Clinical Trial Results:
A Phase 3, Open-Label, Randomized, Multi-Center Study to Evaluate the Safety and Immunogenicity after One or Two Doses of Novartis Meningococcal ACWY Conjugate Vaccine Administered to Healthy Infants and Toddlers

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

Summary
EudraCT number	2007-004754-82
Trial protocol	DE
Global end of trial date	22 Oct 2010

Results information
Results version number	v2(current)
This version publication date	04 Jun 2016
First version publication date	01 Nov 2014
Other versions	v1 (removed from public view)
Version creation reason	Correction of full data set Confidence interval shifted among groups.

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

V59P22

ISRCTN number

US NCT number

NCT00667602

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Vaccines and Diagnostics S.r.l

Sponsor organisation address

Via Fiorentina 1, Siena, Italy, 53100

Public contact

Posting Director, Novartis Vaccines, RegistryContactVaccinesUS@novartis.com

Scientific contact

Posting Director, Novartis Vaccines, RegistryContactVaccinesUS@novartis.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-000032-PIP01-07

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

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

Yes

Analysis stage

Final

Date of interim/final analysis

23 May 2012

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

22 Oct 2010

Was the trial ended prematurely?

Main objective of the trial

To assess and compare the immunogenicity of one dose of conjugate meningococcal ACWY vaccine (MenACWY) to one dose of Menjugate® given to healthy toddlers at 12 months of age as measured by the percentage of subjects with serum bactericidal activity using human complement (hSBA) titers ≥1:8 against N. meningitidis serogroup C.

Protection of trial subjects

Novartis Vaccines or the investigator provided the ethics committee (EC) with all appropriate material, including the Informed Consent Form (ICF), according to local regulations. The EC should also was asked for a written statement regarding the composition of the committee and to comply with GCP (Good Clinical Practices) and with the applicable regulatory requirement(s). The trial was not initiated until appropriate EC approval of the protocol and the ICF was obtained. In addition, all documents were submitted to other authorities in compliance with local jurisdictions. Prior to enrollment, the sponsor and the investigator exchanged written confirmation that their ethical and legal responsibilities had been observed. The EC and, if applicable, other authorities were informed of protocol amendments in accordance with local legal requirements. Appropriate reports on the progress of the study were made to the EC and the sponsor by the investigator in accordance with applicable governmental regulations and in agreement with policy established by the sponsor.

Background therapy

Evidence for comparator

Actual start date of recruitment

27 Mar 2008

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 75

Country: Number of subjects enrolled

Germany: 587

Worldwide total number of subjects

662

EEA total number of subjects

587

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)

662

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

All participants enrolled were included in the trial

Screening details

Inclusion Criteria: infants 6 to 8 months old inclusive, who were born after full term pregnancy and previously received three doses of both Prevenar and Infanrix-hexa vaccines at least 30 days before study entry Exclusion Criteria: who previously received any meningococcal vaccine

Period 1 title

overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

MenACWY-CRM197 (2dose) +Concomitant Vaccines

Arm description

Infants received two doses of MenACWY-CRM197 at 6 to 8 and 12 months of age and concomitant dose of PCV7 (Pneumococcal 7-valent Conjugate Vaccine) and DTPa-IPV-HepB-Hib (Diphtheria-Tetanus-acellular Pertussis, Hepatitis B, Inactivated Poliovirus and Haemophilus influenzae type b) at 12 months.

Arm type

Experimental

Investigational medicinal product name

MenACWY-CRM197+PCV7+DTPa-IPV-HepB-Hib

Investigational medicinal product code

Other name

Pharmaceutical forms

Emulsion for injection

Routes of administration

Intramuscular use

Dosage and administration details

1.Two 0.5mL doses of MenACWY conjugate vaccine (MenACWYCRM197) was administered by intramuscular injection. 2. One 0.5mL dose of MenACWY conjugate vaccine (MenACWYCRM197) was administered by intramuscular injection. 3. One 0.5mL dose of Pneumococcal 7-valent Conjugate Vaccine (PCV7) was administered by intramuscular injection. 4.One 0.5mL dose of Combined Diphtheria-Tetanus-acellular Pertussis, Hepatitis B, Inactivated Poliovirus and Haemophilus influenzae type b (DTPa-IPVHepB-Hib) vaccine was administered by intramuscular injection.

MenACWY-CRM197 (1dose) +Concomitant Vaccines

Arm description

Infants received one dose of MenACWY-CRM197 at 12 months of age and concomitant dose of PCV7 (Pneumococcal 7-valent Conjugate Vaccine)and DTPa-IPV-HepB-Hib (Diphtheria-Tetanusacellular Pertussis, Hepatitis B, Inactivated Poliovirus and Haemophilus influenzae type b) at 12 months of age.

Arm type

Experimental

Investigational medicinal product name

MenACWY-CRM197+PCV7+ DTPa-IPV-HepB-Hib

Investigational medicinal product code

Other name

Pharmaceutical forms

Emulsion for injection

Routes of administration

Intramuscular use

Dosage and administration details

1.Two 0.5mL doses of MenACWY conjugate vaccine (MenACWYCRM197) was administered by intramuscular injection. 2. One 0.5mL dose of MenACWY conjugate vaccine (MenACWYCRM197) was administered by intramuscular injection. 3.One 0.5mL dose of Pneumococcal 7-valent Conjugate Vaccine (PCV7) was administered by intramuscular injection. 4.One 0.5mL dose of Combined Diphtheria-Tetanus-acellular Pertussis, Hepatitis B, Inactivated Poliovirus and Haemophilus influenzae type b (DTPa-IPVHepB-Hib) vaccine was administered by intramuscular injection.

MenC (1dose) + Concomitant Vaccines

Arm description

Infants received one dose of MenC vaccine at 12 months of age and concomitant dose of PCV7 (Pneumococcal 7-valent Conjugate Vaccine) and DTPa-IPV-HepB-Hib (Diphtheria-Tetanus-acellular Pertussis, Hepatitis B, Inactivated Poliovirus and Haemophilus influenzae type b) at 12 months of age.

Arm type

Active comparator

Investigational medicinal product name

MenC + PCV7 + DTPa-IPV-HepB-Hib

Investigational medicinal product code

Other name

Pharmaceutical forms

Emulsion for injection

Routes of administration

Intramuscular use

Dosage and administration details

1.One 0.5mL dose of MenC vaccine was administered by intramuscular injection. 2.One 0.5mL dose of Pneumococcal 7-valent Conjugate Vaccine (PCV7) was administered by intramuscular injection. 3.One 0.5mL dose of Combined Diphtheria-Tetanus-acellular Pertussis, Hepatitis B, Inactivated Poliovirus and Haemophilus influenzae type b (DTPa-IPVHepB-Hib) vaccine was administered by intramuscular injection.

Number of subjects in period 1	MenACWY-CRM197 (2dose) +Concomitant Vaccines	MenACWY-CRM197 (1dose) +Concomitant Vaccines	MenC (1dose) + Concomitant Vaccines
Started	219	228	215
Completed	211	213	197
Not completed	8	15	18
Consent withdrawn by subject	4	9	10
Administrative reasons	-	-	2
Lost to follow-up	4	5	6
Protocol deviation	-	1	-

Baseline characteristics

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Reporting group title

MenACWY-CRM197 (2dose) +Concomitant Vaccines

Reporting group description

Reporting group title

MenACWY-CRM197 (1dose) +Concomitant Vaccines

Reporting group description

Reporting group title

MenC (1dose) + Concomitant Vaccines

Reporting group description

Reporting group values	MenACWY-CRM197 (2dose) +Concomitant Vaccines	MenACWY-CRM197 (1dose) +Concomitant Vaccines	MenC (1dose) + Concomitant Vaccines	Total
Number of subjects	219	228	215	662
Age categorical
Units: Subjects
Age continuous
As one site has been excluded, the number of subjects included in the analysis are MenACWYCRM197 (2dose) + Concomitant Vaccines N= 196, MenACWY-CRM197 (1dose) + Concomitant Vaccines N= 205 and MenC (1dose) + Concomitant Vaccines N= 193
Units: days
arithmetic mean (standard deviation)	208.4 ( 23.7 )	209.8 ( 22.2 )	209.3 ( 21.9 )	-
Gender categorical
Units: Subjects
Female	105	106	94	305
Male	114	122	121	357

End points

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Reporting group title

MenACWY-CRM197 (2dose) +Concomitant Vaccines

Reporting group description

Reporting group title

MenACWY-CRM197 (1dose) +Concomitant Vaccines

Reporting group description

Reporting group title

MenC (1dose) + Concomitant Vaccines

Reporting group description

Subject analysis set title

Modified Intention-to-treat (MITT) Population

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

1. Modified Intention-to-treat (MITT) Population, Immune Response One Month after Vaccination at 12 Months of Age All subjects in the ITT population who: -actually received a study vaccination, and -provided at least one evaluable serum sample after vaccination.

Subject analysis set title

Modified Intention-to-treat (MITT) population

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

2. Modified Intention-to-treat (MITT) population, Antibody Persistence All subjects in the ITT population who: - actually received a study vaccination, and - provided at least one evaluable serum sample after vaccination, and - provided an evaluable serum sample at 6-12 months after vaccination at 12 months of age.

Subject analysis set title

Per-protocol (PP) Populations, Immunogenicity

Subject analysis set type

Per protocol

Subject analysis set description

3. Per-protocol (PP) Population, Immune Response one Month after Vaccination at 12 Months of Age All subjects in the MITT population who: - received all the relevant doses of vaccine correctly, and - provided evaluable serum samples at the relevant time points, and - had no major protocol deviation as defined prior to database lock.

Subject analysis set title

Per-protocol (PP) Population

Subject analysis set type

Per protocol

Subject analysis set description

4. Per-protocol (PP) Population, Antibody Persistence All subjects in the MITT population who: - received all the relevant doses of vaccine correctly, and - provided evaluable serum samples at one month after vaccination at 12 months of age and at Visit 6, and - had no major protocol deviation as defined prior to database lock.

Primary: 1. Percentages of Subjects With Serum Bactericidal Titer ≥ 1:8 Against N.Meningitidis Serogroup C

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End point title

1. Percentages of Subjects With Serum Bactericidal Titer ≥ 1:8 Against N.Meningitidis Serogroup C ^[1]

End point description

Immunogenicity of one dose of MenACWY-CRM197 vaccine to one dose of MenC vaccine one month post vaccination was measured using serum bactericidal assay with human complement (hSBA) titer ≥ 1:8 against N.meningitidis serogroup C.

End point type

Primary

End point timeframe

1 month postvaccination

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis is associated to this endpoint.

