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Clinical Trial Results:
A phase III double-blind, cluster-randomized, controlled study to evaluate the impact on nasopharyngeal carriage, acute otitis media, immunogenicity and safety of GSK Biologicals’ 10-valent pneumococcal and non-typeable Haemophilus influenzae protein D conjugate vaccine in children starting vaccination below 18 months of age.

Summary
EudraCT number	2008-006551-51
Trial protocol	FI
Global end of trial date	31 Jan 2012

Results information
Results version number	v4(current)
This version publication date	02 Jan 2021
First version publication date	30 Jul 2015
Other versions	v1 , v2 , v3
Version creation reason	Correction of full data set Results have been amended to account for consistency with other registries.

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

112595

ISRCTN number

US NCT number

NCT00839254

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)

Yes

EMA paediatric investigation plan number(s)

EMEA-000673-PIP01-09

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

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

Yes

Analysis stage

Final

Date of interim/final analysis

22 Apr 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

31 Jan 2012

Was the trial ended prematurely?

Main objective of the trial

To demonstrate the effectiveness of 10Pn-PD-DiT vaccine in preventing culture-confirmed IPD due to vaccine pneumococcal serotypes in children vaccinated with at least one dose of 10Pn-PD-DiT within the first 7 months of life in clusters assigned to a 3-dose primary vaccination course. Criteria for effectiveness: Effectiveness (VE) in preventing culture-confirmed IPD due to the 10 vaccine serotypes will be demonstrated if the 2-sided p-value calculated for the null hypothesis H0 = (vaccine-type [VT] IPD VE =0%) is lower than 5%. Refer to 10PN-PD-DIT-043 study (EudraCT number : 2008-005149-48).

Protection of trial subjects

Vaccinees were observed closely for at least 30 minutes following the administration of vaccines, with appropriate medical treatment readily available in case of a rare anaphylactic reaction. Vaccines/products were administered only to eligible subjects that had no contraindications to any components of the vaccines/products. Subjects were followed up for serious adverse events (SAEs) reported as occurring during the study up to study end. An Independent Data Monitoring Committee (IDMC) was set up for this study to protect the ethical and safety interests of the subjects recruited, while securing as much as possible the scientific validity of the data. The IDMC was the same as in the 10PN-PD-DIT-043 study and will review safety data (SAEs) and all-cause mortality to identify potential treatment harm/benefit. Responsibilities of the IDMC included the following: 1) Review of data collection methods, safety/effectiveness monitoring procedures and making recommendations for additions or adjustments, as applicable.; 2) Recommendations for maintaining, or breaking the blind where necessary, in the course of reviewing the results; 3) Recommendations for stopping the trial for effectiveness or safety reasons when appropriate.

Background therapy

Evidence for comparator

Actual start date of recruitment

18 Feb 2009

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy, Safety

Long term follow-up duration

9 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Finland: 54088

Worldwide total number of subjects

54088

EEA total number of subjects

54088

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)

54088

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

This study is linked with 10PN-PD-DIT-043 (111442) study (NCT00861380.-EudraCT: 2008-005149-48) with which primary objectives and outcomes are common. Subjects of 10PN-PD-DIT-043 study contributed to the results of this study.

Screening details

Out of 6183 subjects enrolled, 6177 were analyzed:(6174 subjects and 3 of them received 2 subject numbers, without any impact on the results of the analyses). Total population assessed for combined analyses performed on both studies included 45977 subjects, see details in groups description.

Number of subjects started

54088

Number of subjects completed

6177

Reason: Number of subjects

10PN043-053 subjects: 45977

Reason: Number of subjects

Control 6W-6M pooled group: 1928

Reason: Number of subjects

Consent withdrawn by subject: 6

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Blinding implementation details

This study was conducted in a double-blind fashion for vaccine/control clusters applying the same 2+1 and 3+1 infant schedules. Study was run in an open fashion between infant schedules.

Are arms mutually exclusive

Yes

10Pn3+1-6W-6M/053 Group

Arm description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) study, aged 6 weeks to 6 months at enrolment. Subjects received the Synflorix (called also 10Pn-PD-DiT, 10Pn or GSK1024850A) vaccine according to a 3-dose primary vaccination schedule with an interval of at least 4 weeks between doses, followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (3+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh.

Arm type

Experimental

Investigational medicinal product name

10-valent pneumococcal and non-typeable H. influenzae protein D conjugate vaccine

Investigational medicinal product code

10Pn-PD-DiT

Other name

10Pn, Synflorix

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Intramuscularly administration by injection in the thigh.

10Pn2+1-6W-6M/053 Group

Arm description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) study, aged 6 weeks to 6 months at enrolment. Subjects received the Synflorix (called also 10Pn-PD-DiT, 10Pn or GSK1024850A) vaccine according to a 2-dose primary vaccination with an interval of at least 8 weeks, followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (2+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh.

Arm type

Experimental

Investigational medicinal product name

10-valent pneumococcal and non-typeable H. influenzae protein D conjugate vaccine

Investigational medicinal product code

10Pn-PD-DiT

Other name

10Pn, Synflorix

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Intramuscularly administration by injection in the thigh.

Ctrl3+1-6W-6M/053 Group

Arm description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) study, aged 6 weeks to 6 months at enrolment. Subjects received the Engerix B (called also HBV vaccine) according to a 3-dose primary vaccination schedule with an interval of at least 4 weeks between doses followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (3+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh.

Arm type

Active comparator

Investigational medicinal product name

Engerix B-thio free

Investigational medicinal product code

Other name

Engerix-B,HBV

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Intramuscularly administration by injection in the thigh.

Ctrl2+1-6W-6M/053 Group

Arm description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) study, aged 6 weeks to 6 months at enrolment. Subjects received the Engerix B (called also HBV vaccine) according to a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (2+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh.

Arm type

Active comparator

Investigational medicinal product name

Engerix B-thio free

Investigational medicinal product code

Other name

Engerix-B,HBV

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Intramuscularly administration by injection in the thigh.

10Pn7-11M/053 Group

Arm description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) study, aged 7 to 11 months at enrolment. Subjects received the Synflorix (called also 10Pn-PD-DiT, 10Pn or GSK1024850A) vaccine according to a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (7-11M Schedule). The vaccine was administered intramuscularly in the thigh or in the deltoid region of upper arm, provided the muscle size was adequate.

Arm type

Experimental

Investigational medicinal product name

10-valent pneumococcal and non-typeable H. influenzae protein D conjugate vaccine

Investigational medicinal product code

10Pn-PD-DiT

Other name

10Pn, Synflorix

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Intramuscularly administration by injection in the thigh.

Ctrl7-11M/053 Group

Arm description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) study, aged 7 to 11 months at enrolment. Subjects received the Engerix B (called also HBV) vaccine according to a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (7-11M Schedule). The vaccine was administered intramuscularly in the thigh or in the deltoid region of upper arm, provided the muscle size was adequate.

Arm type

Active comparator

Investigational medicinal product name

Engerix B-thio free

Investigational medicinal product code

Other name

Engerix-B,HBV

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Intramuscularly administration by injection in the thigh.

10Pn12-18M/053 Group

Arm description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) study, aged 12 to 18 months at enrolment. Subjects received the Synflorix (called also 10Pn-PD-DiT, 10Pn or GSK1024850A) vaccine according to a 2-dose vaccination with an interval of at least and preferably 6 months between doses (12-18M Schedule). The vaccine was administered intramuscularly in the thigh or in the deltoid region of upper arm, provided the muscle size was adequate.

Arm type

Experimental

Investigational medicinal product name

10-valent pneumococcal and non-typeable H. influenzae protein D conjugate vaccine

Investigational medicinal product code

10Pn-PD-DiT

Other name

10Pn, Synflorix

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Intramuscularly administration by injection in the thigh or in the deltoid region of upper arm, provided the muscle size was adequate.

Ctrl12-18M/053 Group

Arm description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) study, aged 12 to 18 months at enrolment. Subjects received the Havrix (called also HAV) vaccine according to a 2-dose vaccination with an interval of at least and preferably 6 months between doses (12-18M Schedule). The vaccine was administered intramuscularly in the thigh or in the deltoid region of upper arm, provided the muscle size was adequate.

Arm type

Active comparator

Investigational medicinal product name

Havrix-preservative free

Investigational medicinal product code

Other name

HAV, Havrix 720 Junior

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Intramuscularly administration by injection in the thigh or in the deltoid region of upper arm, provided the muscle size was adequate.

Number of subjects in period 1 ^[1]	10Pn3+1-6W-6M/053 Group	10Pn2+1-6W-6M/053 Group	Ctrl3+1-6W-6M/053 Group	Ctrl2+1-6W-6M/053 Group	10Pn7-11M/053 Group	Ctrl7-11M/053 Group	10Pn12-18M/053 Group	Ctrl12-18M/053 Group
Started	1849	1316	1069	859	241	204	368	271
Completed	1696	1224	979	797	204	178	340	256
Not completed	153	92	90	62	37	26	28	15
Consent withdrawn by subject	87	53	54	32	27	15	22	9
Parents wanted pneumococcal vaccine	1	-	-	-	-	1	-	-
Physician decision	-	1	-	-	-	-	-	1
Adverse event, non-fatal	12	6	3	5	2	1	-	1
Withdrawn due to non-compliance	2	-	-	-	-	-	-	-
Wrong group allocation	-	-	-	-	-	-	1	-
Wrong treatment number allocation	-	1	-	-	-	1	-	-
Lost to follow-up	51	30	32	24	8	8	4	2
Protocol deviation	-	1	1	1	-	-	1	2

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: 6183 subjects in total were enrolled in this study, out of which 6177 were actually vaccinated in this study. In addition to these, the Total population assessed for combined analyses performed on both studies included 45977 subjects and an additional pooled group- subjects analysis set has to be defined for the 6W-6M Control group for presenting carriage data.

Baseline characteristics

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Reporting group title

10Pn3+1-6W-6M/053 Group

Reporting group description

Reporting group title

10Pn2+1-6W-6M/053 Group

Reporting group description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) study, aged 6 weeks to 6 months at enrolment. Subjects received the Synflorix (called also 10Pn-PD-DiT, 10Pn or GSK1024850A) vaccine according to a 2-dose primary vaccination with an interval of at least 8 weeks, followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (2+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh.

Reporting group title

Ctrl3+1-6W-6M/053 Group

Reporting group description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) study, aged 6 weeks to 6 months at enrolment. Subjects received the Engerix B (called also HBV vaccine) according to a 3-dose primary vaccination schedule with an interval of at least 4 weeks between doses followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (3+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh.

Reporting group title

Ctrl2+1-6W-6M/053 Group

Reporting group description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) study, aged 6 weeks to 6 months at enrolment. Subjects received the Engerix B (called also HBV vaccine) according to a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (2+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh.

Reporting group title

10Pn7-11M/053 Group

Reporting group description

Reporting group title

Ctrl7-11M/053 Group

Reporting group description

Reporting group title

10Pn12-18M/053 Group

Reporting group description

Reporting group title

Ctrl12-18M/053 Group

Reporting group description

Reporting group values	10Pn3+1-6W-6M/053 Group	10Pn2+1-6W-6M/053 Group	Ctrl3+1-6W-6M/053 Group	Ctrl2+1-6W-6M/053 Group	10Pn7-11M/053 Group	Ctrl7-11M/053 Group	10Pn12-18M/053 Group	Ctrl12-18M/053 Group	Total
Number of subjects	1849	1316	1069	859	241	204	368	271	6177
Age categorical
Units:
28 days - 23 months	1849	1316	1069	859	241	204	368	271	6177
Age Continuous
Units: Months
arithmetic mean (standard deviation)	2.4 ± 1.02	2.3 ± 0.95	2.6 ± 1.19	2.4 ± 1	9 ± 1.44	8.7 ± 1.39	15 ± 1.99	15.2 ± 1.99	-
Sex: Female, Male
Units: Participants
Female	921	681	551	393	118	113	173	142	3092
Male	928	635	518	466	123	91	195	129	3085
Race/Ethnicity, Customized
Units: Subjects
African heritage / African American	1	0	0	0	1	1	2	0	5
White - Arabic / north African heritage	7	5	4	6	3	0	2	0	27
White - Caucasian / European heritage	1822	1303	1058	845	235	201	362	270	6096
Unspecified	19	8	7	8	2	2	2	1	49

End points

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Reporting group title

10Pn3+1-6W-6M/053 Group

Reporting group description

Reporting group title

10Pn2+1-6W-6M/053 Group

Reporting group description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) study, aged 6 weeks to 6 months at enrolment. Subjects received the Synflorix (called also 10Pn-PD-DiT, 10Pn or GSK1024850A) vaccine according to a 2-dose primary vaccination with an interval of at least 8 weeks, followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (2+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh.

Reporting group title

Ctrl3+1-6W-6M/053 Group

Reporting group description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) study, aged 6 weeks to 6 months at enrolment. Subjects received the Engerix B (called also HBV vaccine) according to a 3-dose primary vaccination schedule with an interval of at least 4 weeks between doses followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (3+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh.

Reporting group title

Ctrl2+1-6W-6M/053 Group

Reporting group description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) study, aged 6 weeks to 6 months at enrolment. Subjects received the Engerix B (called also HBV vaccine) according to a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (2+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh.

Reporting group title

10Pn7-11M/053 Group

Reporting group description

Reporting group title

Ctrl7-11M/053 Group

Reporting group description

Reporting group title

10Pn12-18M/053 Group

Reporting group description

Reporting group title

Ctrl12-18M/053 Group

Reporting group description

Subject analysis set title

10Pn3+1-6W-6M/043+053 Group

Subject analysis set type

Per protocol

Subject analysis set description

Subjects analyzed among all subjects who were enrolled in this group in the 10PN-PD-DIT-043 (NCT00861380 - EUDRACT 2008-005149-48) (i.e. 8427 subjects) and 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) studies and aged 6 weeks to 6 months at enrolment. Subjects received the Synflorix (called also 10Pn-PD-DiT, or 10Pn or GSK1024850A) vaccine according to a 3-dose primary vaccination schedule with an interval of at least 4 weeks between doses, followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (3+1 Infant Schedule). Refer to group description for 10Pn3+1-6W-6M/053 Group for details on vaccine specifics and administration route in this group.

Subject analysis set title

10Pn2+1-6W-6M/043+053 Group

Subject analysis set type

Per protocol

Subject analysis set description

Subjects analyzed among all subjects who were enrolled in this group in the 10PN-PD-DIT-043 (NCT00861380 - EUDRACT 2008-005149-48) (i.e. 9112 subjects) and 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) studies and aged 6 weeks to 6 months at enrolment. Subjects received the Synflorix (called also 10Pn-PD-DiT, or 10Pn or GSK1024850A) vaccine according to a 2-dose primary vaccination with an interval of at least 8 weeks, followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (2+1 Infant Schedule). Refer to group description for 10Pn2+1-6W-6M/053 Group for details on vaccine specifics and administration route in this group.

Subject analysis set title

Ctrl-6W-6M/043+053 Group

Subject analysis set type

Per protocol

Subject analysis set description

Subjects analyzed among all subjects who were enrolled in this group in the 10PN-PD-DIT-043 (NCT00861380 - EUDRACT 2008-005149-48) (i.e. 8872 subjects) and 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) studies and aged 6 weeks to 6 months at enrolment. Subjects received the Engerix B (called also HBV vaccine) according to either a 3-dose primary vaccination schedule with an interval of at least 4 weeks between doses followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (3+1 Infant Schedule), or according to a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (2+1 Infant Schedule). Refer to group descriptions for Ctrl3+1-6W-6M/053 and Ctrl2+1-6W-6M/053 groups for details on vaccine specifics and administration route in this group.

Subject analysis set title

10Pn7-11M/043+053 Group

Subject analysis set type

Per protocol

Subject analysis set description

Subjects analyzed among all subjects who were enrolled in this group in the 10PN-PD-DIT-043 (NCT00861380 - EUDRACT 2008-005149-48) (i.e. 3689 subjects) and 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) studies and aged 7 to 11 months at enrolment. Subjects received the Synflorix (called also 10Pn-PD-DiT, or 10Pn or GSK1024850A) vaccine according to a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (7-11M Schedule). Refer to group description for 10Pn7-11M/053 Group for details on vaccine specifics and administration route in this group.

Subject analysis set title

Ctrl7-11M/043+053 Group

Subject analysis set type

Per protocol

Subject analysis set description

Subjects analyzed among all subjects who were enrolled in this group in the 10PN-PD-DIT-043 (NCT00861380 - EUDRACT 2008-005149-48) (i.e. 1812 subjects) and 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) studies and aged 7 to 11 months at enrolment. Subjects received the Engerix B (called also HBV) vaccine according to a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (7-11M Schedule). Refer to group description for Ctrl7-11M/053 Group for details on vaccine specifics and administration route in this group.

Subject analysis set title

10Pn12-18M/043+053 Group

Subject analysis set type

Per protocol

Subject analysis set description

Subjects analyzed among all subjects who were enrolled in this group in the 10PN-PD-DIT-043 (NCT00861380 - EUDRACT 2008-005149-48) (i.e. 6249 subjects) and 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) studies and aged 12 to 18 months at enrolment. Subjects received the Synflorix (called also 10Pn-PD-DiT, or 10Pn or GSK1024850A) vaccine according to a 2-dose vaccination with an interval of at least and preferably 6 months between doses (12-18M Schedule). Refer to group description for 10Pn12-18M/053 Group for details on vaccine specifics and administration route in this group.

Subject analysis set title

Ctrl12-18M/043+053 Group

Subject analysis set type

Per protocol

Subject analysis set description

Subjects analyzed among all subjects who were enrolled in this group in the 10PN-PD-DIT-043 (NCT00861380 - EUDRACT 2008-005149-48) (i.e. 3020 subjects) and 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) studies and aged 12 to 18 months at enrolment. Subjects received the Havrix (called also HAV) vaccine according to a 2-dose vaccination with an interval of at least and preferably 6 months between doses (12-18M Schedule). Refer to group description for Ctrl12-18M/053 Group for details on vaccine specifics and administration route in this group.

Subject analysis set title

Ctrl-6W-6M/053 Group

Subject analysis set type

Per protocol

Subject analysis set description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (NCT00839254 EUDRACT 2008-006551-51) studies and aged 6 weeks to 6 months at enrolment. Subjects received the Engerix B-thio free vaccine (or HBV vaccine) according to either a 3-dose primary vaccination schedule with an interval of at least 4 weeks between doses followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (3+1 Infant Schedule), or according to a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (2+1 Infant Schedule). Refer to group descriptions for Ctrl3+1-6W-6M/053 and Ctrl2+1-6W-6M/053 groups for details on vaccine specifics and administration route in this group.

Primary: Person Year Rate as regards subjects with culture-confirmed IPD due to any of the 10 pneumococcal vaccine serotypes. In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

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End point title

Person Year Rate as regards subjects with culture-confirmed IPD due to any of the 10 pneumococcal vaccine serotypes. In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

End point description

The PYAR (Person-Year Rate) as regards subjects with culture-confirmed invasive pneumococcal disease (IPD) due to any of the pneumococcal vaccine serotypes was tabulated (vaccine pneumococcal serotypes = serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F). PYAR was calculated as follows n (= number of subjects reported with a culture confirmed IPD) divided by T (= sum of follow-up period expressed in years) (per 1000) as well as the corresponding 95% confidence interval (CI), calculated as a 2-sided profile log-likelihood ratio 95% CI using a classical log linear Poisson regression with strata.

End point type

Primary

End point timeframe

Period of follow-up was any time after the administration of first vaccine dose till the end of the blinded invasive disease (ID) Follow-up period (The blinded ID Follow-up period lasted at least 30 months).

End point values	10Pn3+1-6W-6M/043+053 Group	Ctrl-6W-6M/043+053 Group
Number of subjects analysed	10273	10201
Units: Participants per 1000 person-years
number (confidence interval 95%)	0.000 (0.000 to 0.172)	0.564 (0.291 to 0.984)

Statistical analysis 1

Statistical analysis description

Analysis aimed at providing an estimate of vaccine effectiveness (VE) at preventing culture-confirmed IPD by comparing PYARs between groups taking into account the following parameters: T, n, n+ (number of clusters with at least one event culture-confirmed ID), and n/T. VE of the 10Pn vaccine in preventing culture-confirmed IPD due to the 10 vaccine serotypes was demonstrated if the 2-sided p-value calculated for the null hypothesis H0 = (vaccine-type [VT] IPD VE = 0%) was lower than (<) 5%.

Comparison groups

10Pn3+1-6W-6M/043+053 Group v Ctrl-6W-6M/043+053 Group

Number of subjects included in analysis

20474

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

< 0.0001 ^[2]

Method

Regression, Linear

Parameter type

VE (1-RR)

Point estimate

100

Confidence interval

level

95%

sides

2-sided

lower limit

82.8

upper limit

100

Notes
[1] - VE (defined as 1 minus Relative Risk (RR)) was calculated by comparing numbers of culture-confirmed IPD. The number of subjects with IPD in each cluster was compared between groups (10PN3+1 vs Control). This comparison was done using a negative binomial log-linear model with correction for dispersion group- and cluster-related effect.
[2] - P-value was calculated using a classical log linear Poisson regression with strata, without taking into account the multiplicity of the endpoints.

Primary: Person Year Rate as regards subjects with culture-confirmed IPD due to any of the 10 pneumococcal vaccine serotypes. In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course.

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End point title

End point description

End point type

Primary

End point timeframe

End point values	10Pn2+1-6W-6M/043+053 Group	Ctrl-6W-6M/043+053 Group
Number of subjects analysed	10054	10201
Units: Participants per 1000 person-years
number (confidence interval 95%)	0.048 (0.001 to 0.270)	0.564 (0.291 to 0.984)

Statistical analysis 1

Statistical analysis description

Comparison groups

10Pn2+1-6W-6M/043+053 Group v Ctrl-6W-6M/043+053 Group

Number of subjects included in analysis

20255

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.0009 ^[4]

Method

Regression, Linear

Parameter type

VE (1-RR)

Point estimate

91.8

Confidence interval

level

95%

sides

2-sided

lower limit

58.3

upper limit

99.6

Notes
[3] - VE (defined as 1 minus Relative Risk (RR)) was calculated by comparing numbers of culture-confirmed IPD. The number of subjects with IPD in each cluster was compared between groups (10PN2+1 vs Control). This comparison was done using a negative binomial log-linear model with correction for dispersion group- and cluster-related effect.
[4] - p-value was calculated using a classical log linear Poisson regression with strata, without taking into account the multiplicity of the endpoints.

Secondary: Person Year Rate in the prevention of culture-confirmed invasive disease (ID)- In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

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End point title

Person Year Rate in the prevention of culture-confirmed invasive disease (ID)- In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

End point description

The PYAR (Person-Year Rate) was calculated as follows n (= number of subjects reported with a culture confirmed IPD) divided by T (= sum of follow-up period expressed in years) (per 1000) as well as the corresponding 95% confidence interval (CI), calculated as a 2-sided profile log-likelihood ratio 95% CI using a classical log linear Poisson regression with strata.

End point type

Secondary

End point timeframe

End point values	10Pn3+1-6W-6M/043+053 Group	Ctrl-6W-6M/043+053 Group
Number of subjects analysed	10273	10201
Units: Participants per 1000 person-years
number (confidence interval 95%)
Culture confirmed ID	0.093 (0.011 to 0.336)	0.845 (0.501 to 1.336)
Pneumococcal invasive disease (IPD)	0.000 (0.000 to 0.172)	0.657 (0.359 to 1.103)
Serotype 4	0.000 (0.000 to 0.172)	0.000 (0.000 to 0.173)
Serotype 6B	0.000 (0.000 to 0.172)	0.235 (0.076 to 0.548)
Serotype 7F	0.000 (0.000 to 0.172)	0.000 (0.000 to 0.173)
Serotype 14	0.000 (0.000 to 0.172)	0.188 (0.051 to 0.481)
Serotype 18C	0.000 (0.000 to 0.172)	0.047 (0.001 to 0.262)
Serotype 19F	0.000 (0.000 to 0.172)	0.047 (0.001 to 0.262)
Serotype 23F	0.000 (0.000 to 0.172)	0.047 (0.001 to 0.262)
Cross-reactive serotypes	0.000 (0.000 to 0.172)	0.094 (0.011 to 0.339)
Serotype 6A	0.000 (0.000 to 0.172)	0.047 (0.001 to 0.262)
Serotype 19A	0.000 (0.000 to 0.172)	0.047 (0.001 to 0.262)
Other pneumococcal serotypes	0.000 (0.000 to 0.172)	0.000 (0.000 to 0.173)
Serotype 3	0.000 (0.000 to 0.172)	0.000 (0.000 to 0.173)
Serotype 15C	0.000 (0.000 to 0.172)	0.000 (0.000 to 0.173)
H. influenzae ID	0.000 (0.000 to 0.172)	0.047 (0.001 to 0.262)
Non-typeable (NTHI)	0.000 (0.000 to 0.172)	0.047 (0.001 to 0.262)
Other bacteria	0.093 (0.011 to 0.336)	0.188 (0.051 to 0.481)
Neisseria meningitidis	0.093 (0.011 to 0.336)	0.047 (0.001 to 0.262)
Streptococcus pyogenes	0.000 (0.000 to 0.172)	0.094 (0.011 to 0.339)
Moraxella catarrhalis	0.000 (0.000 to 0.172)	0.047 (0.001 to 0.262)

No statistical analyses for this end point

Secondary: Person Year Rate in the prevention of culture-confirmed invasive disease (ID)- In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course.

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End point title

Person Year Rate in the prevention of culture-confirmed invasive disease (ID)- In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course.

End point description

End point type

Secondary

End point timeframe

End point values	10Pn2+1-6W-6M/043+053 Group	Ctrl-6W-6M/043+053 Group
Number of subjects analysed	10054	10201
Units: Participants per 1000 person-years
number (confidence interval 95%)
Culture confirmed ID	0.194 (0.053 to 0.496)	0.845 (0.501 to 1.336)
Pneumococcal invasive disease (IPD)	0.097 (0.012 to 0.350)	0.657 (0.359 to 1.103)
Vaccine serotypes (vaccine type-IPD)	0.048 (0.001 to 0.270)	0.564 (0.291 to 0.984)
Serotype 4	0.000 (0.000 to 0.179)	0.000 (0.000 to 0.173)
Serotype 6B	0.000 (0.000 to 0.179)	0.235 (0.076 to 0.548)
Serotype 7F	0.048 (0.001 to 0.270)	0.000 (0.000 to 0.173)
Serotype 14	0.000 (0.000 to 0.179)	0.188 (0.051 to 0.481)
Serotype 18C	0.000 (0.000 to 0.179)	0.047 (0.001 to 0.262)
Serotype 19F	0.000 (0.000 to 0.179)	0.047 (0.001 to 0.262)
Serotype 23F	0.000 (0.000 to 0.179)	0.047 (0.001 to 0.262)
Cross-reactive serotypes	0.000 (0.000 to 0.179)	0.094 (0.011 to 0.339)
Serotype 6A	0.000 (0.000 to 0.179)	0.047 (0.001 to 0.262)
Serotype 19A	0.000 (0.000 to 0.179)	0.047 (0.001 to 0.262)
Other pneumococcal serotypes	0.048 (0.001 to 0.270)	0.000 (0.000 to 0.173)
Serotype 3	0.048 (0.001 to 0.270)	0.000 (0.000 to 0.173)
Serotype 15C	0.000 (0.000 to 0.179)	0.000 (0.000 to 0.173)
H. influenzae ID	0.048 (0.001 to 0.270)	0.047 (0.001 to 0.262)
Non-typeable (NTHI)	0.048 (0.001 to 0.270)	0.047 (0.001 to 0.262)
Other bacteria	0.048 (0.001 to 0.270)	0.188 (0.051 to 0.481)
Neisseria meningitidis	0.048 (0.001 to 0.270)	0.047 (0.001 to 0.262)
Streptococcus pyogenes	0.000 (0.000 to 0.179)	0.094 (0.011 to 0.339)
Moraxella catarrhalis	0.000 (0.000 to 0.179)	0.047 (0.001 to 0.262)

No statistical analyses for this end point

Secondary: Person Year Rate in the prevention of culture-confirmed invasive disease (ID)- In children starting vaccination in the 7-11 months schedule.

