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Clinical Trial Results:
A Phase III, randomized, multicenter study, double-blind for the immunogenicity and consistency evaluation of 3 lots of GSK Biologicals’ Haemophilus influenzae type b (Hib) conjugate vaccine and single blind and controlled for the evaluation of safety and immunogenicity of GSK Biologicals’ Hib vaccine 208108 compared to the monovalent Hib vaccine ActHIB and open for comparison with the combined DTPa-IPV-Hib vaccine Pentacel when administered to healthy infants at 2, 4, 6 and 15-18 months of age with recommended co-administrations at separate sites.

Summary
EudraCT number	2013-004194-27
Trial protocol	Outside EU/EEA
Global end of trial date	17 Jul 2013

Results information
Results version number	v2(current)
This version publication date	13 Sep 2017
First version publication date	26 Jul 2015
Other versions	v1
Version creation reason	New data added to full data set Correction of full data set Results updated for the secondary endpoints- Anti-HBs concentrations and Anti-polio titers

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

112957

ISRCTN number

US NCT number

NCT01000974

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 Trials Call Center, GlaxoSmithKline Biologicals, 044 2089-904466, GSKClinicalSupportHD@gsk.com

Scientific contact

Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 2089-904466, 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

17 Oct 2013

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

17 Jul 2013

Was the trial ended prematurely?

Main objective of the trial

Consistency of the immune response post-dose 3 to PRP of 3 lots of Hiberix. Non-inferiority of Hiberix to ActHIB in terms of post-dose 3 anti-PRP antibody conc. >= 1.0 & 0.15 µg/mL. Non-inferiority of Pediarix co-ad with Hiberix to Pediarix co-ad with ActHIB in terms of post 3 primary vac. doses of immune response to diphtheria, tetanus, PT, FHA, PRN & polio-1, 2, 3 and acceptability of polio response. Non-inferiority of a 3-dose primary vac. Prevnar 13 co-ad with Hiberix vs Prevnar 13 co-ad with ActHIB of S.pneumoniae GMC(s). To rule out a 10% decrease in seroresponse to PT, FHA & PRN in subjects receiving Pediarix co-ad with Hiberix, vs subjects receiving Pediarix co-ad with ActHIB. Noninferiority of a booster dose of HIberix vs a booster dose of ActHIB in terms of anti-PRP conc. ≥1.0 µg/mL.

Protection of trial subjects

The vaccine recipients were observed closely for at least 30 minutes, with appropriate medical treatment readily available in case of a rare anaphylactic reaction following the administration of vaccine(s).

Background therapy

Evidence for comparator

Actual start date of recruitment

18 Jun 2010

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 4009

Worldwide total number of subjects

4009

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)

4009

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 steps occurred: check for inclusion/exclusion criteria, contraindications/precautions, medical history of the subjects and signing informed consent forms.

Number of subjects started

4009

Number of subjects completed

4003

Reason: Number of subjects

Subject number allocated, no vaccine administered: 6

Period 1 title

Primary Vaccination Phase

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Monitor, Subject, Carer

Blinding implementation details

The study was double-blind for the 3 Test Hib lots, single blind for the Test Hib groups vs Control Hib Group and open for Test Hib groups vs DTPa-IPV/Hib Group,

Are arms mutually exclusive

Yes

Hiberix Group

Arm description

Pooled group of subjects, male or female between, and including, 6 and 12 weeks of age at the time of the first vaccination, who received 3 doses of 3 different lots of Hiberix® vaccine co-administered with 3 doses of Pediarix® and Prevnar13® vaccines at 2, 4 and 6 months of age and 2 doses of Rotarix® vaccine at 2 and 4 months of age. The Hiberix® vaccine was administered intramuscularly in the right thigh. Pediarix® vaccine was administered intramuscularly in the left thigh. The Prevnar13® vaccine was administered intramuscularly in the left thigh or deltoid. The Rotarix® vaccine was administered orally.

Arm type

Experimental

Investigational medicinal product name

GSK Biologicals’ Haemophilus influenzae type b vaccine (GSK 208108)

Investigational medicinal product code

Other name

Hiberix®

Pharmaceutical forms

Powder and solvent for solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Three doses of 3 different manufacturing lots in primary study at 2, 4 and 6 months of age as intramuscular injection and one dose as booster vaccination.

Investigational medicinal product name

Pediarix™

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Three doses in primary epoch at 2, 4 and 6 months of age as intramuscular injection.

Investigational medicinal product name

Prevnar 13™

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Three doses in primary epoch at 2, 4 and 6 months of age as intramuscular injection.

Investigational medicinal product name

Rotarix™

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for oral suspension

Routes of administration

Oral use

Dosage and administration details

Two oral doses in primary epoch at 2 and 4 months of age.

Investigational medicinal product name

Infanrix™

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

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

ActHIB Group

Arm description

Subjects, male or female between, and including, 6 and 12 weeks of age at the time of the first vaccination, who received 3 doses of ActHIB® vaccine co-administered with 3 doses of Pediarix® and Prevnar13® vaccines at 2, 4 and 6 months of age and 2 doses of Rotarix® vaccine at 2 and 4 months of age. The ActHIB® vaccine was administered intramuscularly in the right thigh. The Pediarix® vaccine was administered intramuscularly in the left thigh. The Prevnar13® vaccine was administered intramuscularly in the left thigh or deltoid. The Rotarix® vaccine was administered orally.

Arm type

Active comparator

Investigational medicinal product name

ActHIB™

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Three doses in primary epoch at 2, 4 and 6 months of age as intramuscular injection and one dose as a booster vaccination.

Investigational medicinal product name

Pediarix™

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Three doses in primary epoch at 2, 4 and 6 months of age as intramuscular injection.

Investigational medicinal product name

Prevnar 13™

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Three doses in primary epoch at 2, 4 and 6 months of age as intramuscular injection.

Investigational medicinal product name

Rotarix™

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for oral suspension

Routes of administration

Oral use

Dosage and administration details

Two oral doses in primary epoch at 2 and 4 months of age.

Investigational medicinal product name

Infanrix™

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

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

Pentacel Group

Arm description

Subjects, male or female between, and including, 6 and 12 weeks of age at the time of the first vaccination, who received 3 doses of Pentacel® vaccine co-administered with 3 doses of Prevnar13® vaccine, 2 or 3 doses of Engerix™-B vaccine at 2, 4 and 6 months of age and 2 doses of Rotarix® vaccine at 2 and 4 months of age. The Pentacel® vaccine was administered intramuscularly in the right thigh. The Engerix™-B vaccine was administered intramuscularly in the left thigh. The Prevnar13® vaccine was administered intramuscularly in the left thigh or deltoid. The Rotarix® vaccine was administered orally. If subjects in the Pentacel Group had received a birth dose of Hepatitis B vaccine then they were to receive Engerix™-B vaccine only at 2 and 6 months of age.

Arm type

Active comparator

Investigational medicinal product name

Pentacel™

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and suspension for suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Three doses in primary epoch at 2, 4 and 6 months of age as intramuscular injection and one dose as a booster vaccination.

Investigational medicinal product name

Prevnar 13™

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Three doses in primary epoch at 2, 4 and 6 months of age as intramuscular injection.

Investigational medicinal product name

Rotarix™

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for oral suspension

Routes of administration

Oral use

Dosage and administration details

Two oral doses in primary epoch at 2 and 4 months of age.

Investigational medicinal product name

Engerix™-B

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Two or three doses in primary epoch at 2,( 4) and 6 months of age as intramuscular injection.

Number of subjects in period 1 ^[1]	Hiberix Group	ActHIB Group	Pentacel Group
Started	2963	520	520
Completed	2625	470	457
Not completed	338	50	63
Consent withdrawn by subject	109	17	21
Adverse event, non-fatal	14	2	2
Unspecified	4	9	12
Lost to follow-up	171	19	26
Protocol deviation	40	3	2

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: Subjects not returning for a specific visit were not withdrawn and could participate in the subsequent follow-up study. Actual enrolment differed depending on the rate of return for the follow-up study, so not all enrolled subjects came to each visit.

Period 2 title

Booster Vaccination Phase

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer

Are arms mutually exclusive

Yes

Hiberix Group

Arm description

Arm type

Experimental

Investigational medicinal product name

GSK Biologicals’ Haemophilus influenzae type b vaccine (GSK 208108)

Investigational medicinal product code

Other name

Hiberix®

Pharmaceutical forms

Powder and solvent for solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Three doses of 3 different manufacturing lots in primary study at 2, 4 and 6 months of age as intramuscular injection and one dose as booster vaccination.

Investigational medicinal product name

Pediarix™

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Three doses in primary epoch at 2, 4 and 6 months of age as intramuscular injection.

Investigational medicinal product name

Prevnar 13™

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Three doses in primary epoch at 2, 4 and 6 months of age as intramuscular injection.

Investigational medicinal product name

Rotarix™

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for oral suspension

Routes of administration

Oral use

Dosage and administration details

Two oral doses in primary epoch at 2 and 4 months of age.

Investigational medicinal product name

Infanrix™

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

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

ActHIB Group

Arm description

Arm type

Active comparator

Investigational medicinal product name

ActHIB™

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Three doses in primary epoch at 2, 4 and 6 months of age as intramuscular injection and one dose as a booster vaccination.

Investigational medicinal product name

Pediarix™

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Three doses in primary epoch at 2, 4 and 6 months of age as intramuscular injection.

Investigational medicinal product name

Prevnar 13™

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Three doses in primary epoch at 2, 4 and 6 months of age as intramuscular injection.

Investigational medicinal product name

Rotarix™

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for oral suspension

Routes of administration

Oral use

Dosage and administration details

Two oral doses in primary epoch at 2 and 4 months of age.

Investigational medicinal product name

Infanrix™

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

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

Pentacel Group

Arm description

Arm type

Active comparator

Investigational medicinal product name

Pentacel™

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and suspension for suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Three doses in primary epoch at 2, 4 and 6 months of age as intramuscular injection and one dose as a booster vaccination.