End point values	MenACWY-CRM197 (1dose) +Concomitant Vaccines	MenC (1dose) + Concomitant Vaccines
Number of subjects analysed	146	140
Units: Percentages of subjects
number (confidence interval 95%)	83 (77 to 89)	92 (86 to 95)

statistical analysis 1

Statistical analysis description

The primary criterion for immunogenicity was that the lower limit of the two-sided 95% confidence interval (CI) for the difference between one dose of MenACWY-CRM197 and MenC in the percentage of subjects with hSBA ≥1:8 for serogroup C at 1 month following the 12 months vaccination was greater than -10% .

Comparison groups

MenC (1dose) + Concomitant Vaccines v MenACWY-CRM197 (1dose) +Concomitant Vaccines

Number of subjects included in analysis

286

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Mean difference (final values)

Point estimate

-8

Confidence interval

level

95%

sides

2-sided

lower limit

-15

upper limit

-1

Secondary: 2. Percentages of Subjects With Human Serum Bactericidal Titer ≥ 1:4 Against N.Meningitidis Serogroup C

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End point title

2. Percentages of Subjects With Human Serum Bactericidal Titer ≥ 1:4 Against N.Meningitidis Serogroup C ^[2]

End point description

Immunogenicity of one dose of MenACWY-CRM197 vaccine to one dose of MenC vaccine one month post vaccination was assessed as percentage of subjects with serum bactericidal activity using human complement (hSBA) titers ≥ 1:4 against N.meningitidis serogroup C.

End point type

Secondary

End point timeframe

1 month postvaccination at 12 months of age

Notes
[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: No statistical analysis is associated to this endpoint.

End point values	MenACWY-CRM197 (1dose) +Concomitant Vaccines	MenC (1dose) + Concomitant Vaccines
Number of subjects analysed	175	153
Units: Percentages of subjects
number (confidence interval 95%)	90 (85 to 94)	97 (93 to 99)

statistical analysis 1

Comparison groups

MenACWY-CRM197 (1dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

328

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

Method

Miettinen and Nurminen

Parameter type

Mean difference (final values)

Point estimate

-7

Confidence interval

level

95%

sides

2-sided

lower limit

-13

upper limit

-2

Notes
[3] - The primary criterion for immunogenicity was that the lower limit of the two-sided 95% confidence interval (CI) for the difference between one dose of MenACWY-CRM197 and MenC in the percentage of subjects with hSBA ≥ 1:4 for serogroup C at 1 month following the 12 months vaccination was greater than -10%.

Secondary: 3. Percentages of Subjects With Human Serum Bactericidal Titer ≥ 1:8 and Titer ≥ 1:4 Against N. Meningitidis Serogroups A, C, W, Y

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End point title

3. Percentages of Subjects With Human Serum Bactericidal Titer ≥ 1:8 and Titer ≥ 1:4 Against N. Meningitidis Serogroups A, C, W, Y ^[4]

End point description

1. Immunogenicity of two doses of MenACWY-CRM197 vaccine to one dose of MenC vaccine one month postvaccination was assessed and compared as percentages of subjects with serum bactericidal titer with human complement (hSBA) ≥ 1:8, ≥ 1:4 against N.meningitidis Serogroup C. 2. Immunogenicity of two doses of MenACWY-CRM197 vaccine one month postvaccination was assessed as percentages of subjects with serum bactericidal titer with human complement (hSBA) ≥ 1:8, ≥ 1:4 against N.meningitidis Serogroup A, W, Y.

End point type

Secondary

End point timeframe

1 month postvaccination

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis is associated to this endpoint.

End point values	MenACWY-CRM197 (2dose) +Concomitant Vaccines	MenC (1dose) + Concomitant Vaccines
Number of subjects analysed	166	23
Units: Percentages of subjects
number (confidence interval 95%)
titer ≥ 1:8, prevacc, Men A, (N=159,23)	21 (15 to 29)	0 (0 to 15)
titer ≥ 1:8, postvacc, Men A (N=166,23)	93 (88 to 97)	0 (0 to 15)
titer ≥ 1:8, prevacc, Men C (N=161,152)	78 (71 to 84)	6 (3 to 11)
titer ≥ 1:8, postvacc, Men C (N=167,153)	99 (96 to 100)	92 (86 to 95)
titer ≥ 1:8, prevacc, Men W, (N=157,23)	68 (60 to 75)	0 (0 to 15)
titer ≥ 1:8, postvacc, Men W, (N=165,22)	98 (94 to 99)	5 (0 to 23)
titer ≥ 1:8, prevacc, Men Y, (N=156, 23)	69 (61 to 76)	0 (0 to 15)
titer ≥ 1:8, postvacc, Men Y, (N=163,22)	96 (91 to 98)	5 (0 to 23)
titer ≥ 1:4, prevacc, Men A, (N=159,23)	26 (19 to 33)	0 (0 to 15)
titer ≥ 1:4, postvacc, Men A, (N=166,23)	95 (91 to 98)	0 (0 to 15)
titer ≥ 1:4, prevacc, Men C, (N=161,152)	88 (81 to 92)	7 (4 to 13)
titer ≥ 1:4, postvacc, Men C, (N=167,153)	99 (96 to 100)	97 (93 to 99)
titer ≥ 1:4, prevacc, Men W, (N=157,23)	74 (66 to 81)	0 (0 to 15)
titer ≥ 1:4, postvacc, Men W, (N=165,22)	98 (94 to 99)	5 (0 to 23)
titer ≥ 1:4, prevacc, Men Y, (N=156,23)	78 (71 to 84)	0 (0 to 15)
titer ≥ 1:4, postvacc, Men Y, (N=163,22)	99 (96 to 100)	5 (0 to 23)

Statistical analysis 1

Statistical analysis description

Comparisons to MenC were based on the percentages of subjects with response (hSBA ≥1:8, one month postvaccination) to serogroup C. MenACWY was determined to be noninferior to MenC if the lower limit of the two-sided 95% CI for the difference between MenACWY and MenC in the percentage of subjects with response towards serogroup C was greater than -10%.

Comparison groups

MenACWY-CRM197 (2dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Mean difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical Analysis 2

Statistical analysis description

Comparison groups

MenACWY-CRM197 (2dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

statistical Analysis 3

Statistical analysis description

Comparisons to MenC were based on the percentages of subjects with response (hSBA ≥1:4, prevaccination) to serogroup C. MenACWY was determined to be noninferior to MenC if the lower limit of the two-sided 95% CI for the difference between MenACWY and MenC in the percentage of subjects with response towards serogroup C was greater than -10%.

Comparison groups

MenACWY-CRM197 (2dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Mean difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical analysis 4

Statistical analysis description

Comparisons to MenC were based on the percentages of subjects with response (hSBA ≥1:4,one month postvaccination) to serogroup C. MenACWY was determined to be noninferior to MenC if the lower limit of the two-sided 95% CI for the difference between MenACWY and MenC in the percentage of subjects with response towards serogroup C was greater than -10%.

Comparison groups

MenACWY-CRM197 (2dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Mean difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

Secondary: 4. Percentages of Subjects With Human Serum Bactericidal Titer ≥ 1:8 and Titer ≥ 1:4 Against N. Meningitidis Serogroups A, W, Y

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End point title

4. Percentages of Subjects With Human Serum Bactericidal Titer ≥ 1:8 and Titer ≥ 1:4 Against N. Meningitidis Serogroups A, W, Y ^[5]

End point description

Immunogenicity for one dose of MenACWY was assessed as percentages of subjects with serum bactericidal titer with human complement (hSBA) ≥ 1:8 and titer ≥ 1:4 by serogroups A, W, Y. Serogroup C is not shown here as it is shown in other outcome measures.

End point type

Secondary

End point timeframe

12 months and 1 month postvaccination at 12 months of age.

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis is associated to this endpoint.

End point values	MenACWY-CRM197 (1dose) +Concomitant Vaccines
Number of subjects analysed	175
Units: Percentages of subjects
number (confidence interval 95%)
titer ≥ 1:8, pre-vacc, Men A, (N=171)	1 (0.015 to 3)
titer ≥ 1:8, post-vacc, Men A, (N=172)	49 (41 to 57)
titer ≥ 1:8, pre-vacc, Men W, (N=168)	3 (1 to 7)
titer ≥ 1:8, post-vacc, Men W, (N=170)	61 (53 to 68)
titer ≥ 1:8, pre-vacc, Men Y, (N=160)	3 (1 to 6)
titer ≥ 1:8, post-vacc, Men Y, (N=167)	50 (42 to 58)
titer ≥ 1:4, pre-vacc, Men A, (N=171)	1 (0.015 to 3)
titer ≥ 1:4, post-vacc, Men A, (N=172)	58 (50 to 65)
titer ≥ 1:4, pre-vacc, Men W, (N=168)	4 (1 to 8)
titer ≥ 1:4, post-vacc, Men W, (N=170)	62 (55 to 70)
titer ≥ 1:4, pre-vacc, Men Y, (N=160)	3 (1 to 6)
titer ≥ 1:4, post-vacc, Men Y, (N=167)	56 (48 to 63)

No statistical analyses for this end point

Secondary: 5. Human Serum Bactericidal Activity Geometric Mean Titers After One Dose of MenACWY-CRM197 and MenC Against N.Meningitidis Serogroup C

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End point title

5. Human Serum Bactericidal Activity Geometric Mean Titers After One Dose of MenACWY-CRM197 and MenC Against N.Meningitidis Serogroup C ^[6]

End point description

Immunogenicity of one dose of MenACWY-CRM197 vaccine to one dose of MenC vaccine one month post vaccination was assessed with geometric mean titer (GMT) of serum bactericidal assay with human complement (hSBA) against N. meningitidis serogroup C.

End point type

Secondary

End point timeframe

1 month postvaccination.

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis is associated to this endpoint.

End point values	MenACWY-CRM197 (1dose) +Concomitant Vaccines	MenC (1dose) + Concomitant Vaccines
Number of subjects analysed	174	152
Units: Titers
number (confidence interval 95%)
Prevaccination (month 12) (N=174, 152)	2.11 (1.77 to 2.51)	2.29 (1.9 to 2.75)
Postvaccination (month 13) (N=175,153)	22 (18 to 28)	31 (24 to 39)

Statistical Analysis 1

Statistical analysis description

Human Serum Bactericidal Activity Geometric Mean Titers After One Dose of MenACWY-CRM197 and MenC Against N.Meningitidis Serogroup C

Comparison groups

MenACWY-CRM197 (1dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

326

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[7]

Method

ANOVA

Parameter type

Mean difference (final values)

Point estimate

0.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.76

upper limit

1.12

Notes
[7] - For comparison of the Geometric Mean Titers at one month prevaccination at 12 months of age, MenACWY-CRM197 was determined to be non-inferior to MenC if the lower limit of the 2-sided 95% CI for the ratio of the MenACWY-CRM197 to MenC Geometric Mean Titers for serogroup C was greater than 0.5.

