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Clinical Trial Results:
A phase IIIb, open, randomized, controlled, multicenter study to assess the co-administration of Rotarix (GlaxoSmithKline Biologicals’) with Hib-MenCY-TT (MenHibrix)(GlaxoSmithKline Biologicals’ Meningococcal Groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine) at 2 and 4 months of age, the co-administration of Prevnar 13 (Pfizer) with Hib-MenCY-TT (MenHibrix) at 2, 4 and 6 months of age and the co-administration of Prevnar 13 and Havrix (GlaxoSmithKline Biologicals’) with Hib-MenCY-TT ((MenHibrix) at 12 to 15 months of age.

Summary
EudraCT number	2013-003459-39
Trial protocol	Outside EU/EEA
Global end of trial date	18 Mar 2016

Results information
Results version number	v2(current)
This version publication date	13 Jun 2018
First version publication date	22 Dec 2016
Other versions	v1
Version creation reason

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

112931

ISRCTN number

US NCT number

NCT01978093

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

10 Mar 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

18 Mar 2016

Global end of trial reached?

Yes

Global end of trial date

18 Mar 2016

Was the trial ended prematurely?

Main objective of the trial

To demonstrate non-inferiority of 4 doses of Hib-MenCY-TT compared to 3 doses of PedvaxHIB,when co-administered with Prevnar 13 and Havrix,in terms of anti-PRP concentration Epoch 001:To demonstrate non-inferiority of 2 doses of Rotarix co-administered with Hib-MenCY-TT,Pediarix and Prevnar 13 compared to Rotarix co-administered with PedvaxHIB,Pediarix and Prevnar 13 in terms of Rotarix IgA GMCs .3 doses of Prevnar 13 co-administered with Hib-MenCY-TT,Rotarix and Pediarix compared to Prevnar 13 co-administered with PedvaxHIB,Rotarix and Pediarix in terms of S. pneumoniae GMCs Epoch 002:To demonstrate non-inferiority of 2 doses of Havrix when the 1st dose is co-administered with Hib-MenCY-TT and Prevnar 13 compared to Havrix when the 1st dose is co-administered with PedvaxHIB and Prevnar 13,at 12-15 months of age.4 doses of Prevnar 13 co-administered with Hib-MenCY-TT and Havrix compared to Prevnar 13 co-administered with PedvaxHIB and Havrix in terms of S. pneumoniae GMCs

Protection of trial subjects

The subjects were observed closely for at least 30 minutes following the administration of the vaccines, with appropriate medical treatment readily available in case of anaphylaxis

Background therapy

Evidence for comparator

Actual start date of recruitment

19 Feb 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 600

Worldwide total number of subjects

600

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)

600

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

600 subjects were recruited from 27 centers in the United States. The study consists of 2 epochs: Epoch 001: starting at Day 0 and ending at the day preceding the 4th vaccination (Month 10-13) and Epoch 002: starting at Month 10-13 and ending at Month 17-20, 31 days after the 2nd Havrix vaccination

Screening details

All enrolled subjects were included in the study.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

HibCY Group

Arm description

Subjects received 4 doses of Hib-MenCY-TT vaccine at Day 0, Month 2, Month 4 and Month 10-13, 3 doses of Pediarix vaccine at Day 0, Month 2 and Month 4, 2 doses of Rotarix vaccine at Day 0 and Month 2, 4 doses of Prevnar 13 vaccine at Day 0 and Month 2, Month 4 and Month 10-13 and 2 doses of Havrix vaccine at Month 10-13 and Month 16-19.

Arm type

Experimental

Investigational medicinal product name

Hib-MenCY-TT (MenHibrix )

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solution for solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Four doses administered intramuscularly in the right upper anterolateral thigh at Day 0, Month 2, Month 4 and month 10-13

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 doses administered orally at Day 0 and month 2

Investigational medicinal product name

Havrix 720 Junior

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Two doses administered intramuscularly in the left upper anterolateral thigh at month 10-13 and month 16-19

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

Four doses administered intramuscularly in the left lower anterolateral thigh at Day 0 and Month 2, Month 4 and Month 10-13.

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 administered intramuscularly in the left upper anterolateral thigh at day 0, month 2 and in the right upper anterolateral thigh at month 4.

PedHIB Group

Arm description

Subjects received 3 doses of PedvaxHIB vaccine at Day 0, Month 2 and Month 10-13, 3 doses of Pediarix vaccine at Day 0, Month 2 and Month 4, 2 doses of Rotarix vaccine at Day 0 and Month 2, 4 doses of Prevnar 13 vaccine at Day 0 and Month 2, Month 4 and Month 10-13 and 2 doses of Havrix vaccine at Month 10-13 and Month 16-19.

Arm type

Active comparator

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 doses administered orally at Day 0 and month 2

Investigational medicinal product name

Havrix 720 Junior

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Two doses administered intramuscularly in the left upper anterolateral thigh at month 10-13 and month 16-19

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

Four doses administered intramuscularly in the left lower anterolateral thigh at Day 0 and Month 2, Month 4 and Month 10-13.

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 administered intramuscularly in the left upper anterolateral thigh at day 0, month 2 and in the right upper anterolateral thigh at month 4.

Investigational medicinal product name

Pedvax HIB

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Three doses administered intramuscularly in the right upper anterolateral thigh at day 0, month 2 and month 10-13.

Number of subjects in period 1	HibCY Group	PedHIB Group
Started	297	303
Completed	232	230
Not completed	65	73
Adverse event, serious fatal	1	-
Loss of kaiser coverage	4	10
Consent withdrawn by subject	29	25
N/A for vaccine administration	-	1
Adverse event, non-fatal	-	5
Child was in care of grandmother	-	1
Mother lost custody of child	-	1
Migrated/moved from study area	11	13
Lost to follow-up	11	15
Lost kaiser health plan unable to contac	1	-
Protocol deviation	8	2

Baseline characteristics

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Reporting group title

HibCY Group

Reporting group description

Reporting group title

PedHIB Group

Reporting group description

Reporting group values	HibCY Group	PedHIB Group	Total
Number of subjects	297	303	600
Age categorical
Units: Subjects
Infants and Toddlers	297	303	600
Age continuous
Units: weeks
arithmetic mean (standard deviation)	8.6 ( 1.1 )	8.6 ( 1.1 )	-
Gender categorical
Units: Subjects
Female	148	140	288
Male	149	163	312
Race/Ethnicity, Customized
Units: Subjects
African Heritage / African American	29	19	48
American Indian or Alaskan Native	11	12	23
Asian - Central/South Asian Heritage	5	4	9
Asian - East Asian Heritage	2	2	4
Asian - Japanese Heritage	1	0	1
Asian - South East Asian Heritage	9	8	17
Native Hawaiian or Other Pacific Islander	2	6	8
White - Arabic / North African Heritage	1	2	3
White - Caucasian / European Heritage	201	218	419
Unspecified	36	32	68

End points

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Reporting group title

HibCY Group

Reporting group description

Reporting group title

PedHIB Group

Reporting group description

Primary: Percentage of subjects with Anti-Polyribosylribitol phosphate (Anti-PRP) antibody concentrations greater than or equal to (≥) 1.0 µg/mL

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End point title

Percentage of subjects with Anti-Polyribosylribitol phosphate (Anti-PRP) antibody concentrations greater than or equal to (≥) 1.0 µg/mL

End point description

Percentage of subjects with Anti-PRP antibody concentrations≥1.0 µg/mL were assessed. Analysis of Immunogenicity is performed on blood sample (BS) sub-cohorts. Assignment to a BS sub-cohort depends on the date of enrolment of the subject: BS sub-cohort for the first 200 , for the next 200 subjects or for the last 200 subjects. Within each BS sub-cohort subjects have been randomized 1:1 to either HibCY or PedHIB groups.As per an hierarchical procedure, the primary objective about Anti-PRP will first need to be met to be able to conclude on any other primary objective, and within each subsequent arm, the first primary objective will have to be reached to conclude on the second primary objective of that Epoch.

End point type

Primary

End point timeframe

1 month after the fourth dose for HibCY Group and 1 month after third dose for PedHIB Group [Month (M) 11-14]

End point values	HibCY Group	PedHIB Group
Number of subjects analysed	223	218
Units: Percentage of subjects
number (confidence interval 95%)
Anti-PRP≥1.0μg/mL (N=223,218)	98.2 (95.5 to 99.5)	97.2 (94.1 to 99.0)

Statistical analysis 1

Statistical analysis description

Difference between HibCY and PedHIB groups in percentage of subjects with anti-PRP concentrations equal to or above the cut-off value of 1.0 µg/mL one month after the fourth dose in HibCY Group and third dose in PedHIB Group.

Comparison groups

PedHIB Group v HibCY Group

Number of subjects included in analysis

441

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[1]

Method

Group difference in proportions

Parameter type

Difference in percentage of subjects

Point estimate

0.96

Confidence interval

level

95%

sides

2-sided

lower limit

-2.12

upper limit

4.3

Notes
[1] - Lower limit of the standardized asymptotic 95% CI for the difference (HibCY group minus the PedHIB group) in the percentage of subjects with anti-PRP concentrations ≥1.0 mg/mL is to be ≥-10% (clinical limit for non-inferiority).Before concluding on the primary objectives for Rotarix, Prevnar 13 and Havrix, this primary objective regarding anti-PRP needs to be reached.

Primary: Anti-rotavirus serum Immunoglobulin A (IgA) Geometric Mean concentrations (GMCs).

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End point title

Anti-rotavirus serum Immunoglobulin A (IgA) Geometric Mean concentrations (GMCs).

End point description

Anti-rotavirus serum IgA was assessed by ELISA, tabulated as GMCs and expressed in Units per mililiter (U/mL).Analysis of Immunogenicity is performed on blood sample (BS) sub-cohorts. Assignment to a BS sub-cohort depends on the date of enrolment of the subject: BS sub-cohort for the first 200 , for the next 200 subjects or for the last 200 subjects. Within each BS sub-cohort subjects have been randomized 1:1 to either HibCY or PedHIB groups.As per a hierarchical procedure, the primary objective about Anti-PRP will first need to be met to be able to conclude on any other primary objective, and within each subsequent arm, the first primary objective will have to be reached to conclude on the second primary objective of that Epoch

End point type

Primary

End point timeframe

2 months post-dose 2 of Rotarix (Month 4)

End point values	HibCY Group	PedHIB Group
Number of subjects analysed	155	161
Units: U/mL
geometric mean (confidence interval 95%)
Anti-rotavirus serum IgA GMCs (N=155,161)	138.9 (104.0 to 185.5)	115.0 (87.5 to 151.0)

Statistical analysis 1

Statistical analysis description

GMC ratios between HibCY and PedHIB groups for anti-Rota IgA concentrations 2 months after the second dose of Rotarix vaccine. GMC adjusted for BS sub-cohorts;97.5% confidence interval calculated for adjusted GMC ratio(Ancova model:adjustment for BS subcohorts-pooled variance)

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

316

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[2]

Method

ANCOVA

Parameter type

Adjusted GMC ratios

Point estimate

1.21

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.77

upper limit

1.9

Notes
[2] - Non-inferiority is concluded if lower limit of the two-sided standardized asymptotic 97.5% CI on the ratio of anti-rotavirus IgA GMC (HibCY group over PedHIB group) is to be ≥0.5. To be able to conclude independently on primary objectives of Epoch 001(Rotarix & Prevnar13 Post dose 3)& Epoch 002 (Havrix & Prevnar13 post dose 4),a Bonferroni correction is used in order to test these objectives(1.25% 1sided for Epoch 001 & 002)

Primary: Anti-Streptococcus (S) pneumoniae GMCs

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End point title

Anti-Streptococcus (S) pneumoniae GMCs

End point description

Antibody concentrations against S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F were assessed by ELISA, tabulated as GMCs and expressed in µg/mL. Analysis of Immunogenicity is performed on blood sample (BS) sub-cohorts.Assignment to a BS sub-cohort depends on the date of enrolment of the subject: BS sub-cohort for the first 200 , for the next 200 subjects or for the last 200 subjects. Within each BS sub-cohort subjects have been randomized 1:1 to either HibCY or PedHIB groups.As per an hierarchical procedure, the primary objective about Anti-PRP will first need to be met to be able to conclude on any other primary objective, and within each subsequent arm, the first primary objective will have to be reached to conclude on the second primary objective of that Epoch.