Investigational medicinal product name

Prevnar 13™

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Three doses in primary epoch at 2, 4 and 6 months of age as intramuscular injection.

Investigational medicinal product name

Rotarix™

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for oral suspension

Routes of administration

Oral use

Dosage and administration details

Two oral doses in primary epoch at 2 and 4 months of age.

Investigational medicinal product name

Engerix™-B

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Two or three doses in primary epoch at 2,( 4) and 6 months of age as intramuscular injection.

Number of subjects in period 2 ^[2]	Hiberix Group	ActHIB Group	Pentacel Group
Started	2337	435	400
Completed	2270	423	386
Not completed	67	12	14
Consent withdrawn by subject	3	1	1
Unspecified	24	6	4
Lost to follow-up	40	5	7
Protocol deviation	-	-	2

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: Subjects not returning for a specific visit were not withdrawn and could participate in the subsequent follow-up study. Actual enrolment differed depending on the rate of return for the follow-up study, so not all enrolled subjects came to each visit.

Baseline characteristics

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Reporting group title

Hiberix Group

Reporting group description

Reporting group title

ActHIB Group

Reporting group description

Reporting group title

Pentacel Group

Reporting group description

Reporting group values	Hiberix Group	ActHIB Group	Pentacel Group	Total
Number of subjects	2963	520	520	4003
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 ± 1.08	8.6 ± 1.13	8.7 ± 1.12	-
Gender categorical
Units: Subjects
Female	1424	271	258	1953
Male	1539	249	262	2050

End points

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Reporting group title

Hiberix Group

Reporting group description

Reporting group title

ActHIB Group

Reporting group description

Reporting group title

Pentacel Group

Reporting group description

Reporting group title

Hiberix Group

Reporting group description

Reporting group title

ActHIB Group

Reporting group description

Reporting group title

Pentacel Group

Reporting group description

Subject analysis set title

Test-Hib A Group

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects received 3 doses of Test Hib vaccine lot A co-administered with 3 doses of DTPa-HBV-IPV and 13Pn vaccines at 2, 4 and 6 months of age and 2 doses of HRV vaccine at 2 and 4 months of age

Subject analysis set title

Test Hib B Group

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects received 3 doses of Test Hib vaccine lot B co-administered with 3 doses of DTPa-HBV-IPV and 13Pn vaccines at 2, 4 and 6 months of age and 2 doses of HRV vaccine at 2 and 4 months of age

Subject analysis set title

Test Hib C Group

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects received 3 doses of Test Hib vaccine lot C co-administered with 3 doses of DTPa-HBV-IPV and 13Pn vaccines at 2, 4 and 6 months of age and 2 doses of HRV vaccine at 2 and 4 months of age

Primary: Number of subjects with anti-polyribosylribitol phosphate (anti-PRP) antibody concentrations greater than or equal to (≥) 0.15 microgram per milliliter (µg/mL) and ≥ 1.0 µg/mL.

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End point title

Number of subjects with anti-polyribosylribitol phosphate (anti-PRP) antibody concentrations greater than or equal to (≥) 0.15 microgram per milliliter (µg/mL) and ≥ 1.0 µg/mL.

End point description

End point type

Primary

End point timeframe

At 1 month after last dose of primary vaccination.

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	1590	274	253
Units: Subjects
Anti-PRP ≥ 0.15 µg/mL	1536	265	234
Anti-PRP ≥ 1.0 µg/mL	1291	246	198

Non-inferiority Anti-PRP concentration ≥ 1.0 μg/mL

Statistical analysis description

To demonstrate the non-inferiority of Test Hib to Control Hib, each co-administered with DTPa-HBV-IPV, 13Pn and HRV vaccines, following 3 primary vaccine doses in terms of anti-PRP antibody concentration ≥ 1.0 μg/mL.

Comparison groups

ActHIB Group v Hiberix Group

Number of subjects included in analysis

1864

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[1]

Method

Parameter type

Difference in percentage

Point estimate

-8.59

Confidence interval

level

95%

sides

2-sided

lower limit

-12.28

upper limit

-4.07

Notes
[1] - Criterion for non-inferiority (1 month after the last dose of primary vaccination): Lower limit (LL) of the standardized asymptotic 95% CI for the difference (pooled Sub-cohorts Test Hib A-PRP, Test Hib B-PRP and Test Hib C-PRP minus Sub-cohort Control Hib) in the percentage of subjects with anti-PRP concentrations ≥ 1.0 μg/mL was ≥ -10% (clinical limit for non-inferiority).

Non-inferiority Anti-PRP concentration ≥ 0.15 μg/m

Statistical analysis description

Comparison groups

Hiberix Group v ActHIB Group

Number of subjects included in analysis

1864

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[2]

Method

Parameter type

Difference in percentage

Point estimate

-0.11

Confidence interval

level

95%

sides

2-sided

lower limit

-1.98

upper limit

2.82

Notes
[2] - Criterion for non-inferiority (1 month after the last dose of primary vaccination): LL of the standardized asymptotic 95% CI for the difference (pooled Sub-cohorts Test Hib A-PRP, Test Hib B-PRP and Test Hib C-PRP minus Sub-cohort Control Hib) in the percentage of subjects with anti-PRP concentrations ≥ 0.15 μg/mL was ≥ -5% (clinical limit for non-inferiority).

Primary: Number of subjects with anti-Protein-D (anti-D) and anti-Protein-T (anti-T) antibody concentrations ≥ 0.1 International Units per milliliter (IU/mL).

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End point title

Number of subjects with anti-Protein-D (anti-D) and anti-Protein-T (anti-T) antibody concentrations ≥ 0.1 International Units per milliliter (IU/mL).

End point description

End point type

Primary

End point timeframe

At 1 month after last dose of primary vaccination.

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	393	274	250
Units: Subjects
Anti-D [N=393,273,250]	393	273	249
Anti-T [N=393,274,250]	393	274	249

Non-inferiority Anti-D antibody concentrations

Statistical analysis description

To demonstrate the non-inferiority of DTPa-HBV-IPV co-administered with Test Hib, 13Pn and HRV to DTPa-HBV-IPV co-administered with Control Hib, 13Pn and HRV, following 3 primary vaccine doses in terms of immune response to diphtheria (Anti-D).

Comparison groups

Hiberix Group v ActHIB Group

Number of subjects included in analysis

667

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

Method

Parameter type

Difference in percentage

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1.26

upper limit

1.81

Notes
[3] - Criteria for non-inferiority (1 month after the last dose of primary vaccination): LL of the standardized asymptotic 97.5% CIs on the differences (Subset Test Hib Co-Ad minus Sub-cohort Control Hib) in the percentages of subjects with seroprotective concentrations (≥ 0.1 IU/mL) of anti-diphtheria antibodies was ≥ -10% (clinical limit for non-inferiority).

Non-inferiority Anti-T antibody concentrations

Statistical analysis description

Comparison groups

ActHIB Group v Hiberix Group

Number of subjects included in analysis

667

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[4]

Method

Parameter type

Difference in percentage

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1.26

upper limit

1.8

Notes
[4] - Criteria for non-inferiority (1 month after the last dose of primary vaccination): LL of the standardized asymptotic 97.5% CIs on the differences (Subset Test Hib Co-Ad minus Sub-cohort Control Hib) in the percentages of subjects with seroprotective concentrations (≥ 0.1 IU/mL) of anti-tetanus antibodies was ≥ -10% (clinical limit for non-inferiority).

Primary: Anti-polyribosylribitol phosphate (anti-PRP) antibody concentrations.

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End point title

Anti-polyribosylribitol phosphate (anti-PRP) antibody concentrations. ^[5]

End point description

Antibody concentrations were given as Geometric Mean Concentrations (GMCs) expressed in micrograms per milliliter (µg/mL).

End point type

Primary

End point timeframe

At 1 month after last dose of primary vaccination.

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No Statistical analysis was performed for this endpoint.

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	1590	274	253
Units: µg/mL
geometric mean (confidence interval 95%)	5.193 (4.765 to 5.658)	6.743 (5.593 to 8.129)	3.64 (2.891 to 4.583)

No statistical analyses for this end point

Primary: Anti-pertussis toxoid (anti-PT), anti-pertactin (anti-PRN) and anti-filamentous hemagglutinin (anti-FHA) antibody concentrations.

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End point title

Anti-pertussis toxoid (anti-PT), anti-pertactin (anti-PRN) and anti-filamentous hemagglutinin (anti-FHA) antibody concentrations.

End point description

Antibody concentrations were given as geometric mean concentrations (GMCs) expressed as enzyme-linked immuno-sorbent assay (ELISA) units per milliliter i.e. EL.U/mL.

End point type

Primary

End point timeframe

At 1 month after last dose of primary vaccination.

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	792	275	251
Units: EL.U/mL
geometric mean (confidence interval 95%)
Anti-PT [N=792,275,251]	73.2 (69.8 to 76.6)	71.9 (66.6 to 77.6)	41.9 (38.4 to 45.8)
Anti-PRN [N=789,275,250]	111.6 (104.5 to 119.2)	93.5 (83.7 to 104.4)	51.9 (45.4 to 59.3)
Anti-FHA [N=791,275,249]	321.8 (307 to 337.3)	295.8 (276 to 317)	174.8 (160 to 191)

Non-inferiority GMC ratio anti-PT

Statistical analysis description

Comparison groups

Hiberix Group v ActHIB Group

Number of subjects included in analysis

1067

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[6]

Method

Parameter type

GMC ratio

Point estimate

1.017

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.918

upper limit

1.127

Notes
[6] - Criteria for non-inferiority (1 month after the last dose of primary vaccination): LL of the 97.5% CIs on the GMC ratios (Subset Test Hib Co-Ad divided by Sub-cohort Control Hib) for antibodies to the pertussis antigen PT was ≥ 0.67 (clinical limit for non-inferiority)

Non-inferiority GMC ratio anti-FHA

Statistical analysis description

Comparison groups

Hiberix Group v ActHIB Group

Number of subjects included in analysis

1067

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[7]

Method

Parameter type

GMC ratio

Point estimate

1.088

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.983

upper limit

1.204

Notes
[7] - Criteria for non-inferiority (1 month after the last dose of primary vaccination): LL of the 97.5% CIs on the GMC ratios (Subset Test Hib Co-Ad divided by Sub-cohort Control Hib) for antibodies to the pertussis antigen FHA was ≥ 0.67 (clinical limit for non-inferiority)

Non-inferiority GMC ratio anti-PRN

Statistical analysis description

Comparison groups

Hiberix Group v ActHIB Group

Number of subjects included in analysis

1067

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[8]

Method

Parameter type

GMC ratio

Point estimate

1.193

Confidence interval

level

97.5%

sides

2-sided

lower limit

1.03

upper limit

1.382

Notes
[8] - Criteria for non-inferiority (1 month after the last dose of primary vaccination): LL of the 97.5% CIs on the GMC ratios (Subset Test Hib Co-Ad divided by Sub-cohort Control Hib) for antibodies to the pertussis antigen PRN was ≥ 0.67 (clinical limit for non-inferiority)

Primary: Anti-Streptococcus pneumoniae (S.pneumoniae) antibody concentrations.

