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Clinical Trial Results:
A Phase III, open, randomized, controlled, multicenter study to assess the safety and immunogenicity of GlaxoSmithKline’s Biologicals’ (GSK Biologicals) Neisseria meningitidis serogroups A, C, W-135, Y-tetanus toxoid conjugate (MenACWY-TT) vaccine as compared to GSK Biologicals’ Haemophilus influenzae type b and Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine combined (Hib-MenCY-TT) in healthy toddlers 12-15 months of age who were primed at 2, 4 and 6 months of age with Hib-MenCY-TT and Pediarix®, and to assess the safety and immunogenicity of MenACWY-TT co-administered with Infanrix® in healthy toddlers 15-18 months of age who were primed with HibMenCY-TT and Pediarix® at 2, 4, and 6 months of age as compared to the administration of Infanrix® alone in healthy toddlers 15-18 months of age who were primed with ActHIB® and Pediarix® at 2, 4 and 6 months of age

Summary
EudraCT number	2012-002401-22
Trial protocol	Outside EU/EEA
Global end of trial date	17 Sep 2009

Results information
Results version number	v1(current)
This version publication date	20 Nov 2018
First version publication date	01 Aug 2015
Other versions

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

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Trial information

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Sponsor protocol code

110870,110871

ISRCTN number

US NCT number

NCT00614614

WHO universal trial number (UTN)

Sponsor organisation name

GlaxoSmithKline Biologicals

Sponsor organisation address

Rue de l'Institut 89, Rixensart, Belgium, B-1330

Public contact

Clinical Disclosure Advisor, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.com

Scientific contact

Clinical Disclosure Advisor, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.com

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

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

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

Yes

Analysis stage

Final

Date of interim/final analysis

22 Nov 2010

Is this the analysis of the primary completion data?

Yes

Primary completion date

31 Jul 2009

Global end of trial reached?

Yes

Global end of trial date

17 Sep 2009

Was the trial ended prematurely?

Main objective of the trial

• Immunogenicity of a booster dose of MenACWY-TT at 12–15 months of age • Immunogenicity of a booster dose of MenACWY-TT co-administered with Infanrix® at 15-18 months of age • Non-inferiority of the antibody responses to diphtheria and tetanus toxoid when Infanrix® is co-administered with MenACWY-TT at 15-18 months of age compared to Infanrix® administered alone at 15-18 months of age • Non-inferiority of the antibody responses to pertussis toxoid, filamentous hemagglutinin, and pertactin when Infanrix® is co-administered with MenACWY-TT at 15-18 months of age compared to Infanrix® administered alone • Non-inferiority of a booster dose of MenACWY-TT com-pared to HibMenCY administered at 12–15 months of age • Non-inferiority of a booster dose of MenACWY-TT co-administered with Infanrix® at 15-18 months of age com-pared to HibMenCY when administered at 12–15 months of age

Protection of trial subjects

Vaccines were administered by qualified and trained personnel. Vaccines were administered only to eligible subjects that had no contraindications to any components of the vaccines.

Background therapy

Evidence for comparator

Actual start date of recruitment

13 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?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 1558

Worldwide total number of subjects

1558

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)

1558

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

Screening details

During the screening the following was performed: informed consent was obtained and signed from parents or guardians of subjects, check for inclusion/exclusion criteria and contraindications/precautions was performed, and medical history of subjects was collected. Prior to vaccination, subjects’ pre-vaccination body temperature was evaluated.

Number of subjects started

1558

Number of subjects completed

1554

Reason: Number of subjects

No vaccination received : 4

Period 1 title

Primary Vaccination Phase

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Single blind

Roles blinded

Subject

Blinding implementation details

In a single-blind trial, the investigator and/or his staff are aware of the treatment assignment but the subject is not.

Are arms mutually exclusive

Yes

Menhibrix 1 Group

Arm description

Subjects received 3 doses of Menhibrix + 3 doses of Pediarix® (at 2, 4 and 6 months of age)

Arm type

Experimental

Investigational medicinal product name

Menhibrix

Investigational medicinal product code

Other name

GSK Biologicals’ Hib-meningococcal vaccine GSK 792014

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

Three doses in the priming phase and at 2, 4 and 6 months of age

Investigational medicinal product name

Pediarix®

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

Three doses in the priming phase as intramuscular injection at 2, 4 and 6 months of age

ActHIB- Infanrix Group

Arm description

Subjects received 3 doses of ActHIB vaccine and 3 doses of Pediarix vaccine at 2, 4 and 6 months of age

Arm type

Active comparator

Investigational medicinal product name

ActHIB®

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

Three doses in the priming phase as intramuscular injection at 2, 4 and 6 months of age

Investigational medicinal product name

Pediarix®

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

Three doses in the priming phase as intramuscular injection at 2, 4 and 6 months of age

Number of subjects in period 1 ^[1]	Menhibrix 1 Group	ActHIB- Infanrix Group
Started	1272	282
Completed	1182	265
Not completed	90	17
Consent withdrawn by subject	90	17

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: A total of 1558 subjects (1276 in the Menhibrix 1 Group and 282 in ActHIB- Infanrix Group) were enrolled; however, 4 of these subjects never received the vaccine. Thus, 1554 subjects (1272 in the Menhibrix 1 Group and 282 in ActHIB- Infanrix Group) were vaccinated during primary vaccination phase.

Period 2 title

Booster Vaccination Phase

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Nimenrix 1 Group

Arm description

Subjects received 1 dose of Nimenrix™ at 12-15 months of age and 1 dose of Infanrix® at 15-18 months of age

Arm type

Experimental

Investigational medicinal product name

Nimenrix™

Investigational medicinal product code

Other name

GSK Biologicals’ Meningococcal vaccine GSK134612

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

One dose in the booster phase as intramuscular injection at 12-15 months of age

Investigational medicinal product name

Infanrix®

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

One dose as intramuscular injection at 15-18 months of age

Menhibrix 2 Group

Arm description

Subjects received a fourth dose of Menhibrix at 12-15 months of age and 1 dose of Infanrix® at 15-18 months of age

Arm type

Active comparator

Investigational medicinal product name

Menhibrix

Investigational medicinal product code

Other name

GSK Biologicals’ Hib-meningococcal vaccine GSK 792014

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

One dose as intramuscular injection at 12-15 months of age

Investigational medicinal product name

Infanrix®

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

One dose as intramuscular injection at 15-18 months of age

Nimenrix 2 Group

Arm description

Subjects received 1 dose of Nimenrix co-administered with 1 dose of Infanrix®, at 15-18 months of age

Arm type

Active comparator

Investigational medicinal product name

Nimenrix™

Investigational medicinal product code

Other name

GSK Biologicals’ Meningococcal vaccine GSK134612

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

One dose in the booster phase as intramuscular injection at 15-18 months of age

Investigational medicinal product name

Infanrix®

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

One dose as intramuscular injection at 15-18 months of age

Infanrix Group

Arm description

Subjects received 1 booster dose of ActHIB vaccine vaccine at 15-18 months of age.

Arm type

Active comparator

Investigational medicinal product name

Infanrix®

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

One dose in the booster phase as intramuscular injection at 15-18 months of age

Number of subjects in period 2 ^[2]	Nimenrix 1 Group	Menhibrix 2 Group	Nimenrix 2 Group	Infanrix Group
Started	432	229	409	233
Completed	405	210	396	227
Not completed	27	19	13	6
Consent withdrawn by subject	26	18	13	6
Adverse event, non-fatal	1	1	-	-

Notes
[2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Not all study participants returned in time for every study visit, but they were allowed to continue the study nonetheless. The number of participants who started each study period depends on the actual rate of return of the subjects.

