometric Mean hSBA Titers Against N Meningitis Serogroups A, C, W and Y at Baseline (2 Months of Age) and at 3, 4, 5, and 7 Months of Age.

Secondary: 4. Geometric Mean hSBA Titers Against N Meningitis Serogroups A, C, W and Y at Baseline (2 Months of Age) and at 3, 4, 5, and 7 Months of Age.

Secondary: 5. Percentage of Subjects With hSBA ≥1:8 Following 2 and 3 Infant Doses of MenACWY.

Secondary: 5. Percentage of Subjects With hSBA ≥1:8 Following 2 and 3 Infant Doses of MenACWY.

Secondary: 6. Geometric Mean hSBA Titers Following 2 and 3 Infant Doses of MenACWY

Secondary: 6. Geometric Mean hSBA Titers Following 2 and 3 Infant Doses of MenACWY

Secondary: 7. GMTs at 13 Months of Age After Completion of 3- and 4-Dose Series of MenACWY.

Secondary: 7. GMTs at 13 Months of Age After Completion of 3- and 4-Dose Series of MenACWY.

Secondary: 8. Percentage of Subjects With 4-fold Increase in hSBA Titers Against N Meningitis Serogroups A, C, W and Y Between 12 and 13 Months of Age.

Secondary: 8. Percentage of Subjects With 4-fold Increase in hSBA Titers Against N Meningitis Serogroups A, C, W and Y Between 12 and 13 Months of Age.

Secondary: 9. Effect of Concomitant Administration of 3 or 4 Doses of MenACWY on Immune Response to PCV-13 Antigens at 13 Months of Age.

Secondary: 9. Effect of Concomitant Administration of 3 or 4 Doses of MenACWY on Immune Response to PCV-13 Antigens at 13 Months of Age.

Secondary: 10. Effect of Concomitant Administration of 2 or 3 Doses of MenACWY on Immune Response to PCV-13 Antigens at 7 Months of Age.

Secondary: 10. Effect of Concomitant Administration of 2 or 3 Doses of MenACWY on Immune Response to PCV-13 Antigens at 7 Months of Age.

Secondary: 11. Percentage Of Subjects Reporting at Least One Severe Systemic Solicited Adverse Event

Secondary: 11. Percentage Of Subjects Reporting at Least One Severe Systemic Solicited Adverse Event

Secondary: 12. Number Of Subjects Reporting Solicited Local or Systemic Adverse Events after any vaccination.

Secondary: 12. Number Of Subjects Reporting Solicited Local or Systemic Adverse Events after any vaccination.

Secondary: 13. Number of Subjects Reporting Unsolicited Adverse Events After Any Vaccination

Secondary: 13. Number of Subjects Reporting Unsolicited Adverse Events After Any Vaccination

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase 3b, Randomized, Open-Label, Multi-Center Study to Evaluate the Safety and Immunogenicity of 2 or 3 Doses of MenACWY Conjugate Vaccine in Healthy Infants and the Effects of a Booster Dose of MenACWY Administered in the Second Year of Life.