Top of page

End point title

Anti-Streptococcus pneumoniae (S.pneumoniae) antibody concentrations.

End point description

Antibody concentrations against S.pneumoniae were given as geometric mean concentrations (GMCs) expressed as microgram per milliliter (µg/mL).

End point type

Primary

End point timeframe

At 1 month after last dose of primary vaccination.

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	389	270	247
Units: µg/mL
geometric mean (confidence interval 95%)
Anti-Pneumoniae 1[N = 384,268,245]	2.515 (2.318 to 2.729)	2.5 (2.278 to 2.745)	2.442 (2.19 to 2.722)
Anti-Pneumoniae 3 [N = 382,269,245]	1.056 (0.976 to 1.142)	1.008 (0.933 to 1.089)	1.19 (1.066 to 1.329)
Anti-Pneumoniae 4 [N = 389,268,247]	1.804 (1.684 to 1.932)	1.803 (1.662 to 1.957)	1.819 (1.645 to 2.011)
Anti-Pneumoniae 5 [N = 379,266,246]	3.729 (3.409 to 4.079)	3.656 (3.308 to 4.04)	3.53 (3.128 to 3.984)
Anti-Pneumoniae 6A [N = 381,267,244]	3.442 (3.177 to 3.729)	3.34 (3.032 to 3.679)	3.384 (3.046 to 3.76)
Anti-Pneumoniae 6B [N = 383,267,245]	1.065 (0.95 to 1.196)	0.994 (0.86 to 1.148)	0.875 (0.757 to 1.013)
Anti-Pneumoniae 7F [N = 386,269,246]	4.518 (4.192 to 4.87)	4.115 (3.777 to 4.484)	3.785 (3.412 to 4.199)
Anti-Pneumoniae 9V [N = 386,270,246]	2.516 (2.305 to 2.746)	2.431 (2.204 to 2.681)	2.226 (1.976 to 2.507)
Anti-Pneumoniae 14 [N = 384,267,244]	4.506 (4.105 to 4.946)	4.111 (3.672 to 4.602)	3.938 (3.472 to 4.466)
Anti-Pneumoniae 18C [N = 380,267,244]	3.655 (3.351 to 3.986)	3.507 (3.196 to 3.848)	3.401 (3.033 to 3.814)
Anti-Pneumoniae 19A [N = 384,266,245]	1.556 (1.433 to 1.689)	1.553 (1.391 to 1.735)	1.321 (1.175 to 1.486)
Anti-Pneumoniae 19F [N = 384,268,245]	2.745 (2.552 to 2.952)	2.833 (2.613 to 3.072)	2.531 (2.315 to 2.766)
Anti-Pneumoniae 23F [N = 384,268,245]	2.046 (1.846 to 2.267)	1.985 (1.765 to 2.232)	1.67 (1.444 to 1.931)

Non-inferiority Anti-Pneumoniae 1 concentrations

Statistical analysis description

To demonstrate the non-inferiority of a 3-dose primary vaccination course of 13Pn co-administered with Test Hib, HRV and DTPa-HBV-IPV compared to that of 13Pn co-administered with Control Hib, HRV and DTPa-HBV-IPV in terms of Streptococcus pneumoniae (S.pneumoniae) GMCs.

Comparison groups

Hiberix Group v ActHIB Group

Number of subjects included in analysis

659

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[9]

Method

Parameter type

GMC ratio

Point estimate

1.006

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.873

upper limit

1.159

Notes
[9] - Criteria for evaluation (1 month after the last dose of primary vaccination): LL of the 2-sided 97.5% CIs on the GMC ratio (Subset Test Hib Co-Ad over Sub-cohort Control Hib) for each S. pneumoniae serotype 1 [anti-1] was ≥ 0.5 (clinical limit for non-inferiority).

Non-inferiority Anti-Pneumoniae 3 concentrations

Statistical analysis description

Comparison groups

Hiberix Group v ActHIB Group

Number of subjects included in analysis

659

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[10]

Method

Parameter type

GMC ratio

Point estimate

1.048

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.921

upper limit

1.192

Notes
[10] - Criteria for evaluation (1 month after the last dose of primary vaccination): LL of the 2-sided 97.5% CIs on the GMC ratio (Subset Test Hib Co-Ad over Sub-cohort Control Hib) for each S. pneumoniae serotype 3 [anti-3] was ≥ 0.5 (clinical limit for non-inferiority).

Non-inferiority Anti-Pneumoniae 4 concentrations

Statistical analysis description

Comparison groups

Hiberix Group v ActHIB Group

Number of subjects included in analysis

659

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[11]

Method

Parameter type

GMC ratio

Point estimate

1.001

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.886

upper limit

1.13

Notes
[11] - Criteria for evaluation (1 month after the last dose of primary vaccination): LL of the 2-sided 97.5% CIs on the GMC ratio (Subset Test Hib Co-Ad over Sub-cohort Control Hib) for each S. pneumoniae serotype 4 [anti-4] was ≥ 0.5 (clinical limit for non-inferiority).

Non-inferiority Anti-Pneumoniae 5 concentrations

Statistical analysis description

Comparison groups

Hiberix Group v ActHIB Group

Number of subjects included in analysis

659

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[12]

Method

Parameter type

GMC ratio

Point estimate

1.02

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.874

upper limit

1.19

Notes
[12] - Criteria for evaluation (1 month after the last dose of primary vaccination): LL of the 2-sided 97.5% CIs on the GMC ratio (Subset Test Hib Co-Ad over Sub-cohort Control Hib) for each S. pneumoniae serotype 5 [anti-5] was ≥ 0.5 (clinical limit for non-inferiority).

Non-inferiority Anti-Pneumoniae 6A concentrations

Statistical analysis description

Comparison groups

Hiberix Group v ActHIB Group

Number of subjects included in analysis

659

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[13]

Method

Parameter type

GMC ratio

Point estimate

1.031

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.894

upper limit

1.188

Notes
[13] - Criteria for evaluation (1 month after the last dose of primary vaccination): LL of the 2-sided 97.5% CIs on the GMC ratio (Subset Test Hib Co-Ad over Sub-cohort Control Hib) for each S. pneumoniae serotype 6A [anti-6A] was ≥ 0.5 (clinical limit for non-inferiority).

Non-inferiority Anti-Pneumoniae 6B concentrations

Statistical analysis description

Comparison groups

Hiberix Group v ActHIB Group

Number of subjects included in analysis

659

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[14]

Method

Parameter type

GMC ratio

Point estimate

1.072

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.871

upper limit

1.32

Notes
[14] - Criteria for evaluation (1 month after the last dose of primary vaccination): LL of the 2-sided 97.5% CIs on the GMC ratio (Subset Test Hib Co-Ad over Sub-cohort Control Hib) for each S. pneumoniae serotype 6B [anti-6B] was ≥ 0.5 (clinical limit for non-inferiority).

Non-inferiority Anti-Pneumoniae 7F concentrations

Statistical analysis description

Comparison groups

Hiberix Group v ActHIB Group

Number of subjects included in analysis

659

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[15]

Method

Parameter type

GMC ratio

Point estimate

1.098

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.964

upper limit

1.251

Notes
[15] - Criteria for evaluation (1 month after the last dose of primary vaccination): LL of the 2-sided 97.5% CIs on the GMC ratio (Subset Test Hib Co-Ad over Sub-cohort Control Hib) for each S. pneumoniae serotype 7F [anti-7F] was ≥ 0.5 (clinical limit for non-inferiority).

Non-inferiority Anti-Pneumoniae 9V concentrations

Statistical analysis description

Comparison groups

Hiberix Group v ActHIB Group

Number of subjects included in analysis

659

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[16]

Method

Parameter type

GMC ratio

Point estimate

1.035

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.89

upper limit

1.204

Notes
[16] - Criteria for evaluation (1 month after the last dose of primary vaccination): LL of the 2-sided 97.5% CIs on the GMC ratio (Subset Test Hib Co-Ad over Sub-cohort Control Hib) for each S. pneumoniae serotype 9V [anti-9V] was ≥ 0.5 (clinical limit for non-inferiority).

Non-inferiority Anti-Pneumoniae 14 concentrations

Statistical analysis description

Comparison groups

Hiberix Group v ActHIB Group

Number of subjects included in analysis

659

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[17]

Method

Parameter type

GMC ratio

Point estimate

1.096

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.929

upper limit

1.294

Notes
[17] - Criteria for evaluation (1 month after the last dose of primary vaccination): LL of the 2-sided 97.5% CIs on the GMC ratio (Subset Test Hib Co-Ad over Sub-cohort Control Hib) for each S. pneumoniae serotype 14 [anti-14] was ≥ 0.5 (clinical limit for non-inferiority).