Statistical Analysis 2

Statistical analysis description

Human Serum Bactericidal Activity Geometric Mean Titers After One Dose of MenACWY-CRM197 and MenC Against N.Meningitidis Serogroup C

Comparison groups

MenACWY-CRM197 (1dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

326

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[8]

Method

ANOVA

Parameter type

Mean difference (final values)

Point estimate

0.73

Confidence interval

level

95%

sides

2-sided

lower limit

0.57

upper limit

0.93

Notes
[8] - For comparison of the Geometric Mean Titers at one month postvaccination at 12 months of age, MenACWY-CRM197 was determined to be non-inferior to MenC if the lower limit of the 2-sided 95% CI for the ratio of the MenACWY-CRM197 to MenC Geometric Mean Titers for serogroup C was greater than 0.5.

Secondary: 6. Human Serum Bactericidal Activity Geometric Mean Titers Against N.Meningitidis Serogroups A, W, Y

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End point title

6. Human Serum Bactericidal Activity Geometric Mean Titers Against N.Meningitidis Serogroups A, W, Y ^[9]

End point description

Immunogenicity of one dose of MenACWY-CRM197 one month postvaccination was assessed with GMT of serum bactericidal assay with hSBA against Serogroups A, W, Y.

End point type

Secondary

End point timeframe

1 month postvaccination.

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: No statistical analysis is associated to this endpoint.

End point values	MenACWY-CRM197 (1dose) +Concomitant Vaccines
Number of subjects analysed	172
Units: Titers
number (confidence interval 95%)
prevacc, Men A (N=171)	1.99 (1.72 to 2.3)
postvacc Men A (N=172)	10 (7.71 to 13)
prevacc, Men W (N=168)	2.12 (1.71 to 2.62)
postvacc Men W (N=170)	14 (10 to 19)
prevacc, Men Y (N=160)	1.92 (1.59 to 2.32)
postvacc Men Y (N=167)	7.05 (5.43 to 9.15)

No statistical analyses for this end point

Secondary: 7. Human Serum Bactericidal Activity Geometric Mean Titers Against N.Meningitidis Serogroups A, C, W, Y

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End point title

7. Human Serum Bactericidal Activity Geometric Mean Titers Against N.Meningitidis Serogroups A, C, W, Y ^[10]

End point description

1. The immunogenicity of two doses of MenACWY-CRM197, to a single dose of MenC was assessed and compared as measured by human Serum Bactericidal Activity Geometric Mean Titers directed against N. meningitidis serogroup C. 2. The immunogenicity of two doses of MenACWY-CRM197, to a single dose of MenC was assessed as measured by human Serum Bactericidal Activity Geometric Mean Titers directed against N. meningitidis serogroups A, W, Y.

End point type

Secondary

End point timeframe

1 month postvaccination

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: No statistical analysis is associated to this endpoint.

End point values	MenACWY-CRM197 (2dose) +Concomitant Vaccines	MenC (1dose) + Concomitant Vaccines
Number of subjects analysed	167	153
Units: Participants
geometric mean (confidence interval 95%)
prevacc, Men A (N=159,23)	3.4 (2.92 to 3.97)	2 (1.46 to 2.73)
postvacc Men A (N=166,23)	75 (56 to 99)	2.22 (1.22 to 4.04)
prevacc, Men C (N=161,152)	23 (19 to 28)	2.29 (1.9 to 2.75)
postvacc, Men C (N=167,153)	249 (197 to 314)	31 (24 to 39)
prevacc, Men W (N=157,23)	14 (11 to 17)	1.71 (1.06 to 2.74)
postvacc, Men W (N=165,22)	213 (153 to 295)	2 (0.99 to 4.03)
prevacc, Men Y (N=156,23)	11 (9.44 to 14)	1.76 (1.18 to 2.63)
postvacc, Men Y (N=163,22)	156 (119 to 205)	1.93 (1.06 to 3.52)

Statistical Analysis 1

Statistical analysis description

Human Serum Bactericidal Activity Geometric Mean Titers Against N.Meningitidis Serogroups A, C, W, Y

Comparison groups

MenACWY-CRM197 (2dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

320

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[11]

Method

ANOVA

Parameter type

Ratio

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

8.43

upper limit

Notes
[11] - For comparison of the GMTs (one month postvaccination), MenACWY was determined to be noninferior to MenC if the lower limit of the two-sided 95% CI for the ratio of the MenACWY to MenC GMTs for serogroup C was greater than 0.5 .

Statistical Analysis 2

Statistical analysis description

Human Serum Bactericidal Activity Geometric Mean Titers Against N.Meningitidis Serogroups A, C, W, Y

Comparison groups

MenACWY-CRM197 (2dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

320

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[12]

Method

ANOVA

Parameter type

Ratio

Point estimate

8.1

Confidence interval

level

95%

sides

2-sided

lower limit

6.35

upper limit

Notes
[12] - For comparison of the GMTs (one month postvaccination), MenACWY was determined to be noninferior to MenC if the lower limit of the two-sided 95% CI for the ratio of the MenACWY to MenC GMTs for serogroup C was greater than 0.5 .

Secondary: 8. Percentages of Subjects With Seroresponse Rates After One Dose of DTPa-IPV-HepB-Hib (Concomitant Vaccine)

Top of page

End point title

8. Percentages of Subjects With Seroresponse Rates After One Dose of DTPa-IPV-HepB-Hib (Concomitant Vaccine)

End point description

The immunogenicity of one dose of MenC to one dose of DTPa-IPV-HepB-Hib concomitant vacccine was assessed. For Pertussis antigens, Pertussis Toxin (PT), Filamentous Hemagglutinin (FHA) and Pertactin (PRN), the seroresponse in initially seronegative subjects (pre-vaccination antibody concentration < LLQ) is defined as post-vaccination antibody concentration >= LLQ; in initially seropositive subjects (pre-vaccination antibody concentration >=LLQ) seroresponse is defined as at least two fold increase of the pre-vaccinationantibody concentration. Diptheria and Tetanus: primary endpoint ELISA (Enzyme-linked immunosorbent assay) >=0.1 (international unit -IU) IU/mL and the secondary endpoint is ELISA>=1.0 IU/mL. Polio type 1, 2 and 3: bNT (neutralization test) with >=1:8. HepB (HBV): primary endpoint ELISA >=10mU/mL. PRP-T: primary endpoint ≥ 0.15 mcg/mL and ≥ 1.00 mcg/mL.

End point type

Secondary

End point timeframe

1 month postvaccination.

End point values	MenACWY-CRM197 (2dose) +Concomitant Vaccines	MenACWY-CRM197 (1dose) +Concomitant Vaccines	MenC (1dose) + Concomitant Vaccines
Number of subjects analysed	168	173	152
Units: Percentages of subjects]
arithmetic mean (confidence interval 95%)
Anti-Diphtheria Toxin ≥ 0.1 IU/mL N=(168,173,152)	100 (98 to 100)	100 (98 to 100)	100 (98 to 100)
Anti-Diphtheria Toxin ≥ 1.0 IU/mL N=(168,173,152)	99 (96 to 100)	98 (95 to 100)	98 (94 to 100)
Anti-Tetanus Toxin ≥ 0.1 IU/mL N= (168,173,152)	100 (98 to 100)	100 (98 to 100)	100 (98 to 100)
Anti-Tetanus Toxin ≥ 1.0 IU/mL N= (168,173,152)	96 (92 to 98)	96 (92 to 98)	97 (93 to 99)
FHA ELISA (N=160,169,152)	97 (93 to 99)	91 (86 to 95)	96 (92 to 99)
PRN ELISA (N=160,169,152)	99 (97 to 100)	98 (94 to 99)	99 (95 to 100)
PT ELISA (N=159,165,151)	97 (93 to 99)	95 (90 to 97)	97 (92 to 99)
polio 1 (N=157,161,148)	100 (98 to 100)	100 (98 to 100)	99 (96 to 100)
polio 2 (N=157,161,148)	100 (98 to 100)	99 (97 to 100)	100 (98 to 100)
polio 3 (N=146,151,143)	100 (98 to 100)	100 (98 to 100)	100 (97 to 100)
Hep B (N=157,161,147)	99 (97 to 100)	99 (96 to 100)	99 (96 to 100)
Anti-PRP (HIB) ≥ 0.15 μg/mL (N=168,173,151)	100 (98 to 100)	100 (98 to 100)	100 (98 to 100)
Anti-PRP (HIB) ≥ 1.0 μg/mL (N=168,173,151)	100 (98 to 100)	98 (95 to 100)	99 (96 to 100)

Statistical Analysis 1

Statistical analysis description

Immunogenicity of DTPa-IPV-HepB-Hib (Anti-Diptheria Toxin ≥0.1 IU/mL, one month postvaccination) given concomitantly with two dose of MenACWY was considered non-inferior to DTPa-IPV-HepB-Hib given concomitantly with one dose of MenC, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Comparison groups

MenC (1dose) + Concomitant Vaccines v MenACWY-CRM197 (2dose) +Concomitant Vaccines

Number of subjects included in analysis

320

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

Statistical analysis 2

Statistical analysis description

Comparison groups

MenACWY-CRM197 (1dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

325

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

Statistical Analysis 3

Statistical analysis description

Immunogenicity of DTPa-IPV-HepB-Hib (Anti-Diptheria Toxin ≥1.0 IU/mL, one month postvaccination) given concomitantly with two dose of MenACWY was considered non-inferior to DTPa-IPV-HepB-Hib given concomitantly with one dose of MenC, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Comparison groups

MenC (1dose) + Concomitant Vaccines v MenACWY-CRM197 (2dose) +Concomitant Vaccines

Number of subjects included in analysis

320

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-3

upper limit

Statistical Analysis 4

Statistical analysis description

Comparison groups

MenACWY-CRM197 (1dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

325

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-3

upper limit

Statistical Analysis 5

Statistical analysis description

Immunogenicity of DTPa-IPV-HepB-Hib (Anti-Tetanus Toxin ≥ 0.1 IU/mL, one month postvaccination) given concomitantly with one dose of MenACWY was considered non-inferior to DTPa-IPV-HepB-Hib given concomitantly with one dose of MenC, for any of the antigens, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Comparison groups

MenC (1dose) + Concomitant Vaccines v MenACWY-CRM197 (2dose) +Concomitant Vaccines