End point type

Primary

End point timeframe

1 month post-dose 3 of Prevnar 13 (Month 5)

End point values	HibCY Group	PedHIB Group
Number of subjects analysed	156	158
Units: µg/mL
geometric mean (confidence interval 95%)
Anti-1 antibody (N-156,158)	1.49 (1.30 to 1.70)	1.26 (1.10 to 1.44)
Anti-3 antibody (N=149,150)	0.55 (0.48 to 0.63)	0.48 (0.42 to 0.55)
Anti-4 antibody (N=156,158)	0.81 (0.72 to 0.90)	0.74 (0.66 to 0.84)
Anti-5 antibody (N=156,158)	0.80 (0.71 to 0.91)	0.68 (0.59 to 0.78)
Anti-6A antibody(N=156,158)	1.76 (1.55 to 2.00)	1.37 (1.18 to 1.60)
Anti-6B antibody(N=154,158)	1.00 (0.85 to 1.18)	0.87 (0.73 to 1.05)
Anti-7F antibody (N=156,158)	2.59 (2.29 to 2.93)	2.36 (2.10 to 2.65)
Anti-9V antibody(N=156,157)	0.78 (0.69 to 0.89)	0.63 (0.55 to 0.73)
Anti-14 antibody (N=156,156)	4.77 (4.13 to 5.52)	4.16 (3.50 to 4.94)
Anti-18C antibody (N=156,158)	0.91 (0.81 to 1.03)	0.74 (0.65 to 0.84)
Anti-19A antibody (N=156,158)	1.31 (1.17 to 1.48)	1.13 (0.98 to 1.31)
Anti-19F antibody(N=155,158)	2.25 (2.02 to 2.50)	2.10 (1.87 to 2.37)
Anti-23F antibody(N=156,157)	0.94 (0.80 to 1.10)	0.80 (0.67 to 0.94)

Statistical analysis 1

Statistical analysis description

GMC ratio between HibCY and PedHIB groups for antibodies to S. pneumoniae serotype 1 concentrations one month after the third dose. GMC adjusted for BS sub cohorts;97.5% CI for adjusted GMC ratio (Ancova Model: adjustment for BS sub cohorts-pooled variance)

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

314

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.18

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.95

upper limit

1.47

Notes
[3] - Lower limit of the two-sided 97.5% CI on the GMC ratio (HibCY group over PedHIB group) for antibodies to S. pneumoniae serotype 1 is to be≥0.5 (clinical limit for non-inferiority). To be able to conclude independently on primary objectives of Epoch 001(Rotarix & Prevnar13 post dose 3)& Epoch 002(Havrix & Prevnar13 post dose 4),Bonferroni correction is used to test these primary objectives(1.25% 1sided for Epoch 001 & Epoch 002)

Statistical analysis 2

Statistical analysis description

GMC ratio between HibCY and PedHIB groups for antibodies to S. pneumoniae serotype 3 concentrations one month after the third dose.GMC adjusted for BS subcohorts;97.5% CI for the adjusted GMC ratio(Ancova model:adjustment for BS subcohorts-pooled variance)

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

314

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[4]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.15

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.93

upper limit

1.42

Notes
[4] - Lower limit of the two-sided 97.5% CI on the GMC ratio (HibCY group over PedHIB group) for antibodies to S. pneumoniae serotype 3 is to be ≥0.5 (clinical limit for non-inferiority).To be able to conclude independently on primary objectives of Epoch 001(Rotarix & Prevnar13 post dose 3)& Epoch 002(Havrix&Prevnar13 post dose 4),a Bonferroni correction is used to test these primary objectives(1.25% 1sided for Epoch 001 & Epoch 002)

Statistical analysis 3

Statistical analysis description

GMC ratio between HibCY and PedHIB groups for antibodies to S. pneumoniae serotype 4 concentrations one month after the third dose.GMC adjusted for BS subcohorts;97.5% CI for the adjusted GMC ratio(Ancova model:adjustment for BS subcohorts-pooled variance)

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

314

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[5]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.08

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.9

upper limit

1.31

Notes
[5] - Lower limit of the two-sided 97.5% CI on the GMC ratio (HibCY group over PedHIB group) for antibodies to S. pneumoniae serotype 4 is to be≥ 0.5 (clinical limit for non-inferiority).To be able to conclude independently on primary objectives of Epoch 001(Rotarix & Prevnar13 post dose 3)& Epoch 002(Havrix&Prevnar13 post dose 4),a Bonferroni correction is used to test these primary objectives(1.25% 1sided for Epoch 001 & Epoch 002)

Statistical analysis 4

Statistical analysis description

GMC ratio between HibCY and PedHIB groups for antibodies to S. pneumoniae serotype 5 concentrations one month after the third dose.GMC adjusted for BS subcohorts;97.5% CI for the adjusted GMC ratio(Ancova model:adjustment for BS subcohorts-pooled variance)

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

314

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[6]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.18

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.95

upper limit

1.47

Notes
[6] - Lower limit of the two-sided 97.5% CI on the GMC ratio (HibCY group over PedHIB group) for antibodies to S. pneumoniae serotype 5 is to be ≥ 0.5 (clinical limit for non-inferiority).To be able to conclude independently on primary objectives of Epoch 001(Rotarix & Prevnar13 post dose 3)& Epoch 002(Havrix&Prevnar13 post dose 4),a Bonferroni correction is used to test these primary objectives(1.25% 1sided for Epoch 001 & Epoch 002)

Statistical analysis 5

Statistical analysis description

GMC ratio between HibCY and PedHIB groups for antibodies to S. pneumoniae serotype 6A concentrations one month after the third dose.GMC adjusted for BS subcohorts;97.5% CI for the adjusted GMC ratio(Ancova model:adjustment for BS subcohorts-pooled variance)

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

314

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[7]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.29

Confidence interval

level

97.5%

sides

2-sided

lower limit

1.03

upper limit

1.63

Notes
[7] - Lower limit of the two-sided 97.5% CI on the GMC ratio (HibCY group over PedHIB group) for antibodies to S. pneumoniae serotype 6A is to be≥0.5 (clinical limit for non-inferiority).To be able to conclude independently on primary objectives of Epoch 001(Rotarix & Prevnar13 post dose 3)& Epoch 002(Havrix&Prevnar13 post dose 4),a Bonferroni correction is used to test these primary objectives(1.25% 1sided for Epoch 001 & Epoch 002)

Statistical analysis 6

Statistical analysis description

GMC ratio between HibCY and PedHIB groups for antibodies to S. pneumoniae serotype 6B concentrations one month after the third dose.GMC adjusted for BS subcohorts;97.5% CI for the adjusted GMC ratio(Ancova model:adjustment for BS subcohorts-pooled variance)

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

314

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[8]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.17

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.88

upper limit

1.55

Notes
[8] - Lower limit of the two-sided 97.5% CI on the GMC ratio (HibCY group over PedHIB group) for antibodies to S. pneumoniae serotype 6B is to be ≥0.5 (clinical limit for non-inferiority).To be able to conclude independently on primary objectives of Epoch 001(Rotarix & Prevnar13 post dose 3)& Epoch 002(Havrix&Prevnar13 post dose 4),a Bonferroni correction is used to test these primary objectives(1.25% 1sided for Epoch 001 & Epoch 002)

Statistical analysis 7

Statistical analysis description

GMC ratio between HibCY and PedHIB groups for antibodies to S. pneumoniae serotype 7F concentrations one month after the third dose.GMC adjusted for BS subcohorts;97.5% CI for the adjusted GMC ratio(Ancova model:adjustment for BS subcohorts-pooled variance)

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

314

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[9]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.11

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.91

upper limit

1.34

Notes
[9] - Lower limit of the two-sided 97.5% CI on the GMC ratio (HibCY group over PedHIB group) for antibodies to S. pneumoniae serotype 7F is to be≥0.5 (clinical limit for non-inferiority).To be able to conclude independently on primary objectives of Epoch 001(Rotarix & Prevnar13 post dose 3)& Epoch 002(Havrix&Prevnar13 post dose 4),a Bonferroni correction is used to test these primary objectives(1.25% 1sided for Epoch 001 & Epoch 002)

Statistical analysis 8

Statistical analysis description

GMC ratio between HibCY and PedHIB groups for antibodies to S. pneumoniae serotype 9V concentrations one month after the third dose.GMC adjusted for BS subcohorts;97.5% CI for the adjusted GMC ratio(Ancova model:adjustment for BS subcohorts-pooled variance)

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

314

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[10]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.25

Confidence interval

level

97.5%

sides

2-sided

lower limit

upper limit

1.55

Notes
[10] - Lower limit of the two-sided 97.5% CI on the GMC ratio (HibCY group over PedHIB group) for antibodies to S. pneumoniae serotype 9V is to be≥0.5 (clinical limit for non-inferiority).To be able to conclude independently on primary objectives of Epoch 001(Rotarix & Prevnar13 post dose 3)& Epoch 002(Havrix&Prevnar13 post dose 4),a Bonferroni correction is used to test these primary objectives(1.25% 1sided for Epoch 001 & Epoch 002)

Statistical analysis 9

Statistical analysis description

GMC ratio between HibCY and PedHIB groups for antibodies to S. pneumoniae serotype 14 concentrations one month after the third dose.GMC adjusted for BS subcohorts;97.5% CI for the adjusted GMC ratio(Ancova model:adjustment for BS subcohorts-pooled variance)

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

314

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[11]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.16

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.9

upper limit

1.5

Notes
[11] - Lower limit of the two-sided 97.5% CI on the GMC ratio (HibCY group over PedHIB group) for antibodies to S. pneumoniae serotype 14 is to be≥0.5 (clinical limit for non-inferiority).To be able to conclude independently on primary objectives of Epoch 001(Rotarix & Prevnar13 post dose 3)& Epoch 002(Havrix&Prevnar13 post dose 4),a Bonferroni correction is used to test these primary objectives(1.25% 1sided for Epoch 001 & Epoch 002)

Statistical analysis 10

Statistical analysis description

GMC ratio between HibCY and PedHIB groups for antibodies to S. pneumoniae serotype 18C concentrations one month after the third dose.GMC adjusted for BS subcohorts;97.5% CI for the adjusted GMC ratio(Ancova model:adjustment for BS subcohorts-pooled variance)

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

314

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[12]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.24

Confidence interval

level

97.5%

sides

2-sided

lower limit

1.01

upper limit

1.52

Notes
[12] - Lower limit of the two-sided 97.5% CI on the GMC ratio (HibCY group over PedHIB group) for antibodies to S. pneumoniae serotype 18C is to be ≥0.5 (clinical limit for non-inferiority).To be able to conclude independently on primary objectives of Epoch 001(Rotarix & Prevnar13 post dose 3)& Epoch 002(Havrix&Prevnar13 post dose 4),a Bonferroni correction is used to test these primary objectives(1.25% 1sided for Epoch 001 & Epoch 002)

Statistical analysis 11

Statistical analysis description

GMC ratio between HibCY and PedHIB groups for antibodies to S. pneumoniae serotype 19A concentrations one month after the third dose.GMC adjusted for BS subcohorts;97.5% CI for the adjusted GMC ratio(Ancova model:adjustment for BS subcohorts-pooled variance)

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

314

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[13]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.16

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.94

upper limit

1.43

Notes
[13] - Lower limit of the two-sided 97.5% CI on the GMC ratio (HibCY group over PedHIB group) for antibodies to S. pneumoniae serotype 19A is to be≥0.5 (clinical limit for non-inferiority).To be able to conclude independently on primary objectives of Epoch 001(Rotarix & Prevnar13 post dose 3)& Epoch 002(Havrix&Prevnar13 post dose 4),a Bonferroni correction is used to test these primary objectives(1.25% 1sided for Epoch 001 & Epoch 002)

Statistical analysis 12

Statistical analysis description

GMC ratio between HibCY and PedHIB groups for antibodies to S. pneumoniae serotype 19F concentrations one month after the third dose.GMC adjusted for BS subcohorts;97.5% CI for the adjusted GMC ratio(Ancova model:adjustment for BS subcohorts-pooled variance)

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

314

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[14]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.07

