Clinical Trial Results:
A Phase 3, Open-Label, Randomized, Multi-Center Study to Evaluate the Safety and Immunogenicity of ProQuad™ Vaccine When Administered Concomitantly with Novartis Meningococcal ACWY Conjugate Vaccine to Healthy Toddlers.

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

Summary
EudraCT number	2014-004694-16
Trial protocol	Outside EU/EEA
Global end of trial date	26 Oct 2010

Results information
Results version number	v2(current)
This version publication date	01 Jun 2016
First version publication date	06 Feb 2015
Other versions	v1 (removed from public view)
Version creation reason	Correction of full data set re-QC study because of EudraCT system glitch and updates to results are required.

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

V59P21

ISRCTN number

US NCT number

NCT00626327

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Vaccines and Diagnostics Inc.

Sponsor organisation address

350 Massachusetts Ave, Cambridge, United States, 02139

Public contact

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

Scientific contact

Posting Director, Novartis Vaccines and Diagnostics Inc., 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

11 Feb 2011

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

26 Oct 2010

Was the trial ended prematurely?

Main objective of the trial

- To compare the immune responses of ProQuad™ vaccine when administered with MenACWY vaccine to that of ProQuad™ vaccine alone to children 12 months of age, as measured by seroconversion rates to measles, mumps, and rubella, and seroprotection rates for varicella. - To compare the immune responses of two doses of MenACWY given to children at 7 to 9 and 12 months of age, when either administered with ProQuad™ or given alone, as measured by percentage of subjects with serum bactericidal activity (hSBA) ≥1:8 against N. meningitidis serogroups A, C, W-135, and Y. - To assess the immunogenicity of two doses of MenACWY given to children at 7 to 9 and 12 months of age as measured by the percentage of subjects with hSBA ≥1:8 against N. meningitidis serogroups A, C, W-135, and Y.

Protection of trial subjects

This trial was conducted in accordance with the ethical principles that have their origin in the latest version Declaration of Helsinki accepted by the local authorities, and that are consistent with Good Clinical Practices (GCPs) and the applicable regulatory requirement(s) for the country in which the trial was conducted, Good Clinical Practice (GCP) according to International Conference on Harmonisation (ICH) guidelines, and applicable Standard Operating Procedures (SOPs).

Background therapy

N/A

Evidence for comparator

N/A

Actual start date of recruitment

27 Feb 2008

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

6 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 1630

Worldwide total number of subjects

1630

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

1630

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

Subjects were enrolled at 90 sites in US.

Screening details

All enrolled subjects were included in the trial.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

The trial was designed as an open-label study; both the study personnel and the subjects’ parents/legal guardians knew which vaccine was being administered. However, laboratory immunogenicity analyses were conducted in a blinded fashion with samples blinded to both group and visit.

Are arms mutually exclusive

Yes

ACWY + MMRV

Arm description

Subjects in this group received 2 injections of MenACWY at 7-9 and 12 months; second injection administered concomitantly with MMRV.

Arm type

Experimental

Investigational medicinal product name

ProQuad™

Investigational medicinal product code

Other name

Measles, Mumps, Rubella and Varicella vaccine

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

One dose of 0.5mL

Investigational medicinal product name

MenACWY

Investigational medicinal product code

Other name

Meningococcal (groups A, C, W, and Y) oligosaccharide diphtheria CRM-197 conjugate vaccine

Pharmaceutical forms

Powder and solution for solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Two doses of 0.5mL each

ACWY

Arm description

Subjects in this group received 2 injections of the MenACWY vaccine at 7-9 and 12 months of age followed by 1 injection of MMRV at 13.5 months.

Arm type

Experimental

Investigational medicinal product name

ProQuad™

Investigational medicinal product code

Other name

Measles, Mumps, Rubella and Varicella vaccine

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

One dose of 0.5mL

Investigational medicinal product name

MenACWY

Investigational medicinal product code

Other name

Meningococcal (groups A, C, W, and Y) oligosaccharide diphtheria CRM-197 conjugate vaccine

Pharmaceutical forms

Powder and solution for solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Two doses of 0.5mL each

MMRV

Arm description

Subjects in this group received 1 injection of MMRV vaccine at 12 months of age.

Arm type

Experimental

Investigational medicinal product name

ProQuad™

Investigational medicinal product code

Other name

Measles, Mumps, Rubella and Varicella vaccine

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

One dose of 0.5mL

Number of subjects in period 1	ACWY + MMRV	ACWY	MMRV
Started	504	510	616
Completed	426	422	557
Not completed	78	88	59
Consent withdrawn by subject	21	30	29
Adverse event, non-fatal	1	-	-
Inappropriate enrolment	4	3	5
Lost to follow-up	24	23	21
Administrative reason	2	6	-
Protocol deviation	26	26	4

Baseline characteristics

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Reporting group title

ACWY + MMRV

Reporting group description

Subjects in this group received 2 injections of MenACWY at 7-9 and 12 months; second injection administered concomitantly with MMRV.

Reporting group title

ACWY

Reporting group description

Subjects in this group received 2 injections of the MenACWY vaccine at 7-9 and 12 months of age followed by 1 injection of MMRV at 13.5 months.

Reporting group title

MMRV

Reporting group description

Subjects in this group received 1 injection of MMRV vaccine at 12 months of age.

Reporting group values	ACWY + MMRV	ACWY	MMRV	Total
Number of subjects	504	510	616	1630
Age categorical
Units: Subjects
Age continuous
Units: months
arithmetic mean (standard deviation)	8.5 ( 0.8 )	8.5 ( 0.8 )	12.1 ( 0.3 )	-
Gender categorical
Units: Subjects
Female	251	252	304	807
Male	253	258	312	823

Subject analysis set title

Exposed Population

Subject analysis set type

Intention-to-treat

Subject analysis set description

All enrolled subjects who actually received a study vaccination.