Baseline characteristics

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Reporting group title

Menhibrix 1 Group

Reporting group description

Subjects received 3 doses of Menhibrix + 3 doses of Pediarix® (at 2, 4 and 6 months of age)

Reporting group title

ActHIB- Infanrix Group

Reporting group description

Subjects received 3 doses of ActHIB vaccine and 3 doses of Pediarix vaccine at 2, 4 and 6 months of age

Reporting group values	Menhibrix 1 Group	ActHIB- Infanrix Group	Total
Number of subjects	1272	282	1554
Age categorical
Units: Subjects
In utero			0
Preterm newborn infants (gestational age < 37 wks)			0
Newborns (0-27 days)			0
Infants and toddlers (28 days-23 months)			0
Children (2-11 years)			0
Adolescents (12-17 years)			0
Adults (18-64 years)			0
From 65-84 years			0
85 years and over			0
Age continuous
Units: weeks
arithmetic mean (standard deviation)	8.6 ± 1.25	8.7 ± 1.25	-
Gender categorical
Units: Subjects
Female	606	150	756
Male	666	132	798

End points

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Reporting group title

Menhibrix 1 Group

Reporting group description

Subjects received 3 doses of Menhibrix + 3 doses of Pediarix® (at 2, 4 and 6 months of age)

Reporting group title

ActHIB- Infanrix Group

Reporting group description

Subjects received 3 doses of ActHIB vaccine and 3 doses of Pediarix vaccine at 2, 4 and 6 months of age

Reporting group title

Nimenrix 1 Group

Reporting group description

Subjects received 1 dose of Nimenrix™ at 12-15 months of age and 1 dose of Infanrix® at 15-18 months of age

Reporting group title

Menhibrix 2 Group

Reporting group description

Subjects received a fourth dose of Menhibrix at 12-15 months of age and 1 dose of Infanrix® at 15-18 months of age

Reporting group title

Nimenrix 2 Group

Reporting group description

Subjects received 1 dose of Nimenrix co-administered with 1 dose of Infanrix®, at 15-18 months of age

Reporting group title

Infanrix Group

Reporting group description

Subjects received 1 booster dose of ActHIB vaccine vaccine at 15-18 months of age.

Primary: Number of subjects with serum bactericidal activity using human complement (hSBA) antibody titers for N.meningitidis serogroups MenA, MenW-135, MenC and MenY greater than or equal to (≥) 1:8

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End point title

Number of subjects with serum bactericidal activity using human complement (hSBA) antibody titers for N.meningitidis serogroups MenA, MenW-135, MenC and MenY greater than or equal to (≥) 1:8

End point description

End point type

Primary

End point timeframe

One month post vaccination at 12-15 months of age (Month 11)

End point values	Nimenrix 1 Group	Menhibrix 2 Group
Number of subjects analysed	291	157
Units: Subjects
hSBA-MenA [N=257;131]	254	1
hSBA-MenC [N=286;155]	286	155
hSBA-MenW-135 [N=273;137]	270	129
hSBA-MenY [N=291;157]	291	157

Difference in % for hSBA-MenC antibodies

Comparison groups

Nimenrix 1 Group v Menhibrix 2 Group

Number of subjects included in analysis

448

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

≥ 10

Method

t-test, 2-sided

Parameter type

Difference in % for hSBA-MenC antibodies

Confidence interval

level

95%

sides

2-sided

lower limit

-1.33

upper limit

2.42

Difference in % for hSBA-MenY antibodies

Comparison groups

Nimenrix 1 Group v Menhibrix 2 Group

Number of subjects included in analysis

448

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

≥ 10

Method

t-test, 2-sided

Parameter type

Difference in % for hSBA-MenY antibodies

Confidence interval

level

95%

sides

2-sided

lower limit

-1.31

upper limit

2.39

Primary: Number of subjects with hSBA-MenA, hSBA-MenW-135, hSBA-MenC and hSBA-MenY antibody titers ≥ 1:8

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End point title

Number of subjects with hSBA-MenA, hSBA-MenW-135, hSBA-MenC and hSBA-MenY antibody titers ≥ 1:8

End point description

End point type

Primary

End point timeframe

One month post vaccination at 15-18 months of age (Month 14)

End point values	Menhibrix 2 Group	Nimenrix 2 Group
Number of subjects analysed	151	303
Units: Subjects
hSBA-MenA [N=139;258]	1	248
hSBA-MenC [N=147;293]	147	293
hSBA-MenW-135 [N=140;283]	113	279
hSBA-MenY [N=151;303]	150	303

Difference in % for hSBA-MenC antibodies

Comparison groups

Menhibrix 2 Group v Nimenrix 2 Group

Number of subjects included in analysis

454

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

Difference in % for hSBA-MenC antibodies

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1.3

upper limit

2.42

Difference in % for hSBA-MenY antibodies

Comparison groups

Menhibrix 2 Group v Nimenrix 2 Group

Number of subjects included in analysis

454

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

Difference in % for hSBA-MenY antibodies

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1.25

upper limit

2.39

Primary: Antibody titers for hSBA-MenC and hSBA-MenY

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End point title

Antibody titers for hSBA-MenC and hSBA-MenY

End point description

End point type

Primary

End point timeframe

One month post vaccination at 12-15 months of age (Month 11)

End point values	Nimenrix 1 Group	Menhibrix 2 Group
Number of subjects analysed	291	157
Units: Titers
geometric mean (confidence interval 95%)
hSBA-MenC [N=286;155]	3845 (3310.8 to 4465.4)	2676.1 (2131.8 to 3359.5)
hSBA-MenY [N=291;157]	4800.9 (4162 to 5537.9)	2227.7 (1881.9 to 2637)

Difference in % for hSBA-MenC antibodies

Comparison groups

Nimenrix 1 Group v Menhibrix 2 Group

Number of subjects included in analysis

448

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

Difference in % for hSBA-MenC antibodies

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1.33

upper limit

2.42

Difference in % for hSBA-MenY antibodies

Comparison groups

Nimenrix 1 Group v Menhibrix 2 Group

Number of subjects included in analysis

448

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

Difference in % for hSBA-MenY antibodies

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1.31

upper limit

2.39

Primary: Antibody titers for hSBA-MenC and hSBA-MenY

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End point title

Antibody titers for hSBA-MenC and hSBA-MenY

End point description

End point type

Primary

End point timeframe

One month post vaccination at 15-18 months of age (Month 14)

End point values	Menhibrix 2 Group	Nimenrix 2 Group
Number of subjects analysed	151	303
Units: Titers
geometric mean (confidence interval 95%)
hSBA-MenC [N=143;293]	580.4 (460.9 to 730.9)	7230.5 (6244.1 to 8372.8)
hSBA-MenY [N=151;303]	786.7 (657.3 to 941.7)	7487.6 (6604.4 to 8488.9)