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.89

upper limit

1.29

Notes
[14] - Lower limit of the two-sided 97.5% CI on the GMC ratio (HibCY group over PedHIB group) for antibodies to S. pneumoniae serotype 19F is to be≥0.5 (clinical limit for non-inferiority).To be able to conclude independently on primary objectives of Epoch 001(Rotarix & Prevnar13 post dose 3)& Epoch 002(Havrix&Prevnar13 post dose 4),a Bonferroni correction is used to test these primary objectives(1.25% 1sided for Epoch 001 & Epoch 002)

Statistical analysis 13

Statistical analysis description

GMC ratio between HibCY and PedHIB groups for antibodies to S. pneumoniae serotype 23F concentrations one month after the third dose. GMC adjusted for BS subcohorts;97.5% CI for the adjusted GMC ratio(Ancova model:adjustment for BS subcohorts-pooled variance

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

314

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[15]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.18

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.91

upper limit

1.53

Notes
[15] - Lower limit of the two-sided 97.5% CI on the GMC ratio (HibCY group over PedHIB group) for antibodies to S. pneumoniae serotype 23F is to be ≥0.5 (clinical limit for non-inferiority).To be able to conclude independently on primary objectives of Epoch 001(Rotarix & Prevnar13 post dose 3)& Epoch 002(Havrix&Prevnar13 post dose 4),a Bonferroni correction is used to test these primary objectives(1.25% 1sided for Epoch 001 & Epoch 002)

Primary: Percentage of subjects with Anti-Hepatitis A Vaccine (Anti-Havrix) antibody concentrations ≥ 15mIU/mL

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End point title

Percentage of subjects with Anti-Hepatitis A Vaccine (Anti-Havrix) antibody concentrations ≥ 15mIU/mL

End point description

Percentage of subjects with Anti-Havrix (Anti-HAV) antibody concentrations was assessed. The cut-off value is ≥15 mIU/mL. Analysis of Immunogenicity is performed on blood sample (BS) sub-cohorts.Assignment to a BS sub-cohort depends on the date of enrolment of the subject: BS sub-cohort for the first 200 , for the next 200 subjects or for the last 200 subjects. Within each BS sub-cohort subjects have been randomized 1:1 to either HibCY or PedHIB groups.As per an hierarchical procedure, the primary objective about Anti-PRP will first need to be met to be able to conclude on any other primary objective, and within each subsequent arm, the first primary objective will have to be reached to conclude on the second primary objective of that Epoch

End point type

Primary

End point timeframe

1 month post-dose 2 of Havrix (Month 17-20)

End point values	HibCY Group	PedHIB Group
Number of subjects analysed	129	124
Units: Percentage of subjects
number (confidence interval 95%)
Anti-Havrix antibody≥15 mIU/mL (N=129,124)	100 (97.2 to 100)	100 (97.1 to 100)

Statistical analysis 1

Statistical analysis description

Difference between HibCY and PedHIB groups in percentage of subjects with anti-HAV concentrations equal to or above the cut-off value of 15 mIU/mL one month after the second Havrix dose.

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

253

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[16]

Method

Group difference in proportions

Parameter type

Difference in percentage of subjects

Point estimate

Confidence interval

level

97.5%

sides

2-sided

lower limit

-3.76

upper limit

3.91

Notes
[16] - Lower limit of the two-sided standardized asymptotic 97.5% CI on the difference (HibCY group minus the PedHIB group) in the percentage of subjects with anti-HAV concentrations ≥15 mIU/mL is to be≥-10% (clinical limit for non-inferiority).To be able to conclude independently on primary objectives of Epoch 001(Rotarix & Prevnar13 post dose 3)& Epoch 002(Havrix & Prevnar13 post dose 4),Bonferroni correction is used to test these primary objectives(1.25% 1sided for Epoch 001 & Epoch 002)

Primary: Anti-S. pneumoniae GMCs

Top of page

End point title

Anti-S. pneumoniae GMCs

End point description

End point type

Primary

End point timeframe

1 month post-dose 4 of Prevnar 13 (Month 11-14)

End point values	HibCY Group	PedHIB Group
Number of subjects analysed	216	205
Units: µg/mL
geometric mean (confidence interval 95%)
Anti-1 antibody (N=216,205)	2.00 (1.78 to 2.25)	1.60 (1.43 to 1.79)
Anti-3 antibody (N=169,167)	0.52 (0.46 to 0.58)	0.51 (0.44 to 0.59)
Anti-4 antibody (N=216,205)	1.36 (1.23 to 1.50)	1.24 (1.10 to 1.39)
Anti-5 antibody (N=215,205)	2.36 (2.10 to 2.64)	2.23 (1.97 to 2.52)
Anti-6A antibody (N=216,205)	6.80 (6.10 to 7.57)	5.63 (5.05 to 6.26)
Anti-6B antibody (N=215,205)	5.57 (4.97 to 6.24)	4.94 (4.40 to 5.55)
Anti-7F antibody (N=216,205)	4.16 (3.76 to 4.61)	3.81 (3.45 to 4.21)
Anti-9V antibody (N=215,205)	1.38 (1.25 to 1.53)	1.24 (1.11 to 1.39)
Anti-14 antibody (N=216,205)	7.14 (6.32 to 8.07)	6.13 (5.48 to 6.86)
Anti-18C antibody(N=216,204)	1.62 (1.46 to 1.80)	1.42 (1.28 to 1.57)
Anti-19A antibody (N=216,204)	5.47 (4.87 to 6.14)	5.03 (4.47 to 5.64)
Anti-19F antibody (N=215,205)	6.23 (5.61 to 6.92)	5.54 (4.97 to 6.18)
Anti-23F antibody (N=216,205)	3.28 (2.90 to 3.71)	2.68 (2.37 to 3.05)

Statistical analysis 1

Statistical analysis description

GMC ratios between HibCY and PedHIB groups for antibodies to S. pneumoniae serotype 1 concentrations one month after the fourth dose. GMC adjusted for BS sub cohorts;97.5% CI for adjusted GMC ratio(Ancova model:adjustment for BS sub cohorts-pooled variance)

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

421

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[17]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.25

Confidence interval

level

97.5%

sides

2-sided

lower limit

1.04

upper limit

1.51

Notes
[17] - Lower limit of the two-sided 97.5% CI on the GMC ratio (HibCY group over PedHIB group) for antibodies to S. pneumoniae serotype 1 is to be ≥0.5 (clinical limit for non-inferiority).To be able to conclude independently on primary objectives of Epoch 001 & Epoch 002, a Bonferroni correction is used to test these primary objectives(1.25% one-sided for Epoch 001 and Epoch 002)

Statistical analysis 2

Statistical analysis description

GMC ratios between HibCY and PedHIB groups for antibodies to S. pneumoniae serotype 3 concentrations one month after the fourth dose. GMC adjusted for BS sub cohorts;97.5% CI for adjusted GMC ratio(Ancova model:adjustment for BS sub cohorts-pooled variance)

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

421

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[18]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.01

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.83

upper limit

1.24

Notes
[18] - Lower limit of the two-sided 97.5% CI on the GMC ratio (HibCY group over PedHIB group) for antibodies to S. pneumoniae serotype 3 is to be≥0.5 (clinical limit for non-inferiority).To be able to conclude independently on primary objectives of Epoch 001 & Epoch 002, a Bonferroni correction is used to test these primary objectives(1.25% one-sided for Epoch 001 and Epoch 002)

Statistical analysis 3

Statistical analysis description

GMC ratios between HibCY and PedHIB groups for antibodies to S. pneumoniae serotype 4 concentrations one month after the fourth dose.GMC adjusted for BS sub cohorts;97.5% CI for adjusted GMC ratio(Ancova model:adjustment for BS sub cohorts-pooled variance)

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

421

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[19]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.1

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.92

upper limit

1.31

Notes
[19] - Lower limit of the two-sided 97.5% CI on the GMC ratio (HibCY group over PedHIB group) for antibodies to S. pneumoniae serotype 4 is to be≥0.5 (clinical limit for non-inferiority).To be able to conclude independently on primary objectives of Epoch 001 & Epoch 002, a Bonferroni correction is used to test these primary objectives(1.25% one-sided for Epoch 001 and Epoch 002)

Statistical analysis 4

Statistical analysis description

GMC ratios between HibCY and PedHIB groups for antibodies to S. pneumoniae serotype 5 concentrations one month after the fourth dose. GMC adjusted for BS sub cohorts;97.5% CI for adjusted GMC ratio(Ancova model:adjustment for BS sub cohorts-pooled variance)

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

421

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[20]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.06

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.87

upper limit

1.28

Notes
[20] - Lower limit of the two-sided 97.5% CI on the GMC ratio (HibCY group over PedHIB group) for antibodies to S. pneumoniae serotype 5 is to be ≥0.5 (clinical limit for non-inferiority).To be able to conclude independently on primary objectives of Epoch 001 & Epoch 002, a Bonferroni correction is used to test these primary objectives(1.25% one-sided for Epoch 001 and Epoch 002)

Statistical analysis 5

Statistical analysis description

GMC ratios between HibCY and PedHIB groups for antibodies to S. pneumoniae serotype 6A concentrations one month after the fourth dose. GMC adjusted for BS sub cohorts;97.5% CI for adjusted GMC ratio(Ancova model:adjustment for BS sub cohorts-pooled variance)

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

421

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[21]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.21

Confidence interval

level

97.5%

sides

2-sided

lower limit

1.01

upper limit

1.44

Notes
[21] - Lower limit of the two-sided 97.5% CI on the GMC ratio (HibCY group over PedHIB group) for antibodies to S. pneumoniae serotype 6A is to be≥0.5 (clinical limit for non-inferiority).To be able to conclude independently on primary objectives of Epoch 001 & Epoch 002, a Bonferroni correction is used to test these primary objectives(1.25% one-sided for Epoch 001 and Epoch 002)

Statistical analysis 6

Statistical analysis description

GMC ratios between HibCY and PedHIB groups for antibodies to S. pneumoniae serotype 6B concentrations one month after the fourth dose. GMC adjusted for BS sub cohorts;97.5% CI for adjusted GMC ratio(Ancova model:adjustment for BS sub cohorts-pooled variance)

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

421

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[22]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.13

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.94

upper limit

1.36

Notes
[22] - Lower limit of the two-sided 97.5% CI on the GMC ratio (HibCY group over PedHIB group) for antibodies to S. pneumoniae serotype 6B is to be≥0.5 (clinical limit for non-inferiority).To be able to conclude independently on primary objectives of Epoch 001 & Epoch 002, a Bonferroni correction is used to test these primary objectives(1.25% one-sided for Epoch 001 and Epoch 002)

Statistical analysis 7

Statistical analysis description

GMC ratios between HibCY and PedHIB groups for antibodies to S. pneumoniae serotype 7F concentrations one month after the fourth dose. GMC adjusted for BS sub cohorts;97.5% CI for adjusted GMC ratio(Ancova model:adjustment for BS sub cohorts-pooled variance)

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

421

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[23]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.09

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.93

upper limit

1.29

Notes
[23] - Lower limit of the two-sided 97.5% CI on the GMC ratio (HibCY group over PedHIB group) for antibodies to S. pneumoniae serotype 7F is to be≥0.5 (clinical limit for non-inferiority).To be able to conclude independently on primary objectives of Epoch 001 & Epoch 002, a Bonferroni correction is used to test these primary objectives(1.25% one-sided for Epoch 001 and Epoch 002)

Statistical analysis 8

Statistical analysis description

GMC ratios between HibCY and PedHIB groups for antibodies to S. pneumoniae serotype 9V concentrations one month after the fourth dose. GMC adjusted for BS sub cohorts;97.5% CI for adjusted GMC ratio(Ancova model:adjustment for BS sub cohorts-pooled variance)

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

421

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[24]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.12

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.94

upper limit

1.33

Notes
[24] - Lower limit of the two-sided 97.5% CI on the GMC ratio (HibCY group over PedHIB group) for antibodies to S. pneumoniae serotype 9V is to be≥0.5 (clinical limit for non-inferiority).To be able to conclude independently on primary objectives of Epoch 001 & Epoch 002, a Bonferroni correction is used to test these primary objectives(1.25% one-sided for Epoch 001 and Epoch 002)