Non-inferiority Anti-Pneumoniae 18C concentrations

Statistical analysis description

Comparison groups

Hiberix Group v ActHIB Group

Number of subjects included in analysis

659

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[18]

Method

Parameter type

GMC ratio

Point estimate

1.042

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.9

upper limit

1.207

Notes
[18] - Criteria for evaluation (1 month after the last dose of primary vaccination): LL of the 2-sided 97.5% CIs on the GMC ratio (Subset Test Hib Co-Ad over Sub-cohort Control Hib) for each S. pneumoniae serotype 18C [anti-18C] was ≥ 0.5 (clinical limit for non-inferiority).

Non-inferiority Anti-Pneumoniae 19A concentrations

Statistical analysis description

Comparison groups

Hiberix Group v ActHIB Group

Number of subjects included in analysis

659

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[19]

Method

Parameter type

GMC ratio

Point estimate

1.001

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.859

upper limit

1.167

Notes
[19] - Criteria for evaluation (1 month after the last dose of primary vaccination): LL of the 2-sided 97.5% CIs on the GMC ratio (Subset Test Hib Co-Ad over Sub-cohort Control Hib) for each S. pneumoniae serotype 19A [anti-19A] was ≥ 0.5 (clinical limit for non-inferiority).

Non-inferiority Anti-Pneumoniae 19F concentrations

Statistical analysis description

Comparison groups

Hiberix Group v ActHIB Group

Number of subjects included in analysis

659

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[20]

Method

Parameter type

GMC ratio

Point estimate

0.969

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.855

upper limit

1.098

Notes
[20] - Criteria for evaluation (1 month after the last dose of primary vaccination): LL of the 2-sided 97.5% CIs on the GMC ratio (Subset Test Hib Co-Ad over Sub-cohort Control Hib) for each S. pneumoniae serotype 19F [anti-19F] was ≥ 0.5 (clinical limit for non-inferiority).

Non-inferiority Anti-Pneumoniae 23F concentrations

Statistical analysis description

Comparison groups

Hiberix Group v ActHIB Group

Number of subjects included in analysis

659

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[21]

Method

Parameter type

GMC ratio

Point estimate

1.031

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.862

upper limit

1.232

Notes
[21] - Criteria for evaluation (1 month after the last dose of primary vaccination): LL of the 2-sided 97.5% CIs on the GMC ratio (Subset Test Hib Co-Ad over Sub-cohort Control Hib) for each S. pneumoniae serotype 23F [anti-23F] was ≥ 0.5 (clinical limit for non-inferiority).

Primary: Number of subjects with seroresponse (95%) to anti-pertussis toxoid (anti-PT), anti-pertactin (anti-PRN) and anti-filamentous hemagglutinin (anti-FHA).

Top of page

End point title

Number of subjects with seroresponse (95%) to anti-pertussis toxoid (anti-PT), anti-pertactin (anti-PRN) and anti-filamentous hemagglutinin (anti-FHA).

End point description

Seroresponse (95%) was defined as the number of subjects showing a concentration above a threshold that leads to 95% seroresponse in the ActHIB group.

End point type

Primary

End point timeframe

At 1 month after last dose of primary vaccination.

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	792	275	251
Units: Subjects
Anti-PT [N = 792,275,251]	764	264	201
Anti-PRN [N = 789,275,250]	762	262	213
Anti-FHA [N=791,275,249]	744	263	191

Difference in seroresponse Anti-FHA

Statistical analysis description

To rule out a 10% decrease in seroresponse to FHA in subjects receiving DTPa-HBV-IPV co-administered with Test Hib, 13Pn and HRV vaccines compared to subjects receiving DTPa-HBV-IPV co-administered with Control Hib, 13Pn and HRV vaccines, following 3 primary vaccine doses where seroresponse was defined as the percentage of subjects showing a concentration above a threshold that led to 95% seroresponse in the control group.

Comparison groups

Hiberix Group v ActHIB Group

Number of subjects included in analysis

1067

Analysis specification

Pre-specified

Analysis type

other ^[22]

P-value

< 0.0001 ^[23]

Method

t-test, 1-sided

Confidence interval

Notes
[22] - Criteria for evaluation (1 month after the last dose of primary vaccination): P-value on the difference in seroresponse between groups was < 1.25% for FHA antigen (p-value was computed by integrating on the p-value for the null hypothesis that the seroresponse rate in the Subset Pertussis Co-Ad was < 85% and the a-posteriori probability of the cut-off in the Sub-cohort Control Hib).
[23] - P-value is computed by integrating on the p-values of one-sided test with alpha=0.025 and the posterior probability of the cut-off in the control group

Difference in seroresponse Anti-PT

Statistical analysis description

To rule out a 10% decrease in seroresponse to PT in subjects receiving DTPa-HBV-IPV co-administered with Test Hib, 13Pn and HRV vaccines compared to subjects receiving DTPa-HBV-IPV co-administered with Control Hib, 13Pn and HRV vaccines, following 3 primary vaccine doses where seroresponse was defined as the percentage of subjects showing a concentration above a threshold that led to 95% seroresponse in the control group.

Comparison groups

Hiberix Group v ActHIB Group

Number of subjects included in analysis

1067

Analysis specification

Pre-specified

Analysis type

other ^[24]

P-value

< 0.0001 ^[25]

Method

t-test, 1-sided

Confidence interval

Notes
[24] - Criteria for evaluation (1 month after the last dose of primary vaccination): P-value on the difference in seroresponse between groups was < 1.25% for PT antigen (p-value was computed by integrating on the p-value for the null hypothesis that the seroresponse rate in the Subset Pertussis Co-Ad was < 85% and the a-posteriori probability of the cut-off in the Sub-cohort Control Hib).
[25] - P-value is computed by integrating on the p-values of one-sided test with alpha=0.025 and the posterior probability of the cut-off in the control group

Difference in seroresponse Anti-PRN

Statistical analysis description

To rule out a 10% decrease in seroresponse to PRN in subjects receiving DTPa-HBV-IPV co-administered with Test Hib, 13Pn and HRV vaccines compared to subjects receiving DTPa-HBV-IPV co-administered with Control Hib, 13Pn and HRV vaccines, following 3 primary vaccine doses where seroresponse was defined as the percentage of subjects showing a concentration above a threshold that led to 95% seroresponse in the control group.

Comparison groups

Hiberix Group v ActHIB Group

Number of subjects included in analysis

1067

Analysis specification

Pre-specified

Analysis type

other ^[26]

P-value

< 0.0001 ^[27]

Method

t-test, 1-sided

Confidence interval

Notes
[26] - Criteria for evaluation (1 month after the last dose of primary vaccination): P-value on the difference in seroresponse between groups was < 1.25% for PRN antigen (p-value was computed by integrating on the p-value for the null hypothesis that the seroresponse rate in the Subset Pertussis Co-Ad was < 85% and the a-posteriori probability of the cut-off in the Sub-cohort Control Hib).
[27] - P-value is computed by integrating on the p-values of one-sided test with alpha=0.025 and the posterior probability of the cut-off in the control group

Primary: Number of subjects with anti-Polio 1,2,3 antibody titres greater than or equal to cut-off value.

Top of page

End point title

Number of subjects with anti-Polio 1,2,3 antibody titres greater than or equal to cut-off value.

End point description

The cut-off value was defined as a concentration ≥ 8 ED50 (ED50 is the concentration at which the protein exhibits 50% of its maximum activity).

End point type

Primary

End point timeframe

At 1 month after last dose of primary vaccination.

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	478	334	331
Units: Subjects
Anti-Polio 1 [N=447,322,317]	444	322	300
Anti-Polio 2 [N=478,334,331]	473	329	323
Anti-Polio 3 [N=456,323,311]	453	323	310

Non-inferiority Anti-Polio 1 concentrations

Statistical analysis description

Comparison groups

Hiberix Group v ActHIB Group

Number of subjects included in analysis

812

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[28]

Method

Parameter type

Difference in percentage

Point estimate

-0.67

Confidence interval

level

97.5%

sides

2-sided

lower limit

-2.24

upper limit

0.87

Notes
[28] - Criteria for non-inferiority (1 month after the last dose of primary vaccination): LL of the standardized asymptotic 97.5% CIs on the differences (Subset Test Hib Co-Ad minus Sub-cohort Control Hib) in the percentages of subjects with seroprotective titres (≥8) of antibodies to each of the poliovirus antigens was ≥-5% (clinical limit for non-inferiority).

Non-inferiority Anti-Polio 2 concentration

Statistical analysis description

Comparison groups

Hiberix Group v ActHIB Group

Number of subjects included in analysis

812

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[29]

Method

Parameter type

Difference in percentage

Point estimate

0.45

Confidence interval

level

97.5%

sides

2-sided

lower limit

-1.45

upper limit

2.91

Notes
[29] - Criteria for non-inferiority (1 month after the last dose of primary vaccination): LL of the standardized asymptotic 97.5% CIs on the differences (Subset Test Hib Co-Ad minus Sub-cohort Control Hib) in the percentages of subjects with seroprotective titres (≥8) of antibodies to each of the poliovirus antigens was ≥-5% (clinical limit for non-inferiority).

Non-inferiority Anti-Polio 3 concentration

Statistical analysis description

Comparison groups

Hiberix Group v ActHIB Group

Number of subjects included in analysis

812

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[30]

Method

Parameter type

Difference in percentage

Point estimate

-0.66

Confidence interval

level

97.5%

sides

2-sided

lower limit

-2.2

upper limit

0.88

Notes
[30] - Criteria for non-inferiority (1 month after the last dose of primary vaccination): LL of the standardized asymptotic 97.5% CIs on the differences (Subset Test Hib Co-Ad minus Sub-cohort Control Hib) in the percentages of subjects with seroprotective titres (≥8) of antibodies to each of the poliovirus antigens was ≥-5% (clinical limit for non-inferiority).

Primary: Anti-protein-D (anti-D) and anti-protein-T (anti-T) antibody concentrations.