Difference in % for hSBA-MenC antibodies

Comparison groups

Menhibrix 2 Group v Nimenrix 2 Group

Number of subjects included in analysis

454

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

Difference in % for hSBA-MenC antibodies

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1.3

upper limit

2.42

Difference in % for hSBA-MenY antibodies

Comparison groups

Menhibrix 2 Group v Nimenrix 2 Group

Number of subjects included in analysis

454

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

Difference in % for hSBA-MenY antibodies

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1.25

upper limit

2.39

Primary: Number of subjects with Anti-Diptheria (Anti-D) and anti-Tetanus (Anti-T) antibody concentrations ≥ 1.0 International Units per milliliter (IU/mL)

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End point title

Number of subjects with Anti-Diptheria (Anti-D) and anti-Tetanus (Anti-T) antibody concentrations ≥ 1.0 International Units per milliliter (IU/mL)

End point description

End point type

Primary

End point timeframe

One month post vaccination at 15-18 months of age (Month 14)

End point values	Nimenrix 2 Group	Infanrix Group
Number of subjects analysed	254	146
Units: Subjects
Anti-D [N=254;146]	253	146
Anti-T [N=253;146]	253	145

Difference in % for Anti-T antibodies

Comparison groups

Nimenrix 2 Group v Infanrix Group

Number of subjects included in analysis

400

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

Difference in % for Anti-T antibodies

Point estimate

0.68

Confidence interval

level

95%

sides

2-sided

lower limit

-0.82

upper limit

3.78

Difference in % for Anti-D antibodies

Comparison groups

Nimenrix 2 Group v Infanrix Group

Number of subjects included in analysis

400

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

Difference in % for Anti-T antibodies

Point estimate

-0.39

Confidence interval

level

95%

sides

2-sided

lower limit

-2.2

upper limit

2.18

Primary: Number of subjects with hSBA-MenC and hSBA-MenY antibody titers ≥ 1:8

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End point title

Number of subjects with hSBA-MenC and hSBA-MenY antibody titers ≥ 1:8

End point description

End point type

Primary

End point timeframe

One month post vaccination at 12-15 months of age (Month 11)

End point values	Nimenrix 1 Group	Menhibrix 2 Group
Number of subjects analysed	291	157
Units: Subjects
hSBA-MenC [N=286;155]	285	155
hSBA-MenY [N=291;157]	291	157

Difference in % for hSBA-MenC antibodies

Comparison groups

Menhibrix 2 Group v Nimenrix 1 Group

Number of subjects included in analysis

448

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

≥ 10

Method

t-test, 2-sided

Parameter type

Difference in % for hSBA-MenC antibodies

Confidence interval

sides

2-sided

lower limit

-1.33

upper limit

2.42

Difference in % for hSBA-MenY antibodies

Comparison groups

Menhibrix 2 Group v Nimenrix 1 Group

Number of subjects included in analysis

448

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

≥ 10

Method

t-test, 2-sided

Parameter type

Difference in % for hSBA-MenY antibodies

Confidence interval

level

95%

sides

2-sided

lower limit

-1.31

upper limit

2.39

Primary: Antibody concentrations for Anti-PT (pertusis toxoid), anti-FHA (filamentous hemagglutinin) and anti-PRN (pertactin)

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End point title

Antibody concentrations for Anti-PT (pertusis toxoid), anti-FHA (filamentous hemagglutinin) and anti-PRN (pertactin)

End point description

End point type

Primary

End point timeframe

One month after vaccination at 15-18 months of age (Month 14)

End point values	Nimenrix 2 Group	Infanrix Group
Number of subjects analysed	254	146
Units: EL.U/mL
geometric mean (confidence interval 95%)
Anti-PT [N=254;146]	67.7 (62 to 73.9)	91 (81.7 to 101.4)
Anti-FHA [N=253;146]	353.2 (320.8 to 388.9)	422.9 (369 to 484.6)
Anti-PRN [N=253;146]	189.2 (167.2 to 214.1)	315.1 (274.2 to 362.1)

Geometric mean concentration ratio for Anti-PT

Comparison groups

Nimenrix 2 Group v Infanrix Group

Number of subjects included in analysis

400

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

≥ 0.67

Method

t-test, 2-sided

Parameter type

GMC ratio

Confidence interval

level

95%

sides

2-sided

lower limit

0.65

upper limit

0.86

Geometric mean concentration ratio for Anti-FHA

Comparison groups

Nimenrix 2 Group v Infanrix Group

Number of subjects included in analysis

400

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

≥ 0.67

Method

t-test, 2-sided

Parameter type

GMC ratio

Confidence interval

level

95%

sides

2-sided

lower limit

0.71

upper limit

0.98

Geometric mean concentration ratio for Anti-PRN

Comparison groups

Nimenrix 2 Group v Infanrix Group

Number of subjects included in analysis

400

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

≥ 0.67

Method

t-test, 2-sided

Parameter type

GMC ratio

Confidence interval

level

95%

sides

2-sided

lower limit

0.49

upper limit

0.73

Secondary: Number of subjects with hSBA-MenC and hSBA-MenY antibody titers ≥ 1:4

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End point title

Number of subjects with hSBA-MenC and hSBA-MenY antibody titers ≥ 1:4

End point description

End point type

Secondary

End point timeframe

One month after vaccination at 12-15 months of age (Month 11)

End point values	Nimenrix 1 Group	Menhibrix 2 Group
Number of subjects analysed	291	157
Units: Subjects
hSBA-MenC [N=286;155]	286	155
hSBA-MenY [N=291;157]	291	157

No statistical analyses for this end point

Secondary: Number of subjects with hSBA-MenA and hSBA MenW-135 antibody titers ≥ 1:4

Top of page

End point title

Number of subjects with hSBA-MenA and hSBA MenW-135 antibody titers ≥ 1:4

End point description

End point type

Secondary

End point timeframe

One month after vaccination at 12-15 months of age (Month 11)

End point values	Nimenrix 1 Group
Number of subjects analysed	257
Units: Subjects
hSBA-MenA [N=257]	256
hSBA-MenW-135 [N=273]	270

No statistical analyses for this end point

Secondary: Antibody titers for hSBA-MenA and hSBA MenW-135

Top of page

End point title

Antibody titers for hSBA-MenA and hSBA MenW-135

End point description

End point type

Secondary

End point timeframe

One month after vaccination at 12-15 months of age (Month 11)

End point values	Nimenrix 1 Group
Number of subjects analysed	273
Units: Titers
geometric mean (confidence interval 95%)
hSBA-MenA [N=257]	94.8 (84.1 to 106.9)
hSBA-MenW-135 [N=273]	923.9 (776 to 1099.9)

No statistical analyses for this end point

Secondary: Antibody titers for hSBA-MenC and hSBA-MenY

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End point title

Antibody titers for hSBA-MenC and hSBA-MenY

End point description

End point type

Secondary

End point timeframe

Prior to vaccination at 15-18 months of age (Month 13)

End point values	Nimenrix 2 Group
Number of subjects analysed	268
Units: Titers
geometric mean (confidence interval 95%)
hSBA-MenC [N=268]	67.6 (55.5 to 82.3)
hSBA-MenY [N=268]	142.3 (121.1 to 167.2)

No statistical analyses for this end point

Secondary: Number of subjects with hSBA-MenC and hSBA-MenY antibody titers ≥ 1:4 and ≥ 1:8

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End point title

Number of subjects with hSBA-MenC and hSBA-MenY antibody titers ≥ 1:4 and ≥ 1:8

End point description

End point type

Secondary

End point timeframe

Prior to vaccination at 15-18 months of age (Month 13)