Statistical analysis 9

Statistical analysis description

GMC ratios between HibCY and PedHIB groups for antibodies to S. pneumoniae serotype 14 concentrations one month after the fourth dose. GMC adjusted for BS sub cohorts;97.5% CI for adjusted GMC ratio(Ancova model:adjustment for BS sub cohorts-pooled variance)

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

421

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[25]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.16

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.96

upper limit

1.41

Notes
[25] - Lower limit of the two-sided 97.5% CI on the GMC ratio (HibCY group over PedHIB group) for antibodies to S. pneumoniae serotype 14 is to be≥0.5 (clinical limit for non-inferiority).To be able to conclude independently on primary objectives of Epoch 001 & Epoch 002, a Bonferroni correction is used to test these primary objectives(1.25% one-sided for Epoch 001 and Epoch 002)

Statistical analysis 10

Statistical analysis description

GMC ratios between HibCY and PedHIB groups for antibodies to S. pneumoniae serotype 18C concentrations one month after the fourth dose. GMC adjusted for BS sub cohorts;97.5% CI for adjusted GMC ratio(Ancova model:adjustment for BS sub cohorts-pooled variance)

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

421

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[26]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.14

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.97

upper limit

1.35

Notes
[26] - Lower limit of the two-sided 97.5% CI on the GMC ratio (HibCY group over PedHIB group) for antibodies to S. pneumoniae serotype 18C is to be≥0.5 (clinical limit for non-inferiority).To be able to conclude independently on primary objectives of Epoch 001 & Epoch 002, a Bonferroni correction is used to test these primary objectives(1.25% one-sided for Epoch 001 and Epoch 002)

Statistical analysis 11

Statistical analysis description

GMC ratios between HibCY and PedHIB groups for antibodies to S. pneumoniae serotype 19A concentrations one month after the fourth dose.GMC adjusted for BS sub cohorts;97.5% CI for adjusted GMC ratio(Ancova model:adjustment for BS sub cohorts-pooled variance)

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

421

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[27]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.09

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.9

upper limit

1.31

Notes
[27] - Lower limit of the two-sided 97.5% CI on the GMC ratio (HibCY group over PedHIB group) for antibodies to S. pneumoniae serotype 19A is to be≥0.5 (clinical limit for non-inferiority).To be able to conclude independently on primary objectives of Epoch 001 & Epoch 002, a Bonferroni correction is used to test these primary objectives(1.25% one-sided for Epoch 001 and Epoch 002)

Statistical analysis 12

Statistical analysis description

GMC ratios between HibCY and PedHIB groups for antibodies to S. pneumoniae serotype 19F concentrations one month after the fourth dose.GMC adjusted for BS sub cohorts;97.5% CI for adjusted GMC ratio(Ancova model:adjustment for BS sub cohorts-pooled variance)

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

421

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[28]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.12

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.95

upper limit

1.34

Notes
[28] - Lower limit of the two-sided 97.5% CI on the GMC ratio (HibCY group over PedHIB Group) for antibodies to S. pneumoniae serotype 19F is to be≥0.5 (clinical limit for non-inferiority).To be able to conclude independently on primary objectives of Epoch 001 & Epoch 002, a Bonferroni correction is used to test these primary objectives(1.25% one-sided for Epoch 001 and Epoch 002)

Statistical analysis 13

Statistical analysis description

GMC ratios between HibCY and PedHIB groups for antibodies to S. pneumoniae serotype 23F concentrations one month after the fourth dose. GMC adjusted for BS sub cohorts;97.5% CI for adjusted GMC ratio(Ancova model:adjustment for BS sub cohorts-pooled variance)

Comparison groups

HibCY Group v PedHIB Group

Number of subjects included in analysis

421

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[29]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.22

Confidence interval

level

97.5%

sides

2-sided

lower limit

upper limit

1.5

Notes
[29] - Lower limit of the two-sided 97.5% CI on the GMC ratio (HibCY group over PedHIB group) for antibodies to S. pneumoniae serotype 23F is to be≥0.5 (clinical limit for non-inferiority).To be able to conclude independently on primary objectives of Epoch 001 & Epoch 002, a Bonferroni correction is used to test these primary objectives(1.25% one-sided for Epoch 001 and Epoch 002)

Secondary: Percentage of subjects with anti-PRP antibody concentrations ≥0.15 µg/mL.

Top of page

End point title

Percentage of subjects with anti-PRP antibody concentrations ≥0.15 µg/mL.

End point description

The cut-off value for this assay was 0.15 µg/mL. Analysis of Immunogenicity is performed on blood sample (BS) sub-cohorts.Assignment to a BS sub-cohort depends on the date of enrolment of the subject: BS sub-cohort for the first 200 , for the next 200 subjects or for the last 200 subjects. Within each BS sub-cohort subjects have been randomized 1:1 to either HibCY or PedHIB groups.

End point type

Secondary

End point timeframe

2 months post-dose 2 [PedHib Group only (Month 4)], 1 month post-dose 3 (Month 5 for HibCY group and Months 11-14 for PedHib Group) and 1 month post-dose 4 [HibCY Group only (Month 11-14)]

End point values	HibCY Group	PedHIB Group
Number of subjects analysed	223	218
Units: Percentage of subjects
number (confidence interval 95%)
Month 4 (N=0,165)	0 (0 to 0)	98.8 (95.7 to 99.9)
Month 5 (N=167,0)	99.4 (96.7 to 100)	0 (0 to 0)
Month 11-14 (N=223, 218)	99.6 (97.5 to 100)	100 (98.3 to 100)

No statistical analyses for this end point

Secondary: Anti-PRP GMCs ≥ 0.15 µg/mL.

Top of page

End point title

Anti-PRP GMCs ≥ 0.15 µg/mL.

End point description

Anti-PRP antibody concentrations were assessed by Enzyme-Linked-Immunosorbent-Assay (ELISA), tabulated as Geometric Mean Concentrations (GMCs) and expressed in micrograms per mililiter (µg/mL).The cut-off value for this assay was 0.15 µg/mL. Analysis of Immunogenicity is performed on blood sample (BS) sub-cohorts.Assignment to a BS sub-cohort depends on the date of enrolment of the subject: BS sub-cohort for the first 200 , for the next 200 subjects or for the last 200 subjects. Within each BS sub-cohort subjects have been randomized 1:1 to either HibCY or PedHIB groups.

End point type

Secondary

End point timeframe

2 months post-dose 2 [PedHib Group only (Month 4)], 1 month post-dose 3 (Month 5 for HibCY group and Month 11-14 for PedHib Group) and 1 month post-dose 4 [HibCY Group only (Month 11-14)]

End point values	HibCY Group	PedHIB Group
Number of subjects analysed	223	218
Units: µg/mL
geometric mean (confidence interval 95%)
Month 4 (N=0, 165)	0 (0 to 0)	11.053 (8.740 to 13.979)
Month 5 (N=167,0)	8.414 (7.070 to 10.014)	0 (0 to 0)
Month 11-14 (N=223, 218)	28.090 (24.012 to 32.862)	20.869 (17.799 to 24.468)

No statistical analyses for this end point

Secondary: Percentage of subjects with anti-PRP antibody concentrations ≥1.0 µg/mL

Top of page

End point title

Percentage of subjects with anti-PRP antibody concentrations ≥1.0 µg/mL

End point description

The cut-off value for this assay was 1.0 µg/mL. Analysis of Immunogenicity is performed on blood sample (BS) sub-cohorts.Assignment to a BS sub-cohort depends on the date of enrolment of the subject: BS sub-cohort for the first 200 , for the next 200 subjects or for the last 200 subjects. Within each BS sub-cohort subjects have been randomized 1:1 to either HibCY or PedHIB groups.

End point type

Secondary

End point timeframe

2 months post-dose 2 [PedHib group only (Month 4)] and 1 month postdose 3 [HibCY group only (Month 5)].

End point values	HibCY Group	PedHIB Group
Number of subjects analysed	167	165
Units: Percentage of subjects
number (confidence interval 95%)
Month 4 (N=167,0)	0 (0 to 0)	91.5 (86.2 to 95.3)
Month 5 (N=0,165)	94.0 (89.3 to 97.1)	0 (0 to 0)

No statistical analyses for this end point

Secondary: Percentage of subjects with Serum bactericidal assay to N. meningitidis serogroup C (hSBA-MenC) and N. meningitidis serogroup Y (hSBA-MenY) antibody titers ≥1:8, ≥1:16, ≥1:32.

Top of page

End point title

Percentage of subjects with Serum bactericidal assay to N. meningitidis serogroup C (hSBA-MenC) and N. meningitidis serogroup Y (hSBA-MenY) antibody titers ≥1:8, ≥1:16, ≥1:32.

End point description

The cut off values are dilutions of 1:8, 1:16 and 1:32. Analysis of Immunogenicity is performed on blood sample (BS) sub-cohorts.Assignment to a BS sub-cohort depends on the date of enrolment of the subject: BS sub-cohort for the first 200 , for the next 200 subjects or for the last 200 subjects. Within each BS sub-cohort subjects have been randomized 1:1 to either HibCY or PedHIB groups.

End point type

Secondary

End point timeframe

1 month post-dose 3 (Month 5) and 1 month post-dose 4 (Month 11-14).

End point values	HibCY Group	PedHIB Group
Number of subjects analysed	215	187
Units: Percentage of subjects
number (confidence interval 95%)
hSBA-MenC, Month 5, ≥ 8 (N=144,141)	100 (97.5 to 100)	1.4 (0.2 to 5.0)
hSBA-MenC, Month 5, ≥ 16 (N=144,141)	100 (97.5 to 100)	1.4 (0.2 to 5.0)
hSBA-MenC, Month 5, ≥ 32 (N=144,141)	99.3 (96.2 to 100)	0.7 (0.0 to 3.9)
hSBA-MenY, Month 5, ≥ 8 (N=130, 150)	97.7 (93.4 to 99.5)	100 (97.6 to 100)
hSBA-MenY, Month 5, ≥ 16 (N=130, 150)	97.7 (93.4 to 99.5)	100 (97.6 to 100)
hSBA-MenY, Month 5, ≥ 32 (N=130,150)	97.7 (93.4 to 99.5)	100 (97.6 to 100)
hSBA-MenC, Month 11-14, ≥ 8 (N=215,168)	99.1 (96.7 to 99.9)	0.6 (0.0 to 3.3)
hSBA-MenC, Month 11-14, ≥ 16 (N=215, 168)	98.6 (96.0 to 99.7)	0.6 (0.0 to 3.3)
hSBA-MenC, Month 11-14, ≥ 32 (N=215, 168)	98.1 (95.3 to 99.5)	0.0 (0.0 to 2.2)
hSBA-MenY, Month 11-14, ≥ 8 (N=198, 187)	98.5 (95.6 to 99.7)	100 (98.0 to 100)
hSBA-MenY, Month 11-14, ≥ 16 (N=198, 187)	98.5 (95.6 to 99.7)	100 (98.0 to 100)
hSBA-MenY, Month 11-14, ≥ 32 (N=198, 187)	98.5 (95.6 to 99.7)	100 (98.0 to 100)

No statistical analyses for this end point

Secondary: Geometric Mean Titres (GMTs) of human complement serum bactericidal assay to N. meningitidis serogroup C (hSBA-MenC) and to hSBA-MenY

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End point title

Geometric Mean Titres (GMTs) of human complement serum bactericidal assay to N. meningitidis serogroup C (hSBA-MenC) and to hSBA-MenY

End point description

The cut-off values are dilutions of 1:8, 1:16 and 1:32. Analysis of Immunogenicity is performed on blood sample (BS) sub-cohorts.Assignment to a BS sub-cohort depends on the date of enrolment of the subject: BS sub-cohort for the first 200 , for the next 200 subjects or for the last 200 subjects. Within each BS sub-cohort subjects have been randomized 1:1 to either HibCY or PedHIB groups.

End point type

Secondary

End point timeframe

1 month post-dose 3 (Month 5) and 1 month post-dose 4 (Month 11-14).