Top of page

End point title

Anti-protein-D (anti-D) and anti-protein-T (anti-T) antibody concentrations. ^[31]

End point description

Antibody concentrations were given as geometric mean concentrations (GMCs) and expressed as International Units per milliliter (IU/mL).

End point type

Primary

End point timeframe

At 1 month after last dose of primary vaccination.

Notes
[31] - 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: No Statistical analysis was performed for this endpoint.

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	393	274	250
Units: IU/mL
geometric mean (confidence interval 95%)
Anti-D [N = 393,273,250]	2.72 (2.54 to 2.93)	2.45 (2.24 to 2.68)	1.88 (1.69 to 2.09)
Anti-T [N = 393,274,250]	2.23 (2.07 to 2.41)	2.44 (2.2 to 2.71)	1.72 (1.55 to 1.91)

No statistical analyses for this end point

Secondary: Number of subjects with any solicited local symptoms.

Top of page

End point title

Number of subjects with any solicited local symptoms.

End point description

Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of any symptom regardless of intensity grade.

End point type

Secondary

End point timeframe

During a 4-day follow-up period (Days 0-3) following any vaccination.

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	2846	503	496
Units: Subjects
Any pain	1932	366	370
Any redness	1165	233	257
Any swelling	834	174	195

No statistical analyses for this end point

Secondary: Number of subjects with any solicited general symptoms.

Top of page

End point title

Number of subjects with any solicited general symptoms.

End point description

Assessed solicited general symptoms were drowsiness, irritability, fever and loss of appetite. Any = occurrence of any general symptom regardless of intensity grade or relationship to vaccination. Any fever= Rectal temperature equal to or above (≥) 38 degrees Celsius (°C).

End point type

Secondary

End point timeframe

During a 4-day follow-up period (Days 0-3) following any vaccination.

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	2848	503	496
Units: Subjects
Any drowsiness	2179	398	378
Any irritability	2478	449	434
Any loss of appetite	1450	275	253
Any fever	1014	186	143

No statistical analyses for this end point

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

Top of page

End point title

Number of subjects with any unsolicited adverse events (AEs).

End point description

An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination.

End point type

Secondary

End point timeframe

During the 31-day (Day 0-Day 30) follow-up period after primary vaccination.

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	2963	520	520
Units: Subjects
Any AE(s)	1880	350	324

No statistical analyses for this end point

Secondary: Number of subjects with serious adverse events (SAEs).

Top of page

End point title

Number of subjects with serious adverse events (SAEs).

End point description

Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.

End point type

Secondary

End point timeframe

From Day 0 until 6 months following the last primary dose.

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	2963	520	520
Units: Subjects
Any SAE(s)	108	24	21

No statistical analyses for this end point

Secondary: Number of subjects with AEs of specific interest (AESIs).

Top of page

End point title

Number of subjects with AEs of specific interest (AESIs).

End point description

An AESI was defined as an AE including autoimmune diseases and other mediated inflammatory disorders and assessed by the investigator as specific to the treatment administration.

End point type

Secondary

End point timeframe

From Day 0 until 6 months following the last primary dose or the receipt of the booster vaccination, whichever comes first.

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	2963	520	520
Units: Subjects
Any AESI(s)	108	22	15

No statistical analyses for this end point

Secondary: Number of subjects with seroresponse (90%) to anti-PT, anti-PRN and anti-FHA.

Top of page

End point title

Number of subjects with seroresponse (90%) to anti-PT, anti-PRN and anti-FHA.

End point description

Seroresponse (90%) was defined as the number of subjects showing a concentration above a threshold that leads to 90% seroresponse in the ActHIB group.

End point type

Secondary

End point timeframe

At 1 month after last dose of primary vaccination.

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	792	275	251
Units: Subjects
Anti-PT [N = 792,275,251]	706	248	165
Anti-PRN [N = 789,275,250]	741	250	194
Anti-FHA [N=791,275,249]	705	248	166

No statistical analyses for this end point

Secondary: Number of subjects with anti-PT, anti-PRN and anti-FHA antibody concentrations ≥ 5 EL.U/mL.

Top of page

End point title

Number of subjects with anti-PT, anti-PRN and anti-FHA antibody concentrations ≥ 5 EL.U/mL.

End point description

End point type

Secondary

End point timeframe

At 1 month after last dose of primary vaccination.

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	792	275	251
Units: Subjects
Anti-PT [N= 792,275,251]	789	275	249
Anti-PRN [N = 789,275,250]	786	275	244
Anti-FHA [N=791,275,249]	791	275	249

No statistical analyses for this end point

Secondary: Anti-Hepatitis B (Anti-HBs) antibody concentrations.

Top of page

End point title

Anti-Hepatitis B (Anti-HBs) antibody concentrations.

End point description

Antibody concentrations were tabulated as geometric mean concentrations (GMCs) and expressed as milli-international units per milliliter (mIU/mL).

End point type

Secondary

End point timeframe

At 1 month after last dose of primary vaccination.

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	363	258	239
Units: mIU/mL
geometric mean (confidence interval 95%)
Anti-HBs	3684.3 (3287 to 4129.5)	3545.6 (3067.8 to 4098)	1573.4 (1302.6 to 1900.6)

No statistical analyses for this end point

Secondary: Number of subjects with S.pneumoniae antibody concentrations ≥ 0.05 µg/mL, ≥ 0.2 µg/mL and ≥1.0 µg/mL.

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End point title

Number of subjects with S.pneumoniae antibody concentrations ≥ 0.05 µg/mL, ≥ 0.2 µg/mL and ≥1.0 µg/mL.

End point description

End point type

Secondary

End point timeframe

At 1 month after the last dose of primary vaccination.

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	389	270	247
Units: Subjects
≥ 0.05 µg/mL, Anti-Pneumoniae 1 [N = 384,268,245]	384	268	245
≥ 0.05 µg/mL, Anti-Pneumoniae 3 [N = 382,269,245]	382	269	243
≥ 0.05 µg/mL, Anti-Pneumoniae 4 [N = 389,268,247]	389	268	247
≥ 0.05 µg/mL, Anti-Pneumoniae 5 [N = 379,266,246]	379	266	246
≥ 0.05 µg/mL, Anti-Pneumoniae 6A [N = 381,267,244]	381	267	244
≥ 0.05 µg/mL, Anti-Pneumoniae 6B [N = 383,267,245]	378	260	241
≥ 0.05 µg/mL, Anti-Pneumoniae 7F [N = 386,269,246]	386	269	246
≥ 0.05 µg/mL, Anti-Pneumoniae 9V [N = 386,270,246]	385	270	246
≥ 0.05 µg/mL, Anti-Pneumoniae 14 [N = 384,267,244]	384	267	244
≥ 0.05 µg/mL, Anti-Pneumoniae 18C [N =380,267,244]	380	267	244
≥ 0.05 µg/mL, Anti-Pneumoniae 19A[N = 384,266,245]	383	265	244
≥ 0.05 µg/mL, Anti-Pneumoniae 19F[N = 384,268,245]	384	268	245
≥ 0.05 µg/mL, Anti-Pneumoniae 23F[N = 384,268,245]	384	267	244
≥ 0.2 µg/mL, Anti-Pneumoniae 1 [N = 384,268,245]	382	267	244
≥ 0.2 µg/mL, Anti-Pneumoniae 3 [N = 382,269,245]	379	268	243
≥ 0.2 µg/mL, Anti-Pneumoniae 4 [N = 389,268,247]	389	267	247
≥ 0.2 µg/mL, Anti-Pneumoniae 5 [N = 379,266,246]	377	265	245
≥ 0.2 µg/mL, Anti-Pneumoniae 6A [N = 381,267,244]	379	265	243
≥ 0.2 µg/mL, Anti-Pneumoniae 6B [N = 383,267,245]	351	242	224
≥ 0.2 µg/mL, Anti-Pneumoniae 7F [N = 386,269,246]	386	269	246
≥ 0.2 µg/mL, Anti-Pneumoniae 9V [N = 386,270,246]	385	269	243
≥ 0.2 µg/mL, Anti-Pneumoniae 14 [N = 384,267,244]	381	265	241
≥ 0.2 µg/mL, Anti-Pneumoniae 18C [N = 380,267,244]	377	267	244
≥ 0.2 µg/mL, Anti-Pneumoniae 19A [N = 384,266,245]	379	259	235
≥ 0.2 µg/mL, Anti-Pneumoniae 19F [N = 384,268,245]	383	267	244
≥ 0.2 µg/mL, Anti-Pneumoniae 23F [N = 384,268,245]	376	265	231
≥ 1.0 µg/mL, Anti-Pneumoniae 1 [N = 384,268,245]	334	239	213
≥ 1.0 µg/mL, Anti-Pneumoniae 3 [N = 382,269,245]	188	140	138
≥ 1.0 µg/mL, Anti-Pneumoniae 4 [N = 389,268,247]	318	226	199
≥ 1.0 µg/mL, Anti-Pneumoniae 5 [N = 379,266,246]	354	250	225
≥ 1.0 µg/mL, Anti-Pneumoniae 6A [N = 381,267,244]	357	253	229
≥ 1.0 µg/mL, Anti-Pneumoniae 6B [N = 383,267,245]	232	151	117
≥ 1.0 µg/mL, Anti-Pneumoniae 7F [N = 386,269,246]	379	264	239
≥ 1.0 µg/mL, Anti-Pneumoniae 9V [N = 386,270,246]	338	234	203
≥ 1.0 µg/mL, Anti-Pneumoniae 14 [N = 384,267,244]	360	250	223
≥ 1.0 µg/mL, Anti-Pneumoniae 18C [N = 380,267,244]	361	256	229
≥ 1.0 µg/mL, Anti-Pneumoniae 19A [N = 384,266,245]	290	200	164
≥ 1.0 µg/mL, Anti-Pneumoniae 19F [N = 384,268,245]	357	254	231
≥ 1.0 µg/mL, Anti-Pneumoniae 23F [N = 384,268,245]	297	208	180

No statistical analyses for this end point

Secondary: Antibody titers for Poliovirus types 1, 2 and 3.