Subject analysis set title

Enrolled Population

Subject analysis set type

Intention-to-treat

Subject analysis set description

All subjects who signed an informed consent, undergone screening procedure and were randomized (Groups I and II only) or enrolled (Group III).

Subject analysis set title

MMRV Per Protocol Population (PP - MMRV)

Subject analysis set type

Per protocol

Subject analysis set description

All subjects who actually received one study vaccination correctly, provided evaluable serum samples at the relevant time points, were seronegative at baseline for any of the four antigens (MMRV analyses only), were included in the analysis of those antigens, and had no major protocol deviation as defined prior to unblinding. These subjects would have received either ProQuad™ or M-M-R™II + Varivax™.

Subject analysis set title

MenACWY Per Protocol Population (PP - MenACWY)

Subject analysis set type

Per protocol

Subject analysis set description

All subjects who actually received all the relevant doses of vaccine correctly, provided evaluable serum samples at the relevant time points, were included in the analysis of that antigen, and had no major protocol deviation as defined prior to unblinding.

Subject analysis set title

Safety Population

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects in the Exposed Population who provided post-baseline safety data.

Subject analysis sets values	Exposed Population	Enrolled Population	MMRV Per Protocol Population (PP - MMRV)	MenACWY Per Protocol Population (PP - MenACWY)	Safety Population
Number of subjects	1603	1630	1318	1319	1597
Age categorical
Units: Subjects
Age continuous
Units: months
arithmetic mean (standard deviation)	( )	9.8 ( 1.9 )	( )	( )	( )
Gender categorical
Units: Subjects
Female		807
Male		823

End points

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Reporting group title

ACWY + MMRV

Reporting group description

Subjects in this group received 2 injections of MenACWY at 7-9 and 12 months; second injection administered concomitantly with MMRV.

Reporting group title

ACWY

Reporting group description

Subjects in this group received 2 injections of the MenACWY vaccine at 7-9 and 12 months of age followed by 1 injection of MMRV at 13.5 months.

Reporting group title

MMRV

Reporting group description

Subjects in this group received 1 injection of MMRV vaccine at 12 months of age.

Subject analysis set title

Exposed Population

Subject analysis set type

Intention-to-treat

Subject analysis set description

All enrolled subjects who actually received a study vaccination.

Subject analysis set title

Enrolled Population

Subject analysis set type

Intention-to-treat

Subject analysis set description

All subjects who signed an informed consent, undergone screening procedure and were randomized (Groups I and II only) or enrolled (Group III).

Subject analysis set title

MMRV Per Protocol Population (PP - MMRV)

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

MenACWY Per Protocol Population (PP - MenACWY)

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Safety Population

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects in the Exposed Population who provided post-baseline safety data.

Primary: 1. Percentages of Subjects With a Seroresponse to Measles, Mumps, Rubella and Varicella Following Concomitant Administration of MMRV Vaccine With MenACWY Vaccine

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End point title

1. Percentages of Subjects With a Seroresponse to Measles, Mumps, Rubella and Varicella Following Concomitant Administration of MMRV Vaccine With MenACWY Vaccine ^[1]

End point description

Percentages of subjects with seroresponses to measles, mumps, rubella and varicella after one dose of MMRV vaccine (at 12 months) when given concomitantly with MenACWY vaccine compared to when MMRV vaccine was given alone, are reported. Seroresponse was defined as the percentage of initially seronegative subjects who show seroconversion to measles (≥255 mIU/mL), mumps (≥10 ELISA Ab units), rubella (≥10 IU/mL) and varicella (≥5 gp ELISA units/mL). Immunogenicity to measles, mumps, rubella and varicella at 6 weeks after vaccination with one dose of MMRV given concomitantly with MenACWY was considered non-inferior to immunogenicity of MMRV administered alone if the lower limit of two-sided 95% CI of the difference in the percentage of subjects with seroconversion for measles, mumps, and rubella was greater than -5%, and seroprotection for varicella was greater than -10%. The analysis was performed on the MMRV Per Protocol Population.

End point type

Primary

End point timeframe

6 weeks post vaccination

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

End point values	ACWY + MMRV	MMRV
Number of subjects analysed	370	515
Units: Percentages of Subjects
number (confidence interval 95%)
Measles (N=350,467)	98 (96 to 99)	99 (98 to 100)
Mumps (N=365,499)	98 (96 to 99)	96 (94 to 98)
Rubella (370,515)	95 (93 to 97)	97 (95 to 98)
Varicella (N=337,459)	96 (94 to 98)	98 (96 to 99)

Non-inferiority of immune response to measles

Statistical analysis description

Non-inferiority of immune response to measles following one dose of MMRV administered concomitantly with MenACWY as compared to MMRV given alone. The immune response of MenACWY+MMRV group was considered non-inferior to that of MMRV group if the lower limit of the two-sided 95% CI of the difference in the percentage of subjects with seroconversion for measles was greater than -5%, at 6 weeks after MMRV vaccination.

Comparison groups

ACWY + MMRV v MMRV

Number of subjects included in analysis

885

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

95% Confidence Intervals

Parameter type

Percentage group difference

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-3.4

upper limit

0.5

Non-inferiority of immune response to mumps

Statistical analysis description

Non-inferiority of immune response to mumps following one dose of MMRV administered concomitantly with MenACWY as compared to MMRV given alone. The immune response of MenACWY+MMRV group was considered non-inferior to that of MMRV group if the lower limit of the two-sided 95% CI of the difference in the percentage of subjects with seroconversion for mumps was greater than -5%, at 6 weeks after MMRV vaccination.