End point values	Nimenrix 2 Group
Number of subjects analysed	268
Units: Subjects
hSBA-MenC ≥ 1:4 [N=268]	243
hSBA-MenC ≥ 1:8 [N=268]	241
hSBA-MenY ≥ 1:4 [N=268]	258
hSBA-MenY ≥ 1:8 [N=268]	258

No statistical analyses for this end point

Secondary: Anti-D and Anti-T geometric mean antibody concentrations

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End point title

Anti-D and Anti-T geometric mean antibody concentrations

End point description

End point type

Secondary

End point timeframe

One month after vaccination with Infanrix at 15-18 months of age (Month 14) ≥ 1:4

End point values	Nimenrix 1 Group	Menhibrix 2 Group	Nimenrix 2 Group	Infanrix Group
Number of subjects analysed	252	132	254	146
Units: IU/mL
geometric mean (confidence interval 95%)
Anti-D [N=252;132;254;146]	7.214 (6.592 to 7.895)	7.36 (6.508 to 8.323)	7.458 (6.82 to 8.155)	8.259 (7.347 to 9.285)
Anti-T [N=252;132;253;146]	7.4 (6.9 to 7.936)	8.458 (7.762 to 9.215)	11.715 (10.818 to 12.765)	5.5 (4.877 to 6.204)

No statistical analyses for this end point

Secondary: Number of subjects with Anti-D and Anti-T antibody concentrations ≥ 0.1 international units per millilitre (IU/mL)

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End point title

Number of subjects with Anti-D and Anti-T antibody concentrations ≥ 0.1 international units per millilitre (IU/mL)

End point description

End point type

Secondary

End point timeframe

One month after vaccination with Infanrix at 15-18 months of age (Month 14)

End point values	Nimenrix 1 Group	Menhibrix 2 Group	Nimenrix 2 Group	Infanrix Group
Number of subjects analysed	252	132	254	146
Units: Subjects
Anti-D [N=252;132;254;146]	252	132	254	146
Anti-T [N=252;132;253;146]	252	132	253	146

No statistical analyses for this end point

Secondary: Number of subjects with Anti-PT, Anti-FHA and Anti-PRN concentrations to ≥ 5 enzyme-linked immunosorbent assay units per milliliter (EL.U/mL)

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End point title

Number of subjects with Anti-PT, Anti-FHA and Anti-PRN concentrations to ≥ 5 enzyme-linked immunosorbent assay units per milliliter (EL.U/mL)

End point description

End point type

Secondary

End point timeframe

One month after vaccination with Infanrix at 15-18 months of age (Month 14)

End point values	Nimenrix 1 Group	Menhibrix 2 Group	Nimenrix 2 Group	Infanrix Group
Number of subjects analysed	252	132	254	146
Units: Subjects
Anti-PT [N=252;130;254;146]	252	130	254	146
Anti-FHA [N=252;132;253; 146]	252	132	253	146
Anti-PRN [N=252;132;253; 146]	251	132	253	146

No statistical analyses for this end point

Secondary: Antibody concentrations for Anti-PT, anti-FHA and anti-PRN

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End point title

Antibody concentrations for Anti-PT, anti-FHA and anti-PRN

End point description

End point type

Secondary

End point timeframe

One month after vaccination at 15-18 months of age (Month 14)

End point values	Nimenrix 1 Group	Menhibrix 2 Group
Number of subjects analysed	252	132
Units: EL.U/mL
geometric mean (confidence interval 95%)
Anti-PT [N=252;130]	73.7 (66.7 to 80.5)	86.9 (75.7 to 99.8)
Anti-FHA [N=252;132]	321.6 (289.9 to 356.7)	371.7 (321.5 to 429.7)
Anti-PRN [N=252;132]	203.8 (178.7 to 232.5)	220.2 (183.7 to 264)

No statistical analyses for this end point

Secondary: Number of subjects with Anti-D and Anti-T antibody concentrations ≥ 1.0 IU/mL

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End point title

Number of subjects with Anti-D and Anti-T antibody concentrations ≥ 1.0 IU/mL

End point description

End point type

Secondary

End point timeframe

One month after vaccination at 15-18 months of age (Month 14)

End point values	Nimenrix 1 Group	Menhibrix 2 Group
Number of subjects analysed	252	132
Units: Subjects
Anti-D [N=252;132]	250	132
Anti-T [N=252;132]	250	132

No statistical analyses for this end point

Secondary: Number of subjects with hSBA-MenA, hSBA-MenC, hSBA-MenW-135 and hSBA-MenY antibody titers ≥ 1:4

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End point title

Number of subjects with hSBA-MenA, hSBA-MenC, hSBA-MenW-135 and hSBA-MenY antibody titers ≥ 1:4

End point description

End point type

Secondary

End point timeframe

One month after vaccination at 15-18 months of age (Month 14)

End point values	Nimenrix 2 Group
Number of subjects analysed	303
Units: Subjects
hSBA-MenA [N= 258]	253
hSBA-MenC [N= 293]	293
hSBA-MenW-135 [N= 283]	279
hSBA-MenY [N= 303]	303

No statistical analyses for this end point

Secondary: Antibody titers for hSBA-MenA and hSBA-MenW-135

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End point title

Antibody titers for hSBA-MenA and hSBA-MenW-135

End point description

End point type

Secondary

End point timeframe

One month after vaccination with Infanrix at 15-18 months of age (Month 14)

End point values	Nimenrix 2 Group
Number of subjects analysed	283
Units: Titers
geometric mean (confidence interval 95%)
hSBA-MenA [N= 258]	92.4 (80.6 to 105.9)
hSBA-MenW-135 [N= 283]	1582.9 (1321.8 to 1895.5)

No statistical analyses for this end point

Secondary: Number of subjects reporting any and grade 3 solicited local adverse events (AEs) following each dose with Nimenrix or Menhibrix vaccine

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End point title

Number of subjects reporting any and grade 3 solicited local adverse events (AEs) following each dose with Nimenrix or Menhibrix vaccine

End point description

End point type

Secondary

End point timeframe

During the 8-day follow-up period (Day 0-7) after vaccination in the booster phase

End point values	Nimenrix 1 Group	Menhibrix 2 Group	Nimenrix 2 Group
Number of subjects analysed	408	217	386
Units: Subjects
Any pain	156	104	170
Grade 3 pain	7	4	2
Any redness	171	90	169
Grade 3 redness	3	1	5
Any swelling	97	54	105
Grade 3 swelling	3	1	3

No statistical analyses for this end point

Secondary: Number of subjects reporting any, grade 3 and related solicited general AEs in the booster phase, Dose 4

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End point title

Number of subjects reporting any, grade 3 and related solicited general AEs in the booster phase, Dose 4