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End point title

Antibody titers for Poliovirus types 1, 2 and 3.

End point description

Antibody titers were given as geometric mean titers(GMTs).

End point type

Secondary

End point timeframe

At 1 month after last dose of primary vaccination.

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	478	334	331
Units: Titres
geometric mean (confidence interval 95%)
Anti-Polio 1 [N=447,322,317]	570.8 (509.2 to 639.8)	620.9 (540.1 to 713.7)	136 (114.7 to 161.1)
Anti-Polio 2 [N=478,334,331]	471.8 (416.7 to 534.1)	389.9 (337.3 to 450.6)	210.9 (181.9 to 244.5)
Anti-Polio 3 [N=456,323,311]	982.8 (870.1 to 1110.2)	963.2 (843.7 to 1099.5)	297.4 (253.3 to 349.1)

No statistical analyses for this end point

Secondary: Number of subjects with anti-HBs antibody concentrations greater than or equal to cut-off values.

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End point title

Number of subjects with anti-HBs antibody concentrations greater than or equal to cut-off values.

End point description

The cut-off values were defined as a concentration≥ 3.3 mIU/mL (seropositivity) and ≥ 10 mIU/mL (seroprotection).

End point type

Secondary

End point timeframe

At 1 month after last dose of primary vaccination.

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	363	258	239
Units: Subjects
Anti-HBs≥ 3.3 mIU/ml	362	257	239
Anti-HBs≥ 10 mIU/ml	362	257	239

No statistical analyses for this end point

Secondary: Number of subjects with any solicited local symptoms.

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End point title

Number of subjects with any solicited local symptoms.

End point description

Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of any symptom regardless of intensity grade.

End point type

Secondary

End point timeframe

Within 4 days (Days 0-3) following the booster dose.

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	2224	416	379
Units: Subjects
Any Pain	918	179	163
Any Redness	659	127	115
Any Swelling	392	82	75

No statistical analyses for this end point

Secondary: Number of subjects with any solicited general symptoms.

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End point title

Number of subjects with any solicited general symptoms.

End point description

Assessed solicited general symptoms were drowsiness, irritability, fever and loss of appetite. Any = occurrence of any general symptom regardless of intensity grade or relationship to vaccination. Any fever= Axillary temperature equal to or above (≥) 38 degrees Celsius (°C).

End point type

Secondary

End point timeframe

Within 4 days (Days 0-3) following the booster dose.

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	2225	416	379
Units: Subjects
Any Drowsiness	857	164	119
Any Irritability	1293	250	201
Any Loss of appetite	614	141	85
Any Fever	119	18	20

No statistical analyses for this end point

Secondary: Number of subjects with AEs of specific interest (AESIs).

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End point title

Number of subjects with AEs of specific interest (AESIs).

End point description

An AESI was defined as an AE including autoimmune diseases and other mediated inflammatory disorders and assessed by the investigator as specific to the treatment administration.

End point type

Secondary

End point timeframe

From booster dose until 6 months following receipt of the booster dose.

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	2337	435	400
Units: Subjects
Any AESI(s)	47	12	7

No statistical analyses for this end point

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

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End point title

Number of subjects with any unsolicited adverse events (AEs).

End point description

End point type

Secondary

End point timeframe

Within 31 days (Day 0 to Day 30) following the booster dose.

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	2337	435	400
Units: Subjects
Any AE(s)	882	159	138

No statistical analyses for this end point

Secondary: Number of subjects with serious adverse events (SAEs).

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End point title

Number of subjects with serious adverse events (SAEs).

End point description

SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.

End point type

Secondary

End point timeframe

From the booster dose until 6 months following receipt of the booster dose.

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	2337	435	400
Units: Subjects
Any SAE(s)	29	4	2

No statistical analyses for this end point

Secondary: Anti-HBs concentrations and concentrations ≥10.0 mIU/mL and concentrations ≥6.2 mIU/mL

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End point title

Anti-HBs concentrations and concentrations ≥10.0 mIU/mL and concentrations ≥6.2 mIU/mL

End point description

Antibody concentrations were tabulated as geometric mean concentrations (GMCs) and expressed as milli-international units per milliliter (mIU/mL).

End point type

Secondary

End point timeframe

Prior to the booster vaccination

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	316	207	167
Units: mIU/mL
geometric mean (confidence interval 95%)
Anti-HBs≥10.0 mIU/mL	268.3 (226.7 to 317.5)	247 (199.8 to 305.3)	156.4 (117.9 to 207.5)
Anti-HBs≥6.2mIU/mL	98.4 (96.3 to 99.5)	96.1 (92.5 to 98.3)	93.4 (88.5 to 96.7)

No statistical analyses for this end point

Secondary: Anti-polio virus types 1, 2, and 3 antibody titres and titres ≥ 8

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End point title

Anti-polio virus types 1, 2, and 3 antibody titres and titres ≥ 8

End point description

Antibody concentrations were tabulated as geometric mean titers (GMTs) and expressed as titers.

End point type

Secondary

End point timeframe

Prior to the booster vaccination

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	305	212	168
Units: Titers
geometric mean (confidence interval 95%)
Anti-polio 1	106.2 (91.1 to 123.8)	101.6 (84.4 to 122.3)	25.1 (20.3 to 31)
Anti-polio 2	109.4 (92.8 to 129.1)	89.5 (73.4 to 109.1)	48.9 (39.7 to 60.2)
Anti-polio 3	154.8 (129.3 to 185.3)	151.9 (122.4 to 188.5)	40.6 (31.4 to 52.5)

No statistical analyses for this end point

Secondary: Number of subjects with anti-HB antibody concentrations ≥10.0 mlU/mL and ≥6.2mLU/mL

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End point title

Number of subjects with anti-HB antibody concentrations ≥10.0 mlU/mL and ≥6.2mLU/mL

End point description

The cut-off values were defined as a concentration≥ 6.2 mIU/mL (seropositivity) and ≥ 10 mIU/mL (seroprotection).

End point type

Secondary

End point timeframe

Prior to booster vaccination

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	316	207	167
Units: Subjects
Anti-HBs ≥ 6.2 mIU/mL [316,207,167]	311	199	156
Anti-HBs ≥10.0 mIU/mL [316,207,167]	306	198	154

No statistical analyses for this end point

Secondary: Number of subjects with anti-Polio-1,2,3 antibody titers ≥ 8

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End point title

Number of subjects with anti-Polio-1,2,3 antibody titers ≥ 8

End point description

Anti-polio 1,2,3 antibody titers greater or equal to the cut off value were calculated.

End point type

Secondary

End point timeframe

Prior to booster vaccination

End point values	Hiberix Group	ActHIB Group	Pentacel Group
Number of subjects analysed	305	212	168
Units: Subjects
Anti-polio 1 [305,212,168]	294	197	124
Anti-polio 2 [305,212,168]	285	196	144
Anti-polio 3 [305,212,168]	283	201	130

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

SAEs= Day 0 to 6 months following last primary dose and from booster dose until 6 months after receipt of booster dose. Systematically and non-systematically assessed frequent AEs=within 4 and 31 days following primary and booster vaccination respectively

Adverse event reporting additional description

For the systematically assessed frequent AEs, the number of participants at risk included those from the Primary Total Vaccinated cohort and the Booster Total Vaccinated cohort respectively who had their symptom sheet completed.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