Comparison groups

ACWY + MMRV v MMRV

Number of subjects included in analysis

885

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

95% Confidence Intervals

Parameter type

Percentage group difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

3.7

Non-inferiority of immune response to rubella

Statistical analysis description

Non-inferiority of immune response to rubella following one dose of MMRV administered concomitantly with MenACWY as compared to MMRV given alone. The immune response of MenACWY+MMRV group was considered non-inferior to that of MMRV group if the lower limit of the two-sided 95% CI of the difference in the percentage of subjects with seroconversion for rubella was greater than -5%, at 6 weeks after MMRV vaccination.

Comparison groups

ACWY + MMRV v MMRV

Number of subjects included in analysis

885

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

95% Confidence Intervals

Parameter type

Percentage group difference

Point estimate

-2

Confidence interval

level

95%

sides

2-sided

lower limit

-4.5

upper limit

0.8

Non-inferiority of immune response to varicella

Statistical analysis description

Non-inferiority of immune response to varicella following one dose of MMRV administered concomitantly with MenACWY as compared to MMRV given alone. The immune response of MenACWY+MMRV group was considered non-inferior to that of MMRV group if the lower limit of the two-sided 95% CI of the difference in the percentage of subjects with seroconversion for varicella was greater than -10%, at 6 weeks after MMRV vaccination.

Comparison groups

ACWY + MMRV v MMRV

Number of subjects included in analysis

885

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

95% Confidence Intervals

Parameter type

Percentage group difference

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-3.9

upper limit

1.2

Primary: 2. Percentages of Subjects With Serum Bactericidal Titers ≥1:8 Following Concomitant Administration of MenACWY Vaccine With MMRV Vaccine.

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End point title

2. Percentages of Subjects With Serum Bactericidal Titers ≥1:8 Following Concomitant Administration of MenACWY Vaccine With MMRV Vaccine. ^[2]

End point description

Percentages of subjects with hSBA ≥1:8, against N.meningitidis serogroups A, C, W-135, and Y following two doses of MenACWY vaccine (at 7-9 months and 12 months) when concomitantly administered with MMRV vaccine (12 months) compared to when MenACWY vaccine was given alone, are reported. The serum bactericidal antibodies directed against N.meningitidis serogroups A, C, W-135, and Y, were measured by human complement Serum Bactericidal Assay (hSBA). The immune response of MenACWY given concomitantly with MMRV was considered non-inferior to the immunogenicity of MenACWY administered alone if the lower limit of the two-sided 95% CI around the difference of the percentage of subjects with hSBA ≥1:8 at 6 weeks after the second dose of MenACWY given to 12-month old toddlers {P MMRV+MenACWY minus P MenACWY} was greater than -10% for each serogroup. The analysis was performed on the MenACWY Per Protocol population.

End point type

Primary

End point timeframe

6 weeks post vaccination

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: There was no statistical null hypothesis associated with this immunogenicity objective.

End point values	ACWY + MMRV	ACWY
Number of subjects analysed	384	379
Units: Percentages of Subjects
number (confidence interval 95%)
Serogroup A	88 (84 to 91)	88 (84 to 91)
Serogroup C (N=204,195)	100 (98 to 100)	100 (98 to 100)
Serogroup W-135 (N=204,196)	100 (97 to 100)	98 (96 to 100)
Serogroup Y (N=200,198)	98 (95 to 99)	96 (93 to 99)

non-inferiority against serogroup A

Statistical analysis description

Non-inferiority of immune response to MenACWY against serogroup A when administered concomitantly with MMRV vaccine as compared to MenACWY vaccine given alone. The immune response of MenACWY + MMRV group was considered non-inferior to that of MenACWY group if the lower limit of the two-sided 95% CI around the difference of the percentage of subjects with hSBA ≥1:8 at 6 weeks after the second dose of MenACWY given to 12 month old toddlers was greater than -10% for each serogroup.

Comparison groups

ACWY + MMRV v ACWY

Number of subjects included in analysis

763

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

95% Confidence Intervals

Parameter type

Percentage group difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-4.7

upper limit

4.5

non-inferiority against serogroup C

Statistical analysis description

Non-inferiority of immune response to MenACWY against serogroup C when administered concomitantly with MMRV vaccine as compared to MenACWY vaccine given alone. The immune response of MenACWY + MMRV group was considered non-inferior to that of MenACWY group if the lower limit of the two-sided 95% CI around the difference of the percentage of subjects with hSBA ≥1:8 at 6 weeks after the second dose of MenACWY given to 12 month old toddlers was greater than -10% for each serogroup.

Comparison groups

ACWY + MMRV v ACWY

Number of subjects included in analysis

763

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

95% Confidence Intervals

Parameter type

Percentage group difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1.8

upper limit

1.9

non-inferiority against serogroup W-135

Statistical analysis description

Non-inferiority of immune response to MenACWY against serogroup W-135 when administered concomitantly with MMRV vaccine as compared to MenACWY vaccine given alone. The immune response of MenACWY + MMRV group was considered non-inferior to that of MenACWY group if the lower limit of the two-sided 95% CI around the difference of the percentage of subjects with hSBA ≥1:8 at 6 weeks after the second dose of MenACWY given to 12 month old toddlers was greater than -10% for each serogroup.

Comparison groups

ACWY + MMRV v ACWY

Number of subjects included in analysis

763

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

95% Confidence Intervals

Parameter type

Percentage group difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1.3

upper limit

3.9

non-inferiority against serogroup Y

Statistical analysis description

Non-inferiority of immune response to MenACWY against serogroup Y when administered concomitantly with MMRV vaccine as compared to MenACWY vaccine given alone. The immune response of MenACWY + MMRV group was considered non-inferior to that of MenACWY group if the lower limit of the two-sided 95% CI around the difference of the percentage of subjects with hSBA ≥1:8 at 6 weeks after the second dose of MenACWY given to 12 month old toddlers was greater than -10% for each serogroup.