Number of subjects included in analysis

320

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

Statistical Analysis 6

Statistical analysis description

Comparison groups

MenACWY-CRM197 (1dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

325

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

Statistical Analysis 7

Statistical analysis description

Immunogenicity of DTPa-IPV-HepB-Hib (Anti-Tetanus Toxin ≥ 1.0 IU/mL, one month postvaccination) given concomitantly with two dose of MenACWY was considered non-inferior to DTPa-IPV-HepB-Hib given concomitantly with one dose of MenC, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Comparison groups

MenC (1dose) + Concomitant Vaccines v MenACWY-CRM197 (2dose) +Concomitant Vaccines

Number of subjects included in analysis

320

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[13]

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

-2

Confidence interval

level

95%

sides

2-sided

lower limit

-6

upper limit

Notes
[13] - Immunogenicity of DTPa-IPV-HepB-Hib (Anti-Tetanus Toxin ≥ 0.1 IU/mL, one month postvaccination) given concomitantly with one dose of MenACWY was considered non-inferior to DTPa-IPV-HepB-Hib given concomitantly with one dose of MenC, for any of the antigens, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Statistical Analysis 8

Statistical analysis description

Comparison groups

MenACWY-CRM197 (1dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

325

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[14]

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-6

upper limit

Notes
[14] - Immunogenicity of DTPa-IPV-HepB-Hib, given at 12 months of age concomitantly with one dose of MenACWY was considered non-inferior to DTPa-IPV-HepB-Hib given concomitantly with one dose of MenC, for any of the antigens, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Statistical Analysis 9

Statistical analysis description

Immunogenicity of DTPa-IPV-HepB-Hib (polio 1, one month postvaccination), given concomitantly with two dose of MenACWY was considered non-inferior to DTPa-IPV-HepB-Hib given concomitantly with one dose of MenC, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Comparison groups

MenACWY-CRM197 (2dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

320

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

percentage differnce

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

Statistical Analysis 10

Statistical analysis description

Comparison groups

MenACWY-CRM197 (1dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

325

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

Statistical Analysis 11

Statistical analysis description

Immunogenicity of DTPa-IPV-HepB-Hib (polio 2, one month postvaccination) given concomitantly with two dose of MenACWY was considered non-inferior to DTPa-IPV-HepB-Hib given concomitantly with one dose of MenC, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Comparison groups

MenC (1dose) + Concomitant Vaccines v MenACWY-CRM197 (2dose) +Concomitant Vaccines

Number of subjects included in analysis

320

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

Statistical Analysis 12

Statistical analysis description

Comparison groups

MenACWY-CRM197 (1dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

325

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-3

upper limit

Statistical Analysis 13

Statistical analysis description

Immunogenicity of DTPa-IPV-HepB-Hib (polio 3, one month postvaccination) given concomitantly with two dose of MenACWY was considered non-inferior to DTPa-IPV-HepB-Hib given concomitantly with one dose of MenC, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Comparison groups

MenC (1dose) + Concomitant Vaccines v MenACWY-CRM197 (2dose) +Concomitant Vaccines

Number of subjects included in analysis

320

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-3

upper limit

Statistical analysis 14

Statistical analysis description

Comparison groups

MenACWY-CRM197 (1dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

325

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[15]

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

Notes
[15] - Immunogenicity of DTPa-IPV-HepB-Hib (Anti-Diptheria Toxin ≥0.1 IU/mL, one month postvaccination) given concomitantly with two dose of MenACWY was considered non-inferior to DTPa-IPV-HepB-Hib given concomitantly with one dose of MenC, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Statistical analysis 15

Statistical analysis description

Immunogenicity of DTPa-IPV-HepB-Hib (Anti- PRP ≥ 0.15 μg/mL, one month postvaccination) given concomitantly with two dose of MenACWY was considered non-inferior to DTPa-IPV-HepB-Hib given concomitantly with one dose of MenC, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Comparison groups

MenC (1dose) + Concomitant Vaccines v MenACWY-CRM197 (2dose) +Concomitant Vaccines

Number of subjects included in analysis

320

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

Statistical analysis 16

Statistical analysis description

Immunogenicity of DTPa-IPV-HepB-Hib (Anti- PRP ≥ 0.15 μg/mL, one month postvaccination) given concomitantly with one dose of MenACWY was considered non-inferior to DTPa-IPV-HepB-Hib given concomitantly with one dose of MenC, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Comparison groups

MenC (1dose) + Concomitant Vaccines v MenACWY-CRM197 (1dose) +Concomitant Vaccines

Number of subjects included in analysis

325

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

Statistical analysis 17

Statistical analysis description

Immunogenicity of DTPa-IPV-HepB-Hib (Anti- PRP ≥ 1.0 μg/mL, one month postvaccination) given concomitantly with two dose of MenACWY was considered non-inferior to DTPa-IPV-HepB-Hib given concomitantly with one dose of MenC, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Comparison groups

MenC (1dose) + Concomitant Vaccines v MenACWY-CRM197 (2dose) +Concomitant Vaccines

Number of subjects included in analysis

320

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

Statistical analysis 18

Statistical analysis description

Comparison groups

MenC (1dose) + Concomitant Vaccines v MenACWY-CRM197 (1dose) +Concomitant Vaccines

Number of subjects included in analysis

325

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-4

upper limit

Statistical analysis 19

Statistical analysis description

PeImmunogenicity of DTPa-IPV-HepB-Hib (Hep B, one month postvaccination) given concomitantly with two dose of MenACWY was considered non-inferior to DTPa-IPV-HepB-Hib given concomitantly with one dose of MenC, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Comparison groups

MenC (1dose) + Concomitant Vaccines v MenACWY-CRM197 (2dose) +Concomitant Vaccines

Number of subjects included in analysis

320

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-3

upper limit

Statistical analysis 20

Statistical analysis description

Immunogenicity of DTPa-IPV-HepB-Hib (Hep B, one month postvaccination) given concomitantly with two dose of MenACWY was considered non-inferior to DTPa-IPV-HepB-Hib given concomitantly with one dose of MenC, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Comparison groups

MenC (1dose) + Concomitant Vaccines v MenACWY-CRM197 (1dose) +Concomitant Vaccines

Number of subjects included in analysis

325

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-4

upper limit

Secondary: 9. Percentages of Subjects With Seroresponse Rates After One Dose of PCV7 (Concomitant Vaccine)

Top of page

End point title

9. Percentages of Subjects With Seroresponse Rates After One Dose of PCV7 (Concomitant Vaccine)

End point description

To compare the immunogenicity of PCV7 (Pneumococcal 7-valent Conjugate)Vaccine when given concomitantly with one dose or two doses of MenACWY-CRM197 or with MenC to infants at 12 months of age. Seroresponse for PCV7 (PnC 4, PnC 6B, PnC 9V, PnC 14, PnC 18C, PnC 19F, PnC 23F) is defined as: a subject with primary endpoint ELISA ≥ 0.35 mcg/mL and secondary endpoint ELISA ≥ 1.0 mcg/mL.

End point type

Secondary

End point timeframe

1 month postvaccination.

End point values	MenACWY-CRM197 (2dose) +Concomitant Vaccines	MenACWY-CRM197 (1dose) +Concomitant Vaccines	MenC (1dose) + Concomitant Vaccines
Number of subjects analysed	163	168	150
Units: Percentages of subjects
arithmetic mean (confidence interval 95%)
PNC 4 N=(163,168,150)	83 (76 to 88)	82 (75 to 88)	87 (81 to 92)
PNC 6B N=(163,168,149)	92 (87 to 96)	91 (86 to 95)	97 (93 to 99)
PNC 9V N=(163,168,150)	90 (85 to 94)	89 (83 to 93)	93 (88 to 97)
PNC 14 N=(163,167,150)	99 (96 to 100)	99 (97 to 100)	99 (96 to 100)
PNC 18C N=(163,168,150)	71 (63 to 77)	76 (68 to 82)	86 (79 to 91)
PNC 19 F N=(163,168,150)	81 (74 to 87)	80 (74 to 86)	90 (84 to 94)
PNC 23 F N=(163,168,150)	88 (82 to 92)	89 (83 to 93)	94 (89 to 97)

Statistical Analysis 1

Statistical analysis description

Immunogenicity of PCV7 (PNC4, one month postvaccination) given concomitantly with one dose of MenACWY was considered non-inferior to PCV7 given concomitantly with one dose of MenC, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Comparison groups

MenACWY-CRM197 (1dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

-5

Confidence interval

level

95%

sides

2-sided

lower limit

-13

upper limit

Statistical Analysis 2

Statistical analysis description

Immunogenicity of PCV7(PNC 6B, one month postvaccination) given concomitantly with one dose of MenACWY was considered non-inferior to PCV7 given concomitantly with one dose of MenC, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Comparison groups

MenACWY-CRM197 (1dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

-6

Confidence interval

level

95%

sides

2-sided

lower limit

-12

upper limit

-1

Statistical Analysis 3

Statistical analysis description

Immunogenicity of PCV7(PNC 9V, one month postvaccination) given concomitantly with MenACWY-CRM197 or MenC was considered non-inferior, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than -10%.