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End point title

Person Year Rate in the prevention of culture-confirmed invasive disease (ID)- In children starting vaccination in the 7-11 months schedule.

End point description

End point type

Secondary

End point timeframe

End point values	10Pn7-11M/043+053 Group	Ctrl7-11M/043+053 Group
Number of subjects analysed	3880	1908
Units: Participants per 1000 person-years
number (confidence interval 95%)
Culture confirmed ID	0.000 (0.000 to 0.410)	0.446 (0.054 to 1.612)
Pneumococcal invasive disease (IPD)	0.000 (0.000 to 0.410)	0.446 (0.054 to 1.612)
Vaccine serotypes (vaccine type-IPD)	0.000 (0.000 to 0.410)	0.446 (0.054 to 1.612)
Serotype 4	0.000 (0.000 to 0.410)	0.000 (0.000 to 0.823)
Serotype 6B	0.000 (0.000 to 0.410)	0.000 (0.000 to 0.823)
Serotype 7F	0.000 (0.000 to 0.410)	0.223 (0.006 to 1.243)
Serotype 14	0.000 (0.000 to 0.410)	0.223 (0.006 to 1.243)
Serotype 18C	0.000 (0.000 to 0.410)	0.000 (0.000 to 0.823)
Serotype 19F	0.000 (0.000 to 0.410)	0.000 (0.000 to 0.823)
Serotype 23F	0.000 (0.000 to 0.410)	0.000 (0.000 to 0.823)
Cross-reactive serotypes	0.000 (0.000 to 0.410)	0.000 (0.000 to 0.823)
Serotype 6A	0.000 (0.000 to 0.410)	0.000 (0.000 to 0.823)
Serotype 19A	0.000 (0.000 to 0.410)	0.000 (0.000 to 0.823)
Other pneumococcal serotypes	0.000 (0.000 to 0.410)	0.000 (0.000 to 0.823)
Serotype 3	0.000 (0.000 to 0.410)	0.000 (0.000 to 0.823)
Serotype 15C	0.000 (0.000 to 0.410)	0.000 (0.000 to 0.823)
H. influenzae ID	0.000 (0.000 to 0.410)	0.000 (0.000 to 0.823)
Non-typeable (NTHI)	0.000 (0.000 to 0.410)	0.000 (0.000 to 0.823)
Other bacteria	0.000 (0.000 to 0.410)	0.000 (0.000 to 0.823)

No statistical analyses for this end point

Secondary: Person Year Rate in the prevention of culture-confirmed invasive disease (ID)- In children starting vaccination in the 12-18 months schedule.

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End point title

Person Year Rate in the prevention of culture-confirmed invasive disease (ID)- In children starting vaccination in the 12-18 months schedule.

End point description

End point type

Secondary

End point timeframe

End point values	10Pn12-18M/043+053 Group	Ctrl12-18M/043+053 Group
Number of subjects analysed	6535	3126
Units: Participants per 1000 person-years
number (confidence interval 95%)
Culture confirmed ID	0.000 (0.000 to 0.240)	0.674 (0.219 to 1.572)
Pneumococcal invasive disease (IPD)	0.000 (0.000 to 0.240)	0.674 (0.219 to 1.572)
Vaccine serotypes (vaccine type-IPD)	0.000 (0.000 to 0.240)	0.404 (0.083 to 1.181)
Serotype 4	0.000 (0.000 to 0.240)	0.135 (0.003 to 0.751)
Serotype 6B	0.000 (0.000 to 0.240)	0.135 (0.003 to 0.751)
Serotype 7F	0.000 (0.000 to 0.240)	0.000 (0.000 to 0.497)
Serotype 14	0.000 (0.000 to 0.240)	0.000 (0.000 to 0.497)
Serotype 18C	0.000 (0.000 to 0.240)	0.000 (0.000 to 0.497)
Serotype 19F	0.000 (0.000 to 0.240)	0.135 (0.003 to 0.751)
Serotype 23F	0.000 (0.000 to 0.240)	0.000 (0.000 to 0.497)
Cross-reactive serotypes	0.000 (0.000 to 0.240)	0.000 (0.000 to 0.497)
Serotype 6A	0.000 (0.000 to 0.240)	0.000 (0.000 to 0.497)
Serotype 19A	0.000 (0.000 to 0.240)	0.000 (0.000 to 0.497)
Other pneumococcal serotypes	0.000 (0.000 to 0.240)	0.269 (0.033 to 0.974)
Serotype 3	0.000 (0.000 to 0.240)	0.135 (0.003 to 0.751)
Serotype 15C	0.000 (0.000 to 0.240)	0.135 (0.003 to 0.751)
H. influenzae ID	0.000 (0.000 to 0.240)	0.000 (0.000 to 0.497)
Non-typeable (NTHI)	0.000 (0.000 to 0.240)	0.000 (0.000 to 0.497)
Other bacteria	0.000 (0.000 to 0.240)	0.000 (0.000 to 0.497)

No statistical analyses for this end point

Secondary: Person Year Rate in the prevention of probable culture-confirmed invasive disease (ID)- In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

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End point title

Person Year Rate in the prevention of probable culture-confirmed invasive disease (ID)- In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

End point description

The PYAR (Person-Year Rate) was calculated as follows n (= number of subjects reported with a probable or culture confirmed ID) divided by T (= sum of follow-up period expressed in years) (per 1000) as well as the corresponding 95% confidence interval (CI), calculated as a 2-sided profile log-likelihood ratio 95% CI using a classical log linear Poisson regression with strata.

End point type

Secondary

End point timeframe

End point values	10Pn3+1-6W-6M/043+053 Group	Ctrl-6W-6M/043+053 Group
Number of subjects analysed	10273	10201
Units: Participants per 1000 person-years
number (confidence interval 95%)
Probable cases of IPD	0.000 (0.000 to 0.172)	0.141 (0.029 to 0.412)
Confirmed or probable cases of IPD	0.000 (0.000 to 0.172)	0.798 (0.465 to 1.278)

No statistical analyses for this end point

Secondary: Person Year Rate in the prevention of probable or culture-confirmed invasive disease (ID)- In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course.

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End point title

Person Year Rate in the prevention of probable or culture-confirmed invasive disease (ID)- In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course.

End point description

End point type

Secondary

End point timeframe

End point values	10Pn2+1-6W-6M/043+053 Group	Ctrl-6W-6M/043+053 Group
Number of subjects analysed	10054	10201
Units: Participants per 1000 person-years
number (confidence interval 95%)
Probable cases of IPD	0.000 (0.000 to 0.179)	0.141 (0.029 to 0.412)
Confirmed or probable cases of IPD	0.097 (0.012 to 0.350)	0.798 (0.465 to 1.278)

No statistical analyses for this end point

Secondary: Person Year Rate in the prevention of probable or culture-confirmed invasive disease (ID)- In children starting vaccination in the 7-11 months schedule.

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End point title

Person Year Rate in the prevention of probable or culture-confirmed invasive disease (ID)- In children starting vaccination in the 7-11 months schedule.

End point description

End point type

Secondary

End point timeframe

End point values	10Pn7-11M/043+053 Group	Ctrl7-11M/043+053 Group
Number of subjects analysed	3880	1908
Units: Participants per 1000 person-years
number (confidence interval 95%)
Probable cases of IPD	0.000 (0.000 to 0.410)	0.000 (0.000 to 0.823)
Confirmed or probable cases of IPD	0.000 (0.000 to 0.410)	0.446 (0.054 to 1.612)

No statistical analyses for this end point

Secondary: Person Year Rate in the prevention of probable or culture-confirmed invasive disease (ID)- In children starting vaccination in the 12-18 months schedule.

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End point title

Person Year Rate in the prevention of probable or culture-confirmed invasive disease (ID)- In children starting vaccination in the 12-18 months schedule.

End point description

End point type

Secondary

End point timeframe

End point values	10Pn12-18M/043+053 Group	Ctrl12-18M/043+053 Group
Number of subjects analysed	6535	3126
Units: Participants per 1000 person-years
number (confidence interval 95%)
Probable cases of IPD	0.000 (0.000 to 0.240)	0.000 (0.000 to 0.497)
Confirmed or probable cases of IPD	0.000 (0.000 to 0.240)	0.674 (0.219 to 1.572)

No statistical analyses for this end point

Secondary: Person Year Rate in reducing hospital-diagnosed pneumonia- In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

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End point title

Person Year Rate in reducing hospital-diagnosed pneumonia- In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

End point description

PYAR was calculated: n (= number of subjects with hospital-diagnosed pneumonia) divided by T (= sum of follow-up (FU) period expressed in years) (per 1000) with 95% CI (2-sided profile log-likelihood ratio 95% CI-classical log linear Poisson regression with strata). FU period considered as period between Dose 1 administration and cut-off date of 31 December 2011. Hospital-diagnosed pneumonia (HDP) cases identified based on hospital discharge diagnosis using international Classification of Disease (ICD)-10 diagnosis codes: J10.0 (Influenza with HDP, other influenza virus identified), J11.0 (Influenza with HDP, virus not identified), J12 (Viral HDP, not elsewhere classified), J13 (HDP due to Sp.), J14 (for HDP due to Hi.), J15 (all HDP, not elsewhere classified), J16 (HDP due to other infectious organisms, not elsewhere classified), J17 (HDP in diseases classified elsewhere), J18 (HDP organism unspecified), J85.1 (Abscess of lung with HDP), and J86 (Pyothorax including empyema).

End point type

Secondary

End point timeframe

Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) – FU mean time=24 months.

End point values	10Pn3+1-6W-6M/043+053 Group	Ctrl-6W-6M/043+053 Group
Number of subjects analysed	10273	10200
Units: Participants per 1000 person-years
number (confidence interval 95%)	10.131 (8.804 to 11.601)	13.854 (12.287 to 15.566)

No statistical analyses for this end point

Secondary: Person Year Rate in reducing hospital-diagnosed pneumonia - In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course.

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End point title

Person Year Rate in reducing hospital-diagnosed pneumonia - In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course.

End point description

End point type

Secondary

End point timeframe

Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) – FU mean time=24 months.

End point values	10Pn2+1-6W-6M/043+053 Group	Ctrl-6W-6M/043+053 Group
Number of subjects analysed	10054	10200
Units: Participants per 1000 person-years
number (confidence interval 95%)	10.155 (8.800 to 11.660)	13.854 (12.287 to 15.566)

No statistical analyses for this end point

Secondary: Person Year Rate in reducing hospital-diagnosed pneumonia- In children starting vaccination in the 7-11 months schedule.

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End point title

Person Year Rate in reducing hospital-diagnosed pneumonia- In children starting vaccination in the 7-11 months schedule.

End point description

End point type

Secondary

End point timeframe

Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) – FU mean time=27 months.

End point values	10Pn7-11M/043+053 Group	Ctrl7-11M/043+053 Group
Number of subjects analysed	3880	1907
Units: Participants per 1000 person-years
number (confidence interval 95%)	10.263 (8.242 to 12.630)	15.752 (12.232 to 19.970)

No statistical analyses for this end point

Secondary: Person Year Rate in reducing hospital-diagnosed pneumonia - In children starting vaccination in the 12-18 months schedule.

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End point title

Person Year Rate in reducing hospital-diagnosed pneumonia - In children starting vaccination in the 12-18 months schedule.

End point description

End point type

Secondary

End point timeframe

Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) – FU mean time=27 months.

End point values	10Pn12-18M/043+053 Group	Ctrl12-18M/043+053 Group
Number of subjects analysed	6534	3126
Units: Participants per 1000 person-years
number (confidence interval 95%)	9.322 (7.832 to 11.013)	11.739 (9.363 to 14.533)

No statistical analyses for this end point

Secondary: Person Year Rate in reducing hospital-diagnosed pneumonia with Chest X-ray (CXR) reading according to WHO criteria- In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

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End point title

Person Year Rate in reducing hospital-diagnosed pneumonia with Chest X-ray (CXR) reading according to WHO criteria- In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

End point description

PYAR was calculated: n (= number of subjects with hospital-diagnosed pneumonia [HDP]) divided by T (= sum of follow-up (FU) period expressed in years) (per 1000) with 95% CI (2-sided profile log-likelihood ratio 95% CI-classical log linear Poisson regression with strata for non-consolidated HDP and without strata for consolidated HDP). FU period considered as period between Dose 1 administration and cut-off date of 31 December 2011. CXR HDP was defined as a HDP case with the presence of abnormal pulmonary infiltrates on the CXR as per independent review panel judgement using WHO methodology. Abnormal pulmonary infiltrates could be either with (Consolidated HDP) or without (Non-consolidated HDP) alveolar consolidation/pleural effusion. New cases of HDP and CXR HDP were based on a 30-day rule, i.e. a new episode was considered if at least a 30-day interval elapsed from the onset of the previous episode.

End point type

Secondary

End point timeframe

Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) – FU mean time=24 months.

End point values	10Pn3+1-6W-6M/043+053 Group	Ctrl-6W-6M/043+053 Group
Number of subjects analysed	10273	10200
Units: Participants per 1000 person-years
number (confidence interval 95%)
Consolidated pneumonia	2.181 (1.591 to 2.919)	3.965 (3.149 to 4.929)
Non-consolidated pneumonia	2.908 (2.219 to 3.744)	2.937 (2.241 to 3.781)
Consolidated or non-consolidated pneumonia	5.090 (4.163 to 6.161)	6.903 (5.810 to 8.141)

No statistical analyses for this end point

Secondary: Person Year Rate in reducing hospital-diagnosed pneumonia with CXR reading according to WHO criteria - In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course.

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End point title

Person Year Rate in reducing hospital-diagnosed pneumonia with CXR reading according to WHO criteria - In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course.

End point description

End point type

Secondary

End point timeframe

Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) – FU mean time=24 months.

End point values	10Pn2+1-6W-6M/043+053 Group	Ctrl-6W-6M/043+053 Group
Number of subjects analysed	10054	10200
Units: Participants per 1000 person-years
number (confidence interval 95%)
Consolidated pneumonia	2.273 (1.658 to 3.042)	3.965 (3.149 to 4.929)
Non-consolidated pneumonia	2.627 (1.962 to 3.445)	2.937 (2.241 to 3.781)
Consolidated or non-consolidated pneumonia	4.901 (3.974 to 5.978)	6.903 (5.810 to 8.141)

No statistical analyses for this end point

Secondary: Person Year Rate in reducing hospital-diagnosed pneumonia with CXR reading according to WHO criteria - In children starting vaccination in the 7-11 months schedule.

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End point title

Person Year Rate in reducing hospital-diagnosed pneumonia with CXR reading according to WHO criteria - In children starting vaccination in the 7-11 months schedule.

End point description

End point type

Secondary

End point timeframe

Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) – FU mean time=27 months.

End point values	10Pn7-11M/043+053 Group	Ctrl7-11M/043+053 Group
Number of subjects analysed	3880	1907
Units: Participants per 1000 person-years
number (confidence interval 95%)
Consolidated pneumonia	1.960 (1.142 to 3.139)	4.401 (2.650 to 6.873)
Non-consolidated pneumonia	3.344 (2.240 to 4.803)	4.865 (3.011 to 7.436)
Consolidated or non-consolidated pneumonia	5.305 (3.884 to 7.076)	9.266 (6.620 to 12.618)

No statistical analyses for this end point

Secondary: Person Year Rate in reducing hospital-diagnosed pneumonia with CXR reading according to WHO criteria - In children starting vaccination in the 12-18 months schedule.

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End point title

Person Year Rate in reducing hospital-diagnosed pneumonia with CXR reading according to WHO criteria - In children starting vaccination in the 12-18 months schedule.

End point description

End point type

Secondary

End point timeframe

Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) – FU mean time=27 months.

End point values	10Pn12-18M/043+053 Group	Ctrl12-18M/043+053 Group
Number of subjects analysed	6534	3126
Units: Participants per 1000 person-years
number (confidence interval 95%)
Consolidated pneumonia	1.824 (1.202 to 2.654)	3.494 (2.261 to 5.157)
Non-consolidated pneumonia	2.837 (2.045 to 3.835)	2.935 (1.817 to 4.486)
Consolidated or non-consolidated pneumonia	4.661 (3.626 to 5.899)	6.428 (4.706 to 8.574)

No statistical analyses for this end point

Secondary: Person Year Rate in prevention of all tympanostomy tube placements- In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

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End point title

Person Year Rate in prevention of all tympanostomy tube placements- In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

End point description

PYAR was calculated: n (= number of subjects with tympanostomy tube placement[TTP]) divided by T (= sum of follow-up (FU) period expressed in years) (per 1000) with 95% CI (2-sided profile log-likelihood ratio 95% CI-classical log linear Poisson regression with strata). FU period considered as period between Dose 1 administration and cut-off date of 31 December 2011. A TTP episode was defined as a TTP episode classified under the DCA 20 code in the Finnish National Institute of Health and Welfare (THL) and Social Insurance Institution of Finland (KELA) registers, using the Nordic Centre for Classifications in Health Care (NOMESCO) Classification of Surgical Procedures (NCSP), version 1.12 from January 2008, and could refer to either an unilateral or a bilateral TTP procedure. New episodes of TTP defined according to a 30-day rule meaning that a new episode was considered if at least 30-day interval elapsed from the onset of the previous episode.

End point type

Secondary

End point timeframe

Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) – FU mean time=24 months.

End point values	10Pn3+1-6W-6M/043+053 Group	Ctrl-6W-6M/043+053 Group
Number of subjects analysed	10273	10200
Units: Participants per 1000 person-years
number (confidence interval 95%)	68.735 (65.203 to 72.408)	79.504 (75.683 to 83.467)

No statistical analyses for this end point

Secondary: Person Year Rate in prevention of all tympanostomy tube placements - In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course.

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End point title

Person Year Rate in prevention of all tympanostomy tube placements - In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course.

End point description

End point type

Secondary

End point timeframe

Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) – FU mean time=24 months.

End point values	10Pn2+1-6W-6M/043+053 Group	Ctrl-6W-6M/043+053 Group
Number of subjects analysed	10054	10200
Units: Participants per 1000 person-years
number (confidence interval 95%)	66.083 (62.550 to 69.764)	79.504 (75.683 to 83.467)

No statistical analyses for this end point

Secondary: Person Year Rate in prevention of all tympanostomy tube placements - In children starting vaccination in the 7-11 months schedule.

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End point title

Person Year Rate in prevention of all tympanostomy tube placements - In children starting vaccination in the 7-11 months schedule.

End point description

End point type

Secondary

End point timeframe

Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) – FU mean time=27 months.

End point values	10Pn7-11M/043+053 Group	Ctrl7-11M/043+053 Group
Number of subjects analysed	3880	1907
Units: Participants per 1000 person-years
number (confidence interval 95%)	68.153 (62.769 to 73.876)	79.920 (71.708 to 88.814)

No statistical analyses for this end point

Secondary: Person Year Rate in prevention of all tympanostomy tube placements - In children starting vaccination in the 12-18 months schedule.

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End point title

Person Year Rate in prevention of all tympanostomy tube placements - In children starting vaccination in the 12-18 months schedule.

End point description

End point type

Secondary

End point timeframe

Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) – FU mean time=27 months.

End point values	10Pn12-18M/043+053 Group	Ctrl12-18M/043+053 Group
Number of subjects analysed	6534	3126
Units: Participants per 1000 person-years
number (confidence interval 95%)	56.809 (53.034 to 60.782)	58.973 (53.480 to 64.877)

No statistical analyses for this end point

Secondary: Person Year Rate in prevention of all antimicrobial prescriptions- In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

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End point title

Person Year Rate in prevention of all antimicrobial prescriptions- In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

End point description

PYAR was calculated: n (= number of subjects with antimicrobial prescriptions (APs)) divided by T (= sum of follow-up (FU) period expressed in years) (per 1000) with 95% CI (2-sided profile log-likelihood ratio 95% CI-classical log linear Poisson regression with strata). FU period considered as period between Dose 1 administration and cut-off date of 31 December 2011. An APs episode was an episode of APs to an infant/child falling under following Anatomic Therapeutic Chemical [ATC] codes: J01 (APs) and following codes for AP usually recommended for otitis media (OM) and respiratory tract infections (RTI). “For OM and RTI” category corresponds to following definition: APs for antibacterial usually recommended for OM and RTI (ATC codes: J01CA04, J01CR02, J01CE02, J01DC02, J01DC04, J01EE02, J01FA09 and J01FA10). New episodes of APs were analyzed according to a 2-day rule meaning new episode considered if at least 2 day interval elapsed from the onset of the previous episode.

End point type

Secondary

End point timeframe

Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) – FU mean time=24 months.

End point values	10Pn3+1-6W-6M/043+053 Group	Ctrl-6W-6M/043+053 Group
Number of subjects analysed	10273	10200
Units: Participants per 1000 person-years
number (confidence interval 95%)
Antimicrobial prescriptions (ATC code J01)	1592.585 (1575.411 to 1609.901)	1706.194 (1688.328 to 1724.202)
For otitis media and respiratory infections	1451.141 (1434.749 to 1467.674)	1565.692 (1548.579 to 1582.947)

No statistical analyses for this end point

Secondary: Person Year Rate in prevention of all antimicrobial prescriptions - In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course.

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End point title

Person Year Rate in prevention of all antimicrobial prescriptions - In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course.

End point description

End point type

Secondary

End point timeframe

Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) – FU mean time=24 months.

End point values	10Pn2+1-6W-6M/043+053 Group	Ctrl-6W-6M/043+053 Group
Number of subjects analysed	10054	10200
Units: Participants per 1000 person-years
number (confidence interval 95%)
Antimicrobial prescriptions (ATC code J01)	1552.493 (1535.183 to 1569.950)	1706.194 (1688.328 to 1724.202)
For otitis media and respiratory infections	1415.983 (1399.453 to 1432.659)	1565.692 (1548.579 to 1582.947)

No statistical analyses for this end point

Secondary: Person Year Rate in prevention of all antimicrobial prescriptions - In children starting vaccination in the 7-11 months schedule.

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End point title

Person Year Rate in prevention of all antimicrobial prescriptions - In children starting vaccination in the 7-11 months schedule.

End point description

End point type

Secondary

End point timeframe

Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) – FU mean time=27 months.

End point values	10Pn7-11M/043+053 Group	Ctrl7-11M/043+053 Group
Number of subjects analysed	3880	1907
Units: Participants per 1000 person-years
number (confidence interval 95%)
Antimicrobial prescriptions (ATC code J01)	1536.618 (1510.637 to 1562.934)	1649.360 (1611.269 to 1688.124)
For otitis media and respiratory infections	1390.856 (1366.143 to 1415.903)	1499.713 (1463.401 to 1536.698)

No statistical analyses for this end point

Secondary: Person Year Rate in prevention of all antimicrobial prescriptions - In children starting vaccination in the 12-18 months schedule.

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End point title

Person Year Rate in prevention of all antimicrobial prescriptions - In children starting vaccination in the 12-18 months schedule.

End point description

End point type

Secondary

End point timeframe

Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) – FU mean time=27 months.

End point values	10Pn12-18M/043+053 Group	Ctrl12-18M/043+053 Group
Number of subjects analysed	6534	3126
Units: Participants per 1000 person-years
number (confidence interval 95%)
Antimicrobial prescriptions (ATC code J01)	1315.936 (1297.521 to 1334.547)	1421.774 (1394.280 to 1449.675)
For otitis media and respiratory infections	1177.729 (1160.312 to 1195.343)	1271.268 (1245.277 to 1297.665)

No statistical analyses for this end point

Secondary: Number of subjects classified by antimicrobial susceptiblity of IPD isolates in children starting vaccination within 7 months of life and assigned to a 2 or 3-dose primary vaccination course

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End point title

Number of subjects classified by antimicrobial susceptiblity of IPD isolates in children starting vaccination within 7 months of life and assigned to a 2 or 3-dose primary vaccination course

End point description

Antimicrobial susceptibility classification of IPD isolates reported during IPD follow-up with percentages for each serotype for the following categories: S= susceptible; I = intermediate ; R = resistant; N = not available.

End point type

Secondary

End point timeframe

Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) – mean FU time=24 months.