Comparison groups

ACWY + MMRV v ACWY

Number of subjects included in analysis

763

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

95% Confidence Intervals

Parameter type

Percentage group difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1.9

upper limit

5.3

Primary: 3. Percentages of Subjects With hSBA ≥1:8 Following Two Doses of MenACWY Vaccine

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End point title

3. Percentages of Subjects With hSBA ≥1:8 Following Two Doses of MenACWY Vaccine ^[3] ^[4]

End point description

The antibody response following two doses of MenACWY vaccine (at 7-9 months and 12 months) was considered adequate if the lower limit of the two-sided 95% CI for the percentage of subjects with hSBA ≥1:8, at 6 weeks following the second dose of MenACWY, was greater than 85% for serogroups C, W-135, or Y and greater than 65% for serogroup A. The analysis was performed on the MenACWY Per Protocol population.

End point type

Primary

End point timeframe

6 weeks post second vaccination dose

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

End point values	ACWY
Number of subjects analysed	379
Units: Percentages of Subjects
number (confidence interval 95%)
Serogroup A	88 (84 to 91)
Serogroup C (N=195)	100 (98 to 100)
Serogroup W-135 (N=196)	98 (96 to 100)
Serogroup Y (N=198)	96 (93 to 99)

No statistical analyses for this end point

Secondary: 4. Percentages of Subjects With hSBA ≥1:4 Following Two Doses of MenACWY Vaccine

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End point title

4. Percentages of Subjects With hSBA ≥1:4 Following Two Doses of MenACWY Vaccine ^[5]

End point description

The percentages of subjects with hSBA ≥1:4 directed against N. meningitidis serogroups A, C, W-135, and Y following two doses of MenACWY vaccine (at 7- 9 and 12 months of age) when given concomitantly with MMRV vaccine (at 12 months) compared to when MenACWY vaccine was given alone, are reported. The analysis was performed on the MenACWY Per Protocol population.

End point type

Secondary

End point timeframe

6 weeks post second vaccination dose

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

End point values	ACWY + MMRV	ACWY
Number of subjects analysed	384	379
Units: Percentages of Subjects
number (confidence interval 95%)
Serogroup A	90 (86 to 92)	91 (87 to 93)
Serogroup C (N=204,195)	100 (98 to 100)	100 (98 to 100)
Serogroup W-135 (N=204,196)	100 (97 to 100)	99 (96 to 100)
Serogroup Y (N=200,198)	98 (95 to 99)	98 (95 to 99)

No statistical analyses for this end point

Secondary: 5. Geometric Mean Titers Against Serogroups A, C, W-135 and Y, Following Two Doses of MenACWY Vaccine

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End point title

5. Geometric Mean Titers Against Serogroups A, C, W-135 and Y, Following Two Doses of MenACWY Vaccine ^[6]

End point description

The geometric mean titers (GMTs) directed against N. meningitidis serogroups A, C, W-135 and Y, following two doses of MenACWY vaccine (at 7-9 months and 12 months of age), when given concomitantly with MMRV vaccine (at 12 months) compared to when MenACWY vaccine was given alone, are reported. The analysis was performed on the MenACWY Per Protocol population.

End point type

Secondary

End point timeframe

6 weeks post second vaccination dose

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: There was no statistical null hypothesis associated with this immunogenicity objective.

End point values	ACWY + MMRV	ACWY
Number of subjects analysed	384	379
Units: Titers
geometric mean (confidence interval 95%)
Serogroup A	39 (34 to 45)	37 (32 to 42)
Serogroup C (N=204,195)	194 (170 to 220)	180 (158 to 205)
Serogroup W-135 (N=204,196)	132 (113 to 155)	119 (101 to 139)
Serogroup Y (N=200,198)	97 (81 to 116)	88 (73 to 105)

No statistical analyses for this end point

Secondary: 6. Geometric Mean Titers Against Measles, Mumps, Rubella and Varicella Following One Dose of MMRV Vaccine

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End point title

6. Geometric Mean Titers Against Measles, Mumps, Rubella and Varicella Following One Dose of MMRV Vaccine ^[7]

End point description

The GMTs directed against measles, mumps, rubella and varicella, following one dose of MMRV vaccine (at 12 months) when given concomitantly with MenACWY vaccine compared to when MMRV vaccine was given alone, are reported. The analysis was performed on the MMRV Per Protocol population.

End point type

Secondary

End point timeframe

6 weeks post vaccination

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

End point values	ACWY + MMRV	MMRV
Number of subjects analysed	377	518
Units: Titers
geometric mean (confidence interval 95%)
Pre-dose, Measles (N=357,470)	74 (71 to 77)	74 (71 to 77)
Post-dose, Measles (N=350,467)	4049 (3701 to 4430)	3632 (3350 to 3938)
Pre-dose, Mumps (N=372,502)	5 (5 to 5)	5 (5 to 5)
Post-dose, Mumps (N=365,499)	97 (89 to 107)	81 (75 to 88)
Pre-dose, Rubella	5 (5 to 5)	5 (5 to 5)
Post-dose, Rubella (370,515)	57 (52 to 62)	56 (52 to 61)
Pre-dose, Varicella (N=344,461)	0.63 (0.63 to 0.63)	0.63 (0.63 to 0.63)
Post-dose, Varicella (N=337,459)	19 (17 to 20)	18 (17 to 19)

No statistical analyses for this end point

Secondary: 7. Percentages of Subjects Showing Seroconversion Response to Varicella Following Concomitant Administration of MMRV With MenACWY Vaccine

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End point title

7. Percentages of Subjects Showing Seroconversion Response to Varicella Following Concomitant Administration of MMRV With MenACWY Vaccine ^[8]

End point description

The percentages of subjects showing seroconversion response to varicella after concomitant administration of MMRV vaccine (at 12 months) with MenACWY vaccine compared to when MMRV vaccine is given alone, is reported. Seroconversion for varicella is defined as the percentage of subjects who show pre-vaccination antibody titer <1.25 gp ELISA units/mL to a post-vaccination antibody titer ≥1.25 gp ELISA units/mL. The analysis was performed on the MMRV Per Protocol population.