Comparison groups

MenACWY-CRM197 (1dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

-5

Confidence interval

level

95%

sides

2-sided

lower limit

-11

upper limit

Statistical Analysis 4

Statistical analysis description

Immunogenicity of PCV7 (PNC 14, one month postvaccination) given concomitantly with one dose of MenACWY was considered non-inferior to PCV7 given concomitantly with one dose of MenC, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Comparison groups

MenACWY-CRM197 (1dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-3

upper limit

Statistical Analysis 5

Statistical analysis description

Immunogenicity of PCV7( PNC 18C, one month postvaccination) given concomitantly with one dose of MenACWY was considered non-inferior to PCV7 given concomitantly with one dose of MenC, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Comparison groups

MenACWY-CRM197 (1dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

-10

Confidence interval

level

95%

sides

2-sided

lower limit

-19

upper limit

-2

Statistical Analysis 6

Statistical analysis description

Immunogenicity of PCV7 (PNC 19F, one month postvaccination), given concomitantly with one dose of MenACWY was considered non-inferior to PCV7 given concomitantly with one dose of MenC, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Comparison groups

MenACWY-CRM197 (1dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

-10

Confidence interval

level

95%

sides

2-sided

lower limit

-17

upper limit

-2

Statistical Analysis 7

Statistical analysis description

Immunogenicity of PCV7 (PNC 23F, one month postvaccination) given concomitantly with one dose of MenACWY was considered non-inferior to PCV7 given concomitantly with one dose of MenC, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Comparison groups

MenACWY-CRM197 (1dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

-5

Confidence interval

level

95%

sides

2-sided

lower limit

-12

upper limit

Statistical Analysis 8

Statistical analysis description

Immunogenicity of PCV7 (PNC4, one month postvaccination) given concomitantly with two doses of MenACWY was considered non-inferior to PCV7 given concomitantly with one dose of MenC, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Comparison groups

MenC (1dose) + Concomitant Vaccines v MenACWY-CRM197 (2dose) +Concomitant Vaccines

Number of subjects included in analysis

313

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

-5

Confidence interval

level

95%

sides

2-sided

lower limit

-12

upper limit

Statistical Analysis 9

Statistical analysis description

Immunogenicity of PCV7 (PNC6B, one month postvaccination) given concomitantly with two doses of MenACWY was considered non-inferior to PCV7 given concomitantly with one dose of MenC, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Comparison groups

MenC (1dose) + Concomitant Vaccines v MenACWY-CRM197 (2dose) +Concomitant Vaccines

Number of subjects included in analysis

313

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[16]

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

-5

Confidence interval

level

95%

sides

2-sided

lower limit

-11

upper limit

Notes
[16] - Immunogenicity of PCV7 (PNC4, one month postvaccination)given concomitantly with one dose of MenACWY was considered noninferior to PCV7 given concomitantly with one dose of MenC, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Statistical Analysis 10

Statistical analysis description

Immunogenicity of PCV7 (PNC 9V, one month postvaccination) given concomitantly with two doses of MenACWY was considered non-inferior to PCV7 given concomitantly with one dose of MenC, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Comparison groups

MenC (1dose) + Concomitant Vaccines v MenACWY-CRM197 (2dose) +Concomitant Vaccines

Number of subjects included in analysis

313

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

-3

Confidence interval

level

95%

sides

2-sided

lower limit

-10

upper limit

Statistical Analysis 11

Statistical analysis description

Immunogenicity of PCV7 (PNC14, one month postvaccination) given concomitantly with two doses of MenACWY was considered non-inferior to PCV7 given concomitantly with one dose of MenC, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Comparison groups

MenACWY-CRM197 (2dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

313

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-4

upper limit

Statistical Analysis 12

Statistical analysis description

Immunogenicity of PCV7 (PNC18C, one month postvaccination) given concomitantly with two doses of MenACWY was considered non-inferior to PCV7 given concomitantly with one dose of MenC, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Comparison groups

MenC (1dose) + Concomitant Vaccines v MenACWY-CRM197 (2dose) +Concomitant Vaccines

Number of subjects included in analysis

313

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

-15

Confidence interval

level

95%

sides

2-sided

lower limit

-24

upper limit

-6

Statistical Analysis 13

Statistical analysis description

Immunogenicity of PCV7 (PNC19F, one month postvaccination) given concomitantly with two doses of MenACWY was considered non-inferior to PCV7 given concomitantly with one dose of MenC, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Comparison groups

MenC (1dose) + Concomitant Vaccines v MenACWY-CRM197 (2dose) +Concomitant Vaccines

Number of subjects included in analysis

313

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

-9

Confidence interval

level

95%

sides

2-sided

lower limit

-17

upper limit

-1

Statistical Analysis 14

Statistical analysis description

Immunogenicity of PCV7 (PNC23F, one month postvaccination) given concomitantly with two doses of MenACWY was considered non-inferior to PCV7 given concomitantly with one dose of MenC, if the lower limit of the two-sided 95% CI for the difference in the percentage of subjects with antibody response was greater than the cut-off level specified for that antigen was greater than -10%.

Comparison groups

MenC (1dose) + Concomitant Vaccines v MenACWY-CRM197 (2dose) +Concomitant Vaccines

Number of subjects included in analysis

313

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

-6

Confidence interval

level

95%

sides

2-sided

lower limit

-13

upper limit

Secondary: 10. Persistence of Immune Response Measured as Percentages of Subjects With Human Serum Bactericidal Titer ≥ 1:8 and Titer ≥ 1:4 Against N.Meningitidis Serogroup C

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End point title

10. Persistence of Immune Response Measured as Percentages of Subjects With Human Serum Bactericidal Titer ≥ 1:8 and Titer ≥ 1:4 Against N.Meningitidis Serogroup C

End point description

Persistence of immune response to either one or two doses of MenACWY-CRM197 or one dose of MenC as measured by serum bactericidal assay with human complement (hSBA) titers ≥ 1:8, and titers ≥ 1:4 directed against N.meningitidis serogroup C (only for subjects enrolled in Australia).

End point type

Secondary

End point timeframe

1 month postvaccination and 6-18 months postvaccination

End point values	MenACWY-CRM197 (2dose) +Concomitant Vaccines	MenACWY-CRM197 (1dose) +Concomitant Vaccines	MenC (1dose) + Concomitant Vaccines
Number of subjects analysed	17	14	13
Units: Percentages of subjects
geometric mean (confidence interval 95%)
hSBA ≥ 1:8, postvacc, Men C.N=(17,14,13)	100 (80 to 100)	86 (57 to 98)	92 (64 to 100)
hSBA ≥ 1:8, perisistence, Men C.N=(17,14,13)	71 (44 to 90)	64 (35 to 87)	54 (25 to 81)
hSBA ≥ 1:4, postvacc, Men C.N=(17,14,13)	100 (80 to 100)	93 (66 to 100)	100 (75 to 100)
hSBA ≥ 1:4, persistence, Men C.N=(17,14,13)	76 (50 to 93)	71 (42 to 92)	77 (46 to 95)

No statistical analyses for this end point

Secondary: 11. Persistence of Immune Response Measured as Percentages of Subjects With Human Serum Bactericidal Titer ≥ 1:8 ,and Titer ≥ 1:4 Against N.Meningitidis Serogroups A, W, Y

Top of page

End point title

11. Persistence of Immune Response Measured as Percentages of Subjects With Human Serum Bactericidal Titer ≥ 1:8 ,and Titer ≥ 1:4 Against N.Meningitidis Serogroups A, W, Y

End point description

Persistence of immune response to either one or two doses of MenACWY-CRM197 or one dose of MenC as measured by serum bactericidal assay with human complement (hSBA) titer ≥ 1:8 and titer ≥ 1:4 directed against N. meningitidis serogroups A, W and Y (only for subjects enrolled in Australia).

End point type

Secondary

End point timeframe

1 month postvaccination and 6-18 months postvaccination

End point values	MenACWY-CRM197 (2dose) +Concomitant Vaccines	MenACWY-CRM197 (1dose) +Concomitant Vaccines	MenC (1dose) + Concomitant Vaccines
Number of subjects analysed	17	14	13
Units: Percentages of subjects
number (confidence interval 95%)
hsBA ≥ 1:8, postvacc, MenA (N=17,12,2)	88 (64 to 99)	42 (15 to 72)	0 (0 to 84)
hsBA ≥ 1:8, persistence, MenA (N=16,14,12)	31 (11 to 59)	7 (0 to 34)	0 (0 to 26)
hSBA ≥ 1:4, postvacc, MenA (N=17,12,2)	100 (80 to 100)	50 (21 to 79)	0 (0 to 84)
hSBA ≥ 1:4, persistence, MenA (N=16,14,12)	38 (15 to 65)	14 (2 to 43)	0 (0 to 26)
hSBA ≥ 1:8, postvacc, MenW (N=17,12,2)	100 (80 to 100)	67 (35 to 90)	0 (0 to 84)
hSBA ≥ 1:8, persistence, MenW (N=16,14,12)	75 (48 to 93)	71 (42 to 92)	0 (0 to 26)
hSBA ≥ 1:4, postvacc, MenW (N=17,12,2)	100 (80 to 100)	67 (35 to 90)	0 (0 to 84)
hSBA ≥ 1:4, persistence, MenW (N=16,14,12)	88 (62 to 98)	71 (42 to 92)	0 (0 to 26)
hSBA ≥ 1:8, postvacc, MenY (N=17,12,2)	100 (80 to 100)	33 (10 to 65)	0 (0 to 84)
hSBA ≥ 1:8, persistence, MenY (N=14,14,12)	79 (49 to 95)	79 (49 to 95)	0 (0 to 26)
hSBA ≥ 1:4, postvacc, MenY (N=17,12,2)	100 (80 to 100)	50 (21 to 79)	0 (0 to 84)
hSBA ≥ 1:4, persistence, MenY (N=14,14,12)	86 (57 to 98)	93 (66 to 100)	0 (0 to 26)

No statistical analyses for this end point

Secondary: 12. Persistence of Human Serum Bactericidal Activity Geometric Mean Titers Against N.Meningitidis Serogroup C

Top of page

End point title

12. Persistence of Human Serum Bactericidal Activity Geometric Mean Titers Against N.Meningitidis Serogroup C

End point description

Persistence of immunogenicity of either one or two doses of MenACWY or one dose of MenC as measured by human serum bactericidal activity geometric mean titers directed against N.meningitidis serogroup C (only for subjects enrolled in Australia).

End point type

Secondary

End point timeframe

1 month postvaccination and 6-18 months postvaccination

End point values	MenACWY-CRM197 (2dose) +Concomitant Vaccines	MenACWY-CRM197 (1dose) +Concomitant Vaccines	MenC (1dose) + Concomitant Vaccines
Number of subjects analysed	17	14	13
Units: Titers
geometric mean (confidence interval 95%)
Month 13	241 (139 to 419)	36 (19 to 66)	30 (16 to 56)
6 - 18 months after month 12	15 (7.45 to 29)	12 (5.65 to 25)	8.95 (4.15 to 19)

No statistical analyses for this end point

Secondary: 13. Persistence of Human Serum Bactericidal Activity Geometric Mean Titers against N.Meningitidis Serogroup A, W, Y

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End point title

13. Persistence of Human Serum Bactericidal Activity Geometric Mean Titers against N.Meningitidis Serogroup A, W, Y ^[17]

End point description

Immunogenicity of two doses of MenACWY to one dose of MenACWY as measured by hSBA GMTs directed against N.meningitidis serogroups A, W, Y (only for subjects enrolled in Australia)

End point type

Secondary

End point timeframe

6-18 months postvaccination

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: No statistical analysis is associated to this endpoint.