End point values	10Pn3+1-6W-6M/043+053 Group	10Pn2+1-6W-6M/043+053 Group	Ctrl-6W-6M/043+053 Group
Number of subjects analysed	0 ^[5]	2	24
Units: Participants
Serotype-4 -Pencillin-S		0	1
Serotype-6A -Pencillin-S		0	1
Serotype-6B -Pencillin-I		0	3
Serotype-6B -Pencillin-R		0	1
Serotype-6B -Pencillin-S		0	2
Serotype-7F -Pencillin-S		1	1
Serotype-14 -Pencillin-I		0	2
Serotype-14 -Pencillin-R		0	1
Serotype-14 -Pencillin-S		0	2
Serotype-15C -Pencillin-S		0	1
Serotype-18C -Pencillin-S		0	1
Serotype-19A -Pencillin-I		0	1
Serotype-19F -Pencillin-I		0	1
Serotype-19F -Pencillin-S		0	1
Serotype-23F -Pencillin-S		0	1
Serotype-N -Pencillin-N		1	4
Serotype-4 -Erythromycin-S		0	1
Serotype-6A -Erythromycin-S		0	1
Serotype-6B -Erythromycin-R		0	5
Serotype-6B -Erythromycin-S		0	1
Serotype-7F -Erythromycin-S		1	1
Serotype-14 -Erythromycin-R		0	4
Serotype-14 -Erythromycin-S		0	1
Serotype-15C -Erythromycin-S		0	1
Serotype-18C -Erythromycin-S		0	1
Serotype-19A -Erythromycin-S		0	1
Serotype-19F -Erythromycin-R		0	1
Serotype-19F -Erythromycin-S		0	1
Serotype-23F -Erythromycin-S		0	1
Serotype-N -Erythromycin-N		1	4
Serotype-4 -Tetracyclin-S		0	1
Serotype-6A -Tetracyclin-S		0	1
Serotype-6B -Tetracyclin-R		0	4
Serotype-6B -Tetracyclin-S		0	2
Serotype-7F -Tetracyclin-S		1	1
Serotype-14 -Tetracyclin-S		0	5
Serotype-15C -Tetracyclin-S		0	1
Serotype-18C -Tetracyclin-S		0	1
Serotype-19A -Tetracyclin-S		0	1
Serotype-19F -Tetracyclin-R		0	1
Serotype-19F -Tetracyclin-S		0	1
Serotype-23F -Tetracyclin-S		0	1
Serotype-N -Tetracyclin-N		1	4
Serotype-4 -Levoffloxacin-S		0	1
Serotype-6A -Levoffloxacin-S		0	1
Serotype-6B -Levoffloxacin-S		0	6
Serotype-7F -Levoffloxacin-S		1	1
Serotype-14 -Levoffloxacin-S		0	5
Serotype-15C -Levoffloxacin-S		0	1
Serotype-18C -Levoffloxacin-S		0	1
Serotype-19A -Levoffloxacin-S		0	1
Serotype-19F -Levoffloxacin-S		0	2
Serotype-23F -Levoffloxacin-S		0	1
Serotype-N -Levoffloxacin-N		1	4
Serotype-4 -Ceftriaxone-S		0	1
Serotype-6A -Ceftriaxone-S		0	1
Serotype-6B -Ceftriaxone-S		0	6
Serotype-7F -Ceftriaxone-S		1	1
Serotype-14 -Ceftriaxone-I		0	1
Serotype-14 -Ceftriaxone-S		0	4
Serotype-15C -Ceftriaxone-S		0	1
Serotype-18C -Ceftriaxone-S		0	1
Serotype-19A -Ceftriaxone-S		0	1
Serotype-19F -Ceftriaxone-S		0	2
Serotype-23F -Ceftriaxone-S		0	1
Serotype-N -Ceftriaxone-N		1	4
Serotype-4 -Clindamycin-S		0	1
Serotype-6A -Clindamycin-S		0	1
Serotype-6B -Clindamycin-R		0	4
Serotype-6B -Clindamycin-S		0	2
Serotype-7F -Clindamycin-S		1	1
Serotype-14 -Clindamycin-N		0	1
Serotype-14 -Clindamycin-S		0	4
Serotype-15C -Clindamycin-S		0	1
Serotype-18C -Clindamycin-S		0	1
Serotype-19A -Clindamycin-S		0	1
Serotype-19F -Clindamycin-R		0	1
Serotype-19F -Clindamycin-S		0	1
Serotype-23F -Clindamycin-S		0	1
Serotype-N -Clindamycin-N		1	4

Notes
[5] - No data collected for this group

No statistical analyses for this end point

Secondary: Number of subjects with Lower respiratory tract infections (LRTIs) (in a subset of subjects in Turku area )

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End point title

Number of subjects with Lower respiratory tract infections (LRTIs) (in a subset of subjects in Turku area )

End point description

Analysis of this outcome was performed in the Turku area. The number of subjects reporting at least one LRTI any time after the administration of the first vaccine dose was tabulated. The analysis was performed in a subset of vaccinated subjects including all vaccinated subjects enrolled in the 10PNPD-DIT-053 study in the Turku area and those vaccinated subjects enrolled in the 10PN-PD-DIT-043 study in the Turku area who agreed to take part in this assessment.

End point type

Secondary

End point timeframe

From the administration of the first vaccine dose till the end of the blinded invasive disease (ID) Follow-up period (at least 30 months)

End point values	10Pn3+1-6W-6M/043+053 Group	10Pn2+1-6W-6M/043+053 Group	Ctrl-6W-6M/043+053 Group	10Pn7-11M/043+053 Group	Ctrl7-11M/043+053 Group	10Pn12-18M/043+053 Group	Ctrl12-18M/043+053 Group
Number of subjects analysed	243	190	171	31	22	62	48
Units: Participants	19	19	19	3	1	5	2

No statistical analyses for this end point

Secondary: Number of subjects with Upper respiratory tract infections (URTIs) (in a subset of subjects in Turku area)

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End point title

Number of subjects with Upper respiratory tract infections (URTIs) (in a subset of subjects in Turku area)

End point description

Analysis of this outcome was performed in the Turku area. The number of subjects reporting at least one URTI any time after the administration of the first vaccine dose was tabulated. The analysis was performed in a subset of vaccinated subjects including all vaccinated subjects enrolled in the 10PNPD-DIT-053 study in the Turku area and those vaccinated subjects enrolled in the 10PN-PD-DIT-043 study in the Turku area who agreed to take part in this assessment.

End point type

Secondary

End point timeframe

From the administration of the first vaccine dose till the end of the blinded invasive disease (ID) Follow-up period (at least 30 months)

End point values	10Pn3+1-6W-6M/043+053 Group	10Pn2+1-6W-6M/043+053 Group	Ctrl-6W-6M/043+053 Group	10Pn7-11M/043+053 Group	Ctrl7-11M/043+053 Group	10Pn12-18M/043+053 Group	Ctrl12-18M/043+053 Group
Number of subjects analysed	243	190	171	31	22	62	48
Units: Participants	158	124	94	14	15	27	19

No statistical analyses for this end point

Secondary: Number of subjects with any and Grade 3 solicited local symptoms.

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End point title

Number of subjects with any and Grade 3 solicited local symptoms.

End point description

Assessed solicited local symptoms were pain (P), redness (R) and swelling (S). Any = occurrence of the symptom regardless of intensity grade. Grade 3 (G3) pain = cried when limb was moved/spontaneously painful. G3 redness/swelling = redness/swelling spreading beyond 30 millimeters (mm) of injection site.

End point type

Secondary

End point timeframe

Within 4 days (4D) after each vaccination (M0+4D, M1+4D [only for 3+1 schedule], M2+4D, M8+4D [booster dose] for 6W-6M subjects; M0+4D, M2+4D, M6+4D [booster dose] for 7M-11M subjects; M0+4D, M6+4D for 12M-18M subjects)

End point values	10Pn3+1-6W-6M/053 Group	10Pn2+1-6W-6M/053 Group	Ctrl3+1-6W-6M/053 Group	Ctrl2+1-6W-6M/053 Group	10Pn7-11M/053 Group	Ctrl7-11M/053 Group	10Pn12-18M/053 Group	Ctrl12-18M/053 Group
Number of subjects analysed	1846	1302	1066	852	237	202	363	270
Units: Participants
Any P, D1 (N=1846,1302,1066,852,237,202,363,270)	807	611	146	106	120	33	220	65
G3 P, D1 (N=1846,1302,1066,852,237, 202,363,270)	60	43	2	3	6	0	19	0
Any R, D1(N=1846,1302,1066,852,237,202,363,270)	936	675	270	214	137	48	203	93
G3 R, D1 (N=1846,1302,1066,852,237,202,363,270)	56	48	3	0	17	0	39	0
Any S, D1(N=1846,1302,1066,852,237,202,363,270)	636	471	88	64	107	19	142	25
G3 S, D1(N=1846,1302,1066,852,237,202,363,270)	89	69	4	1	20	9	35	1
Any P, D2 (N=1827,1287,1056,847,229,199,345,260)	662	509	114	94	108	38	242	78
G3 P, D2 (N=1827,1287,1056,847,229,199,345,260)	23	28	2	1	11	0	45	0
Any R, D2(N=1827,1287,1056,847,229,199,345,260)	996	690	254	203	124	57	193	85
G3 R, D2 (N=1827,1287,1056,847,229,199,345,260)	48	63	3	0	21	0	49	1
Any S, D2(N=1827,1287,1056,847,229,199,345,260)	686	536	114	79	98	18	148	26
G3 S, D2 (N=1827,1287,1056,847,229,199,345,260)	67	91	4	1	19	0	34	0
Any P, D3 (N=1808,0,1052,0,0,0,0,0)	538	0	102	0	0	0	0	0
G3 P, D3 (N=1808,0,1052,0,0,0,0,0)	12	0	2	0	0	0	0	0
Any R D3 (N=1808,0,1052,0,0,0,0,0)	963	0	300	0	0	0	0	0
G3 R, D3 (N=1808,0,1052,0,0,0,0,0)	52	0	0	0	0	0	0	0
Any S, D3 (N=1808,0,1052,0,0,0,0,0)	676	0	144	0	0	0	0	0
G3 S, D3 (N=1808,0,1052,0,0,0,0,0)	62	0	1	0	0	0	0	0
Any P, B dose (N=1758,1258,1024,827,216,188,0,0)	888	710	250	171	123	40	0	0
G3 P, B dose (N=1758,1258,1024,827,216,188,0,0)	66	41	2	2	14	2	0	0
Any R, B dose(N=1758,1258,1024,827,216,188,0,0)	913	702	345	238	106	54	0	0
G3 R, B dose (N=1758,1258,1024,827,216,188,0,0)	102	103	13	2	18	0	0	0
Any S, B dose(N=1758,1258,1024,827,216,188,0,0)	716	586	229	118	85	31	0	0
G3 S, B dose (N=1758,1258,1024,827,216,188,0,0)	102	111	10	3	14	0	0	0

No statistical analyses for this end point

Secondary: Number of subjects with any, Grade 3 and related solicited general symptoms.

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End point title

Number of subjects with any, Grade 3 and related solicited general symptoms.

End point description

Assessed solicited general symptoms were drowsiness (D), fever [defined as rectal temperature [T(R)] ≥ 38 degrees Celsius (°C) or oral/axillary/tympanic temperature equal to or above 37.5°C], irritability/fussiness (I) and loss pf appetite (L ap). Any = occurrence of the symptom regardless of intensity grade. Grade 3 (G3) drowsiness = drowsiness that prevented normal activity. G3 fever = rectal temperature > 40°C. G3 irritability/fussiness = cried that could not be comforted/prevented normal activity. G3 loss of appetite = not eating at all. Related (Rel) = a symptom assessed by investigator as causally related to the vaccination.

End point type

Secondary

End point timeframe

End point values	10Pn3+1-6W-6M/053 Group	10Pn2+1-6W-6M/053 Group	Ctrl3+1-6W-6M/053 Group	Ctrl2+1-6W-6M/053 Group	10Pn7-11M/053 Group	Ctrl7-11M/053 Group	10Pn12-18M/053 Group	Ctrl12-18M/053 Group
Number of subjects analysed	1846	1302	1066	852	237	202	363	270
Units: Participants
Any D, D1 (N=1846,1302,1066,852,237,202,363,270)	1070	742	462	384	106	62	155	87
G3 D, D1 (N=1846,1302,1066,852,237,202,363,270)	11	8	5	1	1	0	1	2
Rel D, D1 (N=1846,1302,1066,852,237,202,363,270)	1054	738	453	374	103	57	152	81
Any T (R),D1(N=1846,1302,1066,852,237,202,363,270)	388	289	82	78	38	16	74	28
G3 T(R), D1 (N=1846,1302,1066,852,237,202,363,270)	2	0	1	0	8	0	2	2
Rel T(R),D1 (N=1846,1302,1066,852,237,202,363,270)	381	284	78	74	35	13	69	25
Any I, D1 (N=1846,1302,1066,852,237,202,363,270)	1325	942	577	468	157	90	210	103
G3 I, D1 (N=1846,1302,1066,852,237,202,363,270)	76	56	20	14	3	2	6	4
Rel I, D1 (N=1846,1302,1066,852,237,202,363,270)	1298	937	565	460	157	83	201	96
Any L.ap,D1 (N=1846,1302,1066,852,237,202,363,270)	499	335	202	147	84	56	128	82
G3 L.ap, D1 (N=1846,1302,1066,852,237,202,363,270)	1	3	2	0	0	1	2	4
Rel L.ap,D1 (N=1846,1302,1066,852,237,202,363,270)	480	332	196	140	81	48	123	73
Any D, D2 (N=1828,1287,1056,847,229,198,345,260)	868	572	332	258	88	52	126	58
G3 D, D2 (N=1828,1287,1056,847,229,198,345,260)	7	6	1	3	2	1	2	1
Rel D, D2 (N=1828,1287,1056,847,229,198,345,260)	855	564	329	247	85	51	123	55
Any T(R), D2(N=1828,1287,1056,847,229,198,345,260)	380	382	78	80	44	20	55	11
G3 T(R), D2 (N=1828,1287,1056,847,229,198,345,260)	2	0	0	0	0	1	2	1
Rel T(R), D2(N=1828,1287,1056,847,229,198,345,260)	373	378	78	71	43	15	53	8
Any I, D2 (N=1828,1287,1056,847,229,198,345,260)	1254	822	532	408	139	94	193	72
G3 I, D2 (N=1828,1287,1056,847,229,198,345,260)	73	44	13	14	7	1	3	0
Rel I, D2 (N=1828,1287,1056,847,229,198,345,260)	1236	816	523	396	137	93	191	71
Any L.ap, D2(N=1828,1287,1056,847,229,198,345,260)	434	323	187	149	69	56	109	57
G3 L.ap, D2 (N=1828,1287,1056,847,229,198,345,260)	4	2	1	3	44	0	2	1
Rel L.ap, D2(N=1828,1287,1056,847,229,198,345,260)	419	318	181	135	0	52	105	54
Any D, D3 (N=1808, 0, 1052, 0, 0, 0, 0, 0)	645	0	293	0	0	0	0	0
G3 D, D3 (N=1808, 0, 1052, 0, 0, 0, 0, 0)	2	0	2	0	0	0	0	0
Rel D, D3 (N=1808, 0, 1052, 0, 0, 0, 0, 0)	638	0	285	0	0	0	0	0
Any T (R), D3 (N=1808, 0, 1052, 0, 0, 0, 0, 0)	347	0	110	0	0	0	0	0
G3 T (R), D3 (N=1808, 0, 1052, 0, 0, 0, 0, 0)	1	0	1	0	0	0	0	0
Rel T (R), D3 (N=1808, 0, 1052, 0, 0, 0, 0, 0)	336	0	106	0	0	0	0	0
Any I, D3 (N=1808, 0, 1052, 0, 0, 0, 0, 0)	1115	0	496	0	0	0	0	0
G3 I, D3 (N=1808, 0, 1052, 0, 0, 0, 0, 0)	41	0	14	0	0	0	0	0
Rel I, D3 (N=1808, 0, 1052, 0, 0, 0, 0, 0)	1100	0	492	0	0	0	0	0
Any L.ap, D3 (N=1808, 0, 1052, 0, 0, 0, 0, 0)	349	0	178	0	0	0	0	0
G3 L.ap, D3 (N=1808, 0, 1052, 0, 0, 0, 0, 0)	3	0	0	0	0	0	0	0
Rel L.ap, D3 (N=1808, 0, 1052, 0, 0, 0, 0, 0)	336	0	172	0	0	0	0	0
Any D, B dose (N=1757,1257,1024,827,216,188,0,0)	721	561	307	243	92	47	0	0
G3 D, B dose (N=1757,1257,1024,827,216,188,0,0)	8	8	3	4	2	1	0	0
Rel D, B dose (N=1757,1257,1024,827,216,188,0,0)	699	548	300	233	87	46	0	0
Any T(R), B dose(N=1757,1257,1024,827,216,188,0,0)	391	333	142	120	42	11	0	0
G3 T(R), B dose(N=1757,1257,1024,827,216,188,0,0)	3	0	0	1	1	0	0	0
Rel T(R), B dose(N=1757,1257,1024,827,216,188,0,0)	371	319	134	110	41	8	0	0
Any I, B dose (N=1757,1257,1024,827,216,188,0,0)	1124	816	491	410	129	84	0	0
G3 I, B dose (N=1757,1257,1024,827,216,188,0,0)	47	33	14	7	2	1	0	0
Rel I, B dose (N=1757,1257,1024,827,216,188,0,0)	1085	801	481	395	124	80	0	0
Any L.ap, B dose(N=1757,1257,1024,827,216,188,0,0)	549	411	260	186	64	46	0	0
G3 L.ap, B dose(N=1757,1257,1024,827,216,188,0,0)	12	5	6	3	2	1	0	0
Rel L.ap, B dose(N=1757,1257,1024,827,216,188,0,0)	513	398	253	173	60	43	0	0

No statistical analyses for this end point

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

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End point title

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

End point description

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

End point type

Secondary

End point timeframe

Within 31 days (31D) after each vaccination (M0+31D, M1+31D [only for 3+1 schedule], M2+31D, M8+31D [booster dose] for 6W-6M subjects; M0+31D, M2+31D, M6+31D [booster dose] for 7M-11M subjects; M0+31D, M6+31D for 12M-18M subjects)

End point values	10Pn3+1-6W-6M/053 Group	10Pn2+1-6W-6M/053 Group	Ctrl3+1-6W-6M/053 Group	Ctrl2+1-6W-6M/053 Group	10Pn7-11M/053 Group	Ctrl7-11M/053 Group	10Pn12-18M/053 Group	Ctrl12-18M/053 Group
Number of subjects analysed	1849	1316	1069	859	241	204	368	271
Units: Participants
Un AEs, Pr. (N=1849,1316,1069,859,241,204,368,271)	1105	598	554	337	157	132	221	174
Un AEs, Booster (N=1786,1275,1043,837,226,197,0,0)	521	363	277	244	51	48	0	0

No statistical analyses for this end point

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

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End point title

Number of subjects with serious adverse events (SAEs).

End point description

An event is defined as ‘serious’ when it meets one of the pre-defined outcomes described below: results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation; results in disability/incapacity, or is a congenital anomaly/birth defect in the offspring of a study subject. Medical or scientific judgement should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalisation but may jeopardize the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These should also be considered serious.

End point type

Secondary

End point timeframe

Following administration of the first vaccine dose up to study end (M0 up to M18 for subjects aged 6W to 6M at enrollment; M0 up to M16 for subjects aged 7M to 11M at enrollment; M0 up to M9 for subjects aged 12M to 18M at enrollment)

End point values	10Pn3+1-6W-6M/053 Group	10Pn2+1-6W-6M/053 Group	Ctrl3+1-6W-6M/053 Group	Ctrl2+1-6W-6M/053 Group	10Pn7-11M/053 Group	Ctrl7-11M/053 Group	10Pn12-18M/053 Group	Ctrl12-18M/053 Group
Number of subjects analysed	1849	1316	1069	859	241	204	368	271
Units: Participants	163	96	77	74	24	18	23	14

No statistical analyses for this end point

Secondary: Number of subjects enrolled and vaccinated in the 10PN-PD-DIT-043 and 10PN-PD-DIT-053 study with post-study SAEs reported via passive surveillance– Subjects enrolled aged 6 weeks to 6 months and 7 to 18 months

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End point title

Number of subjects enrolled and vaccinated in the 10PN-PD-DIT-043 and 10PN-PD-DIT-053 study with post-study SAEs reported via passive surveillance– Subjects enrolled aged 6 weeks to 6 months and 7 to 18 months

End point description

End point type

Secondary

End point timeframe

From the end of the blinded ID Follow-Up period (at least 30 months from the study start) up to the end of 18-month period after study unblinding

End point values	10Pn3+1-6W-6M/043+053 Group	10Pn2+1-6W-6M/043+053 Group	Ctrl-6W-6M/043+053 Group	10Pn7-11M/043+053 Group	Ctrl7-11M/043+053 Group	10Pn12-18M/043+053 Group	Ctrl12-18M/043+053 Group
Number of subjects analysed	10273	10054	10201	3880	1908	6535	3126
Units: Participants	1	2	0	0	0	0	0

No statistical analyses for this end point

Secondary: NUMBER OF NASOPHARYNGEAL SWABS WITH STREPTOCOCCUS PNEUMONIAE PATHOGENS (S. PN.), ANY PATHOGEN. IN SUBJECTS RECEIVING 3+1 AND 2+1 INFANT SCHEDULES OF 10PN

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End point title

NUMBER OF NASOPHARYNGEAL SWABS WITH STREPTOCOCCUS PNEUMONIAE PATHOGENS (S. PN.), ANY PATHOGEN. IN SUBJECTS RECEIVING 3+1 AND 2+1 INFANT SCHEDULES OF 10PN ^[6]

End point description

At each time point where a swab sample result was available, the number/percentage of swabs associated with the specified bacteria was tabulated. The “prior to dose 1” nasopharyngeal swab samples collected from subjects within their first 7 months of age were obtained solely from the Immuno subset (The Immuno subset was constituted of the first +/- 1500 subjects from whom blood samples were collected, according to age and treatment groups).

End point type

Secondary

End point timeframe

At 3 months (mths) of age (prior to dose 1); at 6 mths of age (1 mth post dose 3 or post dose 2); at 11-12 mths of age (pre-booster dose); at 14-15 mths of age (3 mths post-booster); at 18-22 mths of age (10 mths post-booster)

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 6W-6M subjects

End point values	10Pn3+1-6W-6M/053 Group	10Pn2+1-6W-6M/053 Group	Ctrl-6W-6M/053 Group
Number of subjects analysed	1803	1289	1897
Units: swab samples
3 Months (N=253,253,341)	49	31	56
6 Months (N=1803,1289,1897)	412	323	464
11-12 Months (N=1784,1269,1877)	500	383	604
14-15 Months (N=1727, 1227, 1814)	512	370	638
18-22 Months (N=1686, 1216, 1769)	503	430	736

No statistical analyses for this end point

Secondary: NUMBER OF NASOPHARYNGEAL SWABS WITH STREPTOCOCCUS PNEUMONIAE PATHOGENS (S. PN.), ANY PATHOGEN. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN

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End point title

NUMBER OF NASOPHARYNGEAL SWABS WITH STREPTOCOCCUS PNEUMONIAE PATHOGENS (S. PN.), ANY PATHOGEN. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN ^[7]

End point description

At each time point where a swab sample result was available, the number/percentage of swabs associated with the specified bacteria was tabulated.

End point type

Secondary

End point timeframe

At 7-11 months (mths) of age (prior to dose 1); at 9-13 mths of age (1 mth post dose 2); at 13-17 mths of age (pre-booster dose); at 16-20 mths of age (3 mths post-booster); at 23-27 mths of age (10 mths post-booster)

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 7-11M subjects

End point values	10Pn7-11M/053 Group	Ctrl7-11M/053 Group
Number of subjects analysed	236	200
Units: swab samples
7-11 Months (N=236, 198)	69	58
9-13 Months (N=230, 200)	79	56
13-17 Months (N= 225, 197)	81	87
16-20 Months (N= 209, 179)	75	72
23-27 Months (N= 200, 175)	68	75

No statistical analyses for this end point

Secondary: NUMBER OF NASOPHARYNGEAL SWABS WITH STREPTOCOCCUS PNEUMONIAE PATHOGENS (S. PN.), ANY PATHOGEN. IN SUBJECTS RECEIVING 12-18M SCHEDULE OF 10PN

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End point title

NUMBER OF NASOPHARYNGEAL SWABS WITH STREPTOCOCCUS PNEUMONIAE PATHOGENS (S. PN.), ANY PATHOGEN. IN SUBJECTS RECEIVING 12-18M SCHEDULE OF 10PN ^[8]

End point description

At each time point where a swab sample result was available, the number/percentage of swabs associated with the specified bacteria was tabulated.

End point type

Secondary

End point timeframe

At 12-18 months (mths) of age (prior to dose 1); at 19-25 mths of age (1 mth post dose 2); at 21-27 mths of age (3 months post dose 2)

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 12-18M subjects

End point values	10Pn12-18M/053 Group	Ctrl12-18M/053 Group
Number of subjects analysed	358	265
Units: swab samples
12-18 Months (N= 358, 265)	125	88
19-25 Months (N= 340, 255)	152	112
21-27 Months (N= 338, 254)	132	105

No statistical analyses for this end point

Secondary: NUMBER OF NASOPHARYNGEAL SWABS WITH STREPTOCOCCUS PNEUMONIAE (S. PN.) VACCINE SEROTYPES. IN SUBJECTS RECEIVING 3+1 AND 2+1 INFANT SCHEDULES OF 10PN

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End point title

NUMBER OF NASOPHARYNGEAL SWABS WITH STREPTOCOCCUS PNEUMONIAE (S. PN.) VACCINE SEROTYPES. IN SUBJECTS RECEIVING 3+1 AND 2+1 INFANT SCHEDULES OF 10PN ^[9]

End point description

At each time point where a swab sample result was available, the number/percentage of swabs associated with the specified bacteria was tabulated. The “prior to dose 1” nasopharyngeal swab samples collected from subjects within their first 7 months of age were obtained solely from the Immuno subset (The Immuno subset was constituted of the first ± 1500 subjects from whom blood samples were collected, according to age and treatment groups).

End point type

Secondary

End point timeframe

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 6W-6M subjects

End point values	10Pn3+1-6W-6M/053 Group	10Pn2+1-6W-6M/053 Group	Ctrl-6W-6M/053 Group
Number of subjects analysed	1803	1289	1897
Units: swab samples
3 Months (N=253, 253, 341)	29	18	30
6 Months (N= 1803, 1289, 1897)	183	159	237
11-12 Months (N=1784, 1269, 1877)	229	178	342
14-15 Months (N= 1727, 1227, 1814)	209	153	364
18-22 Months (N=1686, 1216, 1769)	169	176	404

No statistical analyses for this end point

Secondary: NUMBER OF NASOPHARYNGEAL SWABS WITH STREPTOCOCCUS PNEUMONIAE (S. PN.) VACCINE SEROTYPES. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN

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End point title

NUMBER OF NASOPHARYNGEAL SWABS WITH STREPTOCOCCUS PNEUMONIAE (S. PN.) VACCINE SEROTYPES. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN ^[10]

End point description

At each time point where a swab sample result was available, the number/percentage of swabs associated with the specified bacteria was tabulated.

End point type

Secondary

End point timeframe

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 7-11M subjects

End point values	10Pn7-11M/053 Group	Ctrl7-11M/053 Group
Number of subjects analysed	236	200
Units: swab samples
7-11 Months (N= 236, 198)	44	34
9-13 Months (N= 230, 200)	43	35
13-17 Months (N= 225, 197)	43	55
16-20 Months (N= 209, 179)	34	47
23-27 Months (N= 200, 175)	28	48

No statistical analyses for this end point

Secondary: NUMBER OF NASOPHARYNGEAL SWABS WITH STREPTOCOCCUS PNEUMONIAE (S. PN.) VACCINE SEROTYPES. IN SUBJECTS RECEIVING 12-18M SCHEDULE OF 10PN

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End point title

NUMBER OF NASOPHARYNGEAL SWABS WITH STREPTOCOCCUS PNEUMONIAE (S. PN.) VACCINE SEROTYPES. IN SUBJECTS RECEIVING 12-18M SCHEDULE OF 10PN ^[11]

End point description

At each time point where a swab sample result was available, the number/percentage of swabs associated with the specified bacteria was tabulated.

End point type

Secondary

End point timeframe

At 12-18 months (mths) of age (prior to dose 1); at 19-25 mths of age (1 mth post dose 2); at 21-27 mths of age (3 months post dose 2)

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 12-18M subjects

End point values	10Pn12-18M/053 Group	Ctrl12-18M/053 Group
Number of subjects analysed	358	265
Units: swab samples
12-18 Months (N= 358, 265)	70	57
19-25 Months (N= 340, 255)	69	70
21-27 Months (N= 338, 254)	64	53

No statistical analyses for this end point

Secondary: NUMBER OF SUBJECTS WITH ACQUISITION OF NEW STREPTOCOCCUS PNEUMONIAE (S. PN.) STRAINS, ANY PATHOGEN, IDENTIFIED IN NASOPHARYNGEAL SWABS. IN SUBJECTS RECEIVING 3+1 AND 2+1 INFANT SCHEDULES OF 10PN

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End point title

NUMBER OF SUBJECTS WITH ACQUISITION OF NEW STREPTOCOCCUS PNEUMONIAE (S. PN.) STRAINS, ANY PATHOGEN, IDENTIFIED IN NASOPHARYNGEAL SWABS. IN SUBJECTS RECEIVING 3+1 AND 2+1 INFANT SCHEDULES OF 10PN ^[12]

End point description

At each time point where a swab sample result was available, the number/percentage of subjects with new acquisition associated to the specified bacteria at the considered time point was tabulated.