End point type

Secondary

End point timeframe

6 weeks post vaccination

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

End point values	ACWY + MMRV	MMRV
Number of subjects analysed	337	459
Units: Percentages of Subjects
number (confidence interval 95%)
Varicella	99 (97 to 100)	99 (98 to 100)

Non-inferiority of immune response to varicella

Statistical analysis description

Non-inferiority of immune response to varicella following one dose of MMRV administered concomitantly with MenACWY as compared to MMRV given alone. The immune response of ACWY+MMRV group was considered non-inferior to that of MMRV group if the lower limit of the two-sided 95% CI of the difference in the percentage of subjects with seroconversion for varicella was greater than -10%, at 6 weeks after MMRV vaccination.

Comparison groups

ACWY + MMRV v MMRV

Number of subjects included in analysis

796

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

95% Confidence Intervals

Parameter type

Percentage group difference

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-2.4

upper limit

0.8

Secondary: 8. Percentages of Subjects With hSBA ≥1:4 and hSBA ≥1:8 Following One Dose of MenACWY Vaccine

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End point title

8. Percentages of Subjects With hSBA ≥1:4 and hSBA ≥1:8 Following One Dose of MenACWY Vaccine ^[9]

End point description

The percentages of subjects with hSBA ≥1:4 and hSBA ≥1:8 after one dose of MenACWY vaccine (at 7-9 months), are reported. The analysis was performed on the MenACWY Per Protocol population.

End point type

Secondary

End point timeframe

1 month post first vaccination dose

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

End point values	ACWY
Number of subjects analysed	349
Units: Percentages of Subjects
number (confidence interval 95%)
Serogroup A hSBA ≥1:4	63 (57 to 68)
Serogroup A hSBA ≥1:8	50 (45 to 56)
Serogroup C (N=199) hSBA ≥1:4	93 (88 to 96)
Serogroup C (N=199) hSBA ≥1:8	88 (83 to 92)
Serogroup W-135 (N=199) hSBA ≥1:4	48 (41 to 55)
Serogroup W-135 (N=199) hSBA ≥1:8	37 (30 to 44)
Serogroup Y (N=196) hSBA ≥1:4	41 (34 to 49)
Serogroup Y (N=196) hSBA ≥1:8	31 (24 to 38)

No statistical analyses for this end point

Secondary: 9. Geometric Mean Titers After One Dose of MenACWY Vaccine

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End point title

9. Geometric Mean Titers After One Dose of MenACWY Vaccine ^[10]

End point description

The immunogenicity of one dose of MenACWY vaccine given at 7 to 9 months of age was assessed in terms of GMTs directed against N.meningitidis serogroups A, C, W-135, and Y. The analysis was performed on the MenACWY Per Protocol population.

End point type

Secondary

End point timeframe

1 month post first vaccination dose

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

End point values	ACWY
Number of subjects analysed	349
Units: Titers
geometric mean (confidence interval 95%)
Serogroup A	8.16 (6.96 to 9.58)
Serogroup C (N=199)	26 (22 to 31)
Serogroup W-135 (N=199)	5.11 (4.15 to 6.29)
Serogroup Y (N=196)	4.09 (3.36 to 4.98)

No statistical analyses for this end point

Secondary: 10. Number of Subjects Reporting Solicited Local and Systemic Adverse Events After Any Vaccination

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End point title

10. Number of Subjects Reporting Solicited Local and Systemic Adverse Events After Any Vaccination

End point description

Safety and tolerability of MenACWY and MMRV vaccines when given concomitantly compared to when either MenACWY or MMRV vaccine was administered alone is reported in terms of the number of subjects with local and systemic adverse events after any vaccination. Systemic reactions including axillary temperature with onset during the first 7 days after any study vaccination were reported. These included the following systemic reactions: Measles-like rash, Rubella-like rash, Varicella-like rash, injection site rash, Mumps-like symptoms and axillary temperature. The analysis was done on the safety population.

End point type

Secondary

End point timeframe

Up to 7 days after each study vaccine injection.

End point values	ACWY + MMRV	ACWY	MMRV
Number of subjects analysed	500	500	597
Units: Subjects
Any Local	278	298	316
Injection (Inj.) site Tenderness [MenACWY]	133	129	0
Inj. site Erythema [MenACWY]	153	159	0
Inj. site Induration [MenACWY]	74	74	0
Inj. site Tenderness [MMRV (N=455,424,592)]	105	102	179
Inj. site Erythema [MMRV (N=456,425,593)]	156	145	224
Inj. site Induration [MMRV (456,424,593)]	90	60	102
Any Systemic Reaction	371	372	381
Rash (N=500,499,595)	54	44	46
Change in eating habits (N=475,483,550)	132	136	105
Sleepiness (N=500,499,595)	219	199	197
Persistent crying (N=475,483,550)	135	152	109
Irritability (N=500,500,595)	273	298	298
Vomiting (N=500,499,595)	66	74	36
Diarrhea (N=500,499,595)	120	123	107
Fever ( ≥ 38C) (N=499,500,596)	58	78	42
Analgesic Antipyr. Meds (N=499,499,594)	208	254	203

No statistical analyses for this end point

Secondary: 11. Number of Subjects Reporting Unsolicited Adverse Events After Vaccination

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End point title

11. Number of Subjects Reporting Unsolicited Adverse Events After Vaccination

End point description

The safety profile of MenACWY and MMRV vaccines when given concomitantly as compared to when MenACWY or MMRV was given alone is reported in terms of number of subjects reporting unsolicited adverse events (AEs), medically significant adverse events and serious adverse events (SAEs) after vaccination. The analysis was done on the safety population.