End point description

End point type

Secondary

End point timeframe

During the 8-day follow-up period (Day 0-7) after dose 4 vaccination

End point values	Nimenrix 1 Group	Menhibrix 2 Group	Nimenrix 2 Group	Infanrix Group
Number of subjects analysed	408	217	384	209
Units: Subjects
Any drowsiness, Dose 4 [N=408;217;384; 209]	171	97	161	79
Grade3 drowsiness, Dose 4 [N=408;217;384; 209]	7	6	8	1
Related drowsiness, Dose 4 [N=408;217;384; 209]	148	80	132	62
Any fever, Dose4 [N=408;217;384; 209]	46	23	37	14
Grade3 fever, Dose 4 [N=408;217;384; 209]	2	2	1	0
Related fever, Dose 4 [N=408;217;384; 209]	32	16	23	7
Any irritability, Dose 4 [N=408;217;384; 209]	230	128	218	114
Grade3 irritability, Dose 4 [N=408;217;384; 209]	13	11	12	7
Related irritability, Dose4 [N=408;217;384; 209]	202	106	188	90
Any loss of appetite, Dose4 [N=408;217;384; 209]	144	73	138	55
Grade3 loss of appetite, Dose4 [N=408;217;384;209]	7	5	7	3
Related loss of apetite, Dose4 [N=408;217;384;209]	115	55	105	42

No statistical analyses for this end point

Secondary: Number of subjects reporting any, grade 3 and related solicited general AEs in the booster phase, Dose 5

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End point title

Number of subjects reporting any, grade 3 and related solicited general AEs in the booster phase, Dose 5

End point description

End point type

Secondary

End point timeframe

During the 8-day follow-up period (Day 0-7) after dose 5 vaccination

End point values	Nimenrix 1 Group	Menhibrix 2 Group
Number of subjects analysed	384	197
Units: Subjects
Any drowsiness, Dose 5 [N=384;197]	132	67
Grade3 drowsiness, Dose 5 [N=384;197]	7	6
Related drowsiness, Dose 5 [N=384;197]	114	60
Any fever, Dose 5 [N=384;197]	34	16
Grade 3 fever, Dose 5 [N=384;197]	0	0
Related fever, Dose 5 [N=384;197]	23	12
Any irritability, Dose 5 [N=384;197]	195	103
Grade 3 irritabity, Dose 5 [N=384;197]	12	8
Related irritability, Dose 5 [N=384;197]	171	99
Any loss of appetite, Dose 5 [N=384;197]	117	62
Grade 3 loss of appetite, Dose 5 [N=384;197]	2	5
Related loss of appetite, Dose 5 [N=384;197]	86	53

No statistical analyses for this end point

Secondary: Number of subjects reporting any rash

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End point title

Number of subjects reporting any rash

End point description

End point type

Secondary

End point timeframe

From the first booster phase visit up to six months after the last vaccination (Month 10-13 up to Month 19-22)

End point values	Nimenrix 1 Group	Menhibrix 2 Group	Nimenrix 2 Group	Infanrix Group
Number of subjects analysed	432	229	409	233
Units: Subjects
Any rash	93	54	83	40

No statistical analyses for this end point

Secondary: Number of subjects reporting any and grade 3 solicited local adverse events (AEs) following vaccination with Infanrix vaccine

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End point title

Number of subjects reporting any and grade 3 solicited local adverse events (AEs) following vaccination with Infanrix vaccine

End point description

End point type

Secondary

End point timeframe

During the 8-day follow-up period (Day 0-7) after vaccination in the booster phase

End point values	Nimenrix 1 Group	Menhibrix 2 Group	Nimenrix 2 Group	Infanrix Group
Number of subjects analysed	384	197	374	210
Units: Subjects
Any pain	145	99	156	99
Grade 3 pain	5	2	4	4
Any redness	175	102	171	121
Grade 3 redness	9	5	2	4
Any swelling	114	73	113	80
Grade 3 swelling	6	5	2	5

No statistical analyses for this end point

Secondary: Number of subjects reporting any New Onset of Chronic Illness (NOCI) and any Emergency Room (ER) visits

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End point title

Number of subjects reporting any New Onset of Chronic Illness (NOCI) and any Emergency Room (ER) visits

End point description

End point type

Secondary

End point timeframe

From the first booster phase visit up to six months after the last vaccination (Month 10-13 up to Month 19-22)

End point values	Nimenrix 1 Group	Menhibrix 2 Group	Nimenrix 2 Group	Infanrix Group
Number of subjects analysed	432	229	409	233
Units: Subjects
Any NOCI(s)	19	11	18	13
Any ER visit(s)	73	49	76	29

No statistical analyses for this end point

Secondary: Number of subjects reporting any New Onset of Chronic Illness (NOCI) and any Emergency Room (ER) visits

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End point title

Number of subjects reporting any New Onset of Chronic Illness (NOCI) and any Emergency Room (ER) visits

End point description

End point type

Secondary

End point timeframe

From the first primary study dose up to/excluding the first booster study dose (Month 0 up to Month 10-13)

End point values	Menhibrix 1 Group	ActHIB- Infanrix Group
Number of subjects analysed	1272	282
Units: Subjects
Any NOCI(s)	128	29
Any ER visit(s)	293	55

No statistical analyses for this end point

Secondary: Number of subjects reporting any unsolicited adverse events (AEs)

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End point title

Number of subjects reporting any unsolicited adverse events (AEs)

End point description

End point type

Secondary

End point timeframe

During a 31-day follow-up period (Day 0-30) after booster vaccination

End point values	Nimenrix 1 Group	Menhibrix 2 Group	Nimenrix 2 Group	Infanrix Group
Number of subjects analysed	432	229	409	233
Units: Subjects
Any AE(s)	194	105	182	101

No statistical analyses for this end point

Secondary: Number of subjects reporting any unsolicited AEs

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End point title

Number of subjects reporting any unsolicited AEs

End point description

End point type

Secondary

End point timeframe

During the 31-day follow-up period (Day 0-30) after the second booster vaccination

End point values	Nimenrix 1 Group	Menhibrix 2 Group
Number of subjects analysed	432	229
Units: Subjects
Any AE(s)	167	79

No statistical analyses for this end point

Secondary: Number of subjects reporting any and related serious adverse events (SAEs)

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End point title

Number of subjects reporting any and related serious adverse events (SAEs)

End point description

End point type

Secondary

End point timeframe

From the first primary study dose up to/excluding the first booster study dose (Month 0 up to Month 10-13).

End point values	Menhibrix 1 Group	ActHIB- Infanrix Group
Number of subjects analysed	1272	282
Units: Subjects
Any SAE(s)	58	14
Related SAE(s)	1	0

No statistical analyses for this end point

Secondary: Number of subjects reporting any and related serious adverse events (SAEs)

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End point title

Number of subjects reporting any and related serious adverse events (SAEs)

End point description

End point type

Secondary

End point timeframe

From the first booster phase visit up to 6 months after the last vaccination (Month 10-13 up to Month 19-22)

End point values	Nimenrix 1 Group	Menhibrix 2 Group	Nimenrix 2 Group	Infanrix Group
Number of subjects analysed	432	229	409	233
Units: Subjects
Any SAE(s)	15	3	9	2
Related SAE(s)	0	0	1	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Solicited local, general AE(s) during (Days 0-7) and unsolicited AE(s) the 31-day period after the first booster phase vaccination at 12-15 months and single booster phase vaccination at 15-18 months. SAE(s) during the primary phase and the booster phase

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

12.1

Reporting group title

Menhibrix 1 Group

Reporting group description

Subjects received 3 doses of Menhibrix + 3 doses of Pediarix® (at 2, 4 and 6 months of age)

Reporting group title

ActHIB- Infanrix Group

Reporting group description

Subjects received 3 doses of ActHIB vaccine and 3 doses of Pediarix vaccine at 2, 4 and 6 months of age

Reporting group title

Nimenrix™ 1 Group

Reporting group description

Subjects received 1 dose of Nimenrix™ (at 12-15 months of age) and 1 dose of Infanrix® (at 15-18 months of age)

Reporting group title

Menhibrix 2 Group

Reporting group description

Subjects received a fourth dose of Menhibrix (at 12-15 months of age) and 1 dose of Infanrix® (at 15-18 months of age)

Reporting group title

Nimenrix 2 Group

Reporting group description

Subjects received 1 dose of Nimenrix co-administered with 1 dose of Infanrix® (at 15-18 months of age)

Reporting group title

Infanrix Group

Reporting group description

Subjects received 1 booster dose of ActHIB vaccine vaccine at 15-18 months of age.