16.0

Reporting group title

Hiberix Group

Reporting group description

Reporting group title

ActHIB Group

Reporting group description

Reporting group title

Pentacel Group

Reporting group description

Reporting group title

Hiberix Group

Reporting group description

Reporting group title

ActHIB Group

Reporting group description

Reporting group title

Pentacel Group

Reporting group description

Serious adverse events	Hiberix Group	ActHIB Group	Pentacel Group	Hiberix Group	ActHIB Group	Pentacel Group
Total subjects affected by serious adverse events
subjects affected / exposed	108 / 2963 (3.64%)	24 / 520 (4.62%)	21 / 520 (4.04%)	29 / 2337 (1.24%)	4 / 435 (0.92%)	2 / 400 (0.50%)
number of deaths (all causes)	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Haemangioma of skin (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Retinoblastoma bilateral (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Vascular disorders
Kawasaki’s disease (primary phase)
subjects affected / exposed	2 / 2963 (0.07%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Cephalhaematoma (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	1 / 2337 (0.04%)	0 / 435 (0.00%)	0 / 400 (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
General disorders and administration site conditions
Pyrexia (primary phase)
subjects affected / exposed	5 / 2963 (0.17%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 5	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
Developmental delay (primary phase)
subjects affected / exposed	0 / 2963 (0.00%)	1 / 520 (0.19%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Immune system disorders
Anaphylactic shock (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	1 / 2337 (0.04%)	0 / 435 (0.00%)	0 / 400 (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
Respiratory, thoracic and mediastinal disorders
Respiratory distress (primary phase)
subjects affected / exposed	5 / 2963 (0.17%)	2 / 520 (0.38%)	1 / 520 (0.19%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 2	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
Hypoxia (primary phase)
subjects affected / exposed	2 / 2963 (0.07%)	2 / 520 (0.38%)	1 / 520 (0.19%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	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
Apparent life threatening event (primary phase)
subjects affected / exposed	3 / 2963 (0.10%)	1 / 520 (0.19%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Asthma (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	1 / 520 (0.19%)	1 / 520 (0.19%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Sleep apnoea syndrome (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Bronchospasm (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Choking (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Cough (primary phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	1 / 520 (0.19%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Foreign body aspiration (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Status asthmaticus (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Wheezing (primary phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	1 / 520 (0.19%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Bronchial hyperreactivity (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	2 / 2337 (0.09%)	1 / 435 (0.23%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthma (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	2 / 2337 (0.09%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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
Pneumothorax (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	1 / 2337 (0.04%)	0 / 435 (0.00%)	0 / 400 (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
Sleep apnoea syndrome (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	1 / 400 (0.25%)
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
Psychiatric disorders
Autism spectrum disorder (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	1 / 2337 (0.04%)	0 / 435 (0.00%)	0 / 400 (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
Breath holding (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	1 / 400 (0.25%)
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
Injury, poisoning and procedural complications
Craniocerebral injury (primary phase)
subjects affected / exposed	2 / 2963 (0.07%)	0 / 520 (0.00%)	1 / 520 (0.19%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 2	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
Skull fracture (primary phase)
subjects affected / exposed	2 / 2963 (0.07%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Accidental exposure (primary phase)
subjects affected / exposed	0 / 2963 (0.00%)	1 / 520 (0.19%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Child maltreatment syndrome (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Extradural haematoma (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Femur fracture (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Foreign body (primary phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	1 / 520 (0.19%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Lower limb fracture (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Rib fracture (primary phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	1 / 520 (0.19%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Foreign body (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	2 / 2337 (0.09%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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
Femur fracture (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	1 / 520 (0.19%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Radius fracture (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	1 / 2337 (0.04%)	0 / 435 (0.00%)	0 / 400 (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
Subdural haemorrhage (booster phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Congenital, familial and genetic disorders
Pyloric stenosis (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	1 / 520 (0.19%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Cerebral palsy (primary phase)
subjects affected / exposed	0 / 2963 (0.00%)	1 / 520 (0.19%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Congenital aplastic anaemia (primary phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	1 / 520 (0.19%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Congenital nystagmus (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Microcephaly (primary phase)
subjects affected / exposed	0 / 2963 (0.00%)	1 / 520 (0.19%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Mitochondrial DNA mutation (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Patent ductus arteriosus (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	1 / 435 (0.23%)	0 / 400 (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
Cardiac disorders
Cyanosis (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	1 / 520 (0.19%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Nervous system disorders
Febrile convulsion (primary phase)
subjects affected / exposed	4 / 2963 (0.13%)	3 / 520 (0.58%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 3	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
Convulsion (primary phase)
subjects affected / exposed	4 / 2963 (0.13%)	1 / 520 (0.19%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	1 / 4	1 / 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
Drooling (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Dyskinesia (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Encephalopathy (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Epilepsy (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Muscle contractions involuntary (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	1 / 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
Myoclonus (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	1 / 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
Sympathomimetic effect (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Febrile convulsion (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	5 / 2337 (0.21%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 5	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
Lymphadenitis (primary phase)
subjects affected / exposed	4 / 2963 (0.13%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 4	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
Anaemia (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Lymphadenopathy (primary phase)
subjects affected / exposed	0 / 2963 (0.00%)	1 / 520 (0.19%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Neutropenia (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Leukocytosis (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	1 / 2337 (0.04%)	0 / 435 (0.00%)	0 / 400 (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
Lymphadenitis (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	1 / 2337 (0.04%)	0 / 435 (0.00%)	0 / 400 (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
Eye disorders
Cataract (primary phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	1 / 520 (0.19%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Gastrointestinal disorders
Gastrooesophageal reflux disease (primary phase)
subjects affected / exposed	2 / 2963 (0.07%)	1 / 520 (0.19%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Intussusception (primary phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	1 / 520 (0.19%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Diarrhoea (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Gastrointestinal inflammation (primary phase)
subjects affected / exposed	0 / 2963 (0.00%)	1 / 520 (0.19%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Haematemesis (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Mallory-weiss syndrome (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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 (primary phase)
subjects affected / exposed	0 / 2963 (0.00%)	1 / 520 (0.19%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Intussusception (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	1 / 2337 (0.04%)	0 / 435 (0.00%)	0 / 400 (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
Renal and urinary disorders
Vesicoureteric reflux (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Growth retardation (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Infections and infestations
Bronchiolitis (primary phase)
subjects affected / exposed	16 / 2963 (0.54%)	2 / 520 (0.38%)	2 / 520 (0.38%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 16	0 / 2	0 / 2	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 (primary phase)
subjects affected / exposed	13 / 2963 (0.44%)	4 / 520 (0.77%)	2 / 520 (0.38%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 13	0 / 4	0 / 2	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 (primary phase)
subjects affected / exposed	14 / 2963 (0.47%)	2 / 520 (0.38%)	2 / 520 (0.38%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 14	0 / 2	0 / 2	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 (primary phase)
subjects affected / exposed	9 / 2963 (0.30%)	0 / 520 (0.00%)	2 / 520 (0.38%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 9	0 / 0	0 / 2	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 infection (primary phase)
subjects affected / exposed	9 / 2963 (0.30%)	2 / 520 (0.38%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 9	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
Croup infectious (primary phase)
subjects affected / exposed	3 / 2963 (0.10%)	0 / 520 (0.00%)	2 / 520 (0.38%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subcutaneous abscess (primary phase)
subjects affected / exposed	2 / 2963 (0.07%)	2 / 520 (0.38%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 2	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
Gastroenteritis (primary phase)
subjects affected / exposed	3 / 2963 (0.10%)	1 / 520 (0.19%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Pertussis (primary phase)
subjects affected / exposed	3 / 2963 (0.10%)	0 / 520 (0.00%)	1 / 520 (0.19%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Upper respiratory tract infection (primary phase)
subjects affected / exposed	2 / 2963 (0.07%)	2 / 520 (0.38%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 2	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
Cellulitis (primary phase)
subjects affected / exposed	0 / 2963 (0.00%)	1 / 520 (0.19%)	1 / 520 (0.19%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 0	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 viral (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	1 / 520 (0.19%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	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 (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	1 / 520 (0.19%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Staphylococcal abscess (primary phase)
subjects affected / exposed	2 / 2963 (0.07%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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 (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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 (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	1 / 520 (0.19%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Abscess neck (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Groin abscess (primary phase)
subjects affected / exposed	0 / 2963 (0.00%)	1 / 520 (0.19%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Mastoiditis (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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 streptococcal (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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 (primary)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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 (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Sinusitis (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Streptococcal bacteraemia (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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 rash (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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 (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	2 / 2337 (0.09%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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
Subcutaneous abscess (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	2 / 2337 (0.09%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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
Bronchiolitis (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	1 / 2337 (0.04%)	0 / 435 (0.00%)	0 / 400 (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
Otitis media (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	1 / 2337 (0.04%)	0 / 435 (0.00%)	0 / 400 (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
Pharyngitis streptococcal (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	1 / 2337 (0.04%)	0 / 435 (0.00%)	0 / 400 (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
Pneumonia (booster phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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 (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	1 / 2337 (0.04%)	0 / 435 (0.00%)	0 / 400 (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
Respiratory syncytial virus infection (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	1 / 2337 (0.04%)	0 / 435 (0.00%)	0 / 400 (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
Tonsillitis (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	1 / 400 (0.25%)
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
Urinary tract infection (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	1 / 2337 (0.04%)	0 / 435 (0.00%)	0 / 400 (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
Metabolism and nutrition disorders
Dehydration (primary phase)
subjects affected / exposed	10 / 2963 (0.34%)	3 / 520 (0.58%)	1 / 520 (0.19%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 10	0 / 3	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
Failure to thrive (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Hyperkalaemia (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Hypoglycaemia (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Weight gain poor (primary phase)
subjects affected / exposed	1 / 2963 (0.03%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (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
Dehydration (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	0 / 2337 (0.00%)	1 / 435 (0.23%)	0 / 400 (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