End point values	MenACWY-CRM197 (2dose) +Concomitant Vaccines	MenACWY-CRM197 (1dose) +Concomitant Vaccines
Number of subjects analysed	17	14
Units: Titers
geometric mean (confidence interval 95%)
Month 12, SerA (N=17,12)	47 (26 to 86)	6.69 (3.28 to 14)
6-18 Months after Mont 12, SerA (N=16,14)	4.41 (2.78 to 7)	2.78 (1.7 to 4.56)
Mont 12, SerW (N=16,14)	180 (95 to 340)	13 (6.26 to 28)
6-18 Months after Month 12, SerW (N=16,14)	20 (10 to 39)	20 (9.77 to 42)
Month 12, SerY (N=16,14)	151 (93 to 246)	5.13 (2.87 to 9.17)
6-8 Months after Month 12, SerY (N=14,14)	22 (12 to 38)	16 (9.15 to 28)

No statistical analyses for this end point

Secondary: 14. Percentages of Subjects With Rabbit Serum Bactericidal ≥ 1:8, ≥ 1:128 and Four Fold Rise Against N.Meningitidis Serogroup C

Top of page

End point title

14. Percentages of Subjects With Rabbit Serum Bactericidal ≥ 1:8, ≥ 1:128 and Four Fold Rise Against N.Meningitidis Serogroup C

End point description

1. Immunogenicity of one dose of MenACWY-CRM197 vaccine to one dose of MenC vaccine one month post vaccination was assessed as percentages of subjects with serum bactericidal titer with rabbit complement (rSBA) ≥ 1:8, ≥ 1:128, and four fold rise in titer against N.meningitidis Serogroup C. 2. Immunogenicity of two doses of MenACWY-CRM197 vaccine to one dose of MenC vaccine one month post vaccination was assessed as percentages of subjects with serum bactericidal titer with rabbit complement (rSBA) ≥ 1:8, ≥ 1:128, and four fold rise in titer against N.meningitidis Serogroup C

End point type

Secondary

End point timeframe

One month postvaccination

End point values	MenACWY-CRM197 (2dose) +Concomitant Vaccines	MenACWY-CRM197 (1dose) +Concomitant Vaccines	MenC (1dose) + Concomitant Vaccines
Number of subjects analysed	156	157	145
Units: Percentage Of Subjects
arithmetic mean (confidence interval 95%)
rSBA titer ≥ 1:8, prevacc (N=140,140,139)	72 (64 to 79)	4 (1 to 8)	1 (0 to 5)
rSBA titer ≥ 1:8, postvacc (N=156,157,145)	98 (94 to 100)	92 (86 to 96)	97 (92 to 99)
rSBA titer ≥ 1:128, prevacc (N=140,140,139)	31 (23 to 39)	1 (0.018 to 4)	0 (0 to 3)
rSBA titer ≥ 1:128, postvacc (N=156,157,145)	92 (87 to 96)	75 (68 to 82)	88 (82 to 93)
four fold rise (N=132,140,139)	86 (79 to 92)	91 (86 to 95)	96 (92 to 99)

Statistical Analysis 1

Statistical analysis description

For the comparisons to MenC based on percentages of subjects with response (rSBA ≥1:8; prevaccination),MenACWY-CRM197 was determined to be non-inferior to MenC if the lower limit of the twosided 95% CI for the difference between MenACWY-CRM197 and MenC in the percentage of subjects with response against serogroup C was greater than -10%.

Comparison groups

MenACWY-CRM197 (2dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

301

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical Analysis 2

Statistical analysis description

For the comparisons to MenC based on percentages of subjects with response (rSBA ≥1:8, one month postvaccination), MenACWY-CRM197 was determined to be non-inferior to MenC if the lower limit of the two-sided 95% CI for the difference between MenACWY-CRM197 and MenC in the percentage of subjects with response against serogroup C was greater than -10%.C

Comparison groups

MenACWY-CRM197 (2dose) +Concomitant Vaccines v MenACWY-CRM197 (1dose) +Concomitant Vaccines

Number of subjects included in analysis

313

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[18]

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-3

upper limit

Notes
[18] - For the comparisons to MenC based on percentages of subjects with response (rSBA ≥1:8),MenACWY-CRM197 was determined to be non-inferior to MenC if the lower limit of the twosided 95% CI for the difference between MenACWY-CRM197 and MenC in the percentage of subjects with response against serogroup C was greater than -10%.

Statistical Analysis 3

Statistical analysis description

For the comparisons to MenC based on percentages of subjects with response (rSBA ≥1:8, prevaccination), MenACWY-CRM197 was determined to be non-inferior to MenC if the lower limit of the two-sided 95% CI for the difference between MenACWY-CRM197 and MenC in the percentage of subjects with response against serogroup C was greater than -10%.

Comparison groups

MenACWY-CRM197 (1dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

302

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

Statistical Analysis 4

Statistical analysis description

Comparison groups

MenACWY-CRM197 (1dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

302

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

-5

Confidence interval

level

95%

sides

2-sided

lower limit

-11

upper limit

Statistical Analysis 5

Statistical analysis description

For the comparisons to MenC based on percentages of subjects with response (rSBA ≥1:128, prevaccination), MenACWY-CRM197 was determined to be non-inferior to MenC if the lower limit of the two-sided 95% CI for the difference between MenACWY-CRM197 and MenC in the percentage of subjects with response against serogroup C was greater than -10%.

Comparison groups

MenC (1dose) + Concomitant Vaccines v MenACWY-CRM197 (2dose) +Concomitant Vaccines

Number of subjects included in analysis

301

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Statistical Analysis 6

Statistical analysis description

For the comparisons to MenC based on percentages of subjects with response (rSBA ≥1:128, one month postvaccination),MenACWY-CRM197 was determined to be non-inferior to MenC if the lower limit of the twosided 95% CI for the difference between MenACWY-CRM197 and MenC in the percentage of subjects with response against serogroup C was greater than -10%.

Comparison groups

MenC (1dose) + Concomitant Vaccines v MenACWY-CRM197 (2dose) +Concomitant Vaccines

Number of subjects included in analysis

301

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-3

upper limit

Statistical Analysis 7

Statistical analysis description

Comparison groups

MenC (1dose) + Concomitant Vaccines v MenACWY-CRM197 (1dose) +Concomitant Vaccines

Number of subjects included in analysis

302

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

Statistical Analysis 8

Statistical analysis description

Comparison groups

MenACWY-CRM197 (1dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

302

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage Difference

Point estimate

-13

Confidence interval

level

95%

sides

2-sided

lower limit

-22

upper limit

-5

Statistical Analysis 9

Statistical analysis description

For the comparisons to MenC based on percentages of subjects with response (four-fold rise in titers),MenACWY-CRM197 was determined to be non-inferior to MenC if the lower limit of the twosided 95% CI for the difference between MenACWY-CRM197 and MenC in the percentage of subjects with response against serogroup C was greater than -10%.

Comparison groups

MenC (1dose) + Concomitant Vaccines v MenACWY-CRM197 (2dose) +Concomitant Vaccines

Number of subjects included in analysis

301

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Miettinen and Nurminen

Parameter type

Percentage Difference

Point estimate

-10

Confidence interval

level

95%

sides

2-sided

lower limit

-17

upper limit

-4

Statistical Analysis 10

Statistical analysis description

Comparison groups

MenACWY-CRM197 (1dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

302

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[19]

Method

Miettinen and Nurminen

Parameter type

Percentage Difference

Point estimate

-5

Confidence interval

level

95%

sides

2-sided

lower limit

-11

upper limit

Notes
[19] - For the comparisons to MenC based on percentages of subjects with response (four-fold rise in titers), MenACWY-CRM197 was determined to be non-inferior to MenC if the lower limit of the two-sided 95% CI for the difference between MenACWY-CRM197 and MenC in the percentage of subjects with response against serogroup C was greater than -10%.

Secondary: 15. Percentages of Subjects With Rabbit Serum Bactericidal ≥ 1:8, ≥ 1:128, and Four Fold Rise Against N.Meningitidis Serogroup A, W, Y

Top of page

End point title

15. Percentages of Subjects With Rabbit Serum Bactericidal ≥ 1:8, ≥ 1:128, and Four Fold Rise Against N.Meningitidis Serogroup A, W, Y ^[20]

End point description

1. Immunogenicity of one dose of MenACWY-CRM197 vaccine to one dose of MenC vaccine one month post vaccination was assessed as percentages ofsubjects with serum bactericidal titer with rabbit complement (rSBA) ≥ 1:8, ≥ 1:128, and four fold rise in titer against N.meningitidis Serogroup A, W, Y. 2. Immunogenicity of two doses of MenACWY-CRM197 vaccine to one dose of MenC vaccine one month post vaccination was assessed as percentages of subjects with serum bactericidal titer with rabbit complement (rSBA) ≥ 1:8, ≥ 1:128, and four fold rise in titer against N.meningitidis Serogroup A, W, Y.

End point type

Secondary

End point timeframe

One month postvaccination

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: No statistical analysis is associated to this endpoint.

End point values	MenACWY-CRM197 (2dose) +Concomitant Vaccines	MenACWY-CRM197 (1dose) +Concomitant Vaccines
Number of subjects analysed	76	83
Units: Percentage of Subjects
number (confidence interval 95%)
rSBA titer ≥ 1:128, Men A	100 (95 to 100)	98 (92 to 100)
rSBA titer ≥ 1:128, Men W	96 (89 to 99)	93 (85 to 97)
rSBA titer ≥ 1:128, Men Y	89 (80 to 95)	86 (76 to 92)
rSBA titer ≥ 1:8, Men A	100 (95 to 100)	98 (92 to 100)
rSBA titer ≥ 1:8, Men W	100 (95 to 100)	95 (88 to 99)
rSBA titer ≥ 1:8, Men Y	97 (91 to 100)	88 (79 to 94)
4-fold rise rSBA titer, MenA (N=73,82)	75 (64 to 85)	95 (88 to 99)
4-fold rise rSBA titer, MenW (N=59,73)	95 (86 to 99)	95 (87 to 99)
4-fold rise rSBA titer, MenY (N=32,47)	91 (75 to 98)	87 (74 to 95)

No statistical analyses for this end point

Secondary: 16. Rabbit Serum Bactericidal Activity Geometric Mean Titers Against N.Meningitidis Serogroup C

Top of page

End point title

16. Rabbit Serum Bactericidal Activity Geometric Mean Titers Against N.Meningitidis Serogroup C

End point description

1. Immunogenicity of one dose of MenACWY-CRM197 to one dose of MenC vaccine at 12 months of age was assessed with geometric mean titer (GMT) of serum bactericidal assay with rabbit complement (rSBA) against Serogroup C. 2. Immunogenicity of two doses of MenACWY-CRM197 to one dose of MenC vaccine at 6 to 8 and 12 months of age was assessed with geometric mean titer (GMT) of serum bactericidal assay with rabbit complement (rSBA) against Serogroup C.