End point type

Secondary

End point timeframe

Day 1- Day 180 (Throughout the study)

End point values	ACWY + MMRV	ACWY	MMRV
Number of subjects analysed	500	500	597
Units: Subjects
Any AEs	335	353	311
At least possibly related AEs	70	63	2
Serious AEs	18	19	9

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

All solicited adverse events (AEs) were collected up to Day 7 after each vaccination. All SAEs and unsolicited AEs were collected throughout the study (Day 1-Day 180).

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

ACWY + MMRV

Reporting group description

Subjects in this group received 2 injections of MenACWY at 7-9 and 12 months; second injection administered concomitantly with MMRV.

Reporting group title

MMRV

Reporting group description

Subjects in this group received 1 injection of MMRV vaccine at 12 months of age.

Reporting group title

ACWY

Reporting group description

Subjects in this group received 2 injections of the MenACWY vaccine at 7-9 and 12 months of age followed by 1 injection of MMRV at 13.5 months

Serious adverse events	ACWY + MMRV	MMRV	ACWY
Total subjects affected by serious adverse events
subjects affected / exposed	18 / 500 (3.60%)	9 / 597 (1.51%)	19 / 500 (3.80%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Injury, poisoning and procedural complications
Gun shot wound
subjects affected / exposed	1 / 500 (0.20%)	0 / 597 (0.00%)	0 / 500 (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
Hand fracture
subjects affected / exposed	0 / 500 (0.00%)	0 / 597 (0.00%)	1 / 500 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Febrile convulsion
subjects affected / exposed	0 / 500 (0.00%)	0 / 597 (0.00%)	2 / 500 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Generalised tonic-clonic seizure
subjects affected / exposed	1 / 500 (0.20%)	0 / 597 (0.00%)	0 / 500 (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
Tethered cord syndrome
subjects affected / exposed	0 / 500 (0.00%)	0 / 597 (0.00%)	1 / 500 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Leukocytosis
subjects affected / exposed	1 / 500 (0.20%)	0 / 597 (0.00%)	0 / 500 (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
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 500 (0.00%)	1 / 597 (0.17%)	0 / 500 (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
Systemic inflammatory response syndrome
subjects affected / exposed	0 / 500 (0.00%)	1 / 597 (0.17%)	0 / 500 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Apnoea
subjects affected / exposed	0 / 500 (0.00%)	0 / 597 (0.00%)	1 / 500 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Asthma
subjects affected / exposed	0 / 500 (0.00%)	1 / 597 (0.17%)	0 / 500 (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
Bronchial hyperreactivity
subjects affected / exposed	1 / 500 (0.20%)	0 / 597 (0.00%)	1 / 500 (0.20%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	1 / 500 (0.20%)	0 / 597 (0.00%)	0 / 500 (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
Respiratory distress
subjects affected / exposed	1 / 500 (0.20%)	0 / 597 (0.00%)	0 / 500 (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
Tachypnoea
subjects affected / exposed	1 / 500 (0.20%)	0 / 597 (0.00%)	0 / 500 (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
Wheezing
subjects affected / exposed	0 / 500 (0.00%)	1 / 597 (0.17%)	0 / 500 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Arthritis bacterial
subjects affected / exposed	0 / 500 (0.00%)	1 / 597 (0.17%)	0 / 500 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchiolitis
subjects affected / exposed	1 / 500 (0.20%)	0 / 597 (0.00%)	1 / 500 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 500 (0.00%)	0 / 597 (0.00%)	1 / 500 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Croup infectious
subjects affected / exposed	1 / 500 (0.20%)	2 / 597 (0.34%)	0 / 500 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Empyema
subjects affected / exposed	0 / 500 (0.00%)	1 / 597 (0.17%)	0 / 500 (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	2 / 500 (0.40%)	0 / 597 (0.00%)	3 / 500 (0.60%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis rotavirus
subjects affected / exposed	1 / 500 (0.20%)	0 / 597 (0.00%)	0 / 500 (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
Gastroenteritis viral
subjects affected / exposed	0 / 500 (0.00%)	0 / 597 (0.00%)	1 / 500 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Impetigo
subjects affected / exposed	1 / 500 (0.20%)	0 / 597 (0.00%)	0 / 500 (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
Lobar pneumonia
subjects affected / exposed	1 / 500 (0.20%)	0 / 597 (0.00%)	0 / 500 (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
Pneumococcal sepsis
subjects affected / exposed	0 / 500 (0.00%)	0 / 597 (0.00%)	1 / 500 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 500 (0.20%)	0 / 597 (0.00%)	1 / 500 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia respiratory syncytial viral
subjects affected / exposed	0 / 500 (0.00%)	1 / 597 (0.17%)	0 / 500 (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
Pneumonia streptococcal
subjects affected / exposed	0 / 500 (0.00%)	1 / 597 (0.17%)	0 / 500 (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
Pneumonia viral
subjects affected / exposed	1 / 500 (0.20%)	0 / 597 (0.00%)	0 / 500 (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
Postoperative wound infection
subjects affected / exposed	1 / 500 (0.20%)	0 / 597 (0.00%)	0 / 500 (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
Respiratory syncytial virus bronchiolitis
subjects affected / exposed	1 / 500 (0.20%)	2 / 597 (0.34%)	1 / 500 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus infection
subjects affected / exposed	0 / 500 (0.00%)	1 / 597 (0.17%)	1 / 500 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	0 / 500 (0.00%)	1 / 597 (0.17%)	0 / 500 (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
Staphylococcal infection
subjects affected / exposed	0 / 500 (0.00%)	0 / 597 (0.00%)	2 / 500 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Streptococcal bacteraemia
subjects affected / exposed	0 / 500 (0.00%)	0 / 597 (0.00%)	1 / 500 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 500 (0.00%)	1 / 597 (0.17%)	0 / 500 (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
Toxic shock syndrome
subjects affected / exposed	0 / 500 (0.00%)	1 / 597 (0.17%)	0 / 500 (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
Urinary tract infection
subjects affected / exposed	0 / 500 (0.00%)	0 / 597 (0.00%)	1 / 500 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	1 / 500 (0.20%)	0 / 597 (0.00%)	0 / 500 (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
Viral upper respiratory tract infection
subjects affected / exposed	0 / 500 (0.00%)	1 / 597 (0.17%)	0 / 500 (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
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	3 / 500 (0.60%)	1 / 597 (0.17%)	3 / 500 (0.60%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Failure to thrive
subjects affected / exposed	1 / 500 (0.20%)	0 / 597 (0.00%)	0 / 500 (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
Feeding disorder
subjects affected / exposed	0 / 500 (0.00%)	0 / 597 (0.00%)	1 / 500 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 500 (0.00%)	0 / 597 (0.00%)	1 / 500 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	1 / 500 (0.20%)	0 / 597 (0.00%)	0 / 500 (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