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

Non-serious adverse events	Hiberix Group	ActHIB Group	Pentacel Group	Hiberix Group	ActHIB Group	Pentacel Group
Total subjects affected by non serious adverse events
subjects affected / exposed	2478 / 2963 (83.63%)	449 / 520 (86.35%)	434 / 520 (83.46%)	1293 / 2337 (55.33%)	250 / 435 (57.47%)	201 / 400 (50.25%)
General disorders and administration site conditions
Pyrexia (primary phase)
subjects affected / exposed	196 / 2963 (6.61%)	36 / 520 (6.92%)	28 / 520 (5.38%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences all number	196	36	28	0	0	0
Drowsiness (primary phase)
alternative assessment type: Systematic
subjects affected / exposed	2179 / 2963 (73.54%)	398 / 520 (76.54%)	378 / 520 (72.69%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences all number	2179	398	378	0	0	0
Irritability (primay phase)
alternative assessment type: Systematic
subjects affected / exposed	2478 / 2963 (83.63%)	449 / 520 (86.35%)	434 / 520 (83.46%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences all number	2478	449	434	0	0	0
Loss of appetite (primary phase)
alternative assessment type: Systematic
subjects affected / exposed	1450 / 2963 (48.94%)	275 / 520 (52.88%)	253 / 520 (48.65%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences all number	1450	275	253	0	0	0
Fever (Rectal) (primary phase)
alternative assessment type: Systematic
subjects affected / exposed	1014 / 2963 (34.22%)	186 / 520 (35.77%)	143 / 520 (27.50%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences all number	1014	186	143	0	0	0
Pain (primary phase)
alternative assessment type: Systematic
subjects affected / exposed	1932 / 2963 (65.20%)	366 / 520 (70.38%)	370 / 520 (71.15%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences all number	1932	366	370	0	0	0
Redness (primay phase)
alternative assessment type: Systematic
subjects affected / exposed	1165 / 2963 (39.32%)	233 / 520 (44.81%)	257 / 520 (49.42%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences all number	1165	233	257	0	0	0
Swelling (primary phase)
alternative assessment type: Systematic
subjects affected / exposed	834 / 2963 (28.15%)	174 / 520 (33.46%)	195 / 520 (37.50%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences all number	834	174	195	0	0	0
Pyrexia (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	120 / 2337 (5.13%)	39 / 435 (8.97%)	27 / 400 (6.75%)
occurrences all number	0	0	0	120	39	27
Pain (booster phase)
alternative assessment type: Systematic
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	918 / 2337 (39.28%)	179 / 435 (41.15%)	163 / 400 (40.75%)
occurrences all number	0	0	0	918	179	163
Redness (booster phase)
alternative assessment type: Systematic
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	659 / 2337 (28.20%)	127 / 435 (29.20%)	115 / 400 (28.75%)
occurrences all number	0	0	0	659	127	115
Swelling (booster phase)
alternative assessment type: Systematic
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	392 / 2337 (16.77%)	82 / 435 (18.85%)	75 / 400 (18.75%)
occurrences all number	0	0	0	392	82	75
Drowsiness (booster phase)
alternative assessment type: Systematic
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	857 / 2337 (36.67%)	164 / 435 (37.70%)	119 / 400 (29.75%)
occurrences all number	0	0	0	857	164	119
Irritability (booster phase)
alternative assessment type: Systematic
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	1293 / 2337 (55.33%)	250 / 435 (57.47%)	201 / 400 (50.25%)
occurrences all number	0	0	0	1293	250	201
Loss of apetite (booster phase)
alternative assessment type: Systematic
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	614 / 2337 (26.27%)	141 / 435 (32.41%)	85 / 400 (21.25%)
occurrences all number	0	0	0	614	141	85
Fever (axillary) (booster phase)
alternative assessment type: Systematic
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	119 / 2337 (5.09%)	18 / 435 (4.14%)	20 / 400 (5.00%)
occurrences all number	0	0	0	119	18	20
Gastrointestinal disorders
Diarrhoea (primary phase)
subjects affected / exposed	162 / 2963 (5.47%)	28 / 520 (5.38%)	22 / 520 (4.23%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences all number	162	28	22	0	0	0
Vomiting (primary phase)
subjects affected / exposed	158 / 2963 (5.33%)	29 / 520 (5.58%)	21 / 520 (4.04%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences all number	158	29	21	0	0	0
Teething (primary phase)
subjects affected / exposed	128 / 2963 (4.32%)	22 / 520 (4.23%)	30 / 520 (5.77%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences all number	128	22	30	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough (primary phase)
subjects affected / exposed	307 / 2963 (10.36%)	49 / 520 (9.42%)	50 / 520 (9.62%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences all number	307	49	50	0	0	0
Rhinorrhoea (primary phase)
subjects affected / exposed	153 / 2963 (5.16%)	35 / 520 (6.73%)	27 / 520 (5.19%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences all number	153	35	27	0	0	0
Nasal congestion (primary phase)
subjects affected / exposed	155 / 2963 (5.23%)	30 / 520 (5.77%)	35 / 520 (6.73%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences all number	155	30	35	0	0	0
Cough (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	108 / 2337 (4.62%)	22 / 435 (5.06%)	31 / 400 (7.75%)
occurrences all number	0	0	0	108	22	31
Infections and infestations
Upper respiratory tract infection (primary phase)
subjects affected / exposed	568 / 2963 (19.17%)	100 / 520 (19.23%)	94 / 520 (18.08%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences all number	568	100	94	0	0	0
Otitis media (primary phase)
subjects affected / exposed	287 / 2963 (9.69%)	44 / 520 (8.46%)	55 / 520 (10.58%)	0 / 2337 (0.00%)	0 / 435 (0.00%)	0 / 400 (0.00%)
occurrences all number	287	44	55	0	0	0
Upper respiratory tract infection (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	155 / 2337 (6.63%)	22 / 435 (5.06%)	26 / 400 (6.50%)
occurrences all number	0	0	0	155	22	26
Otitis media (booster phase)
subjects affected / exposed	0 / 2963 (0.00%)	0 / 520 (0.00%)	0 / 520 (0.00%)	114 / 2337 (4.88%)	24 / 435 (5.52%)	17 / 400 (4.25%)
occurrences all number	0	0	0	114	24	17

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Were there any global substantial amendments to the protocol? Yes

12 Apr 2011

Amendment 3 for the HIB-097 protocol was developed in order to: Ensure scheduling of study visit 3 so that subjects receive final hepatitis B vaccination according to ACIP recommendations (minimum age of 24 weeks for the final hepatitis B dose, with an interval of at least 8 weeks between the 2nd and final hepatitis B dose).  Update the footnote of Table 6 to clarify that it is preferred that subjects come in for Visit 6, at least 30 days after Visit 5.  Update the sections on exclusion criteria for enrolment, contraindications to vaccination and warnings and precautions with information from the updated US Rotarix label.  Update information for sponsor signatories, Clinical Development Manager and Global Study Manager for the study.

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.

Anti-HBs antibody concentration cut off defining seropositivity was based on 6.2 mIU/mL instead of 3.3 mIU/mL for the pre-booster vaccination phase as tested by the commercial assay Centaur

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Clinical trials

Trial information

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Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of subjects with anti-polyribosylribitol phosphate (anti-PRP) antibody concentrations greater than or equal to (≥) 0.15 microgram per milliliter (µg/mL) and ≥ 1.0 µg/mL.

Primary: Number of subjects with anti-polyribosylribitol phosphate (anti-PRP) antibody concentrations greater than or equal to (≥) 0.15 microgram per milliliter (µg/mL) and ≥ 1.0 µg/mL.

Primary: Number of subjects with anti-Protein-D (anti-D) and anti-Protein-T (anti-T) antibody concentrations ≥ 0.1 International Units per milliliter (IU/mL).

Primary: Number of subjects with anti-Protein-D (anti-D) and anti-Protein-T (anti-T) antibody concentrations ≥ 0.1 International Units per milliliter (IU/mL).

Primary: Anti-polyribosylribitol phosphate (anti-PRP) antibody concentrations.

Primary: Anti-polyribosylribitol phosphate (anti-PRP) antibody concentrations.

Primary: Anti-pertussis toxoid (anti-PT), anti-pertactin (anti-PRN) and anti-filamentous hemagglutinin (anti-FHA) antibody concentrations.

Primary: Anti-pertussis toxoid (anti-PT), anti-pertactin (anti-PRN) and anti-filamentous hemagglutinin (anti-FHA) antibody concentrations.

Primary: Anti-Streptococcus pneumoniae (S.pneumoniae) antibody concentrations.

Primary: Anti-Streptococcus pneumoniae (S.pneumoniae) antibody concentrations.

Primary: Number of subjects with seroresponse (95%) to anti-pertussis toxoid (anti-PT), anti-pertactin (anti-PRN) and anti-filamentous hemagglutinin (anti-FHA).

Primary: Number of subjects with seroresponse (95%) to anti-pertussis toxoid (anti-PT), anti-pertactin (anti-PRN) and anti-filamentous hemagglutinin (anti-FHA).

Primary: Number of subjects with anti-Polio 1,2,3 antibody titres greater than or equal to cut-off value.

Primary: Number of subjects with anti-Polio 1,2,3 antibody titres greater than or equal to cut-off value.

Primary: Anti-protein-D (anti-D) and anti-protein-T (anti-T) antibody concentrations.

Primary: Anti-protein-D (anti-D) and anti-protein-T (anti-T) antibody concentrations.

Secondary: Number of subjects with any solicited local symptoms.

Secondary: Number of subjects with any solicited local symptoms.

Secondary: Number of subjects with any solicited general symptoms.

Secondary: Number of subjects with any solicited general symptoms.

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

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

Secondary: Number of subjects with serious adverse events (SAEs).

Secondary: Number of subjects with serious adverse events (SAEs).

Secondary: Number of subjects with AEs of specific interest (AESIs).

Secondary: Number of subjects with AEs of specific interest (AESIs).

Secondary: Number of subjects with seroresponse (90%) to anti-PT, anti-PRN and anti-FHA.

Secondary: Number of subjects with seroresponse (90%) to anti-PT, anti-PRN and anti-FHA.

Secondary: Number of subjects with anti-PT, anti-PRN and anti-FHA antibody concentrations ≥ 5 EL.U/mL.

Secondary: Number of subjects with anti-PT, anti-PRN and anti-FHA antibody concentrations ≥ 5 EL.U/mL.

Secondary: Anti-Hepatitis B (Anti-HBs) antibody concentrations.

Secondary: Anti-Hepatitis B (Anti-HBs) antibody concentrations.

Secondary: Number of subjects with S.pneumoniae antibody concentrations ≥ 0.05 µg/mL, ≥ 0.2 µg/mL and ≥1.0 µg/mL.

Secondary: Number of subjects with S.pneumoniae antibody concentrations ≥ 0.05 µg/mL, ≥ 0.2 µg/mL and ≥1.0 µg/mL.

Secondary: Antibody titers for Poliovirus types 1, 2 and 3.

Secondary: Antibody titers for Poliovirus types 1, 2 and 3.

Secondary: Number of subjects with anti-HBs antibody concentrations greater than or equal to cut-off values.

Secondary: Number of subjects with anti-HBs antibody concentrations greater than or equal to cut-off values.

Secondary: Number of subjects with any solicited local symptoms.

Secondary: Number of subjects with any solicited local symptoms.

Secondary: Number of subjects with any solicited general symptoms.

Secondary: Number of subjects with any solicited general symptoms.

Secondary: Number of subjects with AEs of specific interest (AESIs).

Secondary: Number of subjects with AEs of specific interest (AESIs).

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

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

Secondary: Number of subjects with serious adverse events (SAEs).

Secondary: Number of subjects with serious adverse events (SAEs).

Secondary: Anti-HBs concentrations and concentrations ≥10.0 mIU/mL and concentrations ≥6.2 mIU/mL

Secondary: Anti-HBs concentrations and concentrations ≥10.0 mIU/mL and concentrations ≥6.2 mIU/mL

Secondary: Anti-polio virus types 1, 2, and 3 antibody titres and titres ≥ 8

Secondary: Anti-polio virus types 1, 2, and 3 antibody titres and titres ≥ 8

Secondary: Number of subjects with anti-HB antibody concentrations ≥10.0 mlU/mL and ≥6.2mLU/mL

Secondary: Number of subjects with anti-HB antibody concentrations ≥10.0 mlU/mL and ≥6.2mLU/mL

Secondary: Number of subjects with anti-Polio-1,2,3 antibody titers ≥ 8

Secondary: Number of subjects with anti-Polio-1,2,3 antibody titers ≥ 8

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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