End point type

Secondary

End point timeframe

At 11-12 mths of age (pre-booster dose); at 14-15 mths of age (3 mths post-booster); at 18-22 mths of age (10 mths post-booster)

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 6W-6M subjects

End point values	10Pn3+1-6W-6M/053 Group	10Pn2+1-6W-6M/053 Group	Ctrl-6W-6M/053 Group
Number of subjects analysed	1780	1269	1874
Units: Participants
11-12 Months (N= 1780, 1269, 1874)	331	246	415
14-15 Months (N= 1723, 1222, 1807)	562	400	692
18-22 Months (N= 1675, 1200, 1752)	818	609	1023

No statistical analyses for this end point

Secondary: NUMBER OF SUBJECTS WITH ACQUISITION OF NEW STREPTOCOCCUS PNEUMONIAE (S. PN.) STRAINS, ANY PATHOGEN, IDENTIFIED IN NASOPHARYNGEAL SWABS. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN

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End point title

NUMBER OF SUBJECTS WITH ACQUISITION OF NEW STREPTOCOCCUS PNEUMONIAE (S. PN.) STRAINS, ANY PATHOGEN, IDENTIFIED IN NASOPHARYNGEAL SWABS. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN ^[13]

End point description

At each time point where a swab sample result was available, the number/percentage of subjects with new acquisition associated to the specified bacteria at the considered time point was tabulated.

End point type

Secondary

End point timeframe

At 9-13 mths of age (1 mth post dose 2); at 13-17 mths of age (pre-booster dose); at 16-20 mths of age (3 mths post-booster); at 23-27 mths of age (10 mths post-booster)

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 7-11M subjects

End point values	10Pn7-11M/053 Group	Ctrl7-11M/053 Group
Number of subjects analysed	226	195
Units: Participants
9-13 Months (N= 226, 195)	36	30
13-17 Months (N= 221, 192)	78	83
16-20 Months (N= 205, 175)	95	100
23-27 Months (N= 194, 170)	117	116

No statistical analyses for this end point

Secondary: NUMBER OF SUBJECTS WITH ACQUISITION OF NEW STREPTOCOCCUS PNEUMONIAE (S. PN.) STRAINS, ANY PATHOGEN, IDENTIFIED IN NASOPHARYNGEAL SWABS. IN SUBJECTS RECEIVING 12-18M SCHEDULE OF 10PN

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End point title

NUMBER OF SUBJECTS WITH ACQUISITION OF NEW STREPTOCOCCUS PNEUMONIAE (S. PN.) STRAINS, ANY PATHOGEN, IDENTIFIED IN NASOPHARYNGEAL SWABS. IN SUBJECTS RECEIVING 12-18M SCHEDULE OF 10PN ^[14]

End point description

At each time point where a swab sample result was available, the number/percentage of subjects with new acquisition associated to the specified bacteria at the considered time point was tabulated.

End point type

Secondary

End point timeframe

At 19-25 mths of age (1 mth post dose 2); at 21-27 mths of age (3 months post dose 2)

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 12-18M subjects

End point values	10Pn12-18M/053 Group	Ctrl12-18M/053 Group
Number of subjects analysed	333	249
Units: Participants
19-25 Months (N= 333, 249)	130	94
21-27 Months (N= 330, 246)	166	133

No statistical analyses for this end point

Secondary: NUMBER OF SUBJECTS WITH ACQUISITION OF NEW STREPTOCOCCUS PNEUMONIAE (S. PN.) VACCINE SEROTYPE STRAINS, IDENTIFIED IN NASOPHARYNGEAL SWABS. IN SUBJECTS RECEIVING 3+1 AND 2+1 INFANT SCHEDULES OF 10PN

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End point title

NUMBER OF SUBJECTS WITH ACQUISITION OF NEW STREPTOCOCCUS PNEUMONIAE (S. PN.) VACCINE SEROTYPE STRAINS, IDENTIFIED IN NASOPHARYNGEAL SWABS. IN SUBJECTS RECEIVING 3+1 AND 2+1 INFANT SCHEDULES OF 10PN ^[15]

End point description

At each time point where a swab sample result was available, the number/percentage of subjects with new acquisition associated to the specified bacteria at the considered time point was tabulated.

End point type

Secondary

End point timeframe

At 11-12 mths of age (pre-booster dose); at 14-15 mths of age (3 mths post-booster); at 18-22 mths of age (10 mths post-booster)

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 6W-6M subjects

End point values	10Pn3+1-6W-6M/053 Group	10Pn2+1-6W-6M/053 Group	Ctrl-6W-6M/053 Group
Number of subjects analysed	1780	1269	1874
Units: Participants
11-12 Months (N= 1780, 1269, 1874)	131	97	223
14-15 Months (N= 1723, 1222, 1807)	221	156	387
18-22 Months (N= 1675, 1200, 1752)	326	269	626

No statistical analyses for this end point

Secondary: NUMBER OF SUBJECTS WITH ACQUISITION OF NEW STREPTOCOCCUS PNEUMONIAE (S. PN.) VACCINE SEROTYPE STRAINS, IDENTIFIED IN NASOPHARYNGEAL SWABS. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN

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End point title

NUMBER OF SUBJECTS WITH ACQUISITION OF NEW STREPTOCOCCUS PNEUMONIAE (S. PN.) VACCINE SEROTYPE STRAINS, IDENTIFIED IN NASOPHARYNGEAL SWABS. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN ^[16]

End point description

At each time point where a swab sample result was available, the number/percentage of subjects with new acquisition associated to the specified bacteria at the considered time point was tabulated.

End point type

Secondary

End point timeframe

At 9-13 mths of age (1 mth post dose 2); at 13-17 mths of age (pre-booster dose); at 16-20 mths of age (3 mths post-booster); at 23-27 mths of age (10 mths post-booster)

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 7-11M subjects

End point values	10Pn7-11M/053 Group	Ctrl7-11M/053 Group
Number of subjects analysed	226	195
Units: Participants
9-13 Months (N= 226, 195)	18	17
13-17 Months (N= 221, 192)	41	51
16-20 Months (N= 205, 175)	50	70
23-27 Months (N= 194, 170)	62	88

No statistical analyses for this end point

Secondary: NUMBER OF SUBJECTS WITH ACQUISITION OF NEW STREPTOCOCCUS PNEUMONIAE (S. PN.) VACCINE SEROTYPE STRAINS, IDENTIFIED IN NASOPHARYNGEAL SWABS. IN SUBJECTS RECEIVING 12-18M SCHEDULE OF 10PN

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End point title

NUMBER OF SUBJECTS WITH ACQUISITION OF NEW STREPTOCOCCUS PNEUMONIAE (S. PN.) VACCINE SEROTYPE STRAINS, IDENTIFIED IN NASOPHARYNGEAL SWABS. IN SUBJECTS RECEIVING 12-18M SCHEDULE OF 10PN ^[17]

End point description

At each time point where a swab sample result was available, the number/percentage of subjects with new acquisition associated to the specified bacteria at the considered time point was tabulated.

End point type

Secondary

End point timeframe

At 19-25 mths of age (1 mth post dose 2); at 21-27 mths of age (3 months post dose 2)

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 12-18M subjects

End point values	10Pn12-18M/053 Group	Ctrl12-18M/053 Group
Number of subjects analysed	333	249
Units: Participants
19-25 Months (N= 333, 249)	53	55
21-27 Months (N= 330, 246)	78	74

No statistical analyses for this end point

Secondary: NUMBER OF NASOPHARYNGEAL SWABS WITH HAEMOPHILUS INFLUENZAE (H. INFL.) PATHOGENS. IN SUBJECTS RECEIVING 3+1 AND 2+1 INFANT SCHEDULES OF 10PN

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End point title

NUMBER OF NASOPHARYNGEAL SWABS WITH HAEMOPHILUS INFLUENZAE (H. INFL.) PATHOGENS. IN SUBJECTS RECEIVING 3+1 AND 2+1 INFANT SCHEDULES OF 10PN ^[18]

End point description

At each time point where a swab sample result was available, the number/percentage of swabs associated with the specified bacteria was tabulated. The “prior to dose 1” nasopharyngeal swab samples collected from subjects within their first 7 months of age were obtained solely from the Immuno subset (The Immuno subset was constituted of the first ± 1500 subjects from whom blood samples were collected, according to age and treatment groups). Data presented only include results from samples confirmed as positive for Hi/NTHi after differentiation from H. haemolyticus by PCR assay.

End point type

Secondary

End point timeframe

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 6W-6M subjects

End point values	10Pn3+1-6W-6M/053 Group	10Pn2+1-6W-6M/053 Group	Ctrl-6W-6M/053 Group
Number of subjects analysed	1803	1289	1897
Units: Swab samples
3 Months (N= 253, 253, 341)	6	4	10
6 Months (N= 1803, 1289, 1897)	57	36	46
11-12 Months (N= 1784, 1269, 1877)	84	72	87
14-15 Months (N= 1726, 1227, 1814)	121	84	92
18-22 Months (N= 1684, 1212, 1768)	211	128	190

No statistical analyses for this end point

Secondary: NUMBER OF NASOPHARYNGEAL SWABS WITH HAEMOPHILUS INFLUENZAE (H. INFL.) PATHOGENS. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN

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End point title

NUMBER OF NASOPHARYNGEAL SWABS WITH HAEMOPHILUS INFLUENZAE (H. INFL.) PATHOGENS. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN ^[19]

End point description

At each time point where a swab sample result was available, the number/percentage of swabs associated with the specified bacteria was tabulated. Data presented only include results from samples confirmed as positive for Hi /NTHi after differentiation from H. haemolyticus by PCR assay.

End point type

Secondary

End point timeframe

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 7-11M subjects

End point values	10Pn7-11M/053 Group	Ctrl7-11M/053 Group
Number of subjects analysed	236	200
Units: Swab samples
7-11 Months (N= 236, 198)	6	8
9-13 Months (N= 230, 200)	8	9
13-17 Months (N= 225, 197)	22	14
16-20 Months (N= 209, 179)	17	13
23-27 Months (N= 200, 175)	21	15

No statistical analyses for this end point

Secondary: NUMBER OF NASOPHARYNGEAL SWABS WITH HAEMOPHILUS INFLUENZAE (H. INFL.) PATHOGENS. IN SUBJECTS RECEIVING 12-18M SCHEDULE OF 10PN

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End point title

NUMBER OF NASOPHARYNGEAL SWABS WITH HAEMOPHILUS INFLUENZAE (H. INFL.) PATHOGENS. IN SUBJECTS RECEIVING 12-18M SCHEDULE OF 10PN ^[20]

End point description

At each time point where a swab sample result was available, the number/percentage of swabs associated with the specified bacteria was tabulated. Data presented only include results from samples confirmed as positive for Hi/NTHi after differentiation from H. haemolyticus by PCR assay.

End point type

Secondary

End point timeframe

At 12-18 months (mths) of age (prior to dose 1); at 19-25 mths of age (1 mth post dose 2); at 21-27 mths of age (3 months post dose 2)

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 12-18M subjects

End point values	10Pn12-18M/053 Group	Ctrl12-18M/053 Group
Number of subjects analysed	358	265
Units: Swab samples
12-18 Months (N= 358, 265)	21	12
19-25 Months (N= 340, 255)	24	21
21-27 Months (N= 338, 254)	27	29

No statistical analyses for this end point

Secondary: NUMBER OF SUBJECTS WITH ACQUISITION OF NEW HAEMOPHILUS INFLUENZAE (H. INFL.) PATHOGENS IDENTIFIED IN NASOPHARYNGEAL SWABS. IN SUBJECTS RECEIVING 3+1 AND 2+1 INFANT SCHEDULES OF 10PN

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End point title

NUMBER OF SUBJECTS WITH ACQUISITION OF NEW HAEMOPHILUS INFLUENZAE (H. INFL.) PATHOGENS IDENTIFIED IN NASOPHARYNGEAL SWABS. IN SUBJECTS RECEIVING 3+1 AND 2+1 INFANT SCHEDULES OF 10PN ^[21]

End point description

At each time point where a swab sample result was available, the number/percentage of subjects with new acquisition associated to the specified bacteria at the considered time point was tabulated. Data presented only include results from samples confirmed as positive for Hi/NTHi after differentiation from H. haemolyticus by PCR assay.

End point type

Secondary

End point timeframe

At 11-12 mths of age (pre-booster dose) ; at 14-15 mths of age ( 3 mths post-booster) ; at 18-22 mths of age (10 mths post-booster)

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 6W-6M subjects

End point values	10Pn3+1-6W-6M/053 Group	10Pn2+1-6W-6M/053 Group	Ctrl-6W-6M/053 Group
Number of subjects analysed	1780	1269	1874
Units: Participants
11-12 Months (N= 1780, 1269, 1874)	77	65	83
14-15 Months (N= 1722, 1222, 1807)	176	139	157
18-22 Months (N= 1672, 1196, 1751)	349	240	313

No statistical analyses for this end point

Secondary: NUMBER OF SUBJECTS WITH ACQUISITION OF NEW HAEMOPHILUS INFLUENZAE (H. INFL.) PATHOGENS IDENTIFIED IN NASOPHARYNGEAL SWABS. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN

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End point title

NUMBER OF SUBJECTS WITH ACQUISITION OF NEW HAEMOPHILUS INFLUENZAE (H. INFL.) PATHOGENS IDENTIFIED IN NASOPHARYNGEAL SWABS. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN ^[22]

End point description

End point type

Secondary

End point timeframe

At 9-13 mths of age (1 mth post dose 2); at 13-17 mths of age (pre-booster dose); at 16-20 mths of age (3 mths post-booster) at 23-27 mths of age (10 mths post-booster)

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 7-11M subjects

End point values	10Pn7-11M/053 Group	Ctrl7-11M/053 Group
Number of subjects analysed	226	195
Units: Participants
9-13 Months (N= 226, 195)	8	9
13-17 Months (N= 221, 192)	29	19
16-20 Months (N= 205, 175)	37	28
23-27 Months (N= 194, 170)	55	39

No statistical analyses for this end point

Secondary: NUMBER OF SUBJECTS WITH ACQUISITION OF NEW HAEMOPHILUS INFLUENZAE (H. INFL.) PATHOGENS IDENTIFIED IN NASOPHARYNGEAL SWABS. IN SUBJECTS RECEIVING 12-18M SCHEDULE OF 10PN

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End point title

NUMBER OF SUBJECTS WITH ACQUISITION OF NEW HAEMOPHILUS INFLUENZAE (H. INFL.) PATHOGENS IDENTIFIED IN NASOPHARYNGEAL SWABS. IN SUBJECTS RECEIVING 12-18M SCHEDULE OF 10PN ^[23]

End point description

End point type

Secondary

End point timeframe

At 19-25 mths of age (1 mth post dose 2); at 21-27 mths of age (3 months post dose 2)

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 12-18M subjects

End point values	10Pn12-18M/053 Group	Ctrl12-18M/053 Group
Number of subjects analysed	333	249
Units: Participants
19-25 Months (N= 333, 249)	19	20
21-27 Months (N= 330, 246)	37	41

No statistical analyses for this end point

Secondary: NUMBER OF NASOPHARYNGEAL SWABS WITH MORAXELLA CATARRHALIS PATHOGENS. IN SUBJECTS RECEIVING 3+1 AND 2+1 INFANT SCHEDULES OF 10PN

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End point title

NUMBER OF NASOPHARYNGEAL SWABS WITH MORAXELLA CATARRHALIS PATHOGENS. IN SUBJECTS RECEIVING 3+1 AND 2+1 INFANT SCHEDULES OF 10PN ^[24]

End point description

At each time point where a swab sample result was available, the number/percentage of swabs associated with the specified bacteria was tabulated. The “prior to dose 1” nasopharyngeal swab samples collected from subjects within their first 7 months of age were obtained solely from the Immuno subset (The Immuno subset was constituted of the first 1500 subjects from whom blood samples were collected, according to age and treatment groups).

End point type

Secondary

End point timeframe

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 6W-6M subjects

End point values	10Pn3+1-6W-6M/053 Group	10Pn2+1-6W-6M/053 Group	Ctrl-6W-6M/053 Group
Number of subjects analysed	1803	1289	1897
Units: Swab samples
3 Months (N= 253, 253, 341)	57	58	76
6 Months (N= 1803, 1289, 1897)	459	345	486
11-12 Months (N= 1784, 1269, 1877)	671	493	733
14-15 Months (N= 1727, 1227, 1814)	612	466	668
18-22 Months (N= 1686, 1216, 1769)	794	566	780

No statistical analyses for this end point

Secondary: NUMBER OF NASOPHARYNGEAL SWABS WITH MORAXELLA CATARRHALIS PATHOGENS. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN

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End point title

NUMBER OF NASOPHARYNGEAL SWABS WITH MORAXELLA CATARRHALIS PATHOGENS. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN ^[25]

End point description

At each time point where a swab sample result was available, the number/percentage of swabs associated with the specified bacteria was tabulated.

End point type

Secondary

End point timeframe

At 7-11 months (mths) of age (prior to dose 1); at 9-13 mths of age (1 mth post dose 2) ; at 13-17 mths of age (pre-booster dose) ; at 16-20 mths of age ( 3 mths post-booster) ; at 23-27 mths of age (10 mths post-booster)

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 7-11M subjects

End point values	10Pn7-11M/053 Group	Ctrl7-11M/053 Group
Number of subjects analysed	236	200
Units: Swab samples
7-11 Months (N= 236, 198)	69	59
9-13 Months (N= 230, 200)	73	61
13-17 Months (N= 225, 197)	109	98
16-20 Months (N= 209, 179)	91	81
23-27 Months (N= 200, 175)	83	63

No statistical analyses for this end point

Secondary: NUMBER OF NASOPHARYNGEAL SWABS WITH MORAXELLA CATARRHALIS PATHOGENS. IN SUBJECTS RECEIVING 12-18M SCHEDULE OF 10PN

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End point title

NUMBER OF NASOPHARYNGEAL SWABS WITH MORAXELLA CATARRHALIS PATHOGENS. IN SUBJECTS RECEIVING 12-18M SCHEDULE OF 10PN ^[26]

End point description

At each time point where a swab sample result was available, the number/percentage of swabs associated with the specified bacteria was tabulated.

End point type

Secondary

End point timeframe

At 12-18 months (mths) of age (prior to dose 1); at 19-25 mths of age (1 mth post dose 2); at 21-27 mths of age (3 months post dose 2)

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 12-18M subjects

End point values	10Pn12-18M/053 Group	Ctrl12-18M/053 Group
Number of subjects analysed	358	265
Units: Swab samples
12-18 Months (N= 358, 265)	143	72
19-25 Months (N= 340, 255)	167	129
21-27 Months (N= 338, 254)	143	120

No statistical analyses for this end point

Secondary: NUMBER OF NASOPHARYNGEAL SWABS WITH GROUP A STREPTOCOCCUS PATHOGENS. IN SUBJECTS RECEIVING 3+1 AND 2+1 INFANT SCHEDULES OF 10PN

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End point title

NUMBER OF NASOPHARYNGEAL SWABS WITH GROUP A STREPTOCOCCUS PATHOGENS. IN SUBJECTS RECEIVING 3+1 AND 2+1 INFANT SCHEDULES OF 10PN ^[27]

End point description

At each time point where a swab sample result was available, the number/percentage of swabs associated with the specified bacteria was tabulated. The “prior to dose 1” nasopharyngeal swab samples collected from subjects within their first 7 months of age were obtained solely from the Immuno subset (The Immuno subset was constituted of the first ± 1500 subjects from whom blood samples were collected, according to age and treatment groups).

End point type

Secondary

End point timeframe

At 3 months (mths) of age (prior to dose 1); at 6 mths of age (1 mth post dose 3 or post dose 2) ; at 11-12 mths of age (pre-booster dose) ; at 14-15 mths of age ( 3 mths post-booster) ; at 18-22 mths of age (10 mths post-booster)

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 6W-6M subjects

End point values	10Pn3+1-6W-6M/053 Group	10Pn2+1-6W-6M/053 Group	Ctrl-6W-6M/053 Group
Number of subjects analysed	1803	1289	1897
Units: Swab samples
3 Months (N= 253, 253, 341)	0	0	1
6 Months (N= 1803, 1289, 1897)	10	5	8
11-12 Months (N= 1784, 1269, 1877)	9	8	5
14-15 Months (N= 1727, 1227, 1814)	4	5	10
18-22 Months (N= 1686, 1216, 1769)	5	5	7

No statistical analyses for this end point

Secondary: NUMBER OF NASOPHARYNGEAL SWABS WITH GROUP A STREPTOCOCCUS PATHOGENS. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN

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End point title

NUMBER OF NASOPHARYNGEAL SWABS WITH GROUP A STREPTOCOCCUS PATHOGENS. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN ^[28]

End point description

At each time point where a swab sample result was available, the number/percentage of swabs associated with the specified bacteria was tabulated.

End point type

Secondary

End point timeframe

At 7-11 months (mths) of age (prior to dose 1); at 9-13 mths of age (1 mth post dose 2) ; at 13-17 mths of age (pre-booster dose) ; at 16-20 mths of age ( 3 mths post-booster) ; at 23-27 mths of age (10 mths post-booster)

Notes
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 7-11M subjects

End point values	10Pn7-11M/053 Group	Ctrl7-11M/053 Group
Number of subjects analysed	236	200
Units: Swab samples
7-11 Months (N= 236, 198)	1	1
9-13 Months (N= 230, 200)	0	3
13-17 Months (N= 225, 197)	0	1
16-20 Months (N= 209, 179)	0	2
23-27 Months (N= 200, 175)	2	1

No statistical analyses for this end point

Secondary: NUMBER OF NASOPHARYNGEAL SWABS WITH GROUP A STREPTOCOCCUS PATHOGENS. IN SUBJECTS RECEIVING 12-18M SCHEDULE OF 10PN

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End point title

NUMBER OF NASOPHARYNGEAL SWABS WITH GROUP A STREPTOCOCCUS PATHOGENS. IN SUBJECTS RECEIVING 12-18M SCHEDULE OF 10PN ^[29]

End point description

At each time point where a swab sample result was available, the number/percentage of swabs associated with the specified bacteria was tabulated.

End point type

Secondary

End point timeframe

At 12-18 months (mths) of age (prior to dose 1); at 19-25 mths of age (1 mth post dose 2); at 21-27 mths of age (3 months post dose 2)

Notes
[29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 12-18M subjects

End point values	10Pn12-18M/053 Group	Ctrl12-18M/053 Group
Number of subjects analysed	358	265
Units: Swab samples
12-18 Months (N= 358, 265)	3	0
19-25 Months (N= 340, 255)	2	0
21-27 Months (N= 338, 254)	0	2

No statistical analyses for this end point

Secondary: NUMBER OF NASOPHARYNGEAL SWABS WITH STAPHYLOCOCCUS AUREUS PATHOGENS. IN SUBJECTS RECEIVING 3+1 AND 2+1 INFANT SCHEDULES OF 10PN

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End point title

NUMBER OF NASOPHARYNGEAL SWABS WITH STAPHYLOCOCCUS AUREUS PATHOGENS. IN SUBJECTS RECEIVING 3+1 AND 2+1 INFANT SCHEDULES OF 10PN ^[30]

End point description

At each time point where a swab sample result was available, the number/percentage of swabs associated with the specified bacteria was tabulated. The “prior to dose 1” nasopharyngeal swab samples collected from subjects within their first 7 months of age were obtained solely from the Immuno subset (The Immuno subset was constituted of the first ± 1500 subjects from whom blood samples were collected, according to age and treatment groups).

End point type

Secondary

End point timeframe

At 3 months (mths) of age (prior to dose 1); at 6 mths of age (1 mth post dose 3 or post dose 2) ; at 11-12 mths of age (pre-booster dose) ; at 14-15 mths of age ( 3 mths post-booster) ; at 18-22 mths of age (10 mths post-booster)

Notes
[30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 6W-6M subjects

End point values	10Pn3+1-6W-6M/053 Group	10Pn2+1-6W-6M/053 Group	Ctrl-6W-6M/053 Group
Number of subjects analysed	1803	1289	1897
Units: Swab samples
3 Months (N= 253, 253, 341)	111	108	144
6 Months (N= 1803, 1289, 1897)	762	515	796
11-12 Months (N= 1784, 1269, 1877)	468	306	462
14-15 Months (N= 1727, 1227, 1814)	387	282	373
18-22 Months (N= 1686, 1216, 1769)	255	182	266

No statistical analyses for this end point

Secondary: NUMBER OF NASOPHARYNGEAL SWABS WITH STAPHYLOCOCCUS AUREUS PATHOGENS. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN

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End point title

NUMBER OF NASOPHARYNGEAL SWABS WITH STAPHYLOCOCCUS AUREUS PATHOGENS. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN ^[31]

End point description

At each time point where a swab sample result was available, the number/percentage of swabs associated with the specified bacteria was tabulated.

End point type

Secondary

End point timeframe

At 7-11 months (mths) of age (prior to dose 1); at 9-13 mths of age (1 mth post dose 2) ; at 13-17 mths of age (pre-booster dose) ; at 16-20 mths of age ( 3 mths post-booster) ; at 23-27 mths of age (10 mths post-booster)

Notes
[31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 7-11M subjects

End point values	10Pn7-11M/053 Group	Ctrl7-11M/053 Group
Number of subjects analysed	236	200
Units: Swab samples
7-11 Months (N= 236, 198)	60	53
9-13 Months (N= 230, 200)	53	63
13-17 Months (N= 225, 197)	32	26
16-20 Months (N= 209, 179)	34	31
23-27 Months (N= 200, 175)	30	36

No statistical analyses for this end point

Secondary: NUMBER OF NASOPHARYNGEAL SWABS WITH STAPHYLOCOCCUS AUREUS PATHOGENS. IN SUBJECTS RECEIVING 12-18M SCHEDULE OF 10PN

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End point title

NUMBER OF NASOPHARYNGEAL SWABS WITH STAPHYLOCOCCUS AUREUS PATHOGENS. IN SUBJECTS RECEIVING 12-18M SCHEDULE OF 10PN ^[32]

End point description

At each time point where a swab sample result was available, the number/percentage of swabs associated with the specified bacteria was tabulated.

End point type

Secondary

End point timeframe

At 12-18 months (mths) of age (prior to dose 1); at 19-25 mths of age (1 mth post dose 2); at 21-27 mths of age (3 months post dose 2)

Notes
[32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 12-18M subjects

End point values	10Pn12-18M/053 Group	Ctrl12-18M/053 Group
Number of subjects analysed	358	265
Units: Swab samples
12-18 Months (N= 358, 265)	45	38
19-25 Months (N= 340, 255)	47	41
21-27 Months (N= 338, 254)	39	40

No statistical analyses for this end point

Secondary: PNEUMOCOCCAL ANTIBODY CONCENTRATIONS AGAINST PNEUMOCOCCAL VACCINE SEROTYPES, IN THE IMMUNO SUBSET, IN SUBJECTS RECEIVING 3+1 INFANT SCHEDULES OF 10PN

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End point title

PNEUMOCOCCAL ANTIBODY CONCENTRATIONS AGAINST PNEUMOCOCCAL VACCINE SEROTYPES, IN THE IMMUNO SUBSET, IN SUBJECTS RECEIVING 3+1 INFANT SCHEDULES OF 10PN ^[33]

End point description

Antibody concentrations were measured by 22F -inhibition enzyme-linked Immunosorbent Assay (ELISA), expressed as geometric mean concentrations (GMCs), in micrograms per milliliter (µg/mL). Serotypes assessed were the pneumococcal vaccine serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F. The cut-off of the assay was >= 0.05 µg/mL. The Immuno subset was constituted of the first ± 1500 subjects from whom blood samples were collected, according to age and treatment groups.