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

Non-serious adverse events	ACWY + MMRV	MMRV	ACWY
Total subjects affected by non serious adverse events
subjects affected / exposed	433 / 500 (86.60%)	482 / 597 (80.74%)	442 / 500 (88.40%)
Nervous system disorders
Somnolence
subjects affected / exposed	219 / 500 (43.80%)	197 / 597 (33.00%)	199 / 500 (39.80%)
occurrences all number	424	290	443
General disorders and administration site conditions
Injection site erythema
subjects affected / exposed	219 / 500 (43.80%)	224 / 597 (37.52%)	230 / 500 (46.00%)
occurrences all number	484	263	466
Injection site pain
subjects affected / exposed	163 / 500 (32.60%)	180 / 597 (30.15%)	188 / 500 (37.60%)
occurrences all number	345	233	318
Injection site induration
subjects affected / exposed	128 / 500 (25.60%)	102 / 597 (17.09%)	115 / 500 (23.00%)
occurrences all number	254	130	221
Pyrexia
subjects affected / exposed	90 / 500 (18.00%)	70 / 597 (11.73%)	114 / 500 (22.80%)
occurrences all number	116	84	160
Crying
subjects affected / exposed	135 / 500 (27.00%)	109 / 597 (18.26%)	152 / 500 (30.40%)
occurrences all number	261	161	312
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	125 / 500 (25.00%)	114 / 597 (19.10%)	128 / 500 (25.60%)
occurrences all number	220	185	255
Teething
subjects affected / exposed	41 / 500 (8.20%)	41 / 597 (6.87%)	60 / 500 (12.00%)
occurrences all number	51	48	73
Vomiting
subjects affected / exposed	68 / 500 (13.60%)	43 / 597 (7.20%)	79 / 500 (15.80%)
occurrences all number	113	60	123
Skin and subcutaneous tissue disorders
Dermatitis diaper
subjects affected / exposed	26 / 500 (5.20%)	29 / 597 (4.86%)	30 / 500 (6.00%)
occurrences all number	29	29	34
Rash
subjects affected / exposed	76 / 500 (15.20%)	87 / 597 (14.57%)	52 / 500 (10.40%)
occurrences all number	128	135	102
Psychiatric disorders
Irritability
subjects affected / exposed	273 / 500 (54.60%)	299 / 597 (50.08%)	299 / 500 (59.80%)
occurrences all number	654	481	788
Eating disorder
subjects affected / exposed	132 / 500 (26.40%)	105 / 597 (17.59%)	136 / 500 (27.20%)
occurrences all number	260	166	292
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	71 / 500 (14.20%)	20 / 597 (3.35%)	92 / 500 (18.40%)
occurrences all number	86	22	110
Otitis media
subjects affected / exposed	92 / 500 (18.40%)	40 / 597 (6.70%)	120 / 500 (24.00%)
occurrences all number	126	42	160

More information

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Were there any global substantial amendments to the protocol? Yes

12 Nov 2007

Substantial changes: to add requested new primary immunogenicity objective; to update the immunogenicity criteria to incorporate the new third co-primary objective; to add the null hypothesis for the two-dose immunogenicity; to add statistical power computations for the two-dose MenACWY objective; to clarify SAE reporting; to clarify major deviations and demographic data analysis; to update analysis of immunogenicity criteria for new co-primary objective.

02 Oct 2008

Clarifications on study procedures and terms.

17 Feb 2009

Due to a shortage of ProQuad on the US market, for subjects enrolled into the trial in Groups 1 and 2, M-M-R II and Varivax to be administered in place of ProQuad.

28 May 2009

Statistical and operational changes to allow for use of M-M-R® II and Varivax® instead of ProQuad.

04 Mar 2010

To allow for use of frozen ProQuad and change storage temperatures.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
16 Jan 2009	Due to shortage of ProQuad.	03 Jul 2009

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

N/A

http://www.ncbi.nlm.nih.gov/pubmed/22504039

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Clinical trials

Clinical Trial Results:
A Phase 3, Open-Label, Randomized, Multi-Center Study to Evaluate the Safety and Immunogenicity of ProQuad™ Vaccine When Administered Concomitantly with Novartis Meningococcal ACWY Conjugate Vaccine to Healthy Toddlers.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 1. Percentages of Subjects With a Seroresponse to Measles, Mumps, Rubella and Varicella Following Concomitant Administration of MMRV Vaccine With MenACWY Vaccine

Primary: 1. Percentages of Subjects With a Seroresponse to Measles, Mumps, Rubella and Varicella Following Concomitant Administration of MMRV Vaccine With MenACWY Vaccine

Primary: 2. Percentages of Subjects With Serum Bactericidal Titers ≥1:8 Following Concomitant Administration of MenACWY Vaccine With MMRV Vaccine.