End point type

Secondary

End point timeframe

One month post vaccination

End point values	MenACWY-CRM197 (2dose) +Concomitant Vaccines	MenACWY-CRM197 (1dose) +Concomitant Vaccines	MenC (1dose) + Concomitant Vaccines
Number of subjects analysed	156	157	145
Units: Titers
geometric mean (confidence interval 95%)
GMT, prevacc (N=140,140,139)	26 (21 to 33)	2.22 (1.76 to 2.8)	2.03 (1.62 to 2.54)
GMT, postvacc (N=156,157,145)	353 (260 to 479)	131 (98 to 176)	266 (197 to 359)

statistical analysis 1

Statistical analysis description

For comparison of the Geometric Mean Titers at one month postvaccination at 12 months of age,MenACWY-CRM197 was determined to be non-inferior to MenC if the lower limit of the 2-sided 95% CI for the ratio of the MenACWY-CRM197 to MenC Geometric Mean Titers for serogroup C was greater than 0.5

Comparison groups

MenACWY-CRM197 (2dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

301

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[21]

Method

ANOVA

Parameter type

Mean difference (final values)

Point estimate

1.33

Confidence interval

level

95%

sides

2-sided

lower limit

0.96

upper limit

1.83

Notes
[21] - For comparison of the Geometric Mean Titers at one month postvaccination at 12 months of age,MenACWY-CRM197 was determined to be non-inferior to MenC if the lower limit of the 2-sided 95% CI for the ratio of the MenACWY-CRM197 to MenC Geometric Mean Titers for serogroup C was greater than 0.5

Statistical analysis 2

Statistical analysis description

For comparison of the Geometric Mean Titers at one month postvaccination at 12 months of age, MenACWY–CRM197 was determined to be non-inferior to MenC if the lower limit of the 2-sided 95% CI for the ratio of the MenACWY-CRM197 to MenC Geometric Mean Titers for serogroup C was greater than 0.5.

Comparison groups

MenACWY-CRM197 (1dose) +Concomitant Vaccines v MenC (1dose) + Concomitant Vaccines

Number of subjects included in analysis

302

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

ANOVA

Parameter type

Mean difference (final values)

Point estimate

0.49

Confidence interval

level

95%

sides

2-sided

lower limit

0.36

upper limit

0.68

Secondary: 17. Rabbit Serum Bactericidal Activity Geometric Mean Titers Against N.Meningitidis Serogroup A, W, Y

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End point title

17. Rabbit Serum Bactericidal Activity Geometric Mean Titers Against N.Meningitidis Serogroup A, W, Y ^[22]

End point description

1. Immunogenicity of one dose of MenACWY-CRM197 to one dose of MenC vaccine at 12 months of age was assessed with GMT of SBA with rabbit complement (rSBA) against Serogroup A, W, Y. 2. Immunogenicity of two doses of MenACWY-CRM197 to one dose of MenC vaccine at 6 to 8 and 12 months of age was assessed with geometric mean titer (GMT) of serum bactericidal assay with rabbit complement (rSBA) against Serogroup A, W, Y.

End point type

Secondary

End point timeframe

One month postvaccination

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: No statistical analysis is associated to this endpoint.

End point values	MenACWY-CRM197 (2dose) +Concomitant Vaccines	MenACWY-CRM197 (1dose) +Concomitant Vaccines
Number of subjects analysed	76	83
Units: Titers
geometric mean (confidence interval 95%)
GMT, prevacc, Men A (N=73,82)	281 (134 to 587)	6.83 (3.34 to 14)
GMT, postvacc, Men A	3136 (2013 to 4886)	3258 (2113 to 5022)
GMT, prevacc, Men W (N=59,75)	20 (12 to 33)	2.32 (1.46 to 3.69)
GMT, postvacc, Men W	708 (421 to 1191)	1306 (786 to 2169)
GMT, prevacc, Men Y (N=32,49)	22 (12 to 40)	2.4 (1.42 to 4.06)
GMT, postvacc, Men Y (N=76,81)	574 (320 to 1028)	598 (336 to 1066)

No statistical analyses for this end point

Secondary: 18. Number of Subjects Who Reported Solicited Local and Systemic Reactions (Day 1 to Day 7 Postvaccination), After Any Vaccination

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End point title

18. Number of Subjects Who Reported Solicited Local and Systemic Reactions (Day 1 to Day 7 Postvaccination), After Any Vaccination

End point description

Safety was assessed as the number of subjects who reported solicited local reactions from day 1 to day 7 postvaccination for all the three vaccination groups. safety was assessed as the number of subjects who reported solicited systemic reactions from day 1 to day 7 Following the Month 12 vaccination in all three vaccination groups

End point type

Secondary

End point timeframe

From day 1 to day 7 postvaccination

End point values	MenACWY-CRM197 (2dose) +Concomitant Vaccines	MenACWY-CRM197 (1dose) +Concomitant Vaccines	MenC (1dose) + Concomitant Vaccines
Number of subjects analysed	195	192	179
Units: Number
Any Local (N=195,192,179)	130	131	135
Tenderness (MenACWY 197/MenC; N=194,192,178)	57	65	44
Erythema (MenACWY 197/MenC; N=194,192,178)	94	62	64
Induration (MenACWY 197/MenC; N=194,192,178)	53	24	43
Tenderness (DTPa-HepB-Hib; N=189,190,176)	62	83	73
Erythema (DTPa-HepB-Hib; N=189,190,176)	80	81	96
Induration (DTPa-HepB-Hib; N=189,190,176)	62	66	81
Tenderness (PCV7; N=189,190,176)	58	68	60
Erythema (PCV7; N=189,190,176)	71	68	77
Induration (PCV7; N=189,190,176)	50	50	59
Any Systemic reactions (N=195,192,179)	173	149	150
Change in eating habits (N=194,191,177)	87	66	49
Sleepiness (N=194,191,179)	156	99	94
Persisten crying (N=194,191,177)	100	93	76
Irritability (N=194,191,177)	85	68	73
Vomiting (N=194,191,179)	29	18	16
Diarrhoea (N=194,191,179)	46	41	42
Rash (N=194,191,179)	20	17	7
Fever ≥ 38.5 C (N=195,192,179)	60	62	50
Others (N=191,192,179)	58	62	62
Analgesic-Antipyretic medication (N=195,192,179)	64	62	62

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Throughout study period.

Adverse event reporting additional description

Post-injection solicited Adverse Events (AEs) were collected from Days 1-7 after any vaccination. Other AEs and Serious AEs collected for group MenACWY-CRM197 (2dose) +Concomitant Vaccine (CV) were collected from days 1 to 180 (Month 6-8) and in MenACWY-CRM197 (1 dose) + CV and MenC (1 dose)+ CV were collected from day 1 to 6 months (Month 12)

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

MenACWY-CRM197(2dose) +Concomitant Vaccines

Reporting group description

Infants received two doses of MenACWY-CRM197 at 6-8 months and 12 months and Concomitant dose of PCV7 and DTPa-IPV-HepB-Hib at 12 months.

Reporting group title

MenC (1dose) +Concomitant Vaccines

Reporting group description

Infants received one dose of MenC vaccine at 12 months and Concomitant dose of PCV7 and DTPa-IPV-HepB-Hib at 12 months.

Reporting group title

MenACWY-CRM197(1dose) +Concomitant Vaccines

Reporting group description

Infants received one dose of MenACWY-CRM197 at 12 months and Concomitant dose of PCV7 and DTPa-IPV-HepB-Hib at 12 months