Serious adverse events	Menhibrix 1 Group	ActHIB- Infanrix Group	Nimenrix™ 1 Group	Menhibrix 2 Group	Nimenrix 2 Group	Infanrix Group
Total subjects affected by serious adverse events
subjects affected / exposed	58 / 1272 (4.56%)	14 / 282 (4.96%)	15 / 432 (3.47%)	3 / 229 (1.31%)	9 / 409 (2.20%)	2 / 233 (0.86%)
number of deaths (all causes)	4	0	0	0	0	0
number of deaths resulting from adverse events	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Leukaemia
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Adenoidectomy
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	1 / 432 (0.23%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Irritability
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	3 / 1272 (0.24%)	1 / 282 (0.35%)	1 / 432 (0.23%)	0 / 229 (0.00%)	1 / 409 (0.24%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sudden infant death syndrome
subjects affected / exposed	2 / 1272 (0.16%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Apnoea
subjects affected / exposed	2 / 1272 (0.16%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Apparent life threatening event
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthma
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	1 / 432 (0.23%)	0 / 229 (0.00%)	0 / 409 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchial hyperreactivity
subjects affected / exposed	1 / 1272 (0.08%)	3 / 282 (1.06%)	1 / 432 (0.23%)	1 / 229 (0.44%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory arrest
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	2 / 1272 (0.16%)	1 / 282 (0.35%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchospasm
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	1 / 432 (0.23%)	0 / 229 (0.00%)	1 / 409 (0.24%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Status asthmaticus
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	1 / 409 (0.24%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Burns second degree
subjects affected / exposed	0 / 1272 (0.00%)	1 / 282 (0.35%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skull fracture
subjects affected / exposed	1 / 1272 (0.08%)	2 / 282 (0.71%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Traumatic brain injury
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cyanosis
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Convulsion
subjects affected / exposed	3 / 1272 (0.24%)	1 / 282 (0.35%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile convulsion
subjects affected / exposed	0 / 1272 (0.00%)	1 / 282 (0.35%)	0 / 432 (0.00%)	2 / 229 (0.87%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypotonia
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Somnolence
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	1 / 432 (0.23%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemolytic uraemic syndrome
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leukocytosis
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	1 / 409 (0.24%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	0 / 432 (0.00%)	1 / 229 (0.44%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Dysphagia
subjects affected / exposed	1 / 1272 (0.08%)	1 / 282 (0.35%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric volvulus
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Skin burning sensation
subjects affected / exposed	0 / 1272 (0.00%)	1 / 282 (0.35%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Obstructive uropathy
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Floppy infant
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	1 / 409 (0.24%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Beta haemolytic streptococcal infection
subjects affected / exposed ^[1]	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 408 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchiolitis
subjects affected / exposed	9 / 1272 (0.71%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 9	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 1272 (0.00%)	1 / 282 (0.35%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	3 / 1272 (0.24%)	0 / 282 (0.00%)	1 / 432 (0.23%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Croup infectious
subjects affected / exposed	4 / 1272 (0.31%)	0 / 282 (0.00%)	1 / 432 (0.23%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis viral
subjects affected / exposed	0 / 1272 (0.00%)	1 / 282 (0.35%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Otitis media
subjects affected / exposed	1 / 1272 (0.08%)	3 / 282 (1.06%)	2 / 432 (0.46%)	0 / 229 (0.00%)	1 / 409 (0.24%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Otitis media acute
subjects affected / exposed	2 / 1272 (0.16%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pertussis
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 1272 (0.08%)	2 / 282 (0.71%)	3 / 432 (0.69%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 1272 (0.00%)	1 / 282 (0.35%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus bronchiolitis
subjects affected / exposed	4 / 1272 (0.31%)	0 / 282 (0.00%)	1 / 432 (0.23%)	0 / 229 (0.00%)	1 / 409 (0.24%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus infection
subjects affected / exposed	2 / 1272 (0.16%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	1 / 432 (0.23%)	0 / 229 (0.00%)	1 / 409 (0.24%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	2 / 1272 (0.16%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	1 / 1272 (0.08%)	1 / 282 (0.35%)	1 / 432 (0.23%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	1 / 432 (0.23%)	0 / 229 (0.00%)	1 / 409 (0.24%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abscess
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	1 / 432 (0.23%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Encephalitis viral
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	0 / 432 (0.00%)	1 / 229 (0.44%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	1 / 409 (0.24%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Herpes oesophagitis
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative respiratory distress
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	1 / 432 (0.23%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	0 / 432 (0.00%)	1 / 229 (0.44%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	1 / 409 (0.24%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	7 / 1272 (0.55%)	2 / 282 (0.71%)	5 / 432 (1.16%)	0 / 229 (0.00%)	2 / 409 (0.49%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 7	0 / 2	0 / 5	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Failure to thrive
subjects affected / exposed	1 / 1272 (0.08%)	0 / 282 (0.00%)	0 / 432 (0.00%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acidosis
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	0 / 432 (0.00%)	1 / 229 (0.44%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Notes
[1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The analysis was performed on the Total Vaccinated cohort, only on subjects with their symptom sheets completed.