End point type

Secondary

End point timeframe

At 6 mths of age (1 mth post dose 3); at 11-12 mths of age (pre-booster dose) ; at 12-13 mths of age ( 1 mth post-booster) ; at 18-22 mths of age (10 mths post-booster)

Notes
[33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 6W-6M subjects (3+1 schedule)

End point values	10Pn3+1-6W-6M/053 Group	Ctrl3+1-6W-6M/053 Group
Number of subjects analysed	209	123
Units: µg/mL
geometric mean (confidence interval 95%)
ANTI-1, 6 months (N=208, 121)	1.86 (1.68 to 2.05)	0.03 (0.03 to 0.04)
ANTI-1, 11-12 months (N= 202, 122)	0.54 (0.48 to 0.61)	0.03 (0.03 to 0.03)
ANTI-1, 12-13 months (N= 189, 119)	2.13 (1.88 to 2.41)	0.03 (0.03 to 0.04)
ANTI-1, 18-22 months (N= 185, 113)	0.50 (0.44 to 0.57)	0.04 (0.04 to 0.05)
ANTI-4, 6 months (N= 208, 122)	2.47 (2.23 to 2.75)	0.03 (0.03 to 0.03)
ANTI-4, 11-12 months (N= 203, 122)	0.97 (0.86 to 1.09)	0.03 (0.03 to 0.03)
ANTI-4, 12-13 (N=189, 116)	3.61 (3.20 to 4.06)	0.03 (0.03 to 0.03)
ANTI-4, 18-22 (N= 185, 113)	0.62 (0.54 to 0.71)	0.03 (0.03 to 0.03)
ANTI-5, 6 months (N= 208, 121)	2.73 (2.47 to 3.01)	0.03 (0.03 to 0.03)
ANTI-5, 11-12 months (N= 201, 123)	1.07 (0.95 to 1.19)	0.04 (0.04 to 0.05)
ANTI-5, 12-13 (N= 189, 120)	3.27 (2.87 to 3.73)	0.05 (0.04 to 0.06)
ANTI-5, 18-22 (N= 185, 113)	0.85 (0.75 to 0.97)	0.10 (0.08 to 0.13)
ANTI-6B, 6 months (N= 208, 122)	0.51 (0.43 to 0.62)	0.03 (0.03 to 0.03)
ANTI-6B, 11-12 months (N= 203, 123)	0.58 (0.50 to 0.67)	0.03 (0.03 to 0.03)
ANTI-6B, 12-13 (N= 189, 120)	1.43 (1.22 to 1.68)	0.03 (0.03 to 0.03)
ANTI-6B, 18-22 (N= 185, 113)	0.60 (0.50 to 0.72)	0.04 (0.04 to 0.05)
ANTI-7F, 6 months (N= 209, 120)	2.90 (2.62 to 3.20)	0.03 (0.03 to 0.04)
ANTI-7F, 11-12 months (N= 202, 122)	1.56 (1.40 to 1.74)	0.04 (0.03 to 0.04)
ANTI-7F, 12-13 months (N= 189, 120)	4.25 (3.80 to 4.75)	0.04 (0.03 to 0.04)
ANTI-7F, 18-22 months (N= 185, 113)	1.19 (1.07 to 1.32)	0.05 (0.04 to 0.05)
ANTI-9V, 6 months (N= 208, 122)	2.23 (2.00 to 2.48)	0.03 (0.03 to 0.03)
ANTI-9V, 11-12 months (N= 203, 121)	1.35 (1.20 to 1.51)	0.03 (0.03 to 0.03)
ANTI-9V, 12-13 months (N= 188, 119)	3.98 (3.56 to 4.46)	0.03 (0.03 to 0.03)
ANTI-9V, 18-22 months (N= 185, 113)	1.32 (1.16 to 1.50)	0.03 (0.03 to 0.04)
ANTI-14, 6 months (N= 209, 121)	5.00 (4.46 to 5.61)	0.07 (0.06 to 0.09)
ANTI-14, 11-12 months (N= 202, 121)	2.52 (2.19 to 2.91)	0.05 (0.04 to 0.06)
ANTI-14, 12-13 months (N= 189, 118)	6.40 (5.62 to 7.29)	0.06 (0.05 to 0.07)
ANTI-14, 18-22 months (N= 185, 113)	1.98 (1.70 to 2.30)	0.08 (0.06 to 0.11)
ANTI-18C, 6 months (N= 209, 121)	6.51 (5.63 to 7.54)	0.03 (0.03 to 0.04)
ANTI-18C, 11-12 months (N= 202, 123)	2.45 (2.10 to 2.86)	0.03 (0.03 to 0.03)
ANTI-18C, 12-13 months (N= 189, 119)	10.43 (8.94 to 12.18)	0.03 (0.03 to 0.03)
ANTI-18C, 18-22 months (N= 185, 113)	2.18 (1.89 to 2.53)	0.04 (0.03 to 0.04)
ANTI-19F, 6 months (N= 209, 122)	5.91 (5.06 to 6.89)	0.06 (0.05 to 0.07)
ANTI-19F, 11-12 months (N= 202, 122)	2.73 (2.36 to 3.16)	0.05 (0.04 to 0.06)
ANTI-19F, 12-13 months (N= 189, 116)	8.04 (7.04 to 9.17)	0.04 (0.03 to 0.05)
ANTI-19F, 18-22 months (N= 185, 113)	2.17 (1.84 to 2.55)	0.07 (0.05 to 0.08)
ANTI-23F, 6 months (N= 208, 121)	0.68 (0.56 to 0.83)	0.03 (0.03 to 0.03)
ANTI-23F, 11-12 months (N= 202, 121)	0.73 (0.62 to 0.87)	0.03 (0.03 to 0.03)
ANTI-23F, 12-13 months (N= 189, 119)	2.30 (1.90 to 2.77)	0.03 (0.03 to 0.04)
ANTI-23F, 18-22 months (N= 185, 113)	0.95 (0.79 to 1.13)	0.05 (0.04 to 0.06)

No statistical analyses for this end point

Secondary: PNEUMOCOCCAL ANTIBODY CONCENTRATIONS AGAINST PNEUMOCOCCAL VACCINE SEROTYPES, IN THE IMMUNO SUBSET, IN SUBJECTS RECEIVING 2+1 INFANT SCHEDULES OF 10PN

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End point title

PNEUMOCOCCAL ANTIBODY CONCENTRATIONS AGAINST PNEUMOCOCCAL VACCINE SEROTYPES, IN THE IMMUNO SUBSET, IN SUBJECTS RECEIVING 2+1 INFANT SCHEDULES OF 10PN ^[34]

End point description

Antibody concentrations were measured by 22F-inhibition enzyme-linked Immunosorbent Assay (ELISA), expressed as geometric mean concentrations (GMCs), in micrograms per milliliter (µg/mL). Serotypes assessed were the pneumococcal vaccine serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F. The cut-off of the assay was >= 0.05 µg/mL. The Immuno subset was constituted of the first ± 1500 subjects from whom blood samples were collected, according to age and treatment groups.

End point type

Secondary

End point timeframe

At 6 mths of age (1 mth post dose 2); at 11-12 mths of age (pre-booster dose) ; at 12-13 mths of age ( 1 mth post-booster) ; at 18-22 mths of age (10 mths post-booster)

Notes
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 6W-6M subjects (2+1 schedule)

End point values	10Pn2+1-6W-6M/053 Group	Ctrl2+1-6W-6M/053 Group
Number of subjects analysed	209	142
Units: µg/mL
geometric mean (confidence interval 95%)
ANTI-1, 6 months (N= 205, 142)	1.37 (1.25 to 1.52)	0.03 (0.03 to 0.03)
ANTI-1, 11-12 months (N= 209, 132)	0.42 (0.37 to 0.47)	0.03 (0.03 to 0.04)
ANTI-1, 12-13 months (N= 193, 127)	1.91 (1.72 to 2.12)	0.04 (0.03 to 0.04)
ANTI-1, 18-22 months (N= 189, 122)	0.36 (0.32 to 0.40)	0.05 (0.04 to 0.06)
ANTI-4, 6 months (N= 204, 141)	1.87 (1.68 to 2.07)	0.03 (0.03 to 0.03)
ANTI-4, 11-12 months (N= 209, 134)	0.72 (0.64 to 0.81)	0.03 (0.03 to 0.03)
ANTI-4, 12-13 months (N= 193, 125)	3.16 (2.84 to 3.52)	0.03 (0.03 to 0.04)
ANTI-4, 18-22 months (N= 189, 122)	0.59 (0.52 to 0.67)	0.03 (0.03 to 0.04)
ANTI-5, 6 months (N= 204, 139)	1.97 (1.76 to 2.19)	0.03 (0.03 to 0.04)
ANTI-5, 11-12 months (N= 209, 133)	0.71 (0.63 to 0.80)	0.04 (0.04 to 0.05)
ANTI-5, 12-13 months (N= 193, 128)	2.82 (2.52 to 3.15)	0.06 (0.05 to 0.08)
ANTI-5, 18-22 months (N= 189, 122)	0.83 (0.73 to 0.94)	0.09 (0.08 to 0.11)
ANTI-6B, 6 months (N= 205, 142)	0.32 (0.27 to 0.37)	0.03 (0.03 to 0.03)
ANTI-6B, 11-12 months (N= 209, 133)	0.42 (0.36 to 0.48)	0.03 (0.03 to 0.03)
ANTI-6B, 12-13 months (N= 193, 127)	1.43 (1.25 to 1.65)	0.03 (0.03 to 0.04)
ANTI-6B, 18-22 months (N= 189, 124)	0.58 (0.48 to 0.70)	0.06 (0.05 to 0.07)
ANTI-7F, 6 months (N= 205, 140)	1.76 (1.57 to 1.97)	0.03 (0.03 to 0.04)
ANTI-7F, 11-12 months (N= 209, 132)	0.96 (0.86 to 1.07)	0.03 (0.03 to 0.04)
ANTI-7F, 12-13 months (N= 193, 129)	3.62 (3.28 to 4.01)	0.03 (0.03 to 0.04)
ANTI-7F, 18-22 months (N= 189, 122)	1.27 (1.15 to 1.41)	0.04 (0.04 to 0.05)
ANTI-9V, 6 months (N= 205, 140)	1.38 (1.24 to 1.54)	0.03 (0.03 to 0.03)
ANTI-9V, 11-12 months (N= 209, 133)	0.87 (0.77 to 0.97)	0.03 (0.03 to 0.03)
ANTI-9V, 12-13 months (N= 193, 127)	3.88 (3.47 to 4.33)	0.03 (0.03 to 0.03)
ANTI-9V, 18-22 months (N= 189, 122)	0.92 (0.82 to 1.03)	0.04 (0.03 to 0.04)
ANTI-14, 6 months (N= 205, 140)	3.31 (2.92 to 3.75)	0.06 (0.05 to 0.07)
ANTI-14, 11-12 months (N= 209, 131)	1.32 (1.13 to 1.54)	0.04 (0.04 to 0.05)
ANTI-14, 12-13 months (N= 193, 120)	4.84 (4.26 to 5.51)	0.06 (0.05 to 0.07)
ANTI-14, 18-22 months (N= 189, 122)	1.57 (1.32 to 1.86)	0.12 (0.09 to 0.15)
ANTI-18C, 6 months (N= 205, 141)	3.38 (2.88 to 3.95)	0.04 (0.03 to 0.04)
ANTI-18C, 11-12 months (N= 209, 132)	1.49 (1.29 to 1.73)	0.03 (0.02 to 0.03)
ANTI-18C, 12-13 months (N= 193, 124)	10.60 (9.48 to 11.84)	0.03 (0.03 to 0.03)
ANTI-18C, 18-22 months (N= 189, 120)	2.16 (1.89 to 2.48)	0.04 (0.03 to 0.05)
ANTI-19F, 6 months (N= 205, 140)	3.40 (2.92 to 3.97)	0.06 (0.05 to 0.07)
ANTI-19F, 11-12 months (N= 209, 133)	1.51 (1.29 to 1.75)	0.03 (0.03 to 0.04)
ANTI-19F, 12-13 months (N= 193, 124)	7.41 (6.54 to 8.40)	0.04 (0.04 to 0.05)
ANTI-19F, 18-22 months (N= 189, 123)	2.10 (1.79 to 2.47)	0.07 (0.05 to 0.10)
ANTI-23F, 6 months (N= 205, 142)	0.54 (0.45 to 0.65)	0.04 (0.03 to 0.04)
ANTI-23F, 11-12 months (N= 209, 134)	0.42 (0.35 to 0.50)	0.03 (0.03 to 0.03)
ANTI-23F, 12-13 months (N= 193,123)	2.18 (1.88 to 2.54)	0.03 (0.03 to 0.04)
ANTI-23F, 18-22 months (N= 189, 122)	0.75 (0.63 to 0.88)	0.04 (0.04 to 0.05)

No statistical analyses for this end point

Secondary: PNEUMOCOCCAL ANTIBODY CONCENTRATIONS AGAINST CROSS-REACTIVE PNEUMOCOCCAL SEROTYPES 6A AND 19A, IN THE IMMUNO SUBSET, IN SUBJECTS RECEIVING 3+1 INFANT SCHEDULES OF 10PN

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End point title

PNEUMOCOCCAL ANTIBODY CONCENTRATIONS AGAINST CROSS-REACTIVE PNEUMOCOCCAL SEROTYPES 6A AND 19A, IN THE IMMUNO SUBSET, IN SUBJECTS RECEIVING 3+1 INFANT SCHEDULES OF 10PN ^[35]

End point description

Antibody concentrations were measured by 22F-inhibitionenzyme-linked Immunosorbent Assay (ELISA), expressed as geometric mean concentrations (GMCs), in micrograms per milliliter (µg/mL). Serotypes assessed were the cross-reactive pneumococcal serotypes 6A and 19A. The cut-off of the assay was >= 0.05 µg/mL. The Immuno subset was constituted of the first ± 1500 subjects from whom blood samples were collected, according to age and treatment groups.

End point type

Secondary

End point timeframe

At 6 mths of age (1 mth post dose 3); at 11-12 mths of age (pre-booster dose) ; at 12-13 mths of age ( 1 mth post-booster) ; at 18-22 mths of age (10 mths post-booster)

Notes
[35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 6W-6M subjects (3+1 schedule)

End point values	10Pn3+1-6W-6M/053 Group	Ctrl3+1-6W-6M/053 Group
Number of subjects analysed	208	122
Units: µg/mL
geometric mean (confidence interval 95%)
ANTI-6A, 6 months (N= 208, 120)	0.13 (0.11 to 0.15)	0.03 (0.03 to 0.04)
ANTI-6A, 11-12 months (N= 202, 121)	0.19 (0.16 to 0.23)	0.03 (0.03 to 0.03)
ANTI-6A, 12-13 months (N= 189, 120)	0.53 (0.43 to 0.65)	0.03 (0.03 to 0.03)
ANTI-6A, 18-22 months (N= 185, 113)	0.30 (0.25 to 0.36)	0.04 (0.03 to 0.05)
ANTI-19A, 6 months (N= 208, 120)	0.15 (0.12 to 0.18)	0.04 (0.04 to 0.05)
ANTI-19A, 11-12 months (N= 202, 122)	0.23 (0.19 to 0.28)	0.03 (0.03 to 0.03)
ANTI-19A, 12-13 months (N= 188, 117)	0.95 (0.75 to 1.19)	0.04 (0.03 to 0.05)
ANTI-19A, 18-22 months (N= 185, 113)	0.46 (0.38 to 0.55)	0.06 (0.05 to 0.08)

No statistical analyses for this end point

Secondary: PNEUMOCOCCAL ANTIBODY CONCENTRATIONS AGAINST CROSS-REACTIVE PNEUMOCOCCAL SEROTYPES 6A AND 19A, IN THE IMMUNO SUBSET, IN SUBJECTS RECEIVING 2+1 INFANT SCHEDULES OF 10PN

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End point title

PNEUMOCOCCAL ANTIBODY CONCENTRATIONS AGAINST CROSS-REACTIVE PNEUMOCOCCAL SEROTYPES 6A AND 19A, IN THE IMMUNO SUBSET, IN SUBJECTS RECEIVING 2+1 INFANT SCHEDULES OF 10PN ^[36]

End point description

Antibody concentrations were measured by 22F-inhibitionenzyme-linked Immunosorbent Assay (ELISA), expressed as geometric mean concentrations (GMCs), in micrograms per milliliter (µg/mL). Serotypes assessed were the cross-reactive pneumococcal serotypes 6A and 19A. The cut-off of the assay was >= 0.05 µg/mL. The Immuno subset was constituted of the first ± 1500 subjects from whom blood samples were collected, according to age and treatment groups.

End point type

Secondary

End point timeframe

At 6 mths of age (1 mth post dose 2); at 11-12 mths of age (pre-booster dose) ; at 12-13 mths of age ( 1 mth post-booster) ; at 18-22 mths of age (10 mths post-booster)

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 6W-6M subjects (2+1 schedule)

End point values	10Pn2+1-6W-6M/053 Group	Ctrl2+1-6W-6M/053 Group
Number of subjects analysed	209	142
Units: µg/mL
geometric mean (confidence interval 95%)
ANTI-6A, 6 months (N= 203, 140)	0.09 (0.08 to 0.11)	0.03 (0.03 to 0.04)
ANTI-6A, 11-12 months (N= 209, 133)	0.14 (0.12 to 0.17)	0.03 (0.03 to 0.03)
ANTI-6A, 12-13 months (N= 193, 125)	0.50 (0.42 to 0.60)	0.03 (0.03 to 0.04)
ANTI-6A, 18-22 months (N= 189, 124)	0.27 (0.22 to 0.33)	0.05 (0.04 to 0.06)
ANTI-19A, 6 months (N= 204, 142)	0.13 (0.11 to 0.16)	0.04 (0.04 to 0.05)
ANTI-19A, 11-12 months (N= 209, 132)	0.15 (0.13 to 0.19)	0.03 (0.03 to 0.03)
ANTI-19A, 12-13 months (N= 193, 125)	0.89 (0.74 to 1.07)	0.04 (0.03 to 0.04)
ANTI-19A, 18-22 months (N= 189, 118)	0.36 (0.30 to 0.43)	0.06 (0.05 to 0.08)

No statistical analyses for this end point

Secondary: TITERS FOR OPSONOPHAGOCYTIC ACTIVITY AGAINST VACCINE PNEUMOCOCCAL SEROTYPES, IN THE IMMUNO SUBSET, IN SUBJECTS RECEIVING 3+1 INFANT SCHEDULES OF 10PN

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End point title

TITERS FOR OPSONOPHAGOCYTIC ACTIVITY AGAINST VACCINE PNEUMOCOCCAL SEROTYPES, IN THE IMMUNO SUBSET, IN SUBJECTS RECEIVING 3+1 INFANT SCHEDULES OF 10PN ^[37]

End point description

Titers for opsonophagocytic activity against vaccine pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F. The cut-off of the assay was >= 8. The Immuno subset was constituted of the ± 1500 subjects from whom blood samples were collected, according to age and treatment groups.

End point type

Secondary

End point timeframe

At 6 mths of age (1 mth post dose 3); at 11-12 mths of age (pre-booster dose) ; at 12-13 mths of age ( 1 mth post-booster) ; at 18-22 mths of age (10 mths post-booster)

Notes
[37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 6W-6M subjects (3+1 schedule)

End point values	10Pn3+1-6W-6M/053 Group	Ctrl3+1-6W-6M/053 Group
Number of subjects analysed	202	120
Units: Titers
geometric mean (confidence interval 95%)
OPA-1, 6 months (N= 202, 118)	52.8 (40.7 to 68.4)	4.1 (3.9 to 4.2)
OPA-1, 11-12 months (N= 199, 119)	13.8 (10.8 to 17.6)	4.4 (4.0 to 4.9)
OPA-1, 12-13 months (N= 184, 120)	305.6 (238.9 to 390.8)	4.6 (4.1 to 5.1)
OPA-1, 18-22 months (N= 184, 112)	20.9 (16.1 to 27.1)	4.1 (3.9 to 4.2)
OPA-4, 6 months (N= 199, 112)	845.6 (746.8 to 957.4)	4.6 (3.9 to 5.5)
OPA-4, 11-12 months (N= 190, 119)	78.7 (61.1 to 101.3)	6.0 (4.6 to 7.7)
OPA-4, 12-13 months (N= 184, 115)	1745.7 (1476.3 to 2064.1)	5.8 (4.5 to 7.5)
OPA-4, 18-22 months (N= 172, 109)	105.1 (75.2 to 146.8)	6.6 (4.9 to 8.8)
OPA-5, 6 months (N= 199, 118)	65.9 (55.8 to 77.7)	4.0 (4.0 to 4.1)
OPA-5, 11-12 months (N= 197, 119)	20.6 (16.9 to 25.0)	4.0 (4.0 to 4.0)
OPA-5, 12-13 months (N= 185, 120)	191.6 (155.9 to 235.4)	4.1 (3.9 to 4.2)
OPA-5, 18-22 months (N= 179, 112)	26.9 (22.1 to 32.8)	4.0 (4.0 to 4.0)
OPA-6B, 6 months (N= 195, 111)	740.6 (558.3 to 982.4)	4.4 (3.8 to 5.0)
OPA-6B, 11-12 months (N= 181, 116)	220.3 (161.1 to 301.1)	5.5 (4.2 to 7.2)
OPA-6B, 12-13 months (N= 181, 117)	736.3 (576.2 to 941.0)	6.1 (4.6 to 8.2)
OPA-6B, 18-22 months (N= 179, 106)	75.0 (51.6 to 109.0)	7.4 (5.3 to 10.4)
OPA-7F, 6 months (N= 197, 103)	3894.8 (3320.2 to 4569.0)	87.6 (56.8 to 135.1)
OPA-7F, 11-12 months (N= 199, 114)	1960.7 (1654.4 to 2323.7)	349.0 (252.2 to 483.0)
OPA-7F, 12-13 months (N= 184, 117)	5219.7 (4440.2 to 6136.0)	436.7 (324.7 to 587.4)
OPA-7F, 18-22 months (N= 183, 109)	2124.5 (1813.8 to 2488.5)	643.3 (479.5 to 863.0)
OPA-9V, 6 months (N= 194, 112)	2798.0 (2411.9 to 3246.0)	6.5 (5.1 to 8.3)
OPA-9V, 11-12 months (N= 198, 105)	735.3 (625.6 to 864.3)	19.4 (12.9 to 29.1)
OPA-9V, 12-13 months (N= 183, 110)	3491.2 (3049.2 to 3997.3)	24.7 (16.0 to 38.0)
OPA-9V, 18-22 months (N= 181, 100)	809.1 (677.0 to 966.9)	73.0 (44.9 to 118.5)
OPA-14, 6 months (N= 198, 106)	1831.3 (1572.5 to 2132.7)	10.5 (7.5 to 14.7)
OPA-14, 11-12 months (N= 198, 105)	529.4 (446.6 to 627.6)	18.9 (12.6 to 28.3)
OPA-14, 12-13 months (N= 185, 109)	2657.2 (2280.6 to 3096.1)	14.1 (9.3 to 21.3)
OPA-14, 18-22 months (N= 180, 101)	639.0 (524.6 to 778.4)	45.2 (27.4 to 74.4)
OPA-18C, 6 months (N= 192, 116)	543.3 (444.5 to 664.2)	4.0 (4.0 to 4.0)
OPA-18C, 11-12 months (N= 195, 118)	50.0 (38.0 to 65.7)	4.1 (3.9 to 4.3)
OPA-18C, 12-13 months (N= 183, 118)	1066.1 (890.3 to 1276.6)	4.0 (4.0 to 4.0)
OPA-18C, 18-22 months (N= 179, 110)	70.4 (53.7 to 92.2)	4.1 (3.9 to 4.4)
OPA-19F, 6 months (N= 196, 118)	649.6 (522.7 to 807.4)	4.0 (4.0 to 4.0)
OPA-19F, 11-12 months (N= 198, 117)	63.5 (49.2 to 81.9)	4.2 (3.9 to 4.6)
OPA-19F, 12-13 months (N= 183, 119)	1026.0 (807.3 to 1303.9)	4.4 (3.9 to 4.8)
OPA-19F, 18-22 months (N= 181, 110)	80.1 (60.2 to 106.6)	4.4 (4.0 to 4.8)
OPA-23F, 6 months (N= 196, 111)	1900.7 (1440.0 to 2508.7)	7.0 (4.9 to 10.1)
OPA-23F, 11-12 months (N= 191, 111)	457.1 (313.4 to 666.8)	15.9 (9.6 to 26.3)
OPA-23F, 12-13 months (N= 184, 119)	3248.2 (2705.9 to 3899.2)	21.8 (12.9 to 37.0)
OPA-23F, 18-22 months (N= 174, 109)	398.6 (265.6 to 598.3)	56.4 (29.9 to 106.3)

No statistical analyses for this end point

Secondary: TITERS FOR OPSONOPHAGOCYTIC ACTIVITY AGAINST VACCINE PNEUMOCOCCAL SEROTYPES, IN THE IMMUNO SUBSET, IN SUBJECTS RECEIVING 2+1 INFANT SCHEDULES OF 10PN

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End point title

TITERS FOR OPSONOPHAGOCYTIC ACTIVITY AGAINST VACCINE PNEUMOCOCCAL SEROTYPES, IN THE IMMUNO SUBSET, IN SUBJECTS RECEIVING 2+1 INFANT SCHEDULES OF 10PN ^[38]

End point description

Titers for opsonophagocytic activity against vaccine pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F. The cut-off of the assay was >= 8. The Immuno subset was constituted of the first ± 1500 subjects from whom blood samples were collected, according to age and treatment groups.