Serious adverse events	MenACWY-CRM197(2dose) +Concomitant Vaccines	MenC (1dose) +Concomitant Vaccines	MenACWY-CRM197(1dose) +Concomitant Vaccines
Total subjects affected by serious adverse events
subjects affected / exposed	13 / 195 (6.67%)	12 / 179 (6.70%)	19 / 192 (9.90%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neuroblastoma
subjects affected / exposed	0 / 195 (0.00%)	0 / 179 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental exposure
subjects affected / exposed	0 / 195 (0.00%)	0 / 179 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Concussion
subjects affected / exposed	1 / 195 (0.51%)	0 / 179 (0.00%)	2 / 192 (1.04%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Contusion
subjects affected / exposed	1 / 195 (0.51%)	0 / 179 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thermal burn
subjects affected / exposed	0 / 195 (0.00%)	1 / 179 (0.56%)	0 / 192 (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
Nervous system disorders
Febrile convulsion
subjects affected / exposed	0 / 195 (0.00%)	1 / 179 (0.56%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Lymphadenitis
subjects affected / exposed	0 / 195 (0.00%)	0 / 179 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Hyperpyrexia
subjects affected / exposed	1 / 195 (0.51%)	0 / 179 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Food Allergy
subjects affected / exposed	0 / 195 (0.00%)	1 / 179 (0.56%)	0 / 192 (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
Amphthous stomatitis
subjects affected / exposed	1 / 195 (0.51%)	0 / 179 (0.00%)	0 / 192 (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
Diarrhoea
subjects affected / exposed	0 / 195 (0.00%)	0 / 179 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intussusception
subjects affected / exposed	1 / 195 (0.51%)	0 / 179 (0.00%)	0 / 192 (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
Stomatitis
subjects affected / exposed	0 / 195 (0.00%)	1 / 179 (0.56%)	0 / 192 (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
Vomiting
subjects affected / exposed	0 / 195 (0.00%)	0 / 179 (0.00%)	2 / 192 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	2 / 195 (1.03%)	0 / 179 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 195 (0.00%)	0 / 179 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	2 / 195 (1.03%)	0 / 179 (0.00%)	3 / 192 (1.56%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Croup infectious
subjects affected / exposed	0 / 195 (0.00%)	1 / 179 (0.56%)	0 / 192 (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
Febrile infection
subjects affected / exposed	0 / 195 (0.00%)	1 / 179 (0.56%)	0 / 192 (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
Gastroenteritis
subjects affected / exposed	3 / 195 (1.54%)	4 / 179 (2.23%)	4 / 192 (2.08%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 195 (0.51%)	0 / 179 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malaria
subjects affected / exposed	1 / 195 (0.51%)	0 / 179 (0.00%)	0 / 192 (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
subjects affected / exposed	0 / 195 (0.00%)	3 / 179 (1.68%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 195 (0.00%)	0 / 179 (0.00%)	1 / 192 (0.52%)
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 respiratory syncytial viral
subjects affected / exposed	1 / 195 (0.51%)	0 / 179 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 195 (0.00%)	1 / 179 (0.56%)	0 / 192 (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
Tonsillitis
subjects affected / exposed	0 / 195 (0.00%)	0 / 179 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	1 / 195 (0.51%)	0 / 179 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	0 / 195 (0.00%)	1 / 179 (0.56%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	2 / 195 (1.03%)	1 / 179 (0.56%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
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	MenACWY-CRM197(2dose) +Concomitant Vaccines	MenC (1dose) +Concomitant Vaccines	MenACWY-CRM197(1dose) +Concomitant Vaccines
Total subjects affected by non serious adverse events
subjects affected / exposed	192 / 195 (98.46%)	170 / 179 (94.97%)	184 / 192 (95.83%)
Nervous system disorders
Crying
subjects affected / exposed	100 / 195 (51.28%)	76 / 179 (42.46%)	93 / 192 (48.44%)
occurrences all number	148	86	113
Somnolence
subjects affected / exposed	126 / 195 (64.62%)	94 / 179 (52.51%)	99 / 192 (51.56%)
occurrences all number	197	106	118
General disorders and administration site conditions
Injection site erythema
subjects affected / exposed	110 / 195 (56.41%)	110 / 179 (61.45%)	102 / 192 (53.13%)
occurrences all number	299	251	223
Injection site induration
subjects affected / exposed	86 / 195 (44.10%)	104 / 179 (58.10%)	82 / 192 (42.71%)
occurrences all number	197	197	163
Injection site pain
subjects affected / exposed	90 / 195 (46.15%)	84 / 179 (46.93%)	97 / 192 (50.52%)
occurrences all number	195	184	226
Pyrexia
subjects affected / exposed	127 / 195 (65.13%)	102 / 179 (56.98%)	111 / 192 (57.81%)
occurrences all number	218	158	167
Eye disorders
Conjunctivitis
subjects affected / exposed	36 / 195 (18.46%)	18 / 179 (10.06%)	15 / 192 (7.81%)
occurrences all number	0	0	1
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	54 / 195 (27.69%)	44 / 179 (24.58%)	44 / 192 (22.92%)
occurrences all number	80	57	60
Enteritis
subjects affected / exposed	13 / 195 (6.67%)	5 / 179 (2.79%)	4 / 192 (2.08%)
occurrences all number	15	5	5
Teething
subjects affected / exposed	21 / 195 (10.77%)	7 / 179 (3.91%)	6 / 192 (3.13%)
occurrences all number	25	10	8
Vomiting
subjects affected / exposed	38 / 195 (19.49%)	19 / 179 (10.61%)	24 / 192 (12.50%)
occurrences all number	47	25	27
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	25 / 195 (12.82%)	10 / 179 (5.59%)	11 / 192 (5.73%)
occurrences all number	34	16	17
Skin and subcutaneous tissue disorders
Dermatitis Diaper
subjects affected / exposed	24 / 195 (12.31%)	9 / 179 (5.03%)	20 / 192 (10.42%)
occurrences all number	37	13	30
Rash
subjects affected / exposed	28 / 195 (14.36%)	7 / 179 (3.91%)	24 / 192 (12.50%)
occurrences all number	36	9	28
Psychiatric disorders
Irritability
subjects affected / exposed	85 / 195 (43.59%)	73 / 179 (40.78%)	68 / 192 (35.42%)
occurrences all number	132	86	88
Eating disorder
subjects affected / exposed	87 / 195 (44.62%)	49 / 179 (27.37%)	66 / 192 (34.38%)
occurrences all number	113	54	80
Infections and infestations
Bronchitis
subjects affected / exposed	47 / 195 (24.10%)	29 / 179 (16.20%)	29 / 192 (15.10%)
occurrences all number	70	50	52
Gastroenteritis
subjects affected / exposed	22 / 195 (11.28%)	12 / 179 (6.70%)	14 / 192 (7.29%)
occurrences all number	23	21	18
Nasopharyngitis
subjects affected / exposed	19 / 195 (9.74%)	14 / 179 (7.82%)	14 / 192 (7.29%)
occurrences all number	25	34	19
Otitis media
subjects affected / exposed	33 / 195 (16.92%)	21 / 179 (11.73%)	22 / 192 (11.46%)
occurrences all number	50	32	43
Rhinitis
subjects affected / exposed	24 / 195 (12.31%)	8 / 179 (4.47%)	7 / 192 (3.65%)
occurrences all number	27	10	9
Upper respiratory tract infection
subjects affected / exposed	67 / 195 (34.36%)	29 / 179 (16.20%)	31 / 192 (16.15%)
occurrences all number	109	49	48
Viral infection
subjects affected / exposed	38 / 195 (19.49%)	26 / 179 (14.53%)	26 / 192 (13.54%)
occurrences all number	56	44	45

More information

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Were there any global substantial amendments to the protocol? No

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

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Clinical trials

Clinical Trial Results: A Phase 3, Open-Label, Randomized, Multi-Center Study to Evaluate the Safety and Immunogenicity after One or Two Doses of Novartis Meningococcal ACWY Conjugate Vaccine Administered to Healthy Infants and Toddlers

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 1. Percentages of Subjects With Serum Bactericidal Titer ≥ 1:8 Against N.Meningitidis Serogroup C

Primary: 1. Percentages of Subjects With Serum Bactericidal Titer ≥ 1:8 Against N.Meningitidis Serogroup C

Secondary: 2. Percentages of Subjects With Human Serum Bactericidal Titer ≥ 1:4 Against N.Meningitidis Serogroup C

Secondary: 2. Percentages of Subjects With Human Serum Bactericidal Titer ≥ 1:4 Against N.Meningitidis Serogroup C

Secondary: 3. Percentages of Subjects With Human Serum Bactericidal Titer ≥ 1:8 and Titer ≥ 1:4 Against N. Meningitidis Serogroups A, C, W, Y

Secondary: 3. Percentages of Subjects With Human Serum Bactericidal Titer ≥ 1:8 and Titer ≥ 1:4 Against N. Meningitidis Serogroups A, C, W, Y

Secondary: 4. Percentages of Subjects With Human Serum Bactericidal Titer ≥ 1:8 and Titer ≥ 1:4 Against N. Meningitidis Serogroups A, W, Y

Secondary: 4. Percentages of Subjects With Human Serum Bactericidal Titer ≥ 1:8 and Titer ≥ 1:4 Against N. Meningitidis Serogroups A, W, Y

Secondary: 5. Human Serum Bactericidal Activity Geometric Mean Titers After One Dose of MenACWY-CRM197 and MenC Against N.Meningitidis Serogroup C

Secondary: 5. Human Serum Bactericidal Activity Geometric Mean Titers After One Dose of MenACWY-CRM197 and MenC Against N.Meningitidis Serogroup C

Secondary: 6. Human Serum Bactericidal Activity Geometric Mean Titers Against N.Meningitidis Serogroups A, W, Y

Secondary: 6. Human Serum Bactericidal Activity Geometric Mean Titers Against N.Meningitidis Serogroups A, W, Y

Secondary: 7. Human Serum Bactericidal Activity Geometric Mean Titers Against N.Meningitidis Serogroups A, C, W, Y

Secondary: 7. Human Serum Bactericidal Activity Geometric Mean Titers Against N.Meningitidis Serogroups A, C, W, Y

Secondary: 8. Percentages of Subjects With Seroresponse Rates After One Dose of DTPa-IPV-HepB-Hib (Concomitant Vaccine)

Secondary: 8. Percentages of Subjects With Seroresponse Rates After One Dose of DTPa-IPV-HepB-Hib (Concomitant Vaccine)

Secondary: 9. Percentages of Subjects With Seroresponse Rates After One Dose of PCV7 (Concomitant Vaccine)

Secondary: 9. Percentages of Subjects With Seroresponse Rates After One Dose of PCV7 (Concomitant Vaccine)

Secondary: 10. Persistence of Immune Response Measured as Percentages of Subjects With Human Serum Bactericidal Titer ≥ 1:8 and Titer ≥ 1:4 Against N.Meningitidis Serogroup C

Secondary: 10. Persistence of Immune Response Measured as Percentages of Subjects With Human Serum Bactericidal Titer ≥ 1:8 and Titer ≥ 1:4 Against N.Meningitidis Serogroup C

Secondary: 11. Persistence of Immune Response Measured as Percentages of Subjects With Human Serum Bactericidal Titer ≥ 1:8 ,and Titer ≥ 1:4 Against N.Meningitidis Serogroups A, W, Y

Secondary: 11. Persistence of Immune Response Measured as Percentages of Subjects With Human Serum Bactericidal Titer ≥ 1:8 ,and Titer ≥ 1:4 Against N.Meningitidis Serogroups A, W, Y

Secondary: 12. Persistence of Human Serum Bactericidal Activity Geometric Mean Titers Against N.Meningitidis Serogroup C

Secondary: 12. Persistence of Human Serum Bactericidal Activity Geometric Mean Titers Against N.Meningitidis Serogroup C

Secondary: 13. Persistence of Human Serum Bactericidal Activity Geometric Mean Titers against N.Meningitidis Serogroup A, W, Y

Secondary: 13. Persistence of Human Serum Bactericidal Activity Geometric Mean Titers against N.Meningitidis Serogroup A, W, Y

Secondary: 14. Percentages of Subjects With Rabbit Serum Bactericidal ≥ 1:8, ≥ 1:128 and Four Fold Rise Against N.Meningitidis Serogroup C

Secondary: 14. Percentages of Subjects With Rabbit Serum Bactericidal ≥ 1:8, ≥ 1:128 and Four Fold Rise Against N.Meningitidis Serogroup C

Secondary: 15. Percentages of Subjects With Rabbit Serum Bactericidal ≥ 1:8, ≥ 1:128, and Four Fold Rise Against N.Meningitidis Serogroup A, W, Y

Secondary: 15. Percentages of Subjects With Rabbit Serum Bactericidal ≥ 1:8, ≥ 1:128, and Four Fold Rise Against N.Meningitidis Serogroup A, W, Y

Secondary: 16. Rabbit Serum Bactericidal Activity Geometric Mean Titers Against N.Meningitidis Serogroup C

Secondary: 16. Rabbit Serum Bactericidal Activity Geometric Mean Titers Against N.Meningitidis Serogroup C

Secondary: 17. Rabbit Serum Bactericidal Activity Geometric Mean Titers Against N.Meningitidis Serogroup A, W, Y

Secondary: 17. Rabbit Serum Bactericidal Activity Geometric Mean Titers Against N.Meningitidis Serogroup A, W, Y

Secondary: 18. Number of Subjects Who Reported Solicited Local and Systemic Reactions (Day 1 to Day 7 Postvaccination), After Any Vaccination

Secondary: 18. Number of Subjects Who Reported Solicited Local and Systemic Reactions (Day 1 to Day 7 Postvaccination), 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 3, Open-Label, Randomized, Multi-Center Study to Evaluate the Safety and Immunogenicity after One or Two Doses of Novartis Meningococcal ACWY Conjugate Vaccine Administered to Healthy Infants and Toddlers