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

Non-serious adverse events	Menhibrix 1 Group	ActHIB- Infanrix Group	Nimenrix™ 1 Group	Menhibrix 2 Group	Nimenrix 2 Group	Infanrix Group
Total subjects affected by non serious adverse events
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	230 / 432 (53.24%)	128 / 229 (55.90%)	218 / 409 (53.30%)	121 / 233 (51.93%)
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	20 / 432 (4.63%)	3 / 229 (1.31%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences all number	0	0	20	3	0	0
Injection site nodule
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	0 / 432 (0.00%)	4 / 229 (1.75%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences all number	0	0	0	4	0	0
Pain
alternative assessment type: Systematic
subjects affected / exposed ^[2]	0 / 1272 (0.00%)	0 / 282 (0.00%)	145 / 385 (37.66%)	99 / 197 (50.25%)	156 / 374 (41.71%)	99 / 210 (47.14%)
occurrences all number	0	0	145	99	156	99
Redness
alternative assessment type: Systematic
subjects affected / exposed ^[3]	0 / 1272 (0.00%)	0 / 282 (0.00%)	175 / 385 (45.45%)	102 / 197 (51.78%)	171 / 374 (45.72%)	121 / 210 (57.62%)
occurrences all number	0	0	175	102	171	121
Swelling
alternative assessment type: Systematic
subjects affected / exposed ^[4]	0 / 1272 (0.00%)	0 / 282 (0.00%)	114 / 385 (29.61%)	73 / 197 (37.06%)	113 / 374 (30.21%)	80 / 210 (38.10%)
occurrences all number	0	0	114	73	113	80
Drowsiness Dose 4
alternative assessment type: Systematic
subjects affected / exposed ^[5]	0 / 1272 (0.00%)	0 / 282 (0.00%)	171 / 408 (41.91%)	97 / 217 (44.70%)	161 / 384 (41.93%)	79 / 209 (37.80%)
occurrences all number	0	0	171	97	161	79
Fever Dose 4
alternative assessment type: Systematic
subjects affected / exposed ^[6]	0 / 1272 (0.00%)	0 / 282 (0.00%)	46 / 408 (11.27%)	23 / 217 (10.60%)	37 / 384 (9.64%)	14 / 209 (6.70%)
occurrences all number	0	0	46	23	37	14
Irritability Dose 4
subjects affected / exposed ^[7]	0 / 1272 (0.00%)	0 / 282 (0.00%)	230 / 408 (56.37%)	128 / 217 (58.99%)	218 / 384 (56.77%)	114 / 209 (54.55%)
occurrences all number	0	0	230	128	218	114
Loss of appetite Dose 4
subjects affected / exposed ^[8]	0 / 1272 (0.00%)	0 / 282 (0.00%)	144 / 408 (35.29%)	73 / 217 (33.64%)	138 / 384 (35.94%)	55 / 209 (26.32%)
occurrences all number	0	0	144	73	138	55
Drowsiness Dose 5
subjects affected / exposed ^[9]	0 / 1272 (0.00%)	0 / 282 (0.00%)	132 / 384 (34.38%)	67 / 197 (34.01%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences all number	0	0	132	67	0	0
Fever Dose 5
alternative assessment type: Systematic
subjects affected / exposed ^[10]	0 / 1272 (0.00%)	0 / 282 (0.00%)	34 / 384 (8.85%)	16 / 197 (8.12%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences all number	0	0	34	16	0	0
Irritability Dose 5
alternative assessment type: Systematic
subjects affected / exposed ^[11]	0 / 1272 (0.00%)	0 / 282 (0.00%)	195 / 384 (50.78%)	103 / 197 (52.28%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences all number	0	0	195	103	0	0
Loss of appetite Dose 5
subjects affected / exposed ^[12]	0 / 1272 (0.00%)	0 / 282 (0.00%)	117 / 384 (30.47%)	62 / 197 (31.47%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences all number	0	0	117	62	0	0
Eye disorders
Conjunctivitis
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	12 / 432 (2.78%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences all number	0	0	12	0	0	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	20 / 432 (4.63%)	9 / 229 (3.93%)	20 / 409 (4.89%)	8 / 233 (3.43%)
occurrences all number	0	0	20	9	20	8
Teething
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	19 / 432 (4.40%)	8 / 229 (3.49%)	18 / 409 (4.40%)	10 / 233 (4.29%)
occurrences all number	0	0	19	8	18	10
vomiting
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	7 / 432 (1.62%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences all number	0	0	7	0	0	0
Respiratory, thoracic and mediastinal disorders
Rhinorrhoea
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	13 / 432 (3.01%)	11 / 229 (4.80%)	13 / 409 (3.18%)	7 / 233 (3.00%)
occurrences all number	0	0	13	11	13	7
Cough
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	19 / 432 (4.40%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences all number	0	0	19	0	0	0
Skin and subcutaneous tissue disorders
Dermatitis diaper
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	0 / 432 (0.00%)	9 / 229 (3.93%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences all number	0	0	0	9	0	0
Infections and infestations
Otitis media
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	54 / 432 (12.50%)	24 / 229 (10.48%)	36 / 409 (8.80%)	11 / 233 (4.72%)
occurrences all number	0	0	54	24	36	11
Upper respiratory tract
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	34 / 432 (7.87%)	22 / 229 (9.61%)	36 / 409 (8.80%)	11 / 233 (4.72%)
occurrences all number	0	0	34	22	36	11
Viral infection
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	12 / 432 (2.78%)	0 / 229 (0.00%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences all number	0	0	12	0	0	0
Rhinitis
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	0 / 432 (0.00%)	3 / 229 (1.31%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences all number	0	0	0	3	0	0
Nasopharyngitis
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	0 / 432 (0.00%)	5 / 229 (2.18%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences all number	0	0	0	5	0	0
Gastroenteritis
subjects affected / exposed	0 / 1272 (0.00%)	0 / 282 (0.00%)	0 / 432 (0.00%)	4 / 229 (1.75%)	0 / 409 (0.00%)	0 / 233 (0.00%)
occurrences all number	0	0	0	4	0	0

Notes
[2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Total Vaccinated cohort, only on subjects with their symptom sheets completed.
[3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Total Vaccinated cohort, only on subjects with their symptom sheets completed.
[4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Total Vaccinated cohort, only on subjects with their symptom sheets completed.
[5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Total Vaccinated cohort, only on subjects with their symptom sheets completed.
[6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Total Vaccinated cohort, only on subjects with their symptom sheets completed.
[7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Total Vaccinated cohort, only on subjects with their symptom sheets completed.
[8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Total Vaccinated cohort, only on subjects with their symptom sheets completed.
[9] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Total Vaccinated cohort, only on subjects with their symptom sheets completed.
[10] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Total Vaccinated cohort, only on subjects with their symptom sheets completed.
[11] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Total Vaccinated cohort, only on subjects with their symptom sheets completed.
[12] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Total Vaccinated cohort, only on subjects with their symptom sheets completed.

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Were there any global substantial amendments to the protocol? Yes

20 Jun 2008

Amendment 1 • To allow for increase in enrollment up to approximately 1548 subjects, due to revised assumptions on the percentage of subjects that will be unevaluable or will withdraw. It is planned to monitor the number of evaluable subjects on an ongoing basis throughout the study. If the assumptions for the sample size are found to be inaccurate, the enrollment may be adjusted accordingly. • To remove the PedvaxHIB® booster from the study, in line with CDC recommendations to defer the booster due to a shortage of Hib vaccine in the US, and alter the study design, objectives and endpoints accordingly. • To eliminate testing of samples by rSBA and anti-capsular polysaccharide ELISA. • To specify that subjects in the Control group will be offered the opportunity to receive a dose of Menactra once they reach 2 years of age. This will occur outside of the study, however Menactra will be supplied for these subjects. • To change the primary endpoint from hSBA titers 1:4 to hSBA titers 1:8, in line with FDA-recommended revisions in the Hib-MenCY-TT program. • To revise the criteria for demonstrating immunogenicity of MenACWY as compared to HibMenCY with respect to Neisseria meningitidis serogroups C and Y, in line with FDA recommendations for the HibMenCY program. • To specify that the first booster vaccination at Visit 4 should be given to subjects between 12 and 15 months of age, independent of the time since the last primary vaccination and to collect all SAEs prior to Visit 4 in the primary phase. • To specify that the second booster vaccination at Visit 6 must be given to subjects who are between 15 and 18 months of age and >30 days since the last booster vaccination at Visit 4. Both the criterion with respect to subject age and time since first booster vaccination (when applicable, i.e. in the HibMenCY and MenACWY groups) must be met.