End point type

Secondary

End point timeframe

At 6 mths of age (1 mth post dose 2); at 11-12 mths of age (pre-booster dose) ; at 12-13 mths of age ( 1 mth post-booster) ; at 18-22 mths of age (10 mths post-booster)

Notes
[38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 6W-6M subjects (2+1 schedule)

End point values	10Pn2+1-6W-6M/053 Group	Ctrl2+1-6W-6M/053 Group
Number of subjects analysed	205	139
Units: Titers
geometric mean (confidence interval 95%)
OPA-1, 6 months (N= 196, 139)	38.3 (30.0 to 49.0)	4.1 (3.9 to 4.2)
OPA-1, 11-12 months (N= 205, 132)	9.8 (8.0 to 12.0)	4.6 (4.0 to 5.3)
OPA-1, 12-13 months (N= 185, 125)	256.9 (194.6 to 339.2)	4.2 (3.9 to 4.5)
OPA-1, 18-22 months (N= 187, 119)	13.0 (10.2 to 16.6)	4.2 (4.0 to 4.5)
OPA-4, 6 months (N= 192, 134)	553.0 (484.9 to 630.5)	4.8 (4.1 to 5.6)
OPA-4, 11-12 months (N= 195, 125)	43.4 (32.9 to 57.3)	4.6 (4.0 to 5.2)
OPA-4, 12-13 months (N= 187, 122)	1143.4 (961.9 to 1359.0)	4.7 (4.0 to 5.6)
OPA-4, 18-22 months (N= 181, 115)	51.9 (37.5 to 72.0)	6.3 (5.0 to 7.9)
OPA-5, 6 months (N= 195, 135)	48.5 (40.5 to 58.0)	4.0 (4.0 to 4.0)
OPA-5, 11-12 months (N= 204, 132)	15.6 (13.1 to 18.6)	4.1 (3.9 to 4.3)
OPA-5, 12-13 months (N= 186, 126)	145.6 (120.2 to 176.2)	4.1 (3.9 to 4.3)
OPA-5, 18-22 months (N= 187, 119)	21.2 (17.3 to 26.1)	4.0 (4.0 to 4.0)
OPA-6B, 6 months (N= 186, 132)	268.6 (193.3 to 373.3)	4.2 (3.8 to 4.7)
OPA-6B, 11-12 months (N= 191, 130)	121.6 (85.9 to 172.3)	4.8 (4.0 to 5.9)
OPA-6B, 12-13 months (N= 183, 117)	879.1 (695.4 to 1111.2)	5.3 (4.3 to 6.6)
OPA-6B, 18-22 months (N= 173, 115)	62.0 (41.6 to 92.3)	7.9 (5.7 to 11.1)
OPA-7F, 6 months (N= 190, 118)	2553.5 (2124.7 to 3069.0)	59.6 (38.3 to 92.6)
OPA-7F, 11-12 months (N= 202, 124)	1454.9 (1235.2 to 1713.7)	364.8 (270.9 to 491.3)
OPA-7F, 12-13 months (N= 185, 117)	4863.2 (4211.1 to 5616.3)	522.2 (372.4 to 732.3)
OPA-7F, 18-22 months (N= 186, 113)	2182.7 (1910.6 to 2493.5)	856.5 (617.2 to 1188.6)
OPA-9V, 6 months (N= 186, 130)	1687.2 (1442.7 to 1973.1)	5.3 (4.5 to 6.4)
OPA-9V, 11-12 months (N= 198, 123)	509.4 (431.3 to 601.6)	19.3 (13.2 to 28.4)
OPA-9V, 12-13 months (N= 179, 109)	3196.0 (2718.4 to 3757.6)	24.5 (15.9 to 37.6)
OPA-9V, 18-22 months (N= 185, 108)	700.1 (592.5 to 827.1)	55.9 (35.4 to 88.2)
OPA-14, 6 months (N= 191, 124)	1146.3 (944.2 to 1391.8)	7.3 (5.5 to 9.5)
OPA-14, 11-12 months (N= 198, 123)	233.5 (185.1 to 294.7)	22.2 (14.8 to 33.1)
OPA-14, 12-13 months (N= 187, 114)	1724.2 (1475.5 to 2014.8)	26.2 (17.3 to 39.9)
OPA-14, 18-22 months (N= 182, 104)	463.8 (380.9 to 564.7)	99.2 (64.2 to 153.3)
OPA-18C, 6 months (N= 184, 132)	230.6 (177.0 to 300.4)	4.0 (4.0 to 4.0)
OPA-18C, 11-12 months (N= 197, 131)	28.9 (21.6 to 38.6)	4.1 (3.9 to 4.3)
OPA-18C, 12-13 months (N= 183, 125)	1052.2 (881.8 to 1255.5)	4.2 (3.9 to 4.5)
OPA-18C, 18-22 months (N= 179, 119)	84.9 (63.4 to 113.6)	6.2 (5.2 to 7.4)
OPA-19F, 6 months (N= 187, 138)	197.6 (148.6 to 262.8)	4.1 (4.0 to 4.2)
OPA-19F, 11-12 months (N= 204, 132)	30.1 (23.6 to 38.5)	4.2 (3.9 to 4.5)
OPA-19F, 12-13 months (N= 186, 125)	854.6 (672.1 to 1086.6)	4.0 (4.0 to 4.0)
OPA-19F, 18-22 months (N= 187, 116)	56.7 (42.7 to 75.3)	4.3 (4.0 to 4.7)
OPA-23F, 6 months (N= 188, 131)	897.1 (663.5 to 1212.9)	5.6 (4.4 to 7.1)
OPA-23F, 11-12 months (N= 202, 129)	237.2 (156.6 to 359.3)	17.3 (10.6 to 28.0)
OPA-23F, 12-13 months (N= 184, 121)	2630.7 (2047.9 to 3379.2)	17.3 (10.6 to 28.2)
OPA-23F, 18-22 months (N= 181, 113)	222.7 (139.3 to 356.1)	43.4 (23.8 to 79.0)

No statistical analyses for this end point

Secondary: TITERS FOR OPSONOPHAGOCYTIC ACTIVITY AGAINST CROSS-REACTIVE PNEUMOCOCCAL SEROTYPES 6A AND 19A, IN THE IMMUNO SUBSET. IN SUBJECTS RECEIVING 3+1 INFANT SCHEDULES OF 10PN

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End point title

TITERS FOR OPSONOPHAGOCYTIC ACTIVITY AGAINST CROSS-REACTIVE PNEUMOCOCCAL SEROTYPES 6A AND 19A, IN THE IMMUNO SUBSET. IN SUBJECTS RECEIVING 3+1 INFANT SCHEDULES OF 10PN ^[39]

End point description

Titers for opsonophagocytic activity against cross-reactive pneumococcal serotypes 6A and 19A. The cut-off of the assay was >= 8. The Immuno subset was constituted of the first ± 1500 subjects from whom blood samples were collected, according to age and treatment groups.

End point type

Secondary

End point timeframe

At 6 mths of age (1 mth post dose 3); at 11-12 mths of age (pre-booster dose) ; at 12-13 mths of age ( 1 mth post-booster) ; at 18-22 mths of age (10 mths post-booster)

Notes
[39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 6W-6M subjects (3+1 schedule)

End point values	10Pn3+1-6W-6M/053 Group	Ctrl3+1-6W-6M/053 Group
Number of subjects analysed	197	119
Units: Titers
geometric mean (confidence interval 95%)
OPA-6A, 6 months (N= 191, 116)	90.8 (66.4 to 124.3)	4.1 (3.9 to 4.4)
OPA-6A, 11-12 months (N= 188, 117)	70.9 (50.7 to 99.1)	5.2 (4.2 to 6.4)
OPA-6A, 12-13 months (N= 177, 115)	173.8 (125.7 to 240.4)	5.3 (4.3 to 6.5)
OPA-6A, 18-22 months (N= 179, 109)	32.9 (23.2 to 46.7)	8.0 (5.9 to 11.0)
OPA-19A, 6 months (N= 193, 118)	25.2 (18.3 to 34.8)	4.3 (3.9 to 4.8)
OPA-19A, 11-12 months (N= 197, 118)	8.6 (7.0 to 10.7)	4.3 (3.9 to 4.8)
OPA-19A, 12-13 months (N= 181, 119)	145.0 (104.7 to 200.9)	4.3 (4.0 to 4.8)
OPA-19A, 18-22 months (N= 182, 111)	12.2 (9.2 to 16.1)	4.8 (4.1 to 5.7)

No statistical analyses for this end point

Secondary: TITERS FOR OPSONOPHAGOCYTIC ACTIVITY AGAINST CROSS-REACTIVE PNEUMOCOCCAL SEROTYPES 6A AND 19A, IN THE IMMUNO SUBSET. IN SUBJECTS RECEIVING 2+1 INFANT SCHEDULES OF 10PN

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End point title

TITERS FOR OPSONOPHAGOCYTIC ACTIVITY AGAINST CROSS-REACTIVE PNEUMOCOCCAL SEROTYPES 6A AND 19A, IN THE IMMUNO SUBSET. IN SUBJECTS RECEIVING 2+1 INFANT SCHEDULES OF 10PN ^[40]

End point description

End point type

Secondary

End point timeframe

At 6 mths of age (1 mth post dose 2); at 11-12 mths of age (pre-booster dose) ; at 12-13 mths of age ( 1 mth post-booster) ; at 18-22 mths of age (10 mths post-booster)

Notes
[40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 6W-6M subjects (2+1 schedule)

End point values	10Pn2+1-6W-6M/053 Group	Ctrl2+1-6W-6M/053 Group
Number of subjects analysed	204	137
Units: Titers
geometric mean (confidence interval 95%)
OPA-6A, 6 months (N= 183, 135)	43.1 (31.2 to 59.5)	4.4 (3.8 to 5.0)
OPA-6A, 11-12 months (N= 195, 132)	59.0 (42.0 to 82.9)	5.1 (4.3 to 6.2)
OPA-6A, 12-13 months (N= 168, 113)	285.9 (205.3 to 398.2)	5.3 (4.3 to 6.6)
OPA-6A, 18-22 months (N= 167, 110)	41.8 (28.8 to 60.8)	10.5 (7.4 to 14.8)
OPA-19A, 6 months (N= 190, 137)	11.9 (9.2 to 15.5)	4.1 (4.0 to 4.3)
OPA-19A, 11-12 months (N= 204, 129)	5.8 (5.0 to 6.9)	4.0 (4.0 to 4.1)
OPA-19A, 12-13 months (N= 183, 125)	78.9 (55.5 to 112.2)	4.1 (4.0 to 4.2)
OPA-19A, 18-22 months (N= 181, 118)	8.5 (6.6 to 10.9)	5.1 (4.2 to 6.3)

No statistical analyses for this end point

Secondary: ANTIBODY CONCENTRATIONS AGAINST PROTEIN D (ANTI-PD), IN THE IMMUNO SUBSET. IN SUBJECTS RECEIVING 3+1 INFANT SCHEDULES OF 10PN

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End point title

ANTIBODY CONCENTRATIONS AGAINST PROTEIN D (ANTI-PD), IN THE IMMUNO SUBSET. IN SUBJECTS RECEIVING 3+1 INFANT SCHEDULES OF 10PN ^[41]

End point description

ANTI-PD concentrations are expressed as geometric mean concentrations (GMCs), in enzyme-linked immunosorbent assay (ELISA) unit per milliliter (EL.U/mL). The cut-off of the assay was >= 100 EL.U/mL. The Immuno subset was constituted of the first ± 1500 subjects from whom blood samples were collected, according to age and treatment groups.

End point type

Secondary

End point timeframe

At 6 mths of age (1 mth post dose 3); at 11-12 mths of age (pre-booster dose) ; at 12-13 mths of age ( 1 mth post-booster) ; at 18-22 mths of age (10 mths post-booster)

Notes
[41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 6W-6M subjects (3+1 schedule)

End point values	10Pn3+1-6W-6M/053 Group	Ctrl3+1-6W-6M/053 Group
Number of subjects analysed	209	123
Units: EL.U/mL
geometric mean (confidence interval 95%)
ANTI-PD, 6 months (N= 209, 121)	1869.4 (1670.7 to 2091.7)	60.5 (54.8 to 66.7)
ANTI-PD, 11-12 months (N= 203, 123)	955.2 (837.1 to 1089.9)	62.7 (56.4 to 69.7)
ANTI-PD, 12-13 months (N= 188, 118)	2734.7 (2406.0 to 3108.3)	61.6 (55.0 to 69.0)
ANTI-PD, 18-22 months (N= 185, 113 )	1030.0 (884.3 to 1199.7)	65.5 (57.4 to 74.8)

No statistical analyses for this end point

Secondary: ANTIBODY CONCENTRATIONS AGAINST PROTEIN D(ANTI-PD), IN THE IMMUNO SUBSET. IN SUBJECTS RECEIVING 2+1 INFANT SCHEDULES OF 10PN

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End point title

ANTIBODY CONCENTRATIONS AGAINST PROTEIN D(ANTI-PD), IN THE IMMUNO SUBSET. IN SUBJECTS RECEIVING 2+1 INFANT SCHEDULES OF 10PN ^[42]

End point description

End point type

Secondary

End point timeframe

At 6 mths of age (1 mth post dose 2); at 11-12 mths of age (pre-booster dose) ; at 12-13 mths of age ( 1 mth post-booster) ; at 18-22 mths of age (10 mths post-booster)

Notes
[42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 6W-6M subjects (2+1 schedule)

End point values	10Pn2+1-6W-6M/053 Group	Ctrl2+1-6W-6M/053 Group
Number of subjects analysed	209	139
Units: EL.U/mL
geometric mean (confidence interval 95%)
ANTI-PD, 6 months (N= 203, 139)	1062.9 (936.0 to 1207.0)	66.1 (60.3 to 72.4)
ANTI-PD, 11-12 months (N= 209, 131)	505.6 (439.2 to 582.1)	62.9 (57.0 to 69.5)
ANTI-PD, 12-13 months (N= 193, 127)	1903.9 (1642.7 to 2206.6)	68.2 (61.1 to 76.1)
ANTI-PD, 18-22 months (N= 188, 124)	687.7 (577.8 to 818.4)	78.6 (68.8 to 89.8)

No statistical analyses for this end point

Secondary: PNEUMOCOCCAL ANTIBODY CONCENTRATIONS AGAINST PNEUMOCOCCAL VACCINE SEROTYPES, IN THE IMMUNO SUBSET. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN

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End point title

PNEUMOCOCCAL ANTIBODY CONCENTRATIONS AGAINST PNEUMOCOCCAL VACCINE SEROTYPES, IN THE IMMUNO SUBSET. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN ^[43]

End point description

Antibody concentrations were measured by 22F-inhibitionenzyme-linked Immunosorbent Assay (ELISA), expressed as geometric mean concentrations (GMCs), in micrograms per milliliter (µg/mL). Serotypes assessed were the pneumococcal vaccine serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F. The cut-off of the assay was >= 0.05 µg/mL. The Immuno subset was constituted of the first ± 1500 subjects from whom blood samples were collected, according to age and treatment groups.

End point type

Secondary

End point timeframe

At 8-12 months (mths) of age (1 mth post dose 1); at 9-13 mths of age (1 mth post dose 2) ; at 13-17 mths of age (pre-booster dose) ; at 14-18 mths of age ( 1 mths post-booster) ; at 23-27 mths of age (10 mths post-booster)

Notes
[43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 7-11M subjects

End point values	10Pn7-11M/053 Group	Ctrl7-11M/053 Group
Number of subjects analysed	151	101
Units: µg/mL
geometric mean (confidence interval 95%)
ANTI-1, 9-13 months (N= 151, 100)	1.96 (1.72 to 2.23)	0.03 (0.03 to 0.03)
ANTI-1, 13-17 months (N= 144, 97)	0.66 (0.58 to 0.75)	0.04 (0.03 to 0.05)
ANTI-1, 14-18 months (N= 137, 90)	2.62 (2.33 to 2.94)	0.04 (0.03 to 0.05)
ANTI-1, 23-27 months (N= 124, 88)	0.59 (0.51 to 0.68)	0.05 (0.04 to 0.06)
ANTI-4, 9-13 months (N= 150, 101)	5.85 (5.16 to 6.63)	0.03 (0.02 to 0.03)
ANTI-4, 13-17 months (N= 144, 96)	1.55 (1.36 to 1.76)	0.03 (0.02 to 0.03)
ANTI-4, 14-18 months (N= 135, 90)	5.45 (4.85 to 6.14)	0.03 (0.02 to 0.03)
ANTI-4, 23-27 months (N= 124, 88)	1.21 (1.07 to 1.38)	0.03 (0.03 to 0.03)
ANTI-5, 9-13 months (N= 151, 99)	2.40 (2.13 to 2.72)	0.04 (0.03 to 0.04)
ANTI-5, 13-17 months (N= 144, 96)	1.19 (1.06 to 1.34)	0.06 (0.05 to 0.07)
ANTI-5, 14-18 months (N= 137, 89)	4.11 (3.71 to 4.56)	0.07 (0.05 to 0.08)
ANTI-5, 23-27 months (N= 123, 87)	1.30 (1.12 to 1.51)	0.13 (0.09 to 0.17)
ANTI-6B, 9-13 months (N= 151, 100)	0.27 (0.21 to 0.33)	0.03 (0.03 to 0.03)
ANTI-6B, 13-17 months (N= 144, 97)	0.49 (0.40 to 0.58)	0.03 (0.03 to 0.04)
ANTI-6B, 14-18 months (N= 137, 90)	1.06 (0.85 to 1.31)	0.03 (0.03 to 0.04)
ANTI-6B, 23-27 months (N= 124, 88)	0.52 (0.42 to 0.65)	0.06 (0.04 to 0.07)
ANTI-7F, 9-13 months (N= 150, 100)	3.61 (3.21 to 4.06)	0.03 (0.03 to 0.03)
ANTI-7F, 13-17 months (N= 144, 97)	2.22 (1.97 to 2.51)	0.03 (0.03 to 0.04)
ANTI-7F, 14-18 months (N= 137, 89)	5.44 (4.80 to 6.15)	0.04 (0.03 to 0.05)
ANTI-7F, 23-27 months (N= 123, 88)	2.08 (1.82 to 2.39)	0.05 (0.04 to 0.06)
ANTI-9V, 9-13 months (N= 151, 100)	1.42 (1.24 to 1.64)	0.03 (0.02 to 0.03)
ANTI-9V, 13-17 months (N= 144, 96)	0.88 (0.76 to 1.02)	0.03 (0.03 to 0.04)
ANTI-9V, 14-18 months (N= 137, 90)	2.81 (2.44 to 3.23)	0.03 (0.03 to 0.04)
ANTI-9V, 23-27 months (N= 123, 88)	1.16 (0.99 to 1.37)	0.03 (0.03 to 0.04)
ANTI-14, 9-13 months (N= 150, 100)	3.81 (3.34 to 4.35)	0.05 (0.04 to 0.06)
ANTI-14, 13-17 months (N= 144, 95)	3.06 (2.69 to 3.49)	0.08 (0.06 to 0.11)
ANTI-14, 14-18 months (N= 137, 89)	8.38 (7.42 to 9.47)	0.10 (0.07 to 0.14)
ANTI-14, 23-27 months (N= 123, 88)	2.91 (2.44 to 3.48)	0.13 (0.09 to 0.19)
ANTI-18C, 9-13 months (N= 150, 101)	10.03 (8.67 to 11.61)	0.03 (0.03 to 0.03)
ANTI-18C, 13-17 months (N= 144, 97)	4.70 (4.01 to 5.50)	0.03 (0.03 to 0.04)
ANTI-18C, 14-18 months (N= 137, 90)	19.87 (17.08 to 23.12)	0.03 (0.03 to 0.04)
ANTI-18C, 23-27 months (N= 123, 88)	5.46 (4.61 to 6.46)	0.04 (0.03 to 0.06)
ANTI-19F, 9-13 months (N= 151, 100)	6.64 (5.41 to 8.15)	0.04 (0.03 to 0.05)
ANTI-19F, 13-17 months (N= 144, 93)	3.41 (2.81 to 4.14)	0.05 (0.04 to 0.07)
ANTI-19F, 14-18 months (N= 137, 86)	11.73 (9.73 to 14.13)	0.06 (0.04 to 0.08)
ANTI-19F, 23-27 months (N= 124, 87)	3.69 (3.06 to 4.44)	0.09 (0.07 to 0.13)
ANTI-23F, 9-13 months (N= 151, 100)	0.55 (0.44 to 0.70)	0.03 (0.03 to 0.03)
ANTI-23F, 13-17 months (N= 144, 94)	0.64 (0.54 to 0.77)	0.04 (0.03 to 0.05)
ANTI-23F, 14-18 months (N= 137, 88)	2.04 (1.71 to 2.43)	0.04 (0.03 to 0.05)
ANTI-23F, 23-27 months (N= 123, 87)	0.80 (0.66 to 0.96)	0.06 (0.05 to 0.08)

No statistical analyses for this end point

Secondary: PNEUMOCOCCAL ANTIBODY CONCENTRATIONS AGAINST PNEUMOCOCCAL VACCINE SEROTYPES, IN THE IMMUNO SUBSET. IN SUBJECTS RECEIVING RECEIVING 12-18M SCHEDULE OF 10PN

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End point title

PNEUMOCOCCAL ANTIBODY CONCENTRATIONS AGAINST PNEUMOCOCCAL VACCINE SEROTYPES, IN THE IMMUNO SUBSET. IN SUBJECTS RECEIVING RECEIVING 12-18M SCHEDULE OF 10PN ^[44]

End point description

Antibody concentrations were measured by 22F-inhibitionenzyme-linked Immunosorbent Assay (ELISA), expressed as geometric mean concentrations (GMCs), in micrograms per milliliter (µg/mL). Serotypes assessed were the pneumococcal vaccine serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F. The cut-off of the assay was >= 0.05 µg/mL. The Immuno subset was constituted of the first ± 1500 subjects from whom blood samples were collected, according to age and treatment groups.

End point type

Secondary

End point timeframe

At 13-19 months (mths) of age (1 mth post dose 1); at 19-25 mths of age (1 mth post dose 2); at 21-27 mths of age (3 months post dose 2)

Notes
[44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 12-18M subjects

End point values	10Pn12-18M/053 Group	Ctrl12-18M/053 Group
Number of subjects analysed	181	143
Units: µg/mL
geometric mean (confidence interval 95%)
ANTI-1, 13-19 months (N= 181, 138)	0.73 (0.63 to 0.84)	0.04 (0.04 to 0.05)
ANTI-1, 19-25 months (N= 167, 134)	1.87 (1.67 to 2.09)	0.04 (0.03 to 0.04)
ANTI-1, 21-27 months (N= 162, 132)	0.95 (0.84 to 1.08)	0.04 (0.04 to 0.05)
ANTI-4, 13-19 months (N= 181, 143)	4.64 (4.11 to 5.25)	0.03 (0.03 to 0.03)
ANTI-4, 19-25 months (N= 167, 134)	5.28 (4.77 to 5.84)	0.03 (0.03 to 0.03)
ANTI-4, 21-27 months (N= 162, 133)	2.57 (2.29 to 2.87)	0.03 (0.03 to 0.03)
ANTI-5, 13-19 months (N= 181, 140)	0.77 (0.67 to 0.88)	0.07 (0.06 to 0.08)
ANTI-5, 19-25 months (N= 167, 133)	3.45 (3.05 to 3.90)	0.07 (0.06 to 0.08)
ANTI-5, 21-27 months (N= 162, 133)	2.14 (1.88 to 2.44)	0.08 (0.07 to 0.10)
ANTI-6B, 13-19 months (N= 181, 136)	0.11 (0.09 to 0.13)	0.04 (0.03 to 0.04)
ANTI-6B, 19-25 months (N= 167, 133)	0.69 (0.57 to 0.83)	0.05 (0.04 to 0.06)
ANTI-6B, 21-27 months (N= 162, 133)	0.48 (0.40 to 0.57)	0.06 (0.05 to 0.07)
ANTI-7F, 13-19 months (N= 181, 142)	2.53 (2.22 to 2.89)	0.03 (0.03 to 0.04)
ANTI-7F, 19-25 months (N= 167, 134)	3.95 (3.58 to 4.35)	0.04 (0.03 to 0.05)
ANTI-7F, 21-27 months (N= 162, 133)	2.73 (2.48 to 3.01)	0.05 (0.04 to 0.06)
ANTI-9V, 13-19 months (N= 181, 140)	0.84 (0.73 to 0.97)	0.03 (0.03 to 0.03)
ANTI-9V, 19-25 months (N= 167, 134)	1.60 (1.42 to 1.81)	0.03 (0.03 to 0.04)
ANTI-9V, 21-27 months (N= 163, 129)	1.22 (1.07 to 1.39)	0.03 (0.03 to 0.04)
ANTI-14, 13-19 months (N= 181, 143)	1.07 (0.90 to 1.28)	0.06 (0.05 to 0.08)
ANTI-14, 19-25 months (N= 167, 132)	6.04 (5.37 to 6.79)	0.09 (0.07 to 0.12)
ANTI-14, 21-27 months (N= 161, 133)	3.73 (3.30 to 4.21)	0.21 (0.15 to 0.29)
ANTI-18C, 13-19 months (N= 181,142)	3.76 (3.35 to 4.22)	0.04 (0.03 to 0.04)
ANTI-18C, 19-25 months (N= 166, 134)	21.27 (18.70 to 24.19)	0.04 (0.03 to 0.04)
ANTI-18C, 21-27 months (N= 162, 133)	12.44 (10.88 to 14.22)	0.04 (0.03 to 0.05)
ANTI-19F, 13-19 months (N= 181, 143)	2.63 (2.24 to 3.10)	0.06 (0.05 to 0.08)
ANTI-19F, 19-25 months (N= 166, 134)	12.10 (10.38 to 14.11)	0.09 (0.07 to 0.12)
ANTI-19F, 21-27 months (N= 162, 132)	8.49 (7.39 to 9.74)	0.11 (0.08 to 0.15)
ANTI-23F, 13-19 months (N= 181, 138)	0.16 (0.13 to 0.19)	0.03 (0.03 to 0.04)
ANTI-23F, 19-25 months (N= 167, 134)	1.27 (1.07 to 1.50)	0.05 (0.04 to 0.06)
ANTI-23F, 21-27 months (N= 162, 132)	0.83 (0.70 to 0.99)	0.05 (0.04 to 0.06)

No statistical analyses for this end point

Secondary: PNEUMOCOCCAL ANTIBODY CONCENTRATIONS AGAINST CROSS-REACTIVE PNEUMOCOCCAL SEROTYPES, IN THE IMMUNO SUBSET. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN

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End point title

PNEUMOCOCCAL ANTIBODY CONCENTRATIONS AGAINST CROSS-REACTIVE PNEUMOCOCCAL SEROTYPES, IN THE IMMUNO SUBSET. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN ^[45]

End point description

Antibody concentrations were measured by 22F-inhibitionenzyme-linked Immunosorbent Assay (ELISA), expressed as geometric mean concentrations (GMCs), in micrograms per milliliter (µg/mL). Serotypes assessed were the cross-reactive pneumococcal serotypes 6A and 19A. The cut-off of the assay was >= 0.05 µg/mL. The Immuno subset was constituted of the first ± 1500 subjects from whom blood samples were collected, according to age and treatment groups.

End point type

Secondary

End point timeframe

Notes
[45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 7-11M subjects

End point values	10Pn7-11M/053 Group	Ctrl7-11M/053 Group
Number of subjects analysed	151	100
Units: µg/mL
geometric mean (confidence interval 95%)
ANTI-6A, 9-13 months (N= 150, 99)	0.11 (0.09 to 0.14)	0.03 (0.03 to 0.03)
ANTI-6A, 13-17 months (N= 144, 96)	0.23 (0.18 to 0.29)	0.03 (0.03 to 0.04)
ANTI-6A, 14-18 months (N= 137, 89)	0.70 (0.55 to 0.90)	0.03 (0.03 to 0.04)
ANTI-6A, 23-27 months (N= 123, 88)	0.33 (0.26 to 0.41)	0.06 (0.04 to 0.07)
ANTI-19A, 9-13 months (N= 151, 100)	0.33 (0.26 to 0.42)	0.04 (0.03 to 0.04)
ANTI-19A, 13-17 months (N= 144, 97)	0.49 (0.39 to 0.62)	0.05 (0.04 to 0.06)
ANTI-19A, 14-18 months (N= 137, 90)	1.98 (1.53 to 2.56)	0.04 (0.04 to 0.06)
ANTI-19A, 23-27 months (N= 123, 88)	0.93 (0.70 to 1.23)	0.08 (0.06 to 0.11)

No statistical analyses for this end point

Secondary: PNEUMOCOCCAL ANTIBODY CONCENTRATIONS AGAINST CROSS-REACTIVE PNEUMOCOCCAL SEROTYPES, IN THE IMMUNO SUBSET. IN SUBJECTS RECEIVING RECEIVING 12-18M SCHEDULE OF 10PN

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End point title

PNEUMOCOCCAL ANTIBODY CONCENTRATIONS AGAINST CROSS-REACTIVE PNEUMOCOCCAL SEROTYPES, IN THE IMMUNO SUBSET. IN SUBJECTS RECEIVING RECEIVING 12-18M SCHEDULE OF 10PN ^[46]

End point description

Antibody concentrations were measured by 22F-inhibitionenzyme-linked Immunosorbent Assay (ELISA), expressed as geometric mean concentrations (GMCs), in micrograms per milliliter (µg/mL). Serotypes assessed were the cross-reactive pneumococcal serotypes 6A and 19A. The cut-off of the assay was >= 0.05 µg/mL. The Immuno subset was constituted of the first ± 1500 subjects from whom blood samples were collected, according to age and treatment groups.