Primary: 2. Percentages of Subjects With Serum Bactericidal Titers ≥1:8 Following Concomitant Administration of MenACWY Vaccine With MMRV Vaccine.

Primary: 3. Percentages of Subjects With hSBA ≥1:8 Following Two Doses of MenACWY Vaccine

Primary: 3. Percentages of Subjects With hSBA ≥1:8 Following Two Doses of MenACWY Vaccine

Secondary: 4. Percentages of Subjects With hSBA ≥1:4 Following Two Doses of MenACWY Vaccine

Secondary: 4. Percentages of Subjects With hSBA ≥1:4 Following Two Doses of MenACWY Vaccine

Secondary: 5. Geometric Mean Titers Against Serogroups A, C, W-135 and Y, Following Two Doses of MenACWY Vaccine

Secondary: 5. Geometric Mean Titers Against Serogroups A, C, W-135 and Y, Following Two Doses of MenACWY Vaccine

Secondary: 6. Geometric Mean Titers Against Measles, Mumps, Rubella and Varicella Following One Dose of MMRV Vaccine

Secondary: 6. Geometric Mean Titers Against Measles, Mumps, Rubella and Varicella Following One Dose of MMRV Vaccine

Secondary: 7. Percentages of Subjects Showing Seroconversion Response to Varicella Following Concomitant Administration of MMRV With MenACWY Vaccine

Secondary: 7. Percentages of Subjects Showing Seroconversion Response to Varicella Following Concomitant Administration of MMRV With MenACWY Vaccine

Secondary: 8. Percentages of Subjects With hSBA ≥1:4 and hSBA ≥1:8 Following One Dose of MenACWY Vaccine

Secondary: 8. Percentages of Subjects With hSBA ≥1:4 and hSBA ≥1:8 Following One Dose of MenACWY Vaccine

Secondary: 9. Geometric Mean Titers After One Dose of MenACWY Vaccine

Secondary: 9. Geometric Mean Titers After One Dose of MenACWY Vaccine

Secondary: 10. Number of Subjects Reporting Solicited Local and Systemic Adverse Events After Any Vaccination

Secondary: 10. Number of Subjects Reporting Solicited Local and Systemic Adverse Events After Any Vaccination

Secondary: 11. Number of Subjects Reporting Unsolicited Adverse Events After Vaccination

Secondary: 11. Number of Subjects Reporting Unsolicited Adverse Events After Vaccination

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A Phase 3, Open-Label, Randomized, Multi-Center Study to Evaluate the Safety and Immunogenicity of ProQuad™ Vaccine When Administered Concomitantly with Novartis Meningococcal ACWY Conjugate Vaccine to Healthy Toddlers.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 1. Percentages of Subjects With a Seroresponse to Measles, Mumps, Rubella and Varicella Following Concomitant Administration of MMRV Vaccine With MenACWY Vaccine

Primary: 1. Percentages of Subjects With a Seroresponse to Measles, Mumps, Rubella and Varicella Following Concomitant Administration of MMRV Vaccine With MenACWY Vaccine

Primary: 2. Percentages of Subjects With Serum Bactericidal Titers ≥1:8 Following Concomitant Administration of MenACWY Vaccine With MMRV Vaccine.

Primary: 2. Percentages of Subjects With Serum Bactericidal Titers ≥1:8 Following Concomitant Administration of MenACWY Vaccine With MMRV Vaccine.

Primary: 3. Percentages of Subjects With hSBA ≥1:8 Following Two Doses of MenACWY Vaccine

Primary: 3. Percentages of Subjects With hSBA ≥1:8 Following Two Doses of MenACWY Vaccine

Secondary: 4. Percentages of Subjects With hSBA ≥1:4 Following Two Doses of MenACWY Vaccine

Secondary: 4. Percentages of Subjects With hSBA ≥1:4 Following Two Doses of MenACWY Vaccine

Secondary: 5. Geometric Mean Titers Against Serogroups A, C, W-135 and Y, Following Two Doses of MenACWY Vaccine

Secondary: 5. Geometric Mean Titers Against Serogroups A, C, W-135 and Y, Following Two Doses of MenACWY Vaccine

Secondary: 6. Geometric Mean Titers Against Measles, Mumps, Rubella and Varicella Following One Dose of MMRV Vaccine

Secondary: 6. Geometric Mean Titers Against Measles, Mumps, Rubella and Varicella Following One Dose of MMRV Vaccine

Secondary: 7. Percentages of Subjects Showing Seroconversion Response to Varicella Following Concomitant Administration of MMRV With MenACWY Vaccine

Secondary: 7. Percentages of Subjects Showing Seroconversion Response to Varicella Following Concomitant Administration of MMRV With MenACWY Vaccine

Secondary: 8. Percentages of Subjects With hSBA ≥1:4 and hSBA ≥1:8 Following One Dose of MenACWY Vaccine

Secondary: 8. Percentages of Subjects With hSBA ≥1:4 and hSBA ≥1:8 Following One Dose of MenACWY Vaccine

Secondary: 9. Geometric Mean Titers After One Dose of MenACWY Vaccine

Secondary: 9. Geometric Mean Titers After One Dose of MenACWY Vaccine

Secondary: 10. Number of Subjects Reporting Solicited Local and Systemic Adverse Events After Any Vaccination

Secondary: 10. Number of Subjects Reporting Solicited Local and Systemic Adverse Events After Any Vaccination

Secondary: 11. Number of Subjects Reporting Unsolicited Adverse Events After Vaccination

Secondary: 11. Number of Subjects Reporting Unsolicited Adverse Events After Vaccination

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
A Phase 3, Open-Label, Randomized, Multi-Center Study to Evaluate the Safety and Immunogenicity of ProQuad™ Vaccine When Administered Concomitantly with Novartis Meningococcal ACWY Conjugate Vaccine to Healthy Toddlers.