20 Jun 2008

Amendment 1 • To specify that the interval for post-vaccination blood draw visits 5 and 7 can be 21-48 days following vaccination, although returning after 30 days is strongly encouraged. • To allow injection of vaccines in the booster phase in the arm or the leg. • To specify that subjects will be informed retrospectively what their treatment group assignment was in the primary phase after completion of the primary phase of the study (at Visit 4 or at the ESFU contact for the primary phase). • To remove checking for elimination criteria at the ESFU contacts. • To add exclusion criteria for entry into the booster phase. • To adjust wording allowing for diluent for Hib-MenCY-TT to be in supplied either in a monodose vial or a syringe. • To add in an exploratory analysis comparing the ratio of post-booster hSBA GMTs at Visit 7 for the Infanrix co-ad group (where MenACWY-TT is co-administered with Infanrix) and at Visit 5 for the MenACWY group. • To clarify in the study design when concomitant vaccinations can be administered. To clarify in the table of study procedures for the booster phase which concomitant medications/vaccinations must be recorded in the eCRF.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of subjects with serum bactericidal activity using human complement (hSBA) antibody titers for N.meningitidis serogroups MenA, MenW-135, MenC and MenY greater than or equal to (≥) 1:8

Primary: Number of subjects with serum bactericidal activity using human complement (hSBA) antibody titers for N.meningitidis serogroups MenA, MenW-135, MenC and MenY greater than or equal to (≥) 1:8

Primary: Number of subjects with hSBA-MenA, hSBA-MenW-135, hSBA-MenC and hSBA-MenY antibody titers ≥ 1:8

Primary: Number of subjects with hSBA-MenA, hSBA-MenW-135, hSBA-MenC and hSBA-MenY antibody titers ≥ 1:8

Primary: Antibody titers for hSBA-MenC and hSBA-MenY

Primary: Antibody titers for hSBA-MenC and hSBA-MenY

Primary: Antibody titers for hSBA-MenC and hSBA-MenY

Primary: Antibody titers for hSBA-MenC and hSBA-MenY

Primary: Number of subjects with Anti-Diptheria (Anti-D) and anti-Tetanus (Anti-T) antibody concentrations ≥ 1.0 International Units per milliliter (IU/mL)

Primary: Number of subjects with Anti-Diptheria (Anti-D) and anti-Tetanus (Anti-T) antibody concentrations ≥ 1.0 International Units per milliliter (IU/mL)

Primary: Number of subjects with hSBA-MenC and hSBA-MenY antibody titers ≥ 1:8

Primary: Number of subjects with hSBA-MenC and hSBA-MenY antibody titers ≥ 1:8

Primary: Antibody concentrations for Anti-PT (pertusis toxoid), anti-FHA (filamentous hemagglutinin) and anti-PRN (pertactin)

Primary: Antibody concentrations for Anti-PT (pertusis toxoid), anti-FHA (filamentous hemagglutinin) and anti-PRN (pertactin)

Secondary: Number of subjects with hSBA-MenC and hSBA-MenY antibody titers ≥ 1:4

Secondary: Number of subjects with hSBA-MenC and hSBA-MenY antibody titers ≥ 1:4

Secondary: Number of subjects with hSBA-MenA and hSBA MenW-135 antibody titers ≥ 1:4

Secondary: Number of subjects with hSBA-MenA and hSBA MenW-135 antibody titers ≥ 1:4

Secondary: Antibody titers for hSBA-MenA and hSBA MenW-135

Secondary: Antibody titers for hSBA-MenA and hSBA MenW-135

Secondary: Antibody titers for hSBA-MenC and hSBA-MenY

Secondary: Antibody titers for hSBA-MenC and hSBA-MenY

Secondary: Number of subjects with hSBA-MenC and hSBA-MenY antibody titers ≥ 1:4 and ≥ 1:8

Secondary: Number of subjects with hSBA-MenC and hSBA-MenY antibody titers ≥ 1:4 and ≥ 1:8

Secondary: Anti-D and Anti-T geometric mean antibody concentrations

Secondary: Anti-D and Anti-T geometric mean antibody concentrations

Secondary: Number of subjects with Anti-D and Anti-T antibody concentrations ≥ 0.1 international units per millilitre (IU/mL)

Secondary: Number of subjects with Anti-D and Anti-T antibody concentrations ≥ 0.1 international units per millilitre (IU/mL)

Secondary: Number of subjects with Anti-PT, Anti-FHA and Anti-PRN concentrations to ≥ 5 enzyme-linked immunosorbent assay units per milliliter (EL.U/mL)

Secondary: Number of subjects with Anti-PT, Anti-FHA and Anti-PRN concentrations to ≥ 5 enzyme-linked immunosorbent assay units per milliliter (EL.U/mL)

Secondary: Antibody concentrations for Anti-PT, anti-FHA and anti-PRN

Secondary: Antibody concentrations for Anti-PT, anti-FHA and anti-PRN

Secondary: Number of subjects with Anti-D and Anti-T antibody concentrations ≥ 1.0 IU/mL

Secondary: Number of subjects with Anti-D and Anti-T antibody concentrations ≥ 1.0 IU/mL

Secondary: Number of subjects with hSBA-MenA, hSBA-MenC, hSBA-MenW-135 and hSBA-MenY antibody titers ≥ 1:4

Secondary: Number of subjects with hSBA-MenA, hSBA-MenC, hSBA-MenW-135 and hSBA-MenY antibody titers ≥ 1:4

Secondary: Antibody titers for hSBA-MenA and hSBA-MenW-135

Secondary: Antibody titers for hSBA-MenA and hSBA-MenW-135

Secondary: Number of subjects reporting any and grade 3 solicited local adverse events (AEs) following each dose with Nimenrix or Menhibrix vaccine

Secondary: Number of subjects reporting any and grade 3 solicited local adverse events (AEs) following each dose with Nimenrix or Menhibrix vaccine

Secondary: Number of subjects reporting any, grade 3 and related solicited general AEs in the booster phase, Dose 4

Secondary: Number of subjects reporting any, grade 3 and related solicited general AEs in the booster phase, Dose 4

Secondary: Number of subjects reporting any, grade 3 and related solicited general AEs in the booster phase, Dose 5

Secondary: Number of subjects reporting any, grade 3 and related solicited general AEs in the booster phase, Dose 5

Secondary: Number of subjects reporting any rash

Secondary: Number of subjects reporting any rash

Secondary: Number of subjects reporting any and grade 3 solicited local adverse events (AEs) following vaccination with Infanrix vaccine

Secondary: Number of subjects reporting any and grade 3 solicited local adverse events (AEs) following vaccination with Infanrix vaccine

Secondary: Number of subjects reporting any New Onset of Chronic Illness (NOCI) and any Emergency Room (ER) visits

Secondary: Number of subjects reporting any New Onset of Chronic Illness (NOCI) and any Emergency Room (ER) visits

Secondary: Number of subjects reporting any New Onset of Chronic Illness (NOCI) and any Emergency Room (ER) visits

Secondary: Number of subjects reporting any New Onset of Chronic Illness (NOCI) and any Emergency Room (ER) visits

Secondary: Number of subjects reporting any unsolicited adverse events (AEs)

Secondary: Number of subjects reporting any unsolicited adverse events (AEs)

Secondary: Number of subjects reporting any unsolicited AEs

Secondary: Number of subjects reporting any unsolicited AEs

Secondary: Number of subjects reporting any and related serious adverse events (SAEs)

Secondary: Number of subjects reporting any and related serious adverse events (SAEs)

Secondary: Number of subjects reporting any and related serious adverse events (SAEs)

Secondary: Number of subjects reporting any and related serious adverse events (SAEs)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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