End point type

Secondary

End point timeframe

At 13-19 months (mths) of age (1 mth post dose 1); at 19-25 mths of age (1 mth post dose 2); at 21-27 mths of age (3 months post dose 2)

Notes
[46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 12-18M subjects

End point values	10Pn12-18M/053 Group	Ctrl12-18M/053 Group
Number of subjects analysed	181	143
Units: µg/mL
geometric mean (confidence interval 95%)
ANTI-6A, 13-19 months (N= 181, 143)	0.06 (0.05 to 0.08)	0.04 (0.03 to 0.04)
ANTI-6A, 19-25 months (N= 167, 134)	0.32 (0.26 to 0.41)	0.05 (0.04 to 0.06)
ANTI-6A, 21-27 months (N= 162, 132)	0.29 (0.23 to 0.36)	0.06 (0.05 to 0.08)
ANTI-19A, 13-19 months (N= 181, 136)	0.20 (0.16 to 0.25)	0.05 (0.04 to 0.06)
ANTI-19A, 19-25 months (N= 167, 134)	2.61 (2.12 to 3.22)	0.06 (0.05 to 0.07)
ANTI-19A, 21-27 months (N= 162, 132)	1.72 (1.41 to 2.10)	0.07 (0.05 to 0.09)

No statistical analyses for this end point

Secondary: PERSON YEAR RATE AS REGARDS SUBJECTS WITH ACUTE OTITIS MEDIA (AOM) EPISODE ASSESSED AS WITH LEVEL 1 OF DIAGNOSTIC CERTAINTY. IN SUBJECTS RECEIVING 3+1 AND 2+1 INFANT SCHEDULES OF 10PN

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End point title

PERSON YEAR RATE AS REGARDS SUBJECTS WITH ACUTE OTITIS MEDIA (AOM) EPISODE ASSESSED AS WITH LEVEL 1 OF DIAGNOSTIC CERTAINTY. IN SUBJECTS RECEIVING 3+1 AND 2+1 INFANT SCHEDULES OF 10PN ^[47]

End point description

The PYAR (Person-Year Rate) as regards subjects with AOM episode was tabulated. PYAR was calculated as follows n (= number of subjects reported with event) divided by T (= sum of follow-up period expressed in years) (per 1000). An AOM episode assessed as with level 1 of diagnostic certainty was defined as an AOM event diagnosed by a physician according to the Finnish AOM management guidelines (confirmed cases) and reported by subjects’ parent(s)/guardian(s) regardless the documentation in medical records or other source document. Note that a post-hoc re-analysis of AOM endpoints with a corrected definition of follow-up taking into account individual end of follow-up time was performed; the results of re-analysis as the most prominent for AOM outcome are presented in this summary.

End point type

Secondary

End point timeframe

Period of follow-up was anytime after the administration of first vaccine dose till the end of the blinded invasive disease (ID) follow-up period (31 January 2012).

Notes
[47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 6W-6M subjects

End point values	10Pn3+1-6W-6M/053 Group	10Pn2+1-6W-6M/053 Group	Ctrl-6W-6M/053 Group
Number of subjects analysed	1846	942	1329
Units: Participants per 1000 person-years
number (confidence interval 95%)	420.645 (396.814 to 445.534)	415.560 (382.673 to 450.518)	443.411 (414.786 to 473.491)

No statistical analyses for this end point

Secondary: PERSON YEAR RATE AS REGARDS SUBJECTS WITH ACUTE OTITIS MEDIA (AOM) EPISODE ASSESSED AS WITH LEVEL 1 OF DIAGNOSTIC CERTAINTY. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN

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End point title

PERSON YEAR RATE AS REGARDS SUBJECTS WITH ACUTE OTITIS MEDIA (AOM) EPISODE ASSESSED AS WITH LEVEL 1 OF DIAGNOSTIC CERTAINTY. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN ^[48]

End point description

End point type

Secondary

End point timeframe

Period of follow-up was anytime after the administration of first vaccine dose till the end of the blinded invasive disease (ID) Follow-up period (31 January 2012).

Notes
[48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 7-11M subjects

End point values	10Pn7-11M/053 Group	Ctrl7-11M/053 Group
Number of subjects analysed	191	96
Units: Participants per 1000 person-years
number (confidence interval 95%)	510.388 (422.105 to 611.686)	590.118 (460.887 to 744.354)

No statistical analyses for this end point

Secondary: PERSON YEAR RATE AS REGARDS SUBJECTS WITH ACUTE OTITIS MEDIA (AOM) EPISODE ASSESSED AS WITH LEVEL 1 OF DIAGNOSTIC CERTAINTY. IN SUBJECTS RECEIVING 12-18M SCHEDULE OF 10PN

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End point title

PERSON YEAR RATE AS REGARDS SUBJECTS WITH ACUTE OTITIS MEDIA (AOM) EPISODE ASSESSED AS WITH LEVEL 1 OF DIAGNOSTIC CERTAINTY. IN SUBJECTS RECEIVING 12-18M SCHEDULE OF 10PN ^[49]

End point description

End point type

Secondary

End point timeframe

Period of follow-up was anytime after the administration of first vaccine dose till the end of the blinded invasive disease (ID) Follow-up period (31 January 2012).

Notes
[49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 12-18M subjects

End point values	10Pn12-18M/053 Group	Ctrl12-18M/053 Group
Number of subjects analysed	286	106
Units: Participants per 1000 person-years
number (confidence interval 95%)	598.065 (502.777 to 706.159)	567.194 (419.613 to 749.861)

No statistical analyses for this end point

Secondary: PERSON YEAR RATE AS REGARDS SUBJECTS WITH RECURRENT ACUTE OTITIS MEDIA (AOM) EPISODES ASSESSED AS WITH LEVEL 1 OF DIAGNOSTIC CERTAINTY. IN SUBJECTS RECEIVING 3+1 AND 2+1 INFANT SCHEDULES OF 10PN

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End point title

PERSON YEAR RATE AS REGARDS SUBJECTS WITH RECURRENT ACUTE OTITIS MEDIA (AOM) EPISODES ASSESSED AS WITH LEVEL 1 OF DIAGNOSTIC CERTAINTY. IN SUBJECTS RECEIVING 3+1 AND 2+1 INFANT SCHEDULES OF 10PN ^[50]

End point description

End point type

Secondary

End point timeframe

Period of follow-up was anytime after the administration of first vaccine dose till the end of the blinded invasive disease (ID) Follow-up period (31 January 2012).

Notes
[50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 6W-6M subjects

End point values	10Pn3+1-6W-6M/053 Group	10Pn2+1-6W-6M/053 Group	Ctrl-6W-6M/053 Group
Number of subjects analysed	1846	942	1329
Units: Participants per 1000 person-years
number (confidence interval 95%)	100.550 (89.076 to 113.091)	103.008 (86.977 to 121.137)	94.946 (81.957 to 109.407)

No statistical analyses for this end point

Secondary: PERSON YEAR RATE AS REGARDS SUBJECTS WITH RECURRENT ACUTE OTITIS MEDIA (AOM) EPISODES ASSESSED AS WITH LEVEL 1 OF DIAGNOSTIC CERTAINTY. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN

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End point title

PERSON YEAR RATE AS REGARDS SUBJECTS WITH RECURRENT ACUTE OTITIS MEDIA (AOM) EPISODES ASSESSED AS WITH LEVEL 1 OF DIAGNOSTIC CERTAINTY. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN ^[51]

End point description

End point type

Secondary

End point timeframe

Period of follow-up was anytime after the administration of first vaccine dose till the end of the blinded invasive disease (ID) Follow-up period (31 January 2012).

Notes
[51] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 7-11M subjects

End point values	10Pn7-11M/053 Group	Ctrl7-11M/053 Group
Number of subjects analysed	191	96
Units: Participants per 1000 person-years
number (confidence interval 95%)	78.521 (46.537 to 124.097)	132.984 (76.012 to 215.958)

No statistical analyses for this end point

Secondary: PERSON YEAR RATE AS REGARDS SUBJECTS WITH RECURRENT ACUTE OTITIS MEDIA (AOM) EPISODES ASSESSED AS WITH LEVEL 1 OF DIAGNOSTIC CERTAINTY. IN SUBJECTS RECEIVING 12-18M SCHEDULE OF 10PN

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End point title

PERSON YEAR RATE AS REGARDS SUBJECTS WITH RECURRENT ACUTE OTITIS MEDIA (AOM) EPISODES ASSESSED AS WITH LEVEL 1 OF DIAGNOSTIC CERTAINTY. IN SUBJECTS RECEIVING 12-18M SCHEDULE OF 10PN ^[52]

End point description

End point type

Secondary

End point timeframe

Period of follow-up was anytime after the administration of first vaccine dose till the end of the blinded invasive disease (ID) Follow-up period (31 January 2012).

Notes
[52] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 12-18M subjects

End point values	10Pn12-18M/053 Group	Ctrl12-18M/053 Group
Number of subjects analysed	286	106
Units: Participants per 1000 person-years
number (confidence interval 95%)	90.355 (55.931 to 138.117)	46.302 (12.616 to 118.550)

No statistical analyses for this end point

Secondary: PERSON YEAR RATE AS REGARDS SUBJECTS WITH ACUTE OTITIS MEDIA (AOM) EPISODE ASSESSED AS WITH LEVEL 1 OF DIAGNOSTIC CERTAINTY AND ACCOMPANIED WITH DOCUMENTED ANTIMICROBIAL PRESCRIPTION. IN SUBJECTS RECEIVING 3+1 AND 2+1 INFANT SCHEDULES OF 10PN

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End point title

PERSON YEAR RATE AS REGARDS SUBJECTS WITH ACUTE OTITIS MEDIA (AOM) EPISODE ASSESSED AS WITH LEVEL 1 OF DIAGNOSTIC CERTAINTY AND ACCOMPANIED WITH DOCUMENTED ANTIMICROBIAL PRESCRIPTION. IN SUBJECTS RECEIVING 3+1 AND 2+1 INFANT SCHEDULES OF 10PN ^[53]

End point description

End point type

Secondary

End point timeframe

Period of follow-up was anytime after the administration of first vaccine dose till the end of the blinded invasive disease (ID) Follow-up period (31 January 2012).

Notes
[53] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 6W-6M subjects

End point values	10Pn3+1-6W-6M/053 Group	10Pn2+1-6W-6M/053 Group	Ctrl-6W-6M/053 Group
Number of subjects analysed	1846	942	1329
Units: Participants per 1000 person-years
number (confidence interval 95%)	409.795 (386.277 to 434.369)	408.505 (375.904 to 443.176)	430.984 (402.769 to 460.653)

No statistical analyses for this end point

Secondary: PERSON YEAR RATE AS REGARDS SUBJECTS WITH ACUTE OTITIS MEDIA (AOM) EPISODE ASSESSED AS WITH LEVEL 1 OF DIAGNOSTIC CERTAINTY AND ACCOMPANIED WITH DOCUMENTED ANTIMICROBIAL PRESCRIPTION. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN

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End point title

End point description

End point type

Secondary

End point timeframe

Period of follow-up was anytime after the administration of first vaccine dose till the end of the blinded invasive disease (ID) Follow-up period (31 January 2012).

Notes
[54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 7-11M subjects

End point values	10Pn7-11M/053 Group	Ctrl7-11M/053 Group
Number of subjects analysed	191	96
Units: Participants per 1000 person-years
number (confidence interval 95%)	497.301 (410.212 to 597.410)	581.807 (453.547 to 735.078)

No statistical analyses for this end point

Secondary: PERSON YEAR RATE AS REGARDS SUBJECTS WITH ACUTE OTITIS MEDIA (AOM) EPISODE ASSESSED AS WITH LEVEL 1 OF DIAGNOSTIC CERTAINTY AND ACCOMPANIED WITH DOCUMENTED ANTIMICROBIAL PRESCRIPTION. IN SUBJECTS RECEIVING 12-18M SCHEDULE OF 10PN

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End point title

End point description

End point type

Secondary

End point timeframe

Period of follow-up was anytime after the administration of first vaccine dose till the end of the blinded invasive disease (ID) Follow-up period (31 January 2012).

Notes
[55] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point analysis has been performed on 12-18M subjects

End point values	10Pn12-18M/053 Group	Ctrl12-18M/053 Group
Number of subjects analysed	286	106
Units: Participants per 1000 person-years
number (confidence interval 95%)	593.763 (498.833 to 701.499)	555.619 (409.670 to 736.670)

No statistical analyses for this end point

Secondary: Culture-confirmed Invasive Disease (ID) Person Year Rate - In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course till end of LT FU period.

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End point title

Culture-confirmed Invasive Disease (ID) Person Year Rate - In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course till end of LT FU period.

End point description

End point type

Secondary

End point timeframe

Period of follow-up was any time after the administration of first vaccine dose till the end of the long-term Follow-up period (The Follow-up period lasted at least 77 months).

End point values	10Pn3+1-6W-6M/043+053 Group	Ctrl-6W-6M/043+053 Group
Number of subjects analysed	10272	10201
Units: Participants per 1000 person-years
number (confidence interval 95%)
Culture confirmed ID	0.046 (0.013 to 0.118)	0.268 (0.170 to 0.402)
Pneumococcal invasive disease (IPD)	0.023 (0.003 to 0.084)	0.210 (0.124 to 0.331)
Vaccine serotypes (vaccine type-IPD)	0.0 (0.0 to 0.043)	0.140 (0.072 to 0.244)
Serotype 4	0.0 (0.0 to 0.043)	0.0 (0.0 to 0.043)
Serotype 6B	0.0 (0.0 to 0.043)	0.058 (0.019 to 0.136)
Serotype 7F	0.0 (0.0 to 0.043)	0.0 (0.0 to 0.043)
Serotype 14	0.0 (0.0 to 0.043)	0.047 (0.013 to 0.119)
Serotype 18C	0.0 (0.0 to 0.043)	0.012 (0.0 to 0.065)
Serotype 19F	0.0 (0.0 to 0.043)	0.012 (0.0 to 0.065)
Serotype 23F	0.0 (0.0 to 0.043)	0.012 (0.0 to 0.065)
Cross-reactive serotypes	0.012 (0.0 to 0.064)	0.047 (0.013 to 0.119)
Serotype 6A	0.0 (0.0 to 0.043)	0.012 (0.0 to 0.065)
Serotype 19A	0.012 (0.0 to 0.064)	0.035 (0.007 to 0.102)
Other pneumococcal serotypes	0.012 (0.0 to 0.064)	0.023 (0.003 to 0.084)
Serotype 3	0.012 (0.0 to 0.064)	0.012 (0.0 to 0.065)
Serotype 12F	0.0 (0.0 to 0.043)	0.012 (0.0 to 0.065)
Serotype 15C	0.0 (0.0 to 0.043)	0.0 (0.0 to 0.043)
H. influenzae ID	0.0 (0.0 to 0.043)	0.012 (0.0 to 0.065)
Non-typeable (NTHI)	0.0 (0.0 to 0.043)	0.012 (0.0 to 0.065)
Other bacteria	0.023 (0.003 to 0.084)	0.058 (0.019 to 0.136)
Neisseria meningitidis	0.023 (0.003 to 0.084)	0.023 (0.003 to 0.084)
Streptococcus pyogenes	0.0 (0.0 to 0.043)	0.023 (0.003 to 0.084)
Moraxella catarrhalis	0.0 (0.0 to 0.043)	0.012 (0.0 to 0.065)

No statistical analyses for this end point

Secondary: Culture-confirmed Invasive Disease (ID) Person Year Rate - In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course till end of LT FU period.

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End point title

Culture-confirmed Invasive Disease (ID) Person Year Rate - In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course till end of LT FU period.

End point description

End point type

Secondary

End point timeframe

Period of follow-up was any time after the administration of first vaccine dose till the end of the long-term Follow-up period (The Follow-up period lasted at least 77 months).

End point values	10Pn2+1-6W-6M/043+053 Group	Ctrl-6W-6M/043+053 Group
Number of subjects analysed	10053	10201
Units: Participants per 1000 person-years
number (confidence interval 95%)
Culture confirmed ID	0.047 (0.013 to 0.122)	0.268 (0.170 to 0.402)
Pneumococcal invasive disease (IPD)	0.024 (0.003 to 0.086)	0.210 (0.124 to 0.331)
Vaccine serotypes (vaccine type-IPD)	0.012 (0.0 to 0.066)	0.140 (0.072 to 0.244)
Serotype 4	0.0 (0.0 to 0.044)	0.0 (0.0 to 0.043)
Serotype 6B	0.0 (0.0 to 0.044)	0.058 (0.019 to 0.136)
Serotype 7F	0.012 (0.0 to 0.066)	0.0 (0.0 to 0.043)
Serotype 14	0.0 (0.0 to 0.044)	0.047 (0.013 to 0.119)
Serotype 18C	0.0 (0.0 to 0.044)	0.012 (0.0 to 0.065)
Serotype 19F	0.0 (0.0 to 0.044)	0.012 (0.0 to 0.065)
Serotype 23F	0.0 (0.0 to 0.044)	0.012 (0.0 to 0.065)
Cross-reactive serotypes	0.0 (0.0 to 0.044)	0.047 (0.013 to 0.119)
Serotype 6A	0.0 (0.0 to 0.044)	0.012 (0.0 to 0.065)
Serotype 19A	0.0 (0.0 to 0.044)	0.035 (0.007 to 0.102)
Other pneumococcal serotypes	0.012 (0.0 to 0.065)	0.023 (0.003 to 0.084)
Serotype 3	0.012 (0.0 to 0.066)	0.012 (0.0 to 0.065)
Serotype 12F	0.0 (0.0 to 0.044)	0.012 (0.0 to 0.065)
Serotype 15C	0.0 (0.0 to 0.044)	0.0 (0.0 to 0.043)
H. influenzae ID	0.012 (0.0 to 0.066)	0.012 (0.0 to 0.065)
Non-typeable (NTHI)	0.012 (0.0 to 0.066)	0.012 (0.0 to 0.065)
Other bacteria	0.012 (0.0 to 0.066)	0.058 (0.019 to 0.136)
Neisseria meningitidis	0.012 (0.0 to 0.066)	0.023 (0.003 to 0.084)
Streptococcus pyogenes	0.0 (0.0 to 0.044)	0.023 (0.003 to 0.084)
Moraxella catarrhalis	0.0 (0.0 to 0.044)	0.012 (0.0 to 0.065)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Solicited & unsolicited AEs: 4-day & 31-day post primary/booster vaccination. SAEs from Day 0 to study end: Month (M)18 for 6W-6M groups, M16 for 7-11M groups and M9 for M12-18 groups. Non-serious AE Threshold=4.98% but corrected to 5% (system constraint)

Adverse event reporting additional description

To avoid inconsistency between the AE reporting and the acute otitis media (AOM) questionnaire filled in by subjects’ parent(s)/LAR(s), otitis was not reported as an AE if already reported via the AOM questionnaire. Number of occurrences were not available at the time of the analysis, then put equal to number of subjects affected.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

15.0

Reporting group title

Ctrl3+1-6W-6M/053 Group

Reporting group description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) study, aged 6 weeks to 6 months at enrolment. Subjects received the Engerix B (called also HBV vaccine) according to a 3-dose primary vaccination schedule with an interval of at least 4 weeks between doses followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (3+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh.

Reporting group title

Ctrl2+1-6W-6M/053 Group

Reporting group description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) study, aged 6 weeks to 6 months at enrolment. Subjects received the Engerix B (called also HBV vaccine) according to a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (2+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh.

Reporting group title

10Pn3+1-6W-6M/053 Group

Reporting group description

Reporting group title

Ctrl12-18M/053 Group

Reporting group description

Reporting group title

10Pn7-11M/053 Group

Reporting group description

Reporting group title

Ctrl7-11M/053 Group

Reporting group description

Reporting group title

10Pn2+1-6W-6M/053 Group

Reporting group description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) study, aged 6 weeks to 6 months at enrolment. Subjects received the Synflorix (called also 10Pn-PD-DiT, 10Pn or GSK1024850A) vaccine according to a 2-dose primary vaccination with an interval of at least 8 weeks, followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (2+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh.