End point values	HibCY Group	PedHIB Group
Number of subjects analysed	215	187
Units: Titres
geometric mean (confidence interval 95%)
hSBA-MenC, Month 5 (N=144, 141)	807.3 (659.2 to 988.6)	2.1 (2.0 to 2.3)
hSBA-MenY, Month 5 (N=130, 150)	510.9 (405.7 to 643.3)	550.2 (474.4 to 638.1)
hSBA-MenC, Month 11-14 (N=215, 168)	2566.2 (2046.3 to 3218.1)	2.0 (2.0 to 2.1)
hSBA-MenY, Month 11-14 (N=198,187)	2761.4 (2274.2 to 3353.1)	2728.2 (2412.7 to 3085.0)

No statistical analyses for this end point

Secondary: Percentage of subjects with Anti-rotavirus IgA antibody concentrations ≥ 20 Units (U)/mL

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End point title

Percentage of subjects with Anti-rotavirus IgA antibody concentrations ≥ 20 Units (U)/mL

End point description

The cut-off value is 20 Units (U)/mL Analysis of Immunogenicity is performed on blood sample (BS) sub-cohorts.Assignment to a BS sub-cohort depends on the date of enrolment of the subject: BS sub-cohort for the first 200 , for the next 200 subjects or for the last 200 subjects. Within each BS sub-cohort subjects have been randomized 1:1 to either HibCY or PedHIB groups.

End point type

Secondary

End point timeframe

2 month post-dose 2 of Rotarix (Month 4)

End point values	HibCY Group	PedHIB Group
Number of subjects analysed	155	161
Units: Percentage of subjects
number (confidence interval 95%)
Anti-rota virus IgA ≥20 U/mL (N=155, 161)	81.3 (74.2 to 87.1)	80.1 (73.1 to 86.0)

No statistical analyses for this end point

Secondary: Percentage of subjects with Anti-HAV antibodies ≥ 15 mIU/mL

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End point title

Percentage of subjects with Anti-HAV antibodies ≥ 15 mIU/mL

End point description

The cut-off value is 15 mIU/mL. Analysis of Immunogenicity is performed on blood sample (BS) sub-cohorts.Assignment to a BS sub-cohort depends on the date of enrolment of the subject: BS sub-cohort for the first 200 , for the next 200 subjects or for the last 200 subjects. Within each BS sub-cohort subjects have been randomized 1:1 to either HibCY or PedHIB groups.

End point type

Secondary

End point timeframe

1 month post-dose 1 of Havrix (Month 11-14)

End point values	HibCY Group	PedHIB Group
Number of subjects analysed	182	168
Units: percentage of subjects
number (confidence interval 95%)
Anti-HAV antibodies ≥15mIU/mL (N=182, 168)	85.2 (79.2 to 90.0)	89.3 (83.6 to 93.5)

No statistical analyses for this end point

Secondary: Anti-HAV GMCs ≥ 15 mIU/mL

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End point title

Anti-HAV GMCs ≥ 15 mIU/mL

End point description

End point type

Secondary

End point timeframe

1 month post-dose 1 of HAV (M11-14).

End point values	HibCY Group	PedHIB Group
Number of subjects analysed	182	168
Units: mIU/mL
geometric mean (confidence interval 95%)
Anti-HAV antibodies≥15mIU/mL (N=182, 168)	44.8 (38.3 to 52.5)	47.3 (40.9 to 54.8)

No statistical analyses for this end point

Secondary: GMCs for anti-HAV antibodies ≥15mIU/mL.

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End point title

GMCs for anti-HAV antibodies ≥15mIU/mL.

End point description

End point type

Secondary

End point timeframe

1 month post-dose 2 of HAV (Month 17-20).

End point values	HibCY Group	PedHIB Group
Number of subjects analysed	129	124
Units: mIU/mL
geometric mean (confidence interval 95%)
Anti-HAV antibodies ≥15mIU/mL (N=129, 124)	1590.7 (1312.7 to 1927.5)	1390.6 (1147.8 to 1684.6)

No statistical analyses for this end point

Secondary: Percentage of subjects with S. pneumoniae antibody concentrations ≥ 0.15 µg/mL, ≥ 0.26 µg/mL and ≥ 0.35 µg/mL for serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F

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End point title

Percentage of subjects with S. pneumoniae antibody concentrations ≥ 0.15 µg/mL, ≥ 0.26 µg/mL and ≥ 0.35 µg/mL for serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F

End point description

The cut-off values are 0.15, 0.26, 0.35 µg/mL. Analysis of Immunogenicity is performed on blood sample (BS) sub-cohorts.Assignment to a BS sub-cohort depends on the date of enrolment of the subject: BS sub-cohort for the first 200 , for the next 200 subjects or for the last 200 subjects. Within each BS sub-cohort subjects have been randomized 1:1 to either HibCY or PedHIB groups

End point type

Secondary

End point timeframe

1 month post-dose 3 (Month 5) and 1 month post-dose 4 (Month 11-14)

End point values	HibCY Group	PedHIB Group
Number of subjects analysed	216	205
Units: Percentage of subjects
number (confidence interval 95%)
Anti-1 antibody,Month 5, ≥ 0.15(N=156, 158)	100 (97.7 to 100)	100 (97.7 to 100)
Anti-1 antibody,Month 5, ≥ 0.26(N=156, 158)	98.1 (94.5 to 99.6)	98.7 (95.5 to 99.8)
Anti-1 antibody,Month 5, ≥ 0.35(N=156, 158)	96.8 (92.7 to 99.0)	93.7 (88.7 to 96.9)
Anti-3 antibody,Month 5, ≥ 0.15(N=149, 150)	96.6 (92.3 to 98.9)	94.0 (88.9 to 97.2)
Anti-3 antibody,Month 5, ≥ 0.26(N=149, 150)	84.6 (77.7 to 90.0)	78.7 (71.2 to 84.9)
Anti-3 antibody,Month 5, ≥ 0.35(N=149, 150)	69.8 (61.7 to 77.0)	69.3 (61.3 to 76.6)
Anti-4 antibody,Month 5, ≥ 0.15(N=156, 158)	98.7 (95.4 to 99.8)	98.1 (94.6 to 99.6)
Anti-4 antibody,Month 5, ≥ 0.26(N=156, 158)	96.8 (92.7 to 99.0)	91.8 (86.3 to 95.5)
Anti-4 antibody,Month 5, ≥ 0.35(N=156, 158)	91.0 (85.4 to 95.0)	84.8 (78.2 to 90.0)
Anti-5 antibody,Month 5, ≥ 0.15(N=156, 158)	97.4 (93.6 to 99.3)	96.8 (92.8 to 99.0)
Anti-5 antibody, Month 5, ≥ 0.26(N=156, 158)	93.6 (88.5 to 96.9)	86.7 (80.4 to 91.6)
Anti-5 antibody, Month 5, ≥ 0.35(N=156, 158)	91.0 (85.4 to 95.0)	80.4 (73.3 to 86.3)
Anti-6A antibody, Month 5, ≥ 0.15(N=156, 158)	100 (97.7 to 100)	98.7 (95.5 to 99.8)
Anti-6A antibody, Month 5, ≥ 0.26(N=156, 158)	98.7 (95.4 to 99.8)	94.3 (89.5 to 97.4)
Anti-6A antibody, Month 5, ≥ 0.35(N=156, 158)	98.1 (94.5 to 99.6)	91.8 (86.3 to 95.5)
Anti-6B antibody, Month 5, ≥ 0.15(N=154, 158)	95.5 (90.9 to 98.2)	93.7 (88.7 to 96.9)
Anti-6B antibody, Month 5, ≥ 0.26(N=154, 158)	90.9 (85.2 to 94.9)	86.1 (79.7 to 91.1)
Anti-6B antibody, Month 5, ≥ 0.35(N=154, 158)	83.8 (77.0 to 89.2)	80.4 (73.3 to 86.3)
Anti-7F antibody, Month 5, ≥ 0.15(N=156, 158)	100 (97.7 to 100)	100 (97.7 to 100)
Anti-7F antibody, Month 5, ≥ 0.26(N=156, 158)	100 (97.7 to 100)	100 (97.7 to 100)
Anti-7F antibody, Month 5, ≥ 0.35(N=156, 158)	100 (97.7 to 100)	100 (97.7 to 100)
Anti-9V antibody, Month 5, ≥ 0.15(N=156, 157)	99.4 (96.5 to 100)	94.9 (90.2 to 97.8)
Anti-9V antibody, Month 5, ≥ 0.26(N=156, 157)	92.9 (87.7 to 96.4)	86.6 (80.3 to 91.5)
Anti-9V antibody, Month 5, ≥ 0.35(N=156, 157)	83.3 (76.5 to 88.8)	76.4 (69.0 to 82.8)
Anti-14 antibody, Month 5, ≥ 0.15(N=156, 156)	100 (97.7 to 100)	99.4 (96.5 to 100)
Anti-14 antibody, Month 5, ≥ 0.26(N=156, 156)	100 (97.7 to 100)	98.1 (94.5 to 99.6)
Anti-14 antibody, Month 5, ≥ 0.35(N=156, 156)	99.4 (96.5 to 100)	97.4 (93.6 to 99.3)
Anti-18C antibody, Month 5, ≥ 0.15(N=156, 158)	100 (97.7 to 100)	98.1 (94.6 to 99.6)
Anti-18C antibody, Month 5, ≥ 0.26(N=156, 158)	96.8 (92.7 to 99.0)	91.1 (85.6 to 95.1)
Anti-18C antibody, Month 5, ≥ 0.35(N=156, 158)	87.2 (80.9 to 92.0)	82.3 (75.4 to 87.9)
Anti-19A antibody, Month 5, ≥ 0.15(N=156, 158)	100 (97.7 to 100)	98.1 (94.6 to 99.6)
Anti-19A antibody, Month 5, ≥ 0.26(N=156, 158)	99.4 (96.5 to 100)	93.0 (87.9 to 96.5)
Anti-19A antibody, Month 5, ≥ 0.35(N=156, 158)	97.4 (93.6 to 99.3)	90.5 (84.8 to 94.6)
Anti-19F antibody, Month 5, ≥ 0.15(N=155, 158)	100 (97.6 to 100)	100 (97.7 to 100)
Anti-19F antibody, Month 5, ≥ 0.26(N=155, 158)	100 (97.6 to 100)	100 (97.7 to 100)
Anti-19F antibody, Month 5, ≥ 0.35(N=155, 158)	98.7 (95.4 to 99.8)	100 (97.7 to 100)
Anti-23F antibody, Month 5, ≥ 0.15(N=156, 157)	96.8 (92.7 to 99.0)	96.2 (91.9 to 98.6)
Anti-23F antibody, Month 5, ≥ 0.26(N=156, 157)	91.7 (86.2 to 95.5)	84.1 (77.4 to 89.4)
Anti-23F antibody, Month 5, ≥ 0.35(N=156, 157)	83.3 (76.5 to 88.8)	77.1 (69.7 to 83.4)
Anti-1 antibody, Month 11-14, ≥ 0.15(N=216, 205)	100 (98.3 to 100)	100 (98.2 to 100)
Anti-1 antibody,Month 11-14, ≥ 0.26(N=216, 205)	99.5 (97.4 to 100)	99.5 (97.3 to 100)
Anti-1 antibody,Month 11-14, ≥0.35(N=216, 205)	97.7 (94.7 to 99.2)	97.1 (93.7 to 98.9)
Anti-3 antibody,Month 11-14, ≥ 0.15(N=169,167)	97.0 (93.2 to 99.0)	94.0 (89.3 to 97.1)
Anti-3 antibody,Month 11-14, ≥ 0.26(N=169,167)	85.2 (78.9 to 90.2)	81.4 (74.7 to 87.0)
Anti-3 antibody,Month 11-14, ≥0.35(N=169,167)	71.6 (64.2 to 78.3)	69.5 (61.9 to 76.3)
Anti-4 antibody,Month 11-14, ≥ 0.15(N=216,205)	100 (98.3 to 100)	98.5 (95.8 to 99.7)
Anti-4 antibody,Month 11-14, ≥ 0.26(N=216,205)	98.6 (96.0 to 99.7)	97.1 (93.7 to 98.9)
Anti-4 antibody,Month 11-14, ≥0.35(N=216,205)	97.7 (94.7 to 99.2)	94.1 (90.0 to 96.9)
Anti-5 antibody,Month 11-14, ≥ 0.15(N=215,205)	100 (98.3 to 100)	100 (98.2 to 100)
Anti-5 antibody,Month 11-14, ≥ 0.26(N=215,205)	99.5 (97.4 to 100)	99.5 (97.3 to 100)
Anti-5 antibody,Month 11-14, ≥0.35(N=215,205)	99.1 (96.7 to 99.9)	98.0 (95.1 to 99.5)
Anti-6A antibody,Month 11-14, ≥ 0.15(N=216,205)	100 (98.3 to 100)	100 (98.2 to 100)
Anti-6A antibody,Month 11-14, ≥ 0.26(N=216,205)	100 (98.3 to 100)	100 (98.2 to 100)
Anti-6A antibody,Month 11-14, ≥0.35(N=216,205)	100 (98.3 to 100)	100 (98.2 to 100)
Anti-6B antibody,Month 11-14, ≥ 0.15(N=215,205)	100 (98.3 to 100)	100 (98.2 to 100)
Anti-6B antibody,Month 11-14, ≥ 0.26(N=215,205)	100 (98.3 to 100)	100 (98.2 to 100)
Anti-6B antibody,Month 11-14, ≥0.35(N=215,205)	100 (98.3 to 100)	100 (98.2 to 100)
Anti-7F antibody,Month 11-14, ≥ 0.15(N=216,205)	100 (98.3 to 100)	100 (98.2 to 100)
Anti-7F antibody, Month 11-14, ≥ 0.26(N=216,205)	100 (98.3 to 100)	99.5 (97.3 to 100)
Anti-7F antibody, Month 11-14, ≥0.35(N=216,205)	100 (98.3 to 100)	99.5 (97.3 to 100)
Anti-9V antibody, Month 11-14, ≥ 0.15(N=215,205)	100 (98.3 to 100)	99.0 (96.5 to 99.9)
Anti-9V antibody, Month 11-14, ≥ 0.26(N=215,205)	99.1 (96.7 to 99.9)	98.5 (95.8 to 99.7)
Anti-9V antibody, Month 11-14, ≥0.35(N=215,205)	97.7 (94.7 to 99.2)	96.6 (93.1 to 98.6)
Anti-14 antibody, Month 11-14, ≥ 0.15(N=216,205)	99.5 (97.4 to 100)	100 (98.2 to 100)
Anti-14 antibody, Month 11-14, ≥ 0.26(N=216,205)	99.5 (97.4 to 100)	100 (98.2 to 100)
Anti-14 antibody, Month 11-14, ≥0.35(N=216,205)	99.5 (97.4 to 100)	100 (98.2 to 100)
Anti-18C antibody, Month 11-14, ≥ 0.15(N=216,204)	100 (98.3 to 100)	100 (98.2 to 100)
Anti-18C antibody, Month 11-14, ≥ 0.26(N=216,204)	99.5 (97.4 to 100)	99.0 (96.5 to 99.9)
Anti-18C antibody, Month 11-14, ≥0.35(N=216,204)	98.6 (96.0 to 99.7)	97.5 (94.4 to 99.2)
Anti-19A antibody, Month 11-14, ≥ 0.15(N=216,204)	100 (98.3 to 100)	100 (98.2 to 100)
Anti-19A antibody, Month 11-14, ≥ 0.26(N=216,204)	100 (98.3 to 100)	100 (98.2 to 100)
Anti-19A antibody, Month 11-14, ≥0.35(N=216,204)	100 (98.3 to 100)	100 (98.2 to 100)
Anti-19F antibody, Month 11-14, ≥ 0.15(N=215,205)	100 (98.3 to 100)	100 (98.2 to 100)
Anti-19F antibody, Month 11-14, ≥ 0.26(N=215,205)	100 (98.3 to 100)	100 (98.2 to 100)
Anti-19F antibody, Month 11-14, ≥0.35(N=215,205)	100 (98.3 to 100)	100 (98.2 to 100)
Anti-23F antibody, Month 11-14, ≥ 0.15(N=216,205)	99.5 (97.4 to 100)	100 (98.2 to 100)
Anti-23F antibody, Month 11-14, ≥ 0.26(N=216,205)	99.5 (97.4 to 100)	100 (98.2 to 100)
Anti-23F antibody, Month 11-14, ≥0.35(N=216,205)	98.1 (95.3 to 99.5)	100 (98.2 to 100)

No statistical analyses for this end point

Secondary: Percentage of subjects reporting any solicited local adverse events (AE).

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End point title

Percentage of subjects reporting any solicited local adverse events (AE).

End point description

Solicited local adverse events include pain, redness and swelling at injection site.

End point type

Secondary

End point timeframe

4 days (Day 0 to Day 3) after all vaccines post-primary and post-fourth dose

End point values	HibCY Group	PedHIB Group
Number of subjects analysed	285	291
Units: Percentage of subjects
number (confidence interval 95%)
Pain,Hib-MenCY-TT/PedvaxHIB,Dose 1(N=285, 291)	44.2 (38.4 to 50.2)	61.2 (55.3 to 66.8)
Pain,Pediarix,Dose 1(N=285, 291)	50.5 (44.6 to 56.5)	57.4 (51.5 to 63.1)
Pain,Prevnar 13,Dose 1(N=285, 291)	46.3 (40.4 to 52.3)	58.8 (52.9 to 64.5)
Pain,Hib-MenCY-TT/PedvaxHIB,Dose 2(N=272, 278)	45.6 (39.6 to 51.7)	56.8 (50.8 to 62.7)
Pain,Pediarix,Dose 2(N=272, 278)	45.2 (39.2 to 51.3)	55.8 (49.7 to 61.7)
Pain,Prevnar 13,Dose 2(N=272, 277)	44.5 (38.5 to 50.6)	56.0 (49.9 to 61.9)
Pain,Hib-MenCY-TT/PedvaxHIB,Dose 3(N=N=260, 0)	38.8 (32.9 to 45.1)	0 (0 to 0)
Pain,Pediarix,Dose 3(N=262, 264)	42.7 (36.7 to 49.0)	50.8 (44.6 to 56.9)
Pain,Prevnar 13,Dose 3(N=262, 264)	39.7 (33.7 to 45.9)	47.7 (41.6 to 53.9)
Pain,Havrix,Dose 4(N=241,242)	44.8 (38.4 to 51.3)	50.0 (43.5 to 56.5)
Pain,Hib-MenCY-TT/PedvaxHIB,Dose 4(N=241,242)	42.3 (36.0 to 48.8)	56.2 (49.7 to 62.5)
Pain,Prevnar 13,Dose 4(N=241,242)	41.5 (35.2 to 48.0)	46.7 (40.3 to 53.2)
Redness,Hib-MenCY-TT/PedvaxHIB,Dose 1(N=284,291)	21.1 (16.5 to 26.3)	35.4 (29.9 to 41.2)
Redness,Pediarix,Dose 1(N=284,291)	27.1 (22.0 to 32.7)	25.1 (20.2 to 30.5)
Redness,Prevnar 13,Dose 1(N=284,291)	23.6 (18.8 to 29.0)	24.4 (19.6 to 29.8)
Redness,Hib-MenCY-TT/PedvaxHIB,Dose 2(N=271,278)	30.3 (24.8 to 36.1)	41.4 (35.5 to 47.4)
Redness,Pediarix,Dose 2(N=271,278)	33.9 (28.3 to 39.9)	43.2 (37.3 to 49.2)
Redness,Prevnar 13,Dose 2(N=271,277)	30.6 (25.2 to 36.5)	41.2 (35.3 to 47.2)
Redness,Hib-MenCY-TT/PedvaxHIB,Dose 3(N=260,0)	31.5 (25.9 to 37.6)	0 (0 to 0)
Redness,Pediarix,Dose 3(N=262,264)	38.2 (32.3 to 44.3)	50.4 (44.2 to 56.6)
Redness,Prevnar 13,Dose 3(N=262,264)	36.3 (30.4 to 42.4)	45.8 (39.7 to 52.1)
Redness,Havrix,Dose 4(N=241,242)	38.6 (32.4 to 45.1)	43.8 (37.5 to 50.3)
Redness,Hib-MenCY-TT/PedvaxHIB,Dose 4(N=241,242)	38.6 (32.4 to 45.1)	50.8 (44.3 to 57.3)
Redness,Prevnar 13,Dose 4(N=241,242)	41.1 (34.8 to 47.6)	44.6 (38.3 to 51.1)
Swelling,Hib-MenCY-TT/PedvaxHIB,Dose 1(N=284,291)	11.3 (7.8 to 15.5)	22.0 (17.4 to 27.2)
Swelling,Pediarix,Dose 1(N=284,291)	18.7 (14.3 to 23.7)	16.2 (12.1 to 20.9)
Swelling,Prevnar 13,Dose 1(N=284,291)	14.8 (10.9 to 19.5)	16.2 (12.1 to 20.9)
Swelling,Hib-MenCY-TT/PedvaxHIB,Dose 2(N=271,278)	18.5 (14.0 to 23.6)	30.6 (25.2 to 36.4)
Swelling,Pediarix,Dose 2(N=271,278)	22.1 (17.3 to 27.6)	36.3 (30.7 to 42.3)
Swelling,Prevnar 13,Dose 2(N=271,277)	22.5 (17.7 to 28.0)	28.9 (23.6 to 34.6)
Swelling,Hib-MenCY-TT/PedvaxHIB,Dose 3(N=260,0)	19.2 (14.6 to 24.6)	0 (0 to 0)
Swelling,Pediarix,Dose 3(N=262, 264)	29.4 (23.9 to 35.3)	37.9 (32.0 to 44.0)
Swelling,Prevnar 13,Dose 3(N=262, 264)	24.4 (19.3 to 30.1)	31.4 (25.9 to 37.4)
Swelling,Havrix,Dose 4(N=241, 242)	25.3 (19.9 to 31.3)	26.0 (20.6 to 32.0)
Swelling,Hib-MenCY-TT/PedvaxHIB,Dose 4(N=241, 242)	22.8 (17.7 to 28.6)	34.3 (28.3 to 40.6)
Swelling,Prevnar 13,Dose 4(N=241, 242)	26.1 (20.7 to 32.2)	27.7 (22.1 to 33.8)

No statistical analyses for this end point

Secondary: Percentage of subjects reporting any solicited general AEs.

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End point title

Percentage of subjects reporting any solicited general AEs.

End point description

Solicited general AEs include fever [defined as temperature ≥38.0 degrees Celsius (°C) by any method], drowsiness, irritability/fussiness and loss of appetite.

End point type

Secondary

End point timeframe

4 days (Day 0 to Day 3) after all vaccines post-primary and post-fourth dose.

End point values	HibCY Group	PedHIB Group
Number of subjects analysed	285	291
Units: Percentage of subjects
number (confidence interval 95%)
Any Temperature (°C), Dose 1(N=285, 291)	11.2 (7.8 to 15.5)	20.6 (16.1 to 25.7)
Any Temperature (°C), Dose 2(N=273, 279)	19.4 (14.9 to 24.6)	29.0 (23.8 to 34.7)
Any Temperature (°C), Dose 3(N=262, 265)	16.4 (12.1 to 21.5)	17.0 (12.7 to 22.1)
Any Temperature (°C), Dose 4(N=242, 241)	8.7 (5.5 to 13.0)	10.4 (6.8 to 14.9)
Irritability / Fussiness, Dose 1(N=285,291)	71.2 (65.6 to 76.4)	81.8 (76.9 to 86.0)
Irritability / Fussiness, Dose 2(N=273,278)	70.0 (64.1 to 75.3)	83.5 (78.6 to 87.6)
Irritability / Fussiness, Dose 3(N=262,265)	66.0 (59.9 to 71.7)	69.4 (63.5 to 74.9)
Irritability / Fussiness, Dose 4(N=241,241)	66.0 (59.6 to 71.9)	74.3 (68.3 to 79.7)
Loss Of Appetite, Dose 1(N=285, 291)	31.6 (26.2 to 37.3)	42.3 (36.5 to 48.2)
Loss Of Appetite, Dose 2(N=273,278)	29.7 (24.3 to 35.5)	31.7 (26.2 to 37.5)
Loss Of Appetite, Dose 3(N=262,265)	29.8 (24.3 to 35.7)	28.7 (23.3 to 34.5)
Loss Of Appetite, Dose 4(N=241,241)	33.2 (27.3 to 39.5)	39.8 (33.6 to 46.3)
Drowsiness, Dose 1(N=285, 291)	64.9 (59.1 to 70.4)	70.1 (64.5 to 75.3)
Drowsiness, Dose 2(N=273,278)	54.2 (48.1 to 60.2)	65.1 (59.2 to 70.7)
Drowsiness, Dose 3(N=262,265)	48.9 (42.7 to 55.1)	52.5 (46.3 to 58.6)
Drowsiness, Dose 4(N=241,241)	44.0 (37.6 to 50.5)	48.5 (42.1 to 55.0)

No statistical analyses for this end point

Secondary: Percentage of subjects reporting any unsolicited AEs.

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End point title

Percentage of subjects reporting any unsolicited AEs.

End point description

Any adverse event (AE) reported in addition to those solicited during the clinical study. Also any “solicited” symptom with onset outside the specified period of follow-up for solicited symptoms were reported as an unsolicited adverse event.

End point type

Secondary

End point timeframe

During 31 days (Day 0 to Day 30) after all vaccines post-primary (Dose 1-3) and post-fourth dose (Dose 4)

End point values	HibCY Group	PedHIB Group
Number of subjects analysed	297	303
Units: Percentage of subjects
number (confidence interval 95%)
Dose 1-3 (N=297, 303)	60.6 (54.8 to 66.2)	56.4 (50.6 to 62.1)
Dose 4(N=248, 250)	39.9 (33.8 to 46.3)	42.0 (35.8 to 48.4)

No statistical analyses for this end point

Secondary: Percentage of subjects reporting any serious adverse events (SAEs).

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End point title

Percentage of subjects reporting any 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

During the entire study period (from Day 0 to Month 17-20)

End point values	HibCY Group	PedHIB Group
Number of subjects analysed	297	303
Units: Percentage of subjects
number (confidence interval 95%)
Any SAEs(N=297,303)	2.7 (1.2 to 5.2)	3.6 (1.8 to 6.4)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Solicited adverse events - Day 0-Day 4 Unsolicited Adverse events - Day 0- Day 31 after all vaccines post-primary and post-fourth dose. SAEs - day 0 to study end (Month 17-20)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.1

Reporting group title

PedHIB group

Reporting group description

Reporting group title

HibCY group

Reporting group description

Subjects received 4 doses of Hib-MenCY-TT vaccine at Day 0, Month 2, Month 4 and Month 10-13 , 3 doses of Pediarix vaccine at Day 0, Month 2 and Month 4, 2 doses of Rotarix vaccine at Day 0 and Month 2, 4 doses of Prevnar 13 vaccine at Day 0 and Month 2, Month 4 and Month 10-13 and 2 doses of Havrix vaccine at Month 10-13 and Month 16-19.

Serious adverse events	PedHIB group	HibCY group
Total subjects affected by serious adverse events
subjects affected / exposed	11 / 303 (3.63%)	8 / 297 (2.69%)
number of deaths (all causes)	0	1
number of deaths resulting from adverse events
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Kawasaki's disease
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Histiocytosis haematophagic
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Hypothermia
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden infant death syndrome
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Gastrointestinal disorders
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Apparent life threatening event
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Croup infectious
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 303 (0.00%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory syncytial virus bronchiolitis
subjects affected / exposed	2 / 303 (0.66%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Viral infection
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Failure to thrive
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypernatraemia
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ketoacidosis
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Type 1 diabetes mellitus
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	PedHIB group	HibCY group
Total subjects affected by non serious adverse events
subjects affected / exposed	291 / 303 (96.04%)	282 / 297 (94.95%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Haemangioma
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	1	1
Vascular disorders
Flushing
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Pregnancy, puerperium and perinatal conditions
Umbilical granuloma
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
General disorders and administration site conditions
Administration site haemorrhage
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Administration site rash
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Ill-defined disorder
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Injection site bruising
subjects affected / exposed	3 / 303 (0.99%)	5 / 297 (1.68%)
occurrences all number	3	5
Injection site erythema
subjects affected / exposed	211 / 303 (69.64%)	189 / 297 (63.64%)
occurrences all number	539	442
Injection site induration
subjects affected / exposed	2 / 303 (0.66%)	2 / 297 (0.67%)
occurrences all number	2	2
Injection site mass
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Injection site pain
subjects affected / exposed	248 / 303 (81.85%)	229 / 297 (77.10%)
occurrences all number	648	550
Injection site rash
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Injection site reaction
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Injection site swelling
subjects affected / exposed	182 / 303 (60.07%)	147 / 297 (49.49%)
occurrences all number	413	322
Injection site warmth
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	2	0
Pain
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Peripheral swelling
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Pyrexia
subjects affected / exposed	147 / 303 (48.51%)	124 / 297 (41.75%)
occurrences all number	235	184
Vaccination site induration
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	2	0
Vaccination site nodule
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Vaccination site reaction
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Food allergy
subjects affected / exposed	3 / 303 (0.99%)	2 / 297 (0.67%)
occurrences all number	3	2
Hypersensitivity
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Milk allergy
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Multiple allergies
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Seasonal allergy
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Reproductive system and breast disorders
Genital labial adhesions
subjects affected / exposed	2 / 303 (0.66%)	3 / 297 (1.01%)
occurrences all number	2	3
Genital rash
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Penile adhesion
subjects affected / exposed	0 / 303 (0.00%)	2 / 297 (0.67%)
occurrences all number	0	2
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	2 / 303 (0.66%)	1 / 297 (0.34%)
occurrences all number	2	1
Bronchial hyperreactivity
subjects affected / exposed	4 / 303 (1.32%)	5 / 297 (1.68%)
occurrences all number	4	5
Cough
subjects affected / exposed	31 / 303 (10.23%)	21 / 297 (7.07%)
occurrences all number	32	24
Hiccups
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Increased upper airway secretion
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Nasal congestion
subjects affected / exposed	15 / 303 (4.95%)	15 / 297 (5.05%)
occurrences all number	15	18
Oropharyngeal pain
subjects affected / exposed	3 / 303 (0.99%)	1 / 297 (0.34%)
occurrences all number	3	1
Pneumonitis
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Productive cough
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Respiratory disorder
subjects affected / exposed	7 / 303 (2.31%)	6 / 297 (2.02%)
occurrences all number	12	9
Rhinitis allergic
subjects affected / exposed	4 / 303 (1.32%)	4 / 297 (1.35%)
occurrences all number	4	5
Rhinorrhoea
subjects affected / exposed	19 / 303 (6.27%)	14 / 297 (4.71%)
occurrences all number	21	16
Sinus disorder
subjects affected / exposed	2 / 303 (0.66%)	0 / 297 (0.00%)
occurrences all number	2	0
Sneezing
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Stridor
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Tachypnoea
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Upper respiratory tract congestion
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	1	1
Wheezing
subjects affected / exposed	0 / 303 (0.00%)	9 / 297 (3.03%)
occurrences all number	0	9
Psychiatric disorders
Communication disorder
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Insomnia
subjects affected / exposed	2 / 303 (0.66%)	0 / 297 (0.00%)
occurrences all number	2	0
Irritability
subjects affected / exposed	284 / 303 (93.73%)	267 / 297 (89.90%)
occurrences all number	839	737
Screaming
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Selective eating disorder
subjects affected / exposed	2 / 303 (0.66%)	0 / 297 (0.00%)
occurrences all number	2	0
Sleep disorder
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	1	1
Investigations
Body height below normal
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Body temperature increased
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Cardiac murmur
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	1	1
Mycoplasma test positive
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Weight
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Weight decreased
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Injury, poisoning and procedural complications
Accidental exposure to product
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Animal bite
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Arthropod bite
subjects affected / exposed	1 / 303 (0.33%)	2 / 297 (0.67%)
occurrences all number	1	2
Burns second degree
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Contusion
subjects affected / exposed	3 / 303 (0.99%)	5 / 297 (1.68%)
occurrences all number	3	5
Ear injury
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Eye injury
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Fall
subjects affected / exposed	1 / 303 (0.33%)	2 / 297 (0.67%)
occurrences all number	1	3
Foreign body in gastrointestinal tract
subjects affected / exposed	2 / 303 (0.66%)	0 / 297 (0.00%)
occurrences all number	2	0
Head injury
subjects affected / exposed	1 / 303 (0.33%)	4 / 297 (1.35%)
occurrences all number	1	4
Laceration
subjects affected / exposed	2 / 303 (0.66%)	0 / 297 (0.00%)
occurrences all number	2	0
Limb injury
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Lip injury
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Nail avulsion
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Skin injury
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Thermal burn
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	1	1
Tongue injury
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Tooth fracture
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Congenital, familial and genetic disorders
Ankyloglossia congenital
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Congenital torticollis
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Craniosynostosis
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	1	1
Dacryostenosis congenital
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Developmental hip dysplasia
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Frenulum breve
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Hydrocele
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Laryngomalacia
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Macrocephaly
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	1	1
Plagiocephaly
subjects affected / exposed	6 / 303 (1.98%)	6 / 297 (2.02%)
occurrences all number	6	6
Cardiac disorders
Cyanosis
subjects affected / exposed	2 / 303 (0.66%)	0 / 297 (0.00%)
occurrences all number	2	0
Nervous system disorders
Aphonia
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Fontanelle depressed
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Language disorder
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Lethargy
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Motor developmental delay
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Poor quality sleep
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Somnolence
subjects affected / exposed	254 / 303 (83.83%)	230 / 297 (77.44%)
occurrences all number	641	569
Speech disorder
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Speech disorder developmental
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	1	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Iron deficiency anaemia
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Leukocytosis
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Lymphadenopathy
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	1	1
Ear and labyrinth disorders
Cerumen impaction
subjects affected / exposed	4 / 303 (1.32%)	0 / 297 (0.00%)
occurrences all number	4	0
Ear pain
subjects affected / exposed	4 / 303 (1.32%)	2 / 297 (0.67%)
occurrences all number	4	2
Middle ear effusion
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	1	1
Otorrhoea
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	1	1
Eye disorders
Conjunctivitis allergic
subjects affected / exposed	0 / 303 (0.00%)	2 / 297 (0.67%)
occurrences all number	0	2
Dacryostenosis acquired
subjects affected / exposed	0 / 303 (0.00%)	2 / 297 (0.67%)
occurrences all number	0	2
Eye discharge
subjects affected / exposed	0 / 303 (0.00%)	2 / 297 (0.67%)
occurrences all number	0	2
Hypermetropia
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Strabismus
subjects affected / exposed	2 / 303 (0.66%)	0 / 297 (0.00%)
occurrences all number	2	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	2	1
Abdominal pain
subjects affected / exposed	0 / 303 (0.00%)	2 / 297 (0.67%)
occurrences all number	0	2
Abdominal pain upper
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	1	1
Abnormal faeces
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Aerophagia
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Anal fissure
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	1	1
Constipation
subjects affected / exposed	9 / 303 (2.97%)	13 / 297 (4.38%)
occurrences all number	11	13
Diarrhoea
subjects affected / exposed	18 / 303 (5.94%)	26 / 297 (8.75%)
occurrences all number	20	31
Dysphagia
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Flatulence
subjects affected / exposed	3 / 303 (0.99%)	4 / 297 (1.35%)
occurrences all number	3	6
Gastrooesophageal reflux disease
subjects affected / exposed	13 / 303 (4.29%)	6 / 297 (2.02%)
occurrences all number	13	6
Gingival pain
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Haematochezia
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	1	1
Inguinal hernia
subjects affected / exposed	0 / 303 (0.00%)	2 / 297 (0.67%)
occurrences all number	0	2
Nausea
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Oral mucosal eruption
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Oral pain
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Retching
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Teething
subjects affected / exposed	13 / 303 (4.29%)	13 / 297 (4.38%)
occurrences all number	13	13
Vomiting
subjects affected / exposed	20 / 303 (6.60%)	14 / 297 (4.71%)
occurrences all number	24	14
Vomiting projectile
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Blister
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Cafe au lait spots
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Dermatitis
subjects affected / exposed	2 / 303 (0.66%)	0 / 297 (0.00%)
occurrences all number	2	0
Dermatitis atopic
subjects affected / exposed	15 / 303 (4.95%)	11 / 297 (3.70%)
occurrences all number	15	11
Dermatitis contact
subjects affected / exposed	0 / 303 (0.00%)	2 / 297 (0.67%)
occurrences all number	0	2
Dermatitis diaper
subjects affected / exposed	12 / 303 (3.96%)	14 / 297 (4.71%)
occurrences all number	13	15
Eczema
subjects affected / exposed	8 / 303 (2.64%)	7 / 297 (2.36%)
occurrences all number	8	7
Erythema
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Hyperhidrosis
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Ingrowing nail
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Keratosis pilaris
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	1	1
Miliaria
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Pruritus
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Rash
subjects affected / exposed	13 / 303 (4.29%)	9 / 297 (3.03%)
occurrences all number	14	12
Rash erythematous
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Rash macular
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Rash maculo-papular
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Rash papular
subjects affected / exposed	0 / 303 (0.00%)	2 / 297 (0.67%)
occurrences all number	0	2
Seborrhoea
subjects affected / exposed	2 / 303 (0.66%)	0 / 297 (0.00%)
occurrences all number	2	0
Seborrhoeic dermatitis
subjects affected / exposed	2 / 303 (0.66%)	1 / 297 (0.34%)
occurrences all number	2	1
Skin discolouration
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Urticaria
subjects affected / exposed	3 / 303 (0.99%)	3 / 297 (1.01%)
occurrences all number	4	3
Renal and urinary disorders
Pollakiuria
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Endocrine disorders
Hypothyroidism
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Musculoskeletal and connective tissue disorders
Pain in extremity
subjects affected / exposed	0 / 303 (0.00%)	2 / 297 (0.67%)
occurrences all number	0	2
Positional plagiocephaly
subjects affected / exposed	2 / 303 (0.66%)	1 / 297 (0.34%)
occurrences all number	2	1
Torticollis
subjects affected / exposed	5 / 303 (1.65%)	0 / 297 (0.00%)
occurrences all number	5	0
Infections and infestations
Acarodermatitis
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Body tinea
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	1	1
Bronchiolitis
subjects affected / exposed	9 / 303 (2.97%)	13 / 297 (4.38%)
occurrences all number	9	13
Bronchitis
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Candida infection
subjects affected / exposed	4 / 303 (1.32%)	3 / 297 (1.01%)
occurrences all number	4	3
Candida nappy rash
subjects affected / exposed	4 / 303 (1.32%)	1 / 297 (0.34%)
occurrences all number	4	1
Cellulitis
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Conjunctivitis
subjects affected / exposed	16 / 303 (5.28%)	11 / 297 (3.70%)
occurrences all number	17	11
Conjunctivitis bacterial
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	1	1
Coxsackie viral infection
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Croup infectious
subjects affected / exposed	10 / 303 (3.30%)	1 / 297 (0.34%)
occurrences all number	10	1
Dacryocystitis
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	1	1
Ear infection
subjects affected / exposed	5 / 303 (1.65%)	6 / 297 (2.02%)
occurrences all number	9	9
Erythema infectiosum
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	1	1
Exanthema subitum
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Eye infection
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Fungal infection
subjects affected / exposed	4 / 303 (1.32%)	0 / 297 (0.00%)
occurrences all number	4	0
Fungal skin infection
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	1	1
Furuncle
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Gastroenteritis
subjects affected / exposed	12 / 303 (3.96%)	7 / 297 (2.36%)
occurrences all number	12	7
Gastroenteritis viral
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Hand-foot-and-mouth disease
subjects affected / exposed	4 / 303 (1.32%)	3 / 297 (1.01%)
occurrences all number	4	3
Herpangina
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	1	1
Impetigo
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Influenza
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	1	1
Laryngitis
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Molluscum contagiosum
subjects affected / exposed	1 / 303 (0.33%)	2 / 297 (0.67%)
occurrences all number	1	3
Mycoplasma infection
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	1	1
Nasopharyngitis
subjects affected / exposed	12 / 303 (3.96%)	16 / 297 (5.39%)
occurrences all number	14	17
Oral candidiasis
subjects affected / exposed	2 / 303 (0.66%)	3 / 297 (1.01%)
occurrences all number	2	3
Oropharyngeal candidiasis
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Otitis externa
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Otitis media
subjects affected / exposed	41 / 303 (13.53%)	43 / 297 (14.48%)
occurrences all number	49	48
Otitis media acute
subjects affected / exposed	5 / 303 (1.65%)	6 / 297 (2.02%)
occurrences all number	6	6
Paronychia
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Periorbital cellulitis
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Pharyngitis
subjects affected / exposed	6 / 303 (1.98%)	5 / 297 (1.68%)
occurrences all number	7	5
Pneumonia
subjects affected / exposed	1 / 303 (0.33%)	3 / 297 (1.01%)
occurrences all number	1	3
Pneumonia bacterial
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Pneumonia streptococcal
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Pneumonia viral
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Pyelonephritis
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Respiratory syncytial virus bronchiolitis
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Respiratory syncytial virus infection
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Respiratory tract infection
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Respiratory tract infection viral
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Rhinitis
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Roseola
subjects affected / exposed	1 / 303 (0.33%)	2 / 297 (0.67%)
occurrences all number	1	2
Sinusitis
subjects affected / exposed	2 / 303 (0.66%)	5 / 297 (1.68%)
occurrences all number	2	5
Skin candida
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	1	1
Staphylococcal infection
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Tonsillitis
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Upper respiratory tract infection
subjects affected / exposed	35 / 303 (11.55%)	62 / 297 (20.88%)
occurrences all number	40	78
Urinary tract infection
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Vaginal infection
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Viral infection
subjects affected / exposed	9 / 303 (2.97%)	8 / 297 (2.69%)
occurrences all number	9	8
Viral rash
subjects affected / exposed	4 / 303 (1.32%)	5 / 297 (1.68%)
occurrences all number	5	5
Viral tonsillitis
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Viral upper respiratory tract infection
subjects affected / exposed	5 / 303 (1.65%)	0 / 297 (0.00%)
occurrences all number	5	0
Vulvovaginal candidiasis
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	1	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	200 / 303 (66.01%)	177 / 297 (59.60%)
occurrences all number	384	331
Failure to thrive
subjects affected / exposed	1 / 303 (0.33%)	2 / 297 (0.67%)
occurrences all number	1	2
Feeding disorder
subjects affected / exposed	0 / 303 (0.00%)	2 / 297 (0.67%)
occurrences all number	0	2
Increased appetite
subjects affected / exposed	1 / 303 (0.33%)	0 / 297 (0.00%)
occurrences all number	1	0
Lactose intolerance
subjects affected / exposed	0 / 303 (0.00%)	1 / 297 (0.34%)
occurrences all number	0	1
Poor feeding infant
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	1	1
Underweight
subjects affected / exposed	1 / 303 (0.33%)	1 / 297 (0.34%)
occurrences all number	1	1
Weight gain poor
subjects affected / exposed	2 / 303 (0.66%)	1 / 297 (0.34%)
occurrences all number	2	1

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Were there any global substantial amendments to the protocol? Yes

03 Sep 2013

Since Havrix and Rotarix are administered in this study, the study falls under Article 46 and per our GUI-BIO-RA-9024 v01 a EudraCT number is needed for trials part of an agreed PIP and for paediatric trials falling into to scope of the Regulation (EC) No. 1901/2006 Article 41 - 45 and 46 no matter where the trial is performed.. Therefore, a Eudract number has been issued for this study and included in this Protocol. Additionally, two typographical errors were identified within the body of the Protocol and corrected: 1) The presentation of Rotarix in the vial was erroneously typed in as a white liquid rather than a powder. 2) The site of administration of the 4th dose of Prevnar 13 was erroneously typed in as in the upper thigh rather than the lower thigh. 3) The product information for the vaccines has been updated to be consistent with the vaccine dictionary definitions.

16 May 2014

In order to provide the opportunity for subjects in the control group to receive a meningococcal vaccine, which is not routinely administered in the US to this age group, the protocol has been amended to state that: “...a parent(s)/LAR(s) of a child in the PedvaxHIB control group will be offered the opportunity for their child to be vaccinated with a licensed meningococcal vaccine, which will be provided by the study sponsor, after study end as these subjects did not have the benefit of receiving any meningococcal vaccination during the study. Additionally,  Distribution of a diary card for recording of medications/vaccinations post dose 2 of Havrix has been added.  Treatment allocation is by component rather than dose.  Text mentioning that subjects who do not continue in the booster phase will be contacted for safety information via a phone script at the ESFU timepoint has been added.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of subjects with Anti-Polyribosylribitol phosphate (Anti-PRP) antibody concentrations greater than or equal to (≥) 1.0 µg/mL

Primary: Percentage of subjects with Anti-Polyribosylribitol phosphate (Anti-PRP) antibody concentrations greater than or equal to (≥) 1.0 µg/mL

Primary: Anti-rotavirus serum Immunoglobulin A (IgA) Geometric Mean concentrations (GMCs).

Primary: Anti-rotavirus serum Immunoglobulin A (IgA) Geometric Mean concentrations (GMCs).

Primary: Anti-Streptococcus (S) pneumoniae GMCs

Primary: Anti-Streptococcus (S) pneumoniae GMCs

Primary: Percentage of subjects with Anti-Hepatitis A Vaccine (Anti-Havrix) antibody concentrations ≥ 15mIU/mL

Primary: Percentage of subjects with Anti-Hepatitis A Vaccine (Anti-Havrix) antibody concentrations ≥ 15mIU/mL

Primary: Anti-S. pneumoniae GMCs

Primary: Anti-S. pneumoniae GMCs

Secondary: Percentage of subjects with anti-PRP antibody concentrations ≥0.15 µg/mL.

Secondary: Percentage of subjects with anti-PRP antibody concentrations ≥0.15 µg/mL.

Secondary: Anti-PRP GMCs ≥ 0.15 µg/mL.

Secondary: Anti-PRP GMCs ≥ 0.15 µg/mL.

Secondary: Percentage of subjects with anti-PRP antibody concentrations ≥1.0 µg/mL

Secondary: Percentage of subjects with anti-PRP antibody concentrations ≥1.0 µg/mL

Secondary: Percentage of subjects with Serum bactericidal assay to N. meningitidis serogroup C (hSBA-MenC) and N. meningitidis serogroup Y (hSBA-MenY) antibody titers ≥1:8, ≥1:16, ≥1:32.

Secondary: Percentage of subjects with Serum bactericidal assay to N. meningitidis serogroup C (hSBA-MenC) and N. meningitidis serogroup Y (hSBA-MenY) antibody titers ≥1:8, ≥1:16, ≥1:32.

Secondary: Geometric Mean Titres (GMTs) of human complement serum bactericidal assay to N. meningitidis serogroup C (hSBA-MenC) and to hSBA-MenY

Secondary: Geometric Mean Titres (GMTs) of human complement serum bactericidal assay to N. meningitidis serogroup C (hSBA-MenC) and to hSBA-MenY

Secondary: Percentage of subjects with Anti-rotavirus IgA antibody concentrations ≥ 20 Units (U)/mL

Secondary: Percentage of subjects with Anti-rotavirus IgA antibody concentrations ≥ 20 Units (U)/mL

Secondary: Percentage of subjects with Anti-HAV antibodies ≥ 15 mIU/mL

Secondary: Percentage of subjects with Anti-HAV antibodies ≥ 15 mIU/mL

Secondary: Anti-HAV GMCs ≥ 15 mIU/mL

Secondary: Anti-HAV GMCs ≥ 15 mIU/mL

Secondary: GMCs for anti-HAV antibodies ≥15mIU/mL.

Secondary: GMCs for anti-HAV antibodies ≥15mIU/mL.

Secondary: Percentage of subjects with S. pneumoniae antibody concentrations ≥ 0.15 µg/mL, ≥ 0.26 µg/mL and ≥ 0.35 µg/mL for serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F

Secondary: Percentage of subjects with S. pneumoniae antibody concentrations ≥ 0.15 µg/mL, ≥ 0.26 µg/mL and ≥ 0.35 µg/mL for serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F

Secondary: Percentage of subjects reporting any solicited local adverse events (AE).

Secondary: Percentage of subjects reporting any solicited local adverse events (AE).

Secondary: Percentage of subjects reporting any solicited general AEs.

Secondary: Percentage of subjects reporting any solicited general AEs.

Secondary: Percentage of subjects reporting any unsolicited AEs.

Secondary: Percentage of subjects reporting any unsolicited AEs.

Secondary: Percentage of subjects reporting any serious adverse events (SAEs).

Secondary: Percentage of subjects reporting any serious adverse events (SAEs).

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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