Reporting group title

10Pn12-18M/053 Group

Reporting group description

Serious adverse events	Ctrl3+1-6W-6M/053 Group	Ctrl2+1-6W-6M/053 Group	10Pn3+1-6W-6M/053 Group	Ctrl12-18M/053 Group	10Pn7-11M/053 Group	Ctrl7-11M/053 Group	10Pn2+1-6W-6M/053 Group	10Pn12-18M/053 Group
Total subjects affected by serious adverse events
subjects affected / exposed	77 / 1069 (7.20%)	74 / 859 (8.61%)	163 / 1849 (8.82%)	14 / 271 (5.17%)	24 / 241 (9.96%)	18 / 204 (8.82%)	96 / 1316 (7.29%)	23 / 368 (6.25%)
number of deaths (all causes)	0	0	0	0	0	0	1	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Haemangioma
subjects affected / exposed	0 / 1069 (0.00%)	1 / 859 (0.12%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	4 / 1069 (0.37%)	2 / 859 (0.23%)	4 / 1849 (0.22%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	4 / 1316 (0.30%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 2	0 / 4	0 / 0	0 / 0	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Crying
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Developmental delay
subjects affected / exposed	0 / 1069 (0.00%)	1 / 859 (0.12%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sudden death
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Immune system disorders
Milk allergy
subjects affected / exposed	1 / 1069 (0.09%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anaphylactic reaction
subjects affected / exposed	0 / 1069 (0.00%)	1 / 859 (0.12%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	4 / 1069 (0.37%)	3 / 859 (0.35%)	4 / 1849 (0.22%)	2 / 271 (0.74%)	4 / 241 (1.66%)	1 / 204 (0.49%)	2 / 1316 (0.15%)	4 / 368 (1.09%)
occurrences causally related to treatment / all	0 / 4	0 / 3	0 / 4	0 / 2	0 / 4	0 / 1	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 1069 (0.09%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	2 / 1316 (0.15%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Apnoea
subjects affected / exposed	0 / 1069 (0.00%)	1 / 859 (0.12%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cough
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	1 / 204 (0.49%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Breath holding
subjects affected / exposed	0 / 1069 (0.00%)	1 / 859 (0.12%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Confusional state
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	1 / 271 (0.37%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Cardiac murmur
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femur fracture
subjects affected / exposed	2 / 1069 (0.19%)	1 / 859 (0.12%)	2 / 1849 (0.11%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	1 / 368 (0.27%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Foreign body
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	2 / 1316 (0.15%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thermal burn
subjects affected / exposed	1 / 1069 (0.09%)	1 / 859 (0.12%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	1 / 241 (0.41%)	1 / 204 (0.49%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	0 / 1069 (0.00%)	1 / 859 (0.12%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Contusion
subjects affected / exposed	1 / 1069 (0.09%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Electric shock
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	1 / 1069 (0.09%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Poisoning
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Concussion
subjects affected / exposed	0 / 1069 (0.00%)	2 / 859 (0.23%)	3 / 1849 (0.16%)	0 / 271 (0.00%)	1 / 241 (0.41%)	0 / 204 (0.00%)	2 / 1316 (0.15%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 3	0 / 0	0 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Burns second degree
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chemical poisoning
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skull fracture
subjects affected / exposed	0 / 1069 (0.00%)	1 / 859 (0.12%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Accidental drug intake by child
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	1 / 368 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Accidental poisoning
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	1 / 368 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Amaurotic familial idiocy
subjects affected / exposed	0 / 1069 (0.00%)	1 / 859 (0.12%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Patent ductus arteriosus
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	2 / 1849 (0.11%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular septal defect
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Combined immunodeficiency
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Craniosynostosis
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyloric stenosis
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coarctation of the aorta
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Krabbe's disease
subjects affected / exposed	0 / 1069 (0.00%)	1 / 859 (0.12%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mitochondrial encephalomyopathy
subjects affected / exposed	0 / 1069 (0.00%)	1 / 859 (0.12%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cyanosis
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Febrile convulsion
subjects affected / exposed	1 / 1069 (0.09%)	2 / 859 (0.23%)	5 / 1849 (0.27%)	1 / 271 (0.37%)	0 / 241 (0.00%)	1 / 204 (0.49%)	6 / 1316 (0.46%)	2 / 368 (0.54%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 5	0 / 1	0 / 0	0 / 1	0 / 6	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Convulsion
subjects affected / exposed	2 / 1069 (0.19%)	1 / 859 (0.12%)	5 / 1849 (0.27%)	0 / 271 (0.00%)	1 / 241 (0.41%)	1 / 204 (0.49%)	2 / 1316 (0.15%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 5	0 / 0	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	1 / 1069 (0.09%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	1 / 241 (0.41%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperreflexia
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	1 / 1069 (0.09%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorder
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Petit mal epilepsy
subjects affected / exposed	1 / 1069 (0.09%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Altered state of consciousness
subjects affected / exposed	0 / 1069 (0.00%)	1 / 859 (0.12%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Balance disorder
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cognitive disorder
subjects affected / exposed	0 / 1069 (0.00%)	1 / 859 (0.12%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysarthria
subjects affected / exposed	0 / 1069 (0.00%)	1 / 859 (0.12%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Aplasia pure red cell
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymphadenitis
subjects affected / exposed	0 / 1069 (0.00%)	1 / 859 (0.12%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	1 / 1069 (0.09%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	1 / 241 (0.41%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enteritis
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	2 / 1849 (0.11%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intussusception
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	2 / 1849 (0.11%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis adenovirus
subjects affected / exposed	1 / 1069 (0.09%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	1 / 241 (0.41%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis rotavirus
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	1 / 271 (0.37%)	1 / 241 (0.41%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	1 / 368 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	1 / 1069 (0.09%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia strangulated
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Melaena
subjects affected / exposed	0 / 1069 (0.00%)	1 / 859 (0.12%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Urticaria
subjects affected / exposed	1 / 1069 (0.09%)	1 / 859 (0.12%)	0 / 1849 (0.00%)	1 / 271 (0.37%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Erythema
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eczema nummular
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Juvenile arthritis
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neck pain
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bronchitis
subjects affected / exposed	19 / 1069 (1.78%)	20 / 859 (2.33%)	33 / 1849 (1.78%)	2 / 271 (0.74%)	9 / 241 (3.73%)	5 / 204 (2.45%)	13 / 1316 (0.99%)	5 / 368 (1.36%)
occurrences causally related to treatment / all	0 / 19	0 / 20	0 / 33	0 / 2	0 / 9	0 / 5	0 / 13	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Otitis media
subjects affected / exposed	9 / 1069 (0.84%)	13 / 859 (1.51%)	22 / 1849 (1.19%)	2 / 271 (0.74%)	1 / 241 (0.41%)	0 / 204 (0.00%)	7 / 1316 (0.53%)	1 / 368 (0.27%)
occurrences causally related to treatment / all	0 / 9	0 / 13	0 / 22	0 / 2	0 / 1	0 / 0	0 / 7	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchiolitis
subjects affected / exposed	5 / 1069 (0.47%)	9 / 859 (1.05%)	9 / 1849 (0.49%)	0 / 271 (0.00%)	1 / 241 (0.41%)	2 / 204 (0.98%)	8 / 1316 (0.61%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 9	0 / 9	0 / 0	0 / 1	0 / 2	0 / 8	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	5 / 1069 (0.47%)	4 / 859 (0.47%)	15 / 1849 (0.81%)	1 / 271 (0.37%)	3 / 241 (1.24%)	1 / 204 (0.49%)	7 / 1316 (0.53%)	2 / 368 (0.54%)
occurrences causally related to treatment / all	0 / 5	0 / 4	0 / 15	0 / 1	0 / 3	0 / 1	0 / 7	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Laryngitis
subjects affected / exposed	4 / 1069 (0.37%)	7 / 859 (0.81%)	12 / 1849 (0.65%)	0 / 271 (0.00%)	1 / 241 (0.41%)	0 / 204 (0.00%)	6 / 1316 (0.46%)	2 / 368 (0.54%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 12	0 / 0	0 / 1	0 / 0	0 / 6	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus bronchiolitis
subjects affected / exposed	4 / 1069 (0.37%)	4 / 859 (0.47%)	11 / 1849 (0.59%)	0 / 271 (0.00%)	1 / 241 (0.41%)	0 / 204 (0.00%)	7 / 1316 (0.53%)	1 / 368 (0.27%)
occurrences causally related to treatment / all	0 / 4	0 / 4	0 / 11	0 / 0	0 / 1	0 / 0	0 / 7	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	3 / 1069 (0.28%)	5 / 859 (0.58%)	10 / 1849 (0.54%)	1 / 271 (0.37%)	1 / 241 (0.41%)	1 / 204 (0.49%)	5 / 1316 (0.38%)	2 / 368 (0.54%)
occurrences causally related to treatment / all	0 / 3	0 / 5	0 / 10	0 / 1	0 / 1	0 / 1	0 / 5	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	2 / 1069 (0.19%)	2 / 859 (0.23%)	10 / 1849 (0.54%)	1 / 271 (0.37%)	0 / 241 (0.00%)	1 / 204 (0.49%)	7 / 1316 (0.53%)	2 / 368 (0.54%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 10	0 / 1	0 / 0	0 / 1	0 / 7	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	3 / 1069 (0.28%)	3 / 859 (0.35%)	5 / 1849 (0.27%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	3 / 1316 (0.23%)	1 / 368 (0.27%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 5	0 / 0	0 / 0	0 / 0	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Otitis media acute
subjects affected / exposed	1 / 1069 (0.09%)	3 / 859 (0.35%)	5 / 1849 (0.27%)	0 / 271 (0.00%)	2 / 241 (0.83%)	0 / 204 (0.00%)	2 / 1316 (0.15%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 5	0 / 0	0 / 2	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	2 / 1069 (0.19%)	2 / 859 (0.23%)	2 / 1849 (0.11%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 2	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus infection
subjects affected / exposed	0 / 1069 (0.00%)	2 / 859 (0.23%)	4 / 1849 (0.22%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 4	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 1069 (0.09%)	1 / 859 (0.12%)	2 / 1849 (0.11%)	0 / 271 (0.00%)	0 / 241 (0.00%)	1 / 204 (0.49%)	2 / 1316 (0.15%)	1 / 368 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 0	0 / 0	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	1 / 1069 (0.09%)	0 / 859 (0.00%)	2 / 1849 (0.11%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia respiratory syncytial viral
subjects affected / exposed	0 / 1069 (0.00%)	1 / 859 (0.12%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	2 / 1316 (0.15%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	2 / 1849 (0.11%)	0 / 271 (0.00%)	1 / 241 (0.41%)	0 / 204 (0.00%)	2 / 1316 (0.15%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Adenovirus infection
subjects affected / exposed	1 / 1069 (0.09%)	0 / 859 (0.00%)	2 / 1849 (0.11%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bacterial infection
subjects affected / exposed	2 / 1069 (0.19%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	1 / 241 (0.41%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumococcal sepsis
subjects affected / exposed	2 / 1069 (0.19%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	1 / 271 (0.37%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	1 / 1069 (0.09%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enterovirus infection
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	2 / 1849 (0.11%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
H1N1 influenza
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	2 / 1849 (0.11%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus bronchitis
subjects affected / exposed	2 / 1069 (0.19%)	4 / 859 (0.47%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	1 / 204 (0.49%)	7 / 1316 (0.53%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 0	0 / 0	0 / 0	0 / 1	0 / 7	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abscess neck
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bacterial sepsis
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	1 / 204 (0.49%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Croup infectious
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear infection
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Groin abscess
subjects affected / exposed	1 / 1069 (0.09%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	1 / 1069 (0.09%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Laryngitis viral
subjects affected / exposed	1 / 1069 (0.09%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Laryngomalcia
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymph gland infection
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meningococcal sepsis
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	1 / 241 (0.41%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumococcal bacteraemia
subjects affected / exposed	1 / 1069 (0.09%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumococcal infection
subjects affected / exposed	1 / 1069 (0.09%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	1 / 1069 (0.09%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection viral
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	0 / 1069 (0.00%)	1 / 859 (0.12%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Streptococcal infection
subjects affected / exposed	1 / 1069 (0.09%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tracheitis
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	4 / 1069 (0.37%)	1 / 859 (0.12%)	1 / 1849 (0.05%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	3 / 1316 (0.23%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	1 / 1069 (0.09%)	3 / 859 (0.35%)	4 / 1849 (0.22%)	0 / 271 (0.00%)	0 / 241 (0.00%)	2 / 204 (0.98%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 4	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Streptococcal sepsis
subjects affected / exposed	0 / 1069 (0.00%)	1 / 859 (0.12%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Varicella
subjects affected / exposed	0 / 1069 (0.00%)	1 / 859 (0.12%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eczema infected
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Exanthema subitum
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	1 / 241 (0.41%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis norovirus
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hand-foot-and-mouth disease
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Impetigo
subjects affected / exposed	0 / 1069 (0.00%)	1 / 859 (0.12%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lobar pneumonia
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mastoiditis
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Parainfluenzae virus infection
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic arthritis streptococcal
subjects affected / exposed	0 / 1069 (0.00%)	1 / 859 (0.12%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea infectious
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	1 / 241 (0.41%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	1 / 204 (0.49%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Otitis media fungal
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	1 / 204 (0.49%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia viral
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	1 / 241 (0.41%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	1 / 241 (0.41%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Roseola
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	1 / 204 (0.49%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rotavirus infection
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	1 / 241 (0.41%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	2 / 368 (0.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	1 / 271 (0.37%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis orbital
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	1 / 368 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	1 / 271 (0.37%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Type 1 diabetes mellitus
subjects affected / exposed	0 / 1069 (0.00%)	1 / 859 (0.12%)	1 / 1849 (0.05%)	1 / 271 (0.37%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Weight gain poor
subjects affected / exposed	1 / 1069 (0.09%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	2 / 1316 (0.15%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	0 / 241 (0.00%)	0 / 204 (0.00%)	1 / 1316 (0.08%)	0 / 368 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Ctrl3+1-6W-6M/053 Group	Ctrl2+1-6W-6M/053 Group	10Pn3+1-6W-6M/053 Group	Ctrl12-18M/053 Group	10Pn7-11M/053 Group	Ctrl7-11M/053 Group	10Pn2+1-6W-6M/053 Group	10Pn12-18M/053 Group
Total subjects affected by non serious adverse events
subjects affected / exposed	1038 / 1069 (97.10%)	805 / 859 (93.71%)	1840 / 1849 (99.51%)	254 / 271 (93.73%)	232 / 241 (96.27%)	193 / 204 (94.61%)	1295 / 1316 (98.40%)	354 / 368 (96.20%)
Nervous system disorders
Somnolence
subjects affected / exposed	723 / 1069 (67.63%)	539 / 859 (62.75%)	1493 / 1849 (80.75%)	118 / 271 (43.54%)	165 / 241 (68.46%)	101 / 204 (49.51%)	1024 / 1316 (77.81%)	214 / 368 (58.15%)
occurrences all number	1394	887	3305	145	286	161	1876	281
General disorders and administration site conditions
Injection site induration
subjects affected / exposed	71 / 1069 (6.64%)	29 / 859 (3.38%)	419 / 1849 (22.66%)	2 / 271 (0.74%)	30 / 241 (12.45%)	5 / 204 (2.45%)	239 / 1316 (18.16%)	45 / 368 (12.23%)
occurrences all number	89	34	720	2	47	6	340	52
Pain
subjects affected / exposed	396 / 1069 (37.04%)	275 / 859 (32.01%)	1399 / 1849 (75.66%)	116 / 271 (42.80%)	176 / 241 (73.03%)	76 / 204 (37.25%)	983 / 1316 (74.70%)	301 / 368 (81.79%)
occurrences all number	614	374	2898	143	351	111	1830	463
Pyrexia
subjects affected / exposed	377 / 1069 (35.27%)	261 / 859 (30.38%)	1030 / 1849 (55.71%)	62 / 271 (22.88%)	115 / 241 (47.72%)	68 / 204 (33.33%)	688 / 1316 (52.28%)	119 / 368 (32.34%)
occurrences all number	483	334	1621	70	154	77	1062	143
Swelling
subjects affected / exposed	382 / 1069 (35.73%)	205 / 859 (23.86%)	1257 / 1849 (67.98%)	42 / 271 (15.50%)	154 / 241 (63.90%)	50 / 204 (24.51%)	878 / 1316 (66.72%)	209 / 368 (56.79%)
occurrences all number	575	262	2716	51	290	68	1594	290
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	75 / 1069 (7.02%)	52 / 859 (6.05%)	140 / 1849 (7.57%)	25 / 271 (9.23%)	22 / 241 (9.13%)	17 / 204 (8.33%)	78 / 1316 (5.93%)	26 / 368 (7.07%)
occurrences all number	84	58	160	28	27	19	86	28
Teething
subjects affected / exposed	61 / 1069 (5.71%)	34 / 859 (3.96%)	66 / 1849 (3.57%)	0 / 271 (0.00%)	11 / 241 (4.56%)	21 / 204 (10.29%)	40 / 1316 (3.04%)	0 / 368 (0.00%)
occurrences all number	70	39	83	0	15	21	45	0
Vomiting
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	12 / 241 (4.98%)	7 / 204 (3.43%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences all number	0	0	0	0	13	7	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	15 / 271 (5.54%)	9 / 241 (3.73%)	11 / 204 (5.39%)	0 / 1316 (0.00%)	14 / 368 (3.80%)
occurrences all number	0	0	0	16	9	13	0	16
Skin and subcutaneous tissue disorders
Erythema
subjects affected / exposed	584 / 1069 (54.63%)	397 / 859 (46.22%)	1522 / 1849 (82.31%)	130 / 271 (47.97%)	182 / 241 (75.52%)	89 / 204 (43.63%)	1042 / 1316 (79.18%)	265 / 368 (72.01%)
occurrences all number	1188	665	3821	179	369	162	2077	398
Psychiatric disorders
Irritability
subjects affected / exposed	914 / 1069 (85.50%)	688 / 859 (80.09%)	1761 / 1849 (95.24%)	142 / 271 (52.40%)	207 / 241 (85.89%)	152 / 204 (74.51%)	1204 / 1316 (91.49%)	283 / 368 (76.90%)
occurrences all number	2134	1304	4864	181	428	272	2592	407
Infections and infestations
Nasopharyngitis
subjects affected / exposed	64 / 1069 (5.99%)	64 / 859 (7.45%)	107 / 1849 (5.79%)	0 / 271 (0.00%)	18 / 241 (7.47%)	11 / 204 (5.39%)	49 / 1316 (3.72%)	0 / 368 (0.00%)
occurrences all number	87	74	127	0	19	14	59	0
Otitis media
subjects affected / exposed	57 / 1069 (5.33%)	24 / 859 (2.79%)	69 / 1849 (3.73%)	22 / 271 (8.12%)	25 / 241 (10.37%)	19 / 204 (9.31%)	32 / 1316 (2.43%)	25 / 368 (6.79%)
occurrences all number	65	24	80	23	26	23	34	29
Rhinitis
subjects affected / exposed	105 / 1069 (9.82%)	72 / 859 (8.38%)	147 / 1849 (7.95%)	25 / 271 (9.23%)	21 / 241 (8.71%)	36 / 204 (17.65%)	74 / 1316 (5.62%)	29 / 368 (7.88%)
occurrences all number	123	83	178	29	25	43	88	33
Upper respiratory tract infection
subjects affected / exposed	131 / 1069 (12.25%)	45 / 859 (5.24%)	233 / 1849 (12.60%)	40 / 271 (14.76%)	38 / 241 (15.77%)	50 / 204 (24.51%)	109 / 1316 (8.28%)	36 / 368 (9.78%)
occurrences all number	161	53	291	47	46	67	122	37
Gastroenteritis
subjects affected / exposed	0 / 1069 (0.00%)	0 / 859 (0.00%)	0 / 1849 (0.00%)	0 / 271 (0.00%)	9 / 241 (3.73%)	12 / 204 (5.88%)	0 / 1316 (0.00%)	0 / 368 (0.00%)
occurrences all number	0	0	0	0	9	13	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	527 / 1069 (49.30%)	356 / 859 (41.44%)	1103 / 1849 (59.65%)	118 / 271 (43.54%)	153 / 241 (63.49%)	105 / 204 (51.47%)	713 / 1316 (54.18%)	191 / 368 (51.90%)
occurrences all number	828	483	1832	140	217	159	1072	238

More information

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Were there any global substantial amendments to the protocol? Yes

11 Dec 2008

Protocol amendment 1, dated 11 December 2008, implemented the following: 1) Addition of 6 clusters located in municipalities where no agreement from the health care center responsible for the municipality primary health care and well-baby clinics had been obtained for participation in the 10PN-PD-DIT-043 study (i.e. Espoo, Vantaa and surroundings municipalities); 2) The addition of a nasopharyngeal swab sampling at the pre-vaccination time point for subjects enrolled within the first 7 months of life and who were part of the Immuno subset and for all subjects enrolled between 7-11 months of age.; 3) Recording of Bacille Calmette Guerin (BCG) vaccination since birth up to 30 days before the first study vaccination; 4) The addition of a sample size justification for acute otitis media (AOM) endpoint; 5) The addition of Infanrix Polio+Hib vaccine as a non-study vaccine to be offered to all subjects in order to comply with the national immunization recommendations; 6) The addition of Rotarix as a non-study vaccine to be offered to children within the first 6 months of life; 7) Physical examination was made optional after Visit 1 (screening), 8) Attribution of a treatment number was added as a study procedure for each vaccination visit.

18 Feb 2009

Protocol amendment 2, dated 18 February 2009, implemented the following changes: 1) Addition of collection of data on respiratory tract infections (RTIs), including detailed acute otitis media (AOM) diagnosis data in a subset of subjects in Turku area; 2) Inclusion of municipalities surrounding Oulu in the list of municipalities where no collaboration with health care centers had been set up in study 10PN-PD-DIT-043 but where there was opportunity for parent(s)/LARs to let their child participate in study 10PN-PD-DIT-053 (i.e. Espoo, Vantaa and surroundings municipalities and municipalities surrounding Oulu); 3) The National Public Health Institute (KTL) and the National Research and Development Centre for Welfare and Health (STAKES) had merged to the National Institute for Health and Welfare (THL); 4) Clarification was added in some tables concerning the age at enrolment; 5) Correction of the interval between some study visits; 6) Wording concerning the Immuno subset was changed to ensure that the subjects in this subset would be enrolled according to the age and treatment groups; 6) Deletion of the specification of the injection side.

17 Nov 2009

Protocol amendment 3, dated 17 November 2009, implemented the following change. Because a higher number of non-evaluable subjects for according-toprotocol (ATP) analysis due to the flu pandemic in 2009 was anticipated and the recruitment rate was lower than expected, especially in the catch-up cohorts (7-18 months of age at enrolment), the target numbers of subjects to be recruited per age group was changed and the recruitment time was extended in order to secure the AOM objective which was related to the infant vaccination cohort (< 7 months of age at enrolment) based on the ATP cohort.

12 Aug 2011

Protocol amendment 4, dated 12 August 2011, was developed for the following reasons: 1) The conditions for triggering IPD effectiveness analysis in this study were linked to the 10PN-PD-DIT-043 study. As the 10PN-PD-DIT-043 study enrolment reached only 50% of the initial recruitment plan, there was a need to redefine the conditions for triggering IPD effectiveness analysis in that study. Consequently, this change was reflected in the 10PN-PD-DIT-053 protocol; 2) In order to align the timing of unblinding (planned after cleaning of the clinical database from both studies) with the 10PN-PD-DIT-043 study, the age range for the last study visit for subjects enrolled between 6 weeks and 6 months of age was enlarged from 21-22 months of age to 18-22 months of age; 3) The protocol was adjusted to reflect the Independent Data Monitoring Committee (IDMC) recommendation to evaluate the chest X-rays from the hospital-diagnosed pneumonia cases in this study by an independent review panel according to WHO guidelines for study purposes, as in the 10PN-PD-DIT-043 study; 4) GSK Biologicals had decided to maintain pneumococcal enzyme-linked immunosorbent assay (ELISA) testing but not to perform the pneumococcal opsonophagocytic activity (OPA) and anti-protein D ELISA testing in the 7-11 and 12-18 months of age groups part of the immuno subset for the following reasons: a) The WHO considers the antibody concentration measured by the ELISA assay as the main licensure criterion for new pneumococcal conjugate vaccines and the outcome of the OPA testing on samples obtained one month post-primary vaccination as supportive for licensure, b) These tests in the catch-up groups were not linked to the primary objective of the study, i.e. IPD effectiveness in the infant cohort; 5) Further details on microbiological testing were included and additional minor corrections were done.

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.

Number allocation errors were identified for 3 subjects after Dose 1, which GSK assessed as not having significant impact. Lower & upper respiratory tract infections endpoint results are not presented, being uninterpretable due to low sample size.

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Clinical trials

Trial information

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Baseline characteristics

Baseline characteristics

End points

End points

Primary: Person Year Rate as regards subjects with culture-confirmed IPD due to any of the 10 pneumococcal vaccine serotypes. In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

Primary: Person Year Rate as regards subjects with culture-confirmed IPD due to any of the 10 pneumococcal vaccine serotypes. In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

Primary: Person Year Rate as regards subjects with culture-confirmed IPD due to any of the 10 pneumococcal vaccine serotypes. In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course.

Primary: Person Year Rate as regards subjects with culture-confirmed IPD due to any of the 10 pneumococcal vaccine serotypes. In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course.

Secondary: Person Year Rate in the prevention of culture-confirmed invasive disease (ID)- In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

Secondary: Person Year Rate in the prevention of culture-confirmed invasive disease (ID)- In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

Secondary: Person Year Rate in the prevention of culture-confirmed invasive disease (ID)- In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course.

Secondary: Person Year Rate in the prevention of culture-confirmed invasive disease (ID)- In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course.

Secondary: Person Year Rate in the prevention of culture-confirmed invasive disease (ID)- In children starting vaccination in the 7-11 months schedule.

Secondary: Person Year Rate in the prevention of culture-confirmed invasive disease (ID)- In children starting vaccination in the 7-11 months schedule.

Secondary: Person Year Rate in the prevention of culture-confirmed invasive disease (ID)- In children starting vaccination in the 12-18 months schedule.

Secondary: Person Year Rate in the prevention of culture-confirmed invasive disease (ID)- In children starting vaccination in the 12-18 months schedule.

Secondary: Person Year Rate in the prevention of probable culture-confirmed invasive disease (ID)- In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

Secondary: Person Year Rate in the prevention of probable culture-confirmed invasive disease (ID)- In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

Secondary: Person Year Rate in the prevention of probable or culture-confirmed invasive disease (ID)- In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course.

Secondary: Person Year Rate in the prevention of probable or culture-confirmed invasive disease (ID)- In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course.

Secondary: Person Year Rate in the prevention of probable or culture-confirmed invasive disease (ID)- In children starting vaccination in the 7-11 months schedule.

Secondary: Person Year Rate in the prevention of probable or culture-confirmed invasive disease (ID)- In children starting vaccination in the 7-11 months schedule.

Secondary: Person Year Rate in the prevention of probable or culture-confirmed invasive disease (ID)- In children starting vaccination in the 12-18 months schedule.

Secondary: Person Year Rate in the prevention of probable or culture-confirmed invasive disease (ID)- In children starting vaccination in the 12-18 months schedule.

Secondary: Person Year Rate in reducing hospital-diagnosed pneumonia- In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

Secondary: Person Year Rate in reducing hospital-diagnosed pneumonia- In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

Secondary: Person Year Rate in reducing hospital-diagnosed pneumonia - In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course.

Secondary: Person Year Rate in reducing hospital-diagnosed pneumonia - In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course.

Secondary: Person Year Rate in reducing hospital-diagnosed pneumonia- In children starting vaccination in the 7-11 months schedule.

Secondary: Person Year Rate in reducing hospital-diagnosed pneumonia- In children starting vaccination in the 7-11 months schedule.

Secondary: Person Year Rate in reducing hospital-diagnosed pneumonia - In children starting vaccination in the 12-18 months schedule.

Secondary: Person Year Rate in reducing hospital-diagnosed pneumonia - In children starting vaccination in the 12-18 months schedule.

Secondary: Person Year Rate in reducing hospital-diagnosed pneumonia with Chest X-ray (CXR) reading according to WHO criteria- In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

Secondary: Person Year Rate in reducing hospital-diagnosed pneumonia with Chest X-ray (CXR) reading according to WHO criteria- In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

Secondary: Person Year Rate in reducing hospital-diagnosed pneumonia with CXR reading according to WHO criteria - In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course.

Secondary: Person Year Rate in reducing hospital-diagnosed pneumonia with CXR reading according to WHO criteria - In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course.

Secondary: Person Year Rate in reducing hospital-diagnosed pneumonia with CXR reading according to WHO criteria - In children starting vaccination in the 7-11 months schedule.

Secondary: Person Year Rate in reducing hospital-diagnosed pneumonia with CXR reading according to WHO criteria - In children starting vaccination in the 7-11 months schedule.

Secondary: Person Year Rate in reducing hospital-diagnosed pneumonia with CXR reading according to WHO criteria - In children starting vaccination in the 12-18 months schedule.

Secondary: Person Year Rate in reducing hospital-diagnosed pneumonia with CXR reading according to WHO criteria - In children starting vaccination in the 12-18 months schedule.

Secondary: Person Year Rate in prevention of all tympanostomy tube placements- In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

Secondary: Person Year Rate in prevention of all tympanostomy tube placements- In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

Secondary: Person Year Rate in prevention of all tympanostomy tube placements - In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course.

Secondary: Person Year Rate in prevention of all tympanostomy tube placements - In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course.

Secondary: Person Year Rate in prevention of all tympanostomy tube placements - In children starting vaccination in the 7-11 months schedule.

Secondary: Person Year Rate in prevention of all tympanostomy tube placements - In children starting vaccination in the 7-11 months schedule.

Secondary: Person Year Rate in prevention of all tympanostomy tube placements - In children starting vaccination in the 12-18 months schedule.

Secondary: Person Year Rate in prevention of all tympanostomy tube placements - In children starting vaccination in the 12-18 months schedule.

Secondary: Person Year Rate in prevention of all antimicrobial prescriptions- In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

Secondary: Person Year Rate in prevention of all antimicrobial prescriptions- In children starting vaccination within 7 months of life and assigned to a 3-dose primary vaccination course.

Secondary: Person Year Rate in prevention of all antimicrobial prescriptions - In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course.

Secondary: Person Year Rate in prevention of all antimicrobial prescriptions - In children starting vaccination within 7 months of life and assigned to a 2-dose primary vaccination course.

Secondary: Person Year Rate in prevention of all antimicrobial prescriptions - In children starting vaccination in the 7-11 months schedule.

Secondary: Person Year Rate in prevention of all antimicrobial prescriptions - In children starting vaccination in the 7-11 months schedule.

Secondary: Person Year Rate in prevention of all antimicrobial prescriptions - In children starting vaccination in the 12-18 months schedule.

Secondary: Person Year Rate in prevention of all antimicrobial prescriptions - In children starting vaccination in the 12-18 months schedule.

Secondary: Number of subjects classified by antimicrobial susceptiblity of IPD isolates in children starting vaccination within 7 months of life and assigned to a 2 or 3-dose primary vaccination course

Secondary: Number of subjects classified by antimicrobial susceptiblity of IPD isolates in children starting vaccination within 7 months of life and assigned to a 2 or 3-dose primary vaccination course

Secondary: Number of subjects with Lower respiratory tract infections (LRTIs) (in a subset of subjects in Turku area )

Secondary: Number of subjects with Lower respiratory tract infections (LRTIs) (in a subset of subjects in Turku area )

Secondary: Number of subjects with Upper respiratory tract infections (URTIs) (in a subset of subjects in Turku area)

Secondary: Number of subjects with Upper respiratory tract infections (URTIs) (in a subset of subjects in Turku area)

Secondary: Number of subjects with any and Grade 3 solicited local symptoms.

Secondary: Number of subjects with any and Grade 3 solicited local symptoms.

Secondary: Number of subjects with any, Grade 3 and related solicited general symptoms.

Secondary: Number of subjects with any, Grade 3 and related solicited general symptoms.

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

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

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

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

Secondary: Number of subjects enrolled and vaccinated in the 10PN-PD-DIT-043 and 10PN-PD-DIT-053 study with post-study SAEs reported via passive surveillance– Subjects enrolled aged 6 weeks to 6 months and 7 to 18 months

Secondary: Number of subjects enrolled and vaccinated in the 10PN-PD-DIT-043 and 10PN-PD-DIT-053 study with post-study SAEs reported via passive surveillance– Subjects enrolled aged 6 weeks to 6 months and 7 to 18 months

Secondary: NUMBER OF NASOPHARYNGEAL SWABS WITH STREPTOCOCCUS PNEUMONIAE PATHOGENS (S. PN.), ANY PATHOGEN. IN SUBJECTS RECEIVING 3+1 AND 2+1 INFANT SCHEDULES OF 10PN

Secondary: NUMBER OF NASOPHARYNGEAL SWABS WITH STREPTOCOCCUS PNEUMONIAE PATHOGENS (S. PN.), ANY PATHOGEN. IN SUBJECTS RECEIVING 3+1 AND 2+1 INFANT SCHEDULES OF 10PN

Secondary: NUMBER OF NASOPHARYNGEAL SWABS WITH STREPTOCOCCUS PNEUMONIAE PATHOGENS (S. PN.), ANY PATHOGEN. IN SUBJECTS RECEIVING 7-11M SCHEDULE